Diabetes

Significant reductions in hemoglobin A1c have occurred over time among adults with type 1 diabetes as their use of diabetes technology has increased, yet there is still room for improvement, new data suggest.

The new findings are from a study involving patients at the Barbara Davis Center for Diabetes Adult Clinic between Jan. 1, 2014, and Dec. 31, 2021. They show that as technology use has increased, A1c levels have dropped in parallel. Moreover, progression from use of stand-alone continuous glucose monitors (CGMs) to automated insulin delivery systems (AIDs), which comprise insulin pumps and connected CGMs, furthered that progress.

The findings “are in agreement with American Diabetes Association standards of care, and recent international consensus recommending CGM and AID for most people with type 1 diabetes, and early initiation of diabetes technology from the onset of type 1 diabetes,” write Kagan E. Karakus, MD, of the University of Colorado’s Barbara Davis Center, Aurora, and colleagues in the article, which was published online in Diabetes Care.

“It’s very rewarding to us. We can see clearly that the uptake is going up and the A1c is dropping,” lead author Viral N. Shah, MD, of the Barbara Davis Center, told this news organization.

On the flip side, A1c levels rose significantly over the study period among nonusers of technology. “We cannot rule out provider bias for not prescribing diabetes technology among those with higher A1c or from disadvantaged socioeconomic backgrounds,” Dr. Karakus and colleagues write.

Also of note, even with use of the most advanced AID systems available during the study period, just under half of patients were still not achieving A1c levels below 7%. “The technology helps, but it’s not perfect,” Dr. Shah observed.

This study is the first to examine the relationship of A1c with technology use over time, in contrast to prior cross-sectional studies. “The intention here was to look at the landscape over a decade,” Dr. Shah said.
 

As overall use of technology use rose, A1c levels fell

The analysis included data for 4,174 unique patients (mean number of patients, 1,988/yr); 15,903 clinic visits were included over the 8-year study period. Technology use was defined as CGM use without an AID system or with an AID system.

Over the study period, diabetes technology use increased from 26.9% to 82.7% of the clinic population (P < .001). At the same time, the overall proportion patients who achieved the A1c goal of less than 7% increased from 32.3% to 41.7%, while the mean A1c level dropped from 7.7% to 7.5% (P < .001).

But among the technology nonusers, A1c rose from 7.85% in 2014 to 8.4% in 2021 (P < .001).

Regardless of diabetes technology use, White patients (about 80% of the total study population) had significantly lower A1c than non-White patients (7.5% vs. 7.7% for technology users [P = .02]; 8.0% vs. 8.3% for nontechnology users [P < .001]).

The non-White group was too small to enable the researchers to break down the data by technology type. Nonetheless, Dr. Shah said, “As a clinician, I can say that the penetration of diabetes technology in non-White populations remains low. These are also the people more vulnerable for socioeconomic and psychosocial reasons.”

The A1c increase among technology nonusers may be a result of a statistical artifact, as the number of those individuals was much lower in 2021 than in 2014. It’s possible that those remaining individuals have exceedingly high A1c levels, bringing the average up. “It’s still not good, though,” Dr. Shah said.
 

The more technology, the lower the A1c

Over the study period, the proportion of stand-alone CGM users rose from 26.9% to 44.1%, while use of AIDs rose from 0% in 2014 and 2015 to 38.6% in 2021. The latter group included patients who used first-generation Medtronic 670G and 770G devices and second-generation Tandem t:slim X2 with Control-IQ devices.

Between 2017 and 2021, AIDs users had significantly lower A1c levels than nontechnology users: 7.4% vs. 8.1% in 2017, and 7.3% vs. 8.4% in 2021 (P < .001 for every year). CGM users also had significantly lower A1c levels than nonusers at all time points (P < .001 per year).

The proportions achieving an A1c less than 7% differed significantly across users of CGMs, AIDs, and no technology (P < .01 for all years). In 2021, the percentage of people who achieved an A1c less than 7% were 50.9% with AIDs and 44.1% for CGMs vs, just 15.2% with no technology.
 

Work to be done: Why aren’t more achieving < 7% with AIDs?

Asked why only slightly more than half of patients who used AIDs achieved A1c levels below 7%, Dr. Shah listed three possibilities:

First, the 7% goal doesn’t apply to everyone with type 1 diabetes, including those with multiple comorbidities or with short life expectancy, for whom the recommended goal is 7.5%-8.0% to prevent hypoglycemia. “We didn’t separate out patients by A1c goals. If we add that, the number might go up,” Dr. Shah said.

Second, AID technology is continually improving, but it’s not perfect. Users still must enter carbohydrate counts and signal the devices for exercise, which can lead to errors. “It’s a wonderful technology for overnight control, but still, during the daytime, there are so many factors with the user interface and how much a person is engaged with the technology,” Dr. Shah explained.

Third, he said, “Unfortunately, obesity is increasing in type 1 diabetes, and insulin doses are increasing. Higher BMI [body mass index] and more insulin resistance can mean higher A1c. I really think for many patients, we probably will need an adjunct therapy, such as an SGLT2 [sodium-glucose cotransporter-2] inhibitor or a GLP-1 [glucagonlike peptide-1] agonist, even though they’re not approved in type 1 diabetes, for both glycemic and metabolic control including weight. I think that’s another missing piece.”

He also pointed out, “If someone has an A1c of 7.5%, I don’t expect a huge change. But if they’re at 10%, a drop to 8% is a huge change.”

Overall, Dr. Shah said, the news from the study is good. “In the past, only 30% were achieving an A1c less than 7%. Now we’re 20% above that. ... It’s a glass half full.”

Dr. Karakus has disclosed no relevant financial relationships. Dr. Shah has received, through the University of Colorado, research support from Novo Nordisk, Insulet, Tandem Diabetes, and Dexcom, and honoraria from Medscape, Lifescan, Novo Nordisk, and DKSH Singapore for advisory board attendance and from Insulet and Dexcom for speaking engagements.

A version of this article first appeared on Medscape.com.

Significant reductions in hemoglobin A1c have occurred over time among adults with type 1 diabetes as their use of diabetes technology has increased, yet there is still room for improvement, new data suggest.

The new findings are from a study involving patients at the Barbara Davis Center for Diabetes Adult Clinic between Jan. 1, 2014, and Dec. 31, 2021. They show that as technology use has increased, A1c levels have dropped in parallel. Moreover, progression from use of stand-alone continuous glucose monitors (CGMs) to automated insulin delivery systems (AIDs), which comprise insulin pumps and connected CGMs, furthered that progress.

The findings “are in agreement with American Diabetes Association standards of care, and recent international consensus recommending CGM and AID for most people with type 1 diabetes, and early initiation of diabetes technology from the onset of type 1 diabetes,” write Kagan E. Karakus, MD, of the University of Colorado’s Barbara Davis Center, Aurora, and colleagues in the article, which was published online in Diabetes Care.

“It’s very rewarding to us. We can see clearly that the uptake is going up and the A1c is dropping,” lead author Viral N. Shah, MD, of the Barbara Davis Center, told this news organization.

On the flip side, A1c levels rose significantly over the study period among nonusers of technology. “We cannot rule out provider bias for not prescribing diabetes technology among those with higher A1c or from disadvantaged socioeconomic backgrounds,” Dr. Karakus and colleagues write.

Also of note, even with use of the most advanced AID systems available during the study period, just under half of patients were still not achieving A1c levels below 7%. “The technology helps, but it’s not perfect,” Dr. Shah observed.

This study is the first to examine the relationship of A1c with technology use over time, in contrast to prior cross-sectional studies. “The intention here was to look at the landscape over a decade,” Dr. Shah said.
 

As overall use of technology use rose, A1c levels fell

The analysis included data for 4,174 unique patients (mean number of patients, 1,988/yr); 15,903 clinic visits were included over the 8-year study period. Technology use was defined as CGM use without an AID system or with an AID system.

Over the study period, diabetes technology use increased from 26.9% to 82.7% of the clinic population (P < .001). At the same time, the overall proportion patients who achieved the A1c goal of less than 7% increased from 32.3% to 41.7%, while the mean A1c level dropped from 7.7% to 7.5% (P < .001).

But among the technology nonusers, A1c rose from 7.85% in 2014 to 8.4% in 2021 (P < .001).

Regardless of diabetes technology use, White patients (about 80% of the total study population) had significantly lower A1c than non-White patients (7.5% vs. 7.7% for technology users [P = .02]; 8.0% vs. 8.3% for nontechnology users [P < .001]).

The non-White group was too small to enable the researchers to break down the data by technology type. Nonetheless, Dr. Shah said, “As a clinician, I can say that the penetration of diabetes technology in non-White populations remains low. These are also the people more vulnerable for socioeconomic and psychosocial reasons.”

The A1c increase among technology nonusers may be a result of a statistical artifact, as the number of those individuals was much lower in 2021 than in 2014. It’s possible that those remaining individuals have exceedingly high A1c levels, bringing the average up. “It’s still not good, though,” Dr. Shah said.
 

The more technology, the lower the A1c

Over the study period, the proportion of stand-alone CGM users rose from 26.9% to 44.1%, while use of AIDs rose from 0% in 2014 and 2015 to 38.6% in 2021. The latter group included patients who used first-generation Medtronic 670G and 770G devices and second-generation Tandem t:slim X2 with Control-IQ devices.

Between 2017 and 2021, AIDs users had significantly lower A1c levels than nontechnology users: 7.4% vs. 8.1% in 2017, and 7.3% vs. 8.4% in 2021 (P < .001 for every year). CGM users also had significantly lower A1c levels than nonusers at all time points (P < .001 per year).

The proportions achieving an A1c less than 7% differed significantly across users of CGMs, AIDs, and no technology (P < .01 for all years). In 2021, the percentage of people who achieved an A1c less than 7% were 50.9% with AIDs and 44.1% for CGMs vs, just 15.2% with no technology.
 

Work to be done: Why aren’t more achieving < 7% with AIDs?

Asked why only slightly more than half of patients who used AIDs achieved A1c levels below 7%, Dr. Shah listed three possibilities:

First, the 7% goal doesn’t apply to everyone with type 1 diabetes, including those with multiple comorbidities or with short life expectancy, for whom the recommended goal is 7.5%-8.0% to prevent hypoglycemia. “We didn’t separate out patients by A1c goals. If we add that, the number might go up,” Dr. Shah said.

Second, AID technology is continually improving, but it’s not perfect. Users still must enter carbohydrate counts and signal the devices for exercise, which can lead to errors. “It’s a wonderful technology for overnight control, but still, during the daytime, there are so many factors with the user interface and how much a person is engaged with the technology,” Dr. Shah explained.

Third, he said, “Unfortunately, obesity is increasing in type 1 diabetes, and insulin doses are increasing. Higher BMI [body mass index] and more insulin resistance can mean higher A1c. I really think for many patients, we probably will need an adjunct therapy, such as an SGLT2 [sodium-glucose cotransporter-2] inhibitor or a GLP-1 [glucagonlike peptide-1] agonist, even though they’re not approved in type 1 diabetes, for both glycemic and metabolic control including weight. I think that’s another missing piece.”

He also pointed out, “If someone has an A1c of 7.5%, I don’t expect a huge change. But if they’re at 10%, a drop to 8% is a huge change.”

Overall, Dr. Shah said, the news from the study is good. “In the past, only 30% were achieving an A1c less than 7%. Now we’re 20% above that. ... It’s a glass half full.”

Dr. Karakus has disclosed no relevant financial relationships. Dr. Shah has received, through the University of Colorado, research support from Novo Nordisk, Insulet, Tandem Diabetes, and Dexcom, and honoraria from Medscape, Lifescan, Novo Nordisk, and DKSH Singapore for advisory board attendance and from Insulet and Dexcom for speaking engagements.

A version of this article first appeared on Medscape.com.

Significant reductions in hemoglobin A1c have occurred over time among adults with type 1 diabetes as their use of diabetes technology has increased, yet there is still room for improvement, new data suggest.

The new findings are from a study involving patients at the Barbara Davis Center for Diabetes Adult Clinic between Jan. 1, 2014, and Dec. 31, 2021. They show that as technology use has increased, A1c levels have dropped in parallel. Moreover, progression from use of stand-alone continuous glucose monitors (CGMs) to automated insulin delivery systems (AIDs), which comprise insulin pumps and connected CGMs, furthered that progress.

The findings “are in agreement with American Diabetes Association standards of care, and recent international consensus recommending CGM and AID for most people with type 1 diabetes, and early initiation of diabetes technology from the onset of type 1 diabetes,” write Kagan E. Karakus, MD, of the University of Colorado’s Barbara Davis Center, Aurora, and colleagues in the article, which was published online in Diabetes Care.

“It’s very rewarding to us. We can see clearly that the uptake is going up and the A1c is dropping,” lead author Viral N. Shah, MD, of the Barbara Davis Center, told this news organization.

On the flip side, A1c levels rose significantly over the study period among nonusers of technology. “We cannot rule out provider bias for not prescribing diabetes technology among those with higher A1c or from disadvantaged socioeconomic backgrounds,” Dr. Karakus and colleagues write.

Also of note, even with use of the most advanced AID systems available during the study period, just under half of patients were still not achieving A1c levels below 7%. “The technology helps, but it’s not perfect,” Dr. Shah observed.

This study is the first to examine the relationship of A1c with technology use over time, in contrast to prior cross-sectional studies. “The intention here was to look at the landscape over a decade,” Dr. Shah said.
 

As overall use of technology use rose, A1c levels fell

The analysis included data for 4,174 unique patients (mean number of patients, 1,988/yr); 15,903 clinic visits were included over the 8-year study period. Technology use was defined as CGM use without an AID system or with an AID system.

Over the study period, diabetes technology use increased from 26.9% to 82.7% of the clinic population (P < .001). At the same time, the overall proportion patients who achieved the A1c goal of less than 7% increased from 32.3% to 41.7%, while the mean A1c level dropped from 7.7% to 7.5% (P < .001).

But among the technology nonusers, A1c rose from 7.85% in 2014 to 8.4% in 2021 (P < .001).

Regardless of diabetes technology use, White patients (about 80% of the total study population) had significantly lower A1c than non-White patients (7.5% vs. 7.7% for technology users [P = .02]; 8.0% vs. 8.3% for nontechnology users [P < .001]).

The non-White group was too small to enable the researchers to break down the data by technology type. Nonetheless, Dr. Shah said, “As a clinician, I can say that the penetration of diabetes technology in non-White populations remains low. These are also the people more vulnerable for socioeconomic and psychosocial reasons.”

The A1c increase among technology nonusers may be a result of a statistical artifact, as the number of those individuals was much lower in 2021 than in 2014. It’s possible that those remaining individuals have exceedingly high A1c levels, bringing the average up. “It’s still not good, though,” Dr. Shah said.
 

The more technology, the lower the A1c

Over the study period, the proportion of stand-alone CGM users rose from 26.9% to 44.1%, while use of AIDs rose from 0% in 2014 and 2015 to 38.6% in 2021. The latter group included patients who used first-generation Medtronic 670G and 770G devices and second-generation Tandem t:slim X2 with Control-IQ devices.

Between 2017 and 2021, AIDs users had significantly lower A1c levels than nontechnology users: 7.4% vs. 8.1% in 2017, and 7.3% vs. 8.4% in 2021 (P < .001 for every year). CGM users also had significantly lower A1c levels than nonusers at all time points (P < .001 per year).

The proportions achieving an A1c less than 7% differed significantly across users of CGMs, AIDs, and no technology (P < .01 for all years). In 2021, the percentage of people who achieved an A1c less than 7% were 50.9% with AIDs and 44.1% for CGMs vs, just 15.2% with no technology.
 

Work to be done: Why aren’t more achieving < 7% with AIDs?

Asked why only slightly more than half of patients who used AIDs achieved A1c levels below 7%, Dr. Shah listed three possibilities:

First, the 7% goal doesn’t apply to everyone with type 1 diabetes, including those with multiple comorbidities or with short life expectancy, for whom the recommended goal is 7.5%-8.0% to prevent hypoglycemia. “We didn’t separate out patients by A1c goals. If we add that, the number might go up,” Dr. Shah said.

Second, AID technology is continually improving, but it’s not perfect. Users still must enter carbohydrate counts and signal the devices for exercise, which can lead to errors. “It’s a wonderful technology for overnight control, but still, during the daytime, there are so many factors with the user interface and how much a person is engaged with the technology,” Dr. Shah explained.

Third, he said, “Unfortunately, obesity is increasing in type 1 diabetes, and insulin doses are increasing. Higher BMI [body mass index] and more insulin resistance can mean higher A1c. I really think for many patients, we probably will need an adjunct therapy, such as an SGLT2 [sodium-glucose cotransporter-2] inhibitor or a GLP-1 [glucagonlike peptide-1] agonist, even though they’re not approved in type 1 diabetes, for both glycemic and metabolic control including weight. I think that’s another missing piece.”

He also pointed out, “If someone has an A1c of 7.5%, I don’t expect a huge change. But if they’re at 10%, a drop to 8% is a huge change.”

Overall, Dr. Shah said, the news from the study is good. “In the past, only 30% were achieving an A1c less than 7%. Now we’re 20% above that. ... It’s a glass half full.”

Dr. Karakus has disclosed no relevant financial relationships. Dr. Shah has received, through the University of Colorado, research support from Novo Nordisk, Insulet, Tandem Diabetes, and Dexcom, and honoraria from Medscape, Lifescan, Novo Nordisk, and DKSH Singapore for advisory board attendance and from Insulet and Dexcom for speaking engagements.

A version of this article first appeared on Medscape.com.

A scientific review by researchers in Spain confirms the negative influence of artificial sweeteners on several primary cardiovascular risk factors. It also shows evidence that these products are not beneficial for controlling excess weight. 

Francisco Gómez-Delgado, MD, PhD, and Pablo Pérez-Martínez, MD, PhD, are members of the Spanish Society of Arteriosclerosis and of the Spanish Society of Internal Medicine. They have coordinated an updated review of the leading scientific evidence surrounding artificial sweeteners: evidence showing that far from positively affecting our health, they have “negative effects for the cardiometabolic system.”

The paper, published in Current Opinion in Cardiology, delves into the consumption of these sweeteners and their negative influence on the development of obesity and of several of the most important cardiometabolic risk factors (hypertension, dyslipidemia, and diabetes).

Globalization and the increase in consumption of ultraprocessed foods have led to a need for greater knowledge on the health impacts of certain nutrients such as artificial sweeteners (nutritive and nonnutritive). This review aims to analyze their role and their effect on cardiometabolic and cardiovascular disease risk.
 

Cardiovascular risk

The detrimental effects of a high-calorie, high-sugar diet have been well established. For this reason, health authorities recommend limiting sugar consumption. The recommendation has led the food industry to develop different artificial sweeteners with specific properties, such as flavor and stability (nutritive artificial sweeteners), and others aimed at limiting sugar in the diet (nonnutritive artificial sweeteners). Recent evidence explores the influence of these two types of artificial sweeteners on cardiovascular disease risk through risk factors such as obesity and type 2 diabetes, among others.

Initially, the consumption of artificial sweeteners was presented as an alternative for reducing calorie intake in the diet as an option for people with excess weight and obesity. However, as this paper explains, the consumption of these artificial sweeteners favors weight gain because of neuroendocrine mechanisms related to satiety that are abnormally activated when artificial sweeteners are consumed.
 

Weight gain

On the other hand, evidence shows that consuming artificial sweeteners does not encourage weight loss. “Quite the contrary,” Dr. Pérez-Martínez, scientific director at the Maimonides Biomedical Research Institute and internist at the University Hospital Reina Sofia, both in Córdoba, told this news organization. “There is evidence showing weight gain resulting from the effect that artificial sweetener consumption has at the neurohormonal level by altering the mechanisms involved in regulating the feeling of satiety.”

However, on the basis of current evidence, sugar cannot be claimed to be less harmful. “What we do know is that in both cases, we should reduce or remove them from our diets and replace them with other healthier alternatives for weight management, such as eating plant-based products or being physically active.”
 

Confronting ignorance 

Nonetheless, these recommendations are conditional, “because the weight of the evidence is not extremely high, since there have not been a whole lot of studies. All nutritional studies must be viewed with caution,” Manuel Anguita, MD, PhD, said in an interview. Dr. Anguita is department head of clinical cardiology at the University Hospital Reina Sofia in Córdoba and past president of the Spanish Society of Cardiology.

“It’s something that should be included within the medical record when you’re assessing cardiovascular risk. In addition to identifying patients who use artificial sweeteners, it’s especially important to emphasize that it’s not an appropriate recommendation for weight management.” Healthier measures include moderate exercise and the Mediterranean diet.

Explaining why this research is valuable, he said, “It’s generally useful because there’s ignorance not only in the population but among physicians as well [about] these negative effects of sweeteners.”
 

Diabetes and metabolic syndrome

Artificial sweeteners cause significant disruptions in the endocrine system, leading our metabolism to function abnormally. The review revealed that consuming artificial sweeteners raises the risk for type 2 diabetes by between 18% and 24% and raises the risk for metabolic syndrome by up to 44%.

Dr. Gómez-Delgado, an internal medicine specialist at the University Hospital of Jaen in Spain and first author of the study, discussed the deleterious effects of sweeteners on metabolism. “On one hand, neurohormonal disorders impact appetite, and the feeling of satiety is abnormally delayed.” On the other hand, “they induce excessive insulin secretion in the pancreas,” which in the long run, encourages metabolic disorders that lead to diabetes. Ultimately, this process produces what we know as “dysbiosis, since our microbiota is unable to process these artificial sweeteners.” Dysbiosis triggers specific pathophysiologic processes that negatively affect cardiometabolic and cardiovascular systems.
 

No differences 

Regarding the type of sweetener, Dr. Gómez-Delgado noted that currently available studies assess the consumption of special dietary products that, in most cases, include various types of artificial sweeteners. “So, it’s not possible to define specific differences between them as to how they impact our health.” Additional studies are needed to confirm this effect at the cardiometabolic level and to analyze the different types of artificial sweeteners individually.

“There’s enough evidence to confirm that consuming artificial sweeteners negatively interferes with our metabolism – especially glucose metabolism – and increases the risk of developing diabetes,” said Dr. Gómez-Delgado.
 

High-sodium drinks

When it comes to the influence of artificial sweeteners on hypertension, “there is no single explanation. The World Health Organization already discussed this issue 4-5 years ago, not only due to their carcinogenic risk, but also due to this cardiovascular risk in terms of a lack of control of obesity, diabetes, and hypertension,” said Dr. Anguita.

Another important point “is that this is not in reference to the sweeteners themselves, but to soft drinks containing those components, which is where we have more studies,” he added. There are two factors explaining this increase in hypertension, which poses a problem at the population level, with medium- to long-term follow-up. “The sugary beverages that we mentioned have a higher sodium content. That is, the sweeteners add this element, which is a factor that’s directly linked to the increase in blood pressure levels.” Another factor that can influence blood pressure is “the increase in insulin secretion that has been described as resulting from sweeteners. In the medium and long term, this is associated with increased blood pressure levels.”
 

Cardiovascular risk factor?

Are artificial sweeteners considered to be a new cardiovascular risk factor? “What they really do is increase the incidence of the other classic risk factors,” including obesity, said Dr. Anguita. It has been shown that artificial sweeteners don’t reduce obesity when used continuously. Nonetheless, “there is still not enough evidence to view it in the same light as the classic risk factors,” added Dr. Anguita. However, it is a factor that can clearly worsen the control of the other factors. Therefore, “it’s appropriate to sound an alarm and explain that it’s not the best way to lose weight; there are many other healthier choices.”

“We need more robust evidence to take a clear position on the use of this type of sweetener and its detrimental effect on health. Meanwhile, it would be ideal to limit their consumption or even avoid adding artificial sweeteners to coffee or teas,” added Dr. Pérez-Martínez.
 

Regulate consumption 

Dr. Pérez-Martínez mentioned that the measures proposed to regulate the consumption of artificial sweeteners and to modify the current legislation must involve “minimizing the consumption of these special dietary products as much as possible and even avoiding adding these artificial sweeteners to the foods that we consume; for example, to coffee and tea.” On the other hand, “we must provide consumers with information that is as clear and simple as possible regarding the composition of the food they consume and how it impacts their health.”

However, “we need more evidence to be able to take a clear position on what type of sweeteners we can consume in our diet and also to what extent we should limit their presence in the foods we consume,” said Dr. Pérez-Martínez. 

Last, “most of the evidence is from short-term observational studies that assess frequencies and patterns of consumption of foods containing these artificial sweeteners.” Of course, “we need studies that specifically analyze their effects at the metabolic level as well as longer-term studies where the nutritional follow-up of participants is more accurate and rigorous, especially when it comes to the consumption of this type of food,” concluded Dr. Gómez-Delgado.

This article was translated from the Medscape Spanish Edition. A version appeared on Medscape.com.

A scientific review by researchers in Spain confirms the negative influence of artificial sweeteners on several primary cardiovascular risk factors. It also shows evidence that these products are not beneficial for controlling excess weight. 

Francisco Gómez-Delgado, MD, PhD, and Pablo Pérez-Martínez, MD, PhD, are members of the Spanish Society of Arteriosclerosis and of the Spanish Society of Internal Medicine. They have coordinated an updated review of the leading scientific evidence surrounding artificial sweeteners: evidence showing that far from positively affecting our health, they have “negative effects for the cardiometabolic system.”

The paper, published in Current Opinion in Cardiology, delves into the consumption of these sweeteners and their negative influence on the development of obesity and of several of the most important cardiometabolic risk factors (hypertension, dyslipidemia, and diabetes).

Globalization and the increase in consumption of ultraprocessed foods have led to a need for greater knowledge on the health impacts of certain nutrients such as artificial sweeteners (nutritive and nonnutritive). This review aims to analyze their role and their effect on cardiometabolic and cardiovascular disease risk.
 

Cardiovascular risk

The detrimental effects of a high-calorie, high-sugar diet have been well established. For this reason, health authorities recommend limiting sugar consumption. The recommendation has led the food industry to develop different artificial sweeteners with specific properties, such as flavor and stability (nutritive artificial sweeteners), and others aimed at limiting sugar in the diet (nonnutritive artificial sweeteners). Recent evidence explores the influence of these two types of artificial sweeteners on cardiovascular disease risk through risk factors such as obesity and type 2 diabetes, among others.

Initially, the consumption of artificial sweeteners was presented as an alternative for reducing calorie intake in the diet as an option for people with excess weight and obesity. However, as this paper explains, the consumption of these artificial sweeteners favors weight gain because of neuroendocrine mechanisms related to satiety that are abnormally activated when artificial sweeteners are consumed.
 

Weight gain

On the other hand, evidence shows that consuming artificial sweeteners does not encourage weight loss. “Quite the contrary,” Dr. Pérez-Martínez, scientific director at the Maimonides Biomedical Research Institute and internist at the University Hospital Reina Sofia, both in Córdoba, told this news organization. “There is evidence showing weight gain resulting from the effect that artificial sweetener consumption has at the neurohormonal level by altering the mechanisms involved in regulating the feeling of satiety.”

However, on the basis of current evidence, sugar cannot be claimed to be less harmful. “What we do know is that in both cases, we should reduce or remove them from our diets and replace them with other healthier alternatives for weight management, such as eating plant-based products or being physically active.”
 

Confronting ignorance 

Nonetheless, these recommendations are conditional, “because the weight of the evidence is not extremely high, since there have not been a whole lot of studies. All nutritional studies must be viewed with caution,” Manuel Anguita, MD, PhD, said in an interview. Dr. Anguita is department head of clinical cardiology at the University Hospital Reina Sofia in Córdoba and past president of the Spanish Society of Cardiology.

“It’s something that should be included within the medical record when you’re assessing cardiovascular risk. In addition to identifying patients who use artificial sweeteners, it’s especially important to emphasize that it’s not an appropriate recommendation for weight management.” Healthier measures include moderate exercise and the Mediterranean diet.

Explaining why this research is valuable, he said, “It’s generally useful because there’s ignorance not only in the population but among physicians as well [about] these negative effects of sweeteners.”
 

Diabetes and metabolic syndrome

Artificial sweeteners cause significant disruptions in the endocrine system, leading our metabolism to function abnormally. The review revealed that consuming artificial sweeteners raises the risk for type 2 diabetes by between 18% and 24% and raises the risk for metabolic syndrome by up to 44%.

Dr. Gómez-Delgado, an internal medicine specialist at the University Hospital of Jaen in Spain and first author of the study, discussed the deleterious effects of sweeteners on metabolism. “On one hand, neurohormonal disorders impact appetite, and the feeling of satiety is abnormally delayed.” On the other hand, “they induce excessive insulin secretion in the pancreas,” which in the long run, encourages metabolic disorders that lead to diabetes. Ultimately, this process produces what we know as “dysbiosis, since our microbiota is unable to process these artificial sweeteners.” Dysbiosis triggers specific pathophysiologic processes that negatively affect cardiometabolic and cardiovascular systems.
 

No differences 

Regarding the type of sweetener, Dr. Gómez-Delgado noted that currently available studies assess the consumption of special dietary products that, in most cases, include various types of artificial sweeteners. “So, it’s not possible to define specific differences between them as to how they impact our health.” Additional studies are needed to confirm this effect at the cardiometabolic level and to analyze the different types of artificial sweeteners individually.

“There’s enough evidence to confirm that consuming artificial sweeteners negatively interferes with our metabolism – especially glucose metabolism – and increases the risk of developing diabetes,” said Dr. Gómez-Delgado.
 

High-sodium drinks

When it comes to the influence of artificial sweeteners on hypertension, “there is no single explanation. The World Health Organization already discussed this issue 4-5 years ago, not only due to their carcinogenic risk, but also due to this cardiovascular risk in terms of a lack of control of obesity, diabetes, and hypertension,” said Dr. Anguita.

Another important point “is that this is not in reference to the sweeteners themselves, but to soft drinks containing those components, which is where we have more studies,” he added. There are two factors explaining this increase in hypertension, which poses a problem at the population level, with medium- to long-term follow-up. “The sugary beverages that we mentioned have a higher sodium content. That is, the sweeteners add this element, which is a factor that’s directly linked to the increase in blood pressure levels.” Another factor that can influence blood pressure is “the increase in insulin secretion that has been described as resulting from sweeteners. In the medium and long term, this is associated with increased blood pressure levels.”
 

Cardiovascular risk factor?

Are artificial sweeteners considered to be a new cardiovascular risk factor? “What they really do is increase the incidence of the other classic risk factors,” including obesity, said Dr. Anguita. It has been shown that artificial sweeteners don’t reduce obesity when used continuously. Nonetheless, “there is still not enough evidence to view it in the same light as the classic risk factors,” added Dr. Anguita. However, it is a factor that can clearly worsen the control of the other factors. Therefore, “it’s appropriate to sound an alarm and explain that it’s not the best way to lose weight; there are many other healthier choices.”

“We need more robust evidence to take a clear position on the use of this type of sweetener and its detrimental effect on health. Meanwhile, it would be ideal to limit their consumption or even avoid adding artificial sweeteners to coffee or teas,” added Dr. Pérez-Martínez.
 

Regulate consumption 

Dr. Pérez-Martínez mentioned that the measures proposed to regulate the consumption of artificial sweeteners and to modify the current legislation must involve “minimizing the consumption of these special dietary products as much as possible and even avoiding adding these artificial sweeteners to the foods that we consume; for example, to coffee and tea.” On the other hand, “we must provide consumers with information that is as clear and simple as possible regarding the composition of the food they consume and how it impacts their health.”

However, “we need more evidence to be able to take a clear position on what type of sweeteners we can consume in our diet and also to what extent we should limit their presence in the foods we consume,” said Dr. Pérez-Martínez. 

Last, “most of the evidence is from short-term observational studies that assess frequencies and patterns of consumption of foods containing these artificial sweeteners.” Of course, “we need studies that specifically analyze their effects at the metabolic level as well as longer-term studies where the nutritional follow-up of participants is more accurate and rigorous, especially when it comes to the consumption of this type of food,” concluded Dr. Gómez-Delgado.

This article was translated from the Medscape Spanish Edition. A version appeared on Medscape.com.

A scientific review by researchers in Spain confirms the negative influence of artificial sweeteners on several primary cardiovascular risk factors. It also shows evidence that these products are not beneficial for controlling excess weight. 

Francisco Gómez-Delgado, MD, PhD, and Pablo Pérez-Martínez, MD, PhD, are members of the Spanish Society of Arteriosclerosis and of the Spanish Society of Internal Medicine. They have coordinated an updated review of the leading scientific evidence surrounding artificial sweeteners: evidence showing that far from positively affecting our health, they have “negative effects for the cardiometabolic system.”

The paper, published in Current Opinion in Cardiology, delves into the consumption of these sweeteners and their negative influence on the development of obesity and of several of the most important cardiometabolic risk factors (hypertension, dyslipidemia, and diabetes).

Globalization and the increase in consumption of ultraprocessed foods have led to a need for greater knowledge on the health impacts of certain nutrients such as artificial sweeteners (nutritive and nonnutritive). This review aims to analyze their role and their effect on cardiometabolic and cardiovascular disease risk.
 

Cardiovascular risk

The detrimental effects of a high-calorie, high-sugar diet have been well established. For this reason, health authorities recommend limiting sugar consumption. The recommendation has led the food industry to develop different artificial sweeteners with specific properties, such as flavor and stability (nutritive artificial sweeteners), and others aimed at limiting sugar in the diet (nonnutritive artificial sweeteners). Recent evidence explores the influence of these two types of artificial sweeteners on cardiovascular disease risk through risk factors such as obesity and type 2 diabetes, among others.

Initially, the consumption of artificial sweeteners was presented as an alternative for reducing calorie intake in the diet as an option for people with excess weight and obesity. However, as this paper explains, the consumption of these artificial sweeteners favors weight gain because of neuroendocrine mechanisms related to satiety that are abnormally activated when artificial sweeteners are consumed.
 

Weight gain

On the other hand, evidence shows that consuming artificial sweeteners does not encourage weight loss. “Quite the contrary,” Dr. Pérez-Martínez, scientific director at the Maimonides Biomedical Research Institute and internist at the University Hospital Reina Sofia, both in Córdoba, told this news organization. “There is evidence showing weight gain resulting from the effect that artificial sweetener consumption has at the neurohormonal level by altering the mechanisms involved in regulating the feeling of satiety.”

However, on the basis of current evidence, sugar cannot be claimed to be less harmful. “What we do know is that in both cases, we should reduce or remove them from our diets and replace them with other healthier alternatives for weight management, such as eating plant-based products or being physically active.”
 

Confronting ignorance 

Nonetheless, these recommendations are conditional, “because the weight of the evidence is not extremely high, since there have not been a whole lot of studies. All nutritional studies must be viewed with caution,” Manuel Anguita, MD, PhD, said in an interview. Dr. Anguita is department head of clinical cardiology at the University Hospital Reina Sofia in Córdoba and past president of the Spanish Society of Cardiology.

“It’s something that should be included within the medical record when you’re assessing cardiovascular risk. In addition to identifying patients who use artificial sweeteners, it’s especially important to emphasize that it’s not an appropriate recommendation for weight management.” Healthier measures include moderate exercise and the Mediterranean diet.

Explaining why this research is valuable, he said, “It’s generally useful because there’s ignorance not only in the population but among physicians as well [about] these negative effects of sweeteners.”
 

Diabetes and metabolic syndrome

Artificial sweeteners cause significant disruptions in the endocrine system, leading our metabolism to function abnormally. The review revealed that consuming artificial sweeteners raises the risk for type 2 diabetes by between 18% and 24% and raises the risk for metabolic syndrome by up to 44%.

Dr. Gómez-Delgado, an internal medicine specialist at the University Hospital of Jaen in Spain and first author of the study, discussed the deleterious effects of sweeteners on metabolism. “On one hand, neurohormonal disorders impact appetite, and the feeling of satiety is abnormally delayed.” On the other hand, “they induce excessive insulin secretion in the pancreas,” which in the long run, encourages metabolic disorders that lead to diabetes. Ultimately, this process produces what we know as “dysbiosis, since our microbiota is unable to process these artificial sweeteners.” Dysbiosis triggers specific pathophysiologic processes that negatively affect cardiometabolic and cardiovascular systems.
 

No differences 

Regarding the type of sweetener, Dr. Gómez-Delgado noted that currently available studies assess the consumption of special dietary products that, in most cases, include various types of artificial sweeteners. “So, it’s not possible to define specific differences between them as to how they impact our health.” Additional studies are needed to confirm this effect at the cardiometabolic level and to analyze the different types of artificial sweeteners individually.

“There’s enough evidence to confirm that consuming artificial sweeteners negatively interferes with our metabolism – especially glucose metabolism – and increases the risk of developing diabetes,” said Dr. Gómez-Delgado.
 

High-sodium drinks

When it comes to the influence of artificial sweeteners on hypertension, “there is no single explanation. The World Health Organization already discussed this issue 4-5 years ago, not only due to their carcinogenic risk, but also due to this cardiovascular risk in terms of a lack of control of obesity, diabetes, and hypertension,” said Dr. Anguita.

Another important point “is that this is not in reference to the sweeteners themselves, but to soft drinks containing those components, which is where we have more studies,” he added. There are two factors explaining this increase in hypertension, which poses a problem at the population level, with medium- to long-term follow-up. “The sugary beverages that we mentioned have a higher sodium content. That is, the sweeteners add this element, which is a factor that’s directly linked to the increase in blood pressure levels.” Another factor that can influence blood pressure is “the increase in insulin secretion that has been described as resulting from sweeteners. In the medium and long term, this is associated with increased blood pressure levels.”
 

Cardiovascular risk factor?

Are artificial sweeteners considered to be a new cardiovascular risk factor? “What they really do is increase the incidence of the other classic risk factors,” including obesity, said Dr. Anguita. It has been shown that artificial sweeteners don’t reduce obesity when used continuously. Nonetheless, “there is still not enough evidence to view it in the same light as the classic risk factors,” added Dr. Anguita. However, it is a factor that can clearly worsen the control of the other factors. Therefore, “it’s appropriate to sound an alarm and explain that it’s not the best way to lose weight; there are many other healthier choices.”

“We need more robust evidence to take a clear position on the use of this type of sweetener and its detrimental effect on health. Meanwhile, it would be ideal to limit their consumption or even avoid adding artificial sweeteners to coffee or teas,” added Dr. Pérez-Martínez.
 

Regulate consumption 

Dr. Pérez-Martínez mentioned that the measures proposed to regulate the consumption of artificial sweeteners and to modify the current legislation must involve “minimizing the consumption of these special dietary products as much as possible and even avoiding adding these artificial sweeteners to the foods that we consume; for example, to coffee and tea.” On the other hand, “we must provide consumers with information that is as clear and simple as possible regarding the composition of the food they consume and how it impacts their health.”

However, “we need more evidence to be able to take a clear position on what type of sweeteners we can consume in our diet and also to what extent we should limit their presence in the foods we consume,” said Dr. Pérez-Martínez. 

Last, “most of the evidence is from short-term observational studies that assess frequencies and patterns of consumption of foods containing these artificial sweeteners.” Of course, “we need studies that specifically analyze their effects at the metabolic level as well as longer-term studies where the nutritional follow-up of participants is more accurate and rigorous, especially when it comes to the consumption of this type of food,” concluded Dr. Gómez-Delgado.

This article was translated from the Medscape Spanish Edition. A version appeared on Medscape.com.

The American Diabetes Association recommends that patients on intensive insulin regimens self-monitor blood glucose (SMBG) to assist in therapy optimization.¹ To be useful, SMBG data must be captured by patients, shared with care teams, and used and interpreted by patients and practitioners.^2,3 Communication of SMBG data from the patient to practitioner can be challenging. Although technology can help in this process, limitations exist, such as manual data entry into systems, patient and/or practitioner technological challenges (eg, accessing interface), and compatibility and integration between SMBG devices and electronic health record (EHR) systems.⁴

The Boise Veterans Affairs Medical Center (BVAMC) in Idaho serves more than 100,000 veterans. It includes a main site, community-based outpatient clinics, and a clinical resource hub that provides telehealth services to veterans residing in rural neighboring states. The BVAMC pharmacy department provides both inpatient and outpatient services. At the BVAMC, clinical pharmacist practitioners (CPPs) are independent practitioners who support their care teams in comprehensive medication management and have the ability to initiate, modify, and discontinue drug therapy for referred patients.⁵ A prominent role of CPPs in primary care teams is to manage patients with uncontrolled diabetes and intensive insulin regimens, in which SMBG data are vital to therapy optimization. As collecting SMBG data from patients is seen anecdotally as time intensive, we determined the mean time spent by CPPs collecting patient SMBG data and its potential implications.

Methods

Pharmacists at BVAMC were asked to estimate and record the following: SMBG data collection method, time spent collecting data, extra time spent documenting or formatting SMBG readings, total patient visit time, and visit type. Time was collected in minutes. Extra time spent documenting or formatting SMBG readings included any additional time formatting or entering data in the clinical note after talking to the patient; if this was done while multitasking and talking to the patient, it was not considered extra time. For total patient visit time, pharmacists were asked to estimate only time spent discussing diabetes care and collecting SMBG data. Visit types were categorized as in-person/face-to-face, telephone, and telehealth using clinical video telehealth (CVT)/VA Video Connect (VVC). Data were collected using a standardized spreadsheet. The spreadsheet was pilot tested by a CPP before distribution to all pharmacists.

CPPs were educated about the project in March 2021 and were asked to record data for a 1-week period between April 5, 2021, and April 30, 2021. One CPP also provided delayed data collected from May 17 to 21, 2021, and these data were included in our analysis.

Descriptive statistics were used to determine the mean time spent by CPPs collecting SMBG data. Unpaired t tests were used to compare time spent collecting SMBG data by different collection methods and patient visit types. A P value of ≤ .05 was considered statistically significant. Data were organized in Microsoft Excel, and statistics were completed with JMP Pro v15.

Results

Eight CPPs provided data from 120 patient encounters. For all patient encounter types, the mean time spent collecting SMBG data was 3.3 minutes, and completing additional documentation/formatting was 1.3 minutes (Table 1).

When compared by the SMBG collection method, the longest time spent collecting SMBG data was with patient report (3.7 minutes), and the longest time spent documenting/formatting time was with meter download/home telehealth (2 minutes). There was no statistically significant difference in the time to collect SMBG data between patient report and other methods (3.7 minutes vs 2.8 minutes; P = .07).

When compared by visit type, there was not a statistically significant difference between time spent collecting SMBG data (3.8 minutes vs 3.2 minutes; P = .39) (Table 2).

Discussion

We found that the mean amount of time spent collecting and documenting/formatting SMBG data was only 4.6 minutes; however, this still represented a substantial portion of visit time. For telephone and CVT/VVC appointments, this represented > 25% of total visit time. While CPPs make important contributions to interprofessional team management of patients with diabetes, their cost is not trivial.^6-8 It is worth exploring the most effective and efficient ways to use CPPs. Our results indicate that streamlining SMBG data collection may be beneficial.

Pharmacy technicians, licensed practical nurses/clinical associates, registered nurses/nurse care managers, or other team members could help improve SMBG data collection. Using other team members is also an opportunity for comanagement, for team collaboration, and for more patients to be seen. For example, if a CPP currently has 12 patient encounters that last 20 minutes each, this results in about 240 minutes of direct patient care. If patient encounters were 16 minutes, CPPS could have 15 patient encounters in 240 minutes. Saved time could be used for other clinical tasks involved in disease management or clinical reminder reviews. While there are benefits to CPPs collecting SMBG data, such as further inquiry about patient-reported values, other team members could also be trained to ask appropriate follow-up questions for abnormal blood glucose readings. In addition, leveraging current team members and optimizing their roles could prevent the need to acquire additional full-time equivalent employees.

Another opportunity to increase efficiency in SMBG data collection is with SMBG devices and EHR integration.^4,9 However, integration can be difficult with different types of SMBG devices and EHR platforms. Education for patients and practitioners could help to ensure accurate and reliable data uploads; patient internet availability; data protection, privacy, and sharing; workflow management; and clear patient-practitioner expectations.¹⁰ For example, if patient SMBG data are automatically uploaded to practitioners, patients’ expectations for practitioner review of data and follow-up need to be determined.

We found a subset of patient encounters (n = 23) where data collection and documenting/formatting represented more than half of the total visit time. In this subset, 13 SMBG reports were pulled from a log or meter, 8 were patient reported, and 3 were meter download or home telehealth.

Limitations

A potential reason for the lack of statistically significant differences in SMBG collection method or visit type in this study includes the small sample size. Participation in this work was voluntary, and all participating CPPs had ≥ 3 years of practice in their current setting, which includes a heavy workload of diabetes management. These pharmacists noted self-established procedures/systems for SMBG data collection, including the use of Excel spreadsheets with pregenerated formulas. For less experienced CPPs, SMBG data collection time may be even longer. Pharmacists also noted that they may limit time spent collecting SMBG data depending on the patient encounter and whether they have gathered sufficient data to guide clinical care. Other limitations of this work include data collection from a single institution and that the time documented represented estimates; there was no external monitor.

Conclusions

In this analysis, we found that CPPs spend about 3 minutes collecting SMBG data from patients, and about an additional 1 minute documenting and formatting data. While 4 to 5 minutes may not represent a substantial amount of time for one patient, it can be when multiplied by several patient encounters. The time spent collecting SMBG data did not significantly differ by collection method or visit type. Opportunities to increase efficiency in SMBG data collection, such as the use of nonpharmacist team members are worth exploring.

Acknowledgments

Thank you to the pharmacists at the Boise Veterans Affairs Medical Center for their time and support of this work: Danielle Ahlstrom, Paul Black, Robyn Cruz, Sarah Naidoo, Anthony Nelson, Laura Spoutz, Eileen Twomey, Donovan Victorine, and Michelle Wilkin.

The American Diabetes Association recommends that patients on intensive insulin regimens self-monitor blood glucose (SMBG) to assist in therapy optimization.¹ To be useful, SMBG data must be captured by patients, shared with care teams, and used and interpreted by patients and practitioners.^2,3 Communication of SMBG data from the patient to practitioner can be challenging. Although technology can help in this process, limitations exist, such as manual data entry into systems, patient and/or practitioner technological challenges (eg, accessing interface), and compatibility and integration between SMBG devices and electronic health record (EHR) systems.⁴

The Boise Veterans Affairs Medical Center (BVAMC) in Idaho serves more than 100,000 veterans. It includes a main site, community-based outpatient clinics, and a clinical resource hub that provides telehealth services to veterans residing in rural neighboring states. The BVAMC pharmacy department provides both inpatient and outpatient services. At the BVAMC, clinical pharmacist practitioners (CPPs) are independent practitioners who support their care teams in comprehensive medication management and have the ability to initiate, modify, and discontinue drug therapy for referred patients.⁵ A prominent role of CPPs in primary care teams is to manage patients with uncontrolled diabetes and intensive insulin regimens, in which SMBG data are vital to therapy optimization. As collecting SMBG data from patients is seen anecdotally as time intensive, we determined the mean time spent by CPPs collecting patient SMBG data and its potential implications.

Methods

Pharmacists at BVAMC were asked to estimate and record the following: SMBG data collection method, time spent collecting data, extra time spent documenting or formatting SMBG readings, total patient visit time, and visit type. Time was collected in minutes. Extra time spent documenting or formatting SMBG readings included any additional time formatting or entering data in the clinical note after talking to the patient; if this was done while multitasking and talking to the patient, it was not considered extra time. For total patient visit time, pharmacists were asked to estimate only time spent discussing diabetes care and collecting SMBG data. Visit types were categorized as in-person/face-to-face, telephone, and telehealth using clinical video telehealth (CVT)/VA Video Connect (VVC). Data were collected using a standardized spreadsheet. The spreadsheet was pilot tested by a CPP before distribution to all pharmacists.

CPPs were educated about the project in March 2021 and were asked to record data for a 1-week period between April 5, 2021, and April 30, 2021. One CPP also provided delayed data collected from May 17 to 21, 2021, and these data were included in our analysis.

Descriptive statistics were used to determine the mean time spent by CPPs collecting SMBG data. Unpaired t tests were used to compare time spent collecting SMBG data by different collection methods and patient visit types. A P value of ≤ .05 was considered statistically significant. Data were organized in Microsoft Excel, and statistics were completed with JMP Pro v15.

Results

Eight CPPs provided data from 120 patient encounters. For all patient encounter types, the mean time spent collecting SMBG data was 3.3 minutes, and completing additional documentation/formatting was 1.3 minutes (Table 1).

When compared by the SMBG collection method, the longest time spent collecting SMBG data was with patient report (3.7 minutes), and the longest time spent documenting/formatting time was with meter download/home telehealth (2 minutes). There was no statistically significant difference in the time to collect SMBG data between patient report and other methods (3.7 minutes vs 2.8 minutes; P = .07).

When compared by visit type, there was not a statistically significant difference between time spent collecting SMBG data (3.8 minutes vs 3.2 minutes; P = .39) (Table 2).

Discussion

We found that the mean amount of time spent collecting and documenting/formatting SMBG data was only 4.6 minutes; however, this still represented a substantial portion of visit time. For telephone and CVT/VVC appointments, this represented > 25% of total visit time. While CPPs make important contributions to interprofessional team management of patients with diabetes, their cost is not trivial.^6-8 It is worth exploring the most effective and efficient ways to use CPPs. Our results indicate that streamlining SMBG data collection may be beneficial.

Pharmacy technicians, licensed practical nurses/clinical associates, registered nurses/nurse care managers, or other team members could help improve SMBG data collection. Using other team members is also an opportunity for comanagement, for team collaboration, and for more patients to be seen. For example, if a CPP currently has 12 patient encounters that last 20 minutes each, this results in about 240 minutes of direct patient care. If patient encounters were 16 minutes, CPPS could have 15 patient encounters in 240 minutes. Saved time could be used for other clinical tasks involved in disease management or clinical reminder reviews. While there are benefits to CPPs collecting SMBG data, such as further inquiry about patient-reported values, other team members could also be trained to ask appropriate follow-up questions for abnormal blood glucose readings. In addition, leveraging current team members and optimizing their roles could prevent the need to acquire additional full-time equivalent employees.

Another opportunity to increase efficiency in SMBG data collection is with SMBG devices and EHR integration.^4,9 However, integration can be difficult with different types of SMBG devices and EHR platforms. Education for patients and practitioners could help to ensure accurate and reliable data uploads; patient internet availability; data protection, privacy, and sharing; workflow management; and clear patient-practitioner expectations.¹⁰ For example, if patient SMBG data are automatically uploaded to practitioners, patients’ expectations for practitioner review of data and follow-up need to be determined.

We found a subset of patient encounters (n = 23) where data collection and documenting/formatting represented more than half of the total visit time. In this subset, 13 SMBG reports were pulled from a log or meter, 8 were patient reported, and 3 were meter download or home telehealth.

Limitations

A potential reason for the lack of statistically significant differences in SMBG collection method or visit type in this study includes the small sample size. Participation in this work was voluntary, and all participating CPPs had ≥ 3 years of practice in their current setting, which includes a heavy workload of diabetes management. These pharmacists noted self-established procedures/systems for SMBG data collection, including the use of Excel spreadsheets with pregenerated formulas. For less experienced CPPs, SMBG data collection time may be even longer. Pharmacists also noted that they may limit time spent collecting SMBG data depending on the patient encounter and whether they have gathered sufficient data to guide clinical care. Other limitations of this work include data collection from a single institution and that the time documented represented estimates; there was no external monitor.

Conclusions

In this analysis, we found that CPPs spend about 3 minutes collecting SMBG data from patients, and about an additional 1 minute documenting and formatting data. While 4 to 5 minutes may not represent a substantial amount of time for one patient, it can be when multiplied by several patient encounters. The time spent collecting SMBG data did not significantly differ by collection method or visit type. Opportunities to increase efficiency in SMBG data collection, such as the use of nonpharmacist team members are worth exploring.

Acknowledgments

Thank you to the pharmacists at the Boise Veterans Affairs Medical Center for their time and support of this work: Danielle Ahlstrom, Paul Black, Robyn Cruz, Sarah Naidoo, Anthony Nelson, Laura Spoutz, Eileen Twomey, Donovan Victorine, and Michelle Wilkin.

The American Diabetes Association recommends that patients on intensive insulin regimens self-monitor blood glucose (SMBG) to assist in therapy optimization.¹ To be useful, SMBG data must be captured by patients, shared with care teams, and used and interpreted by patients and practitioners.^2,3 Communication of SMBG data from the patient to practitioner can be challenging. Although technology can help in this process, limitations exist, such as manual data entry into systems, patient and/or practitioner technological challenges (eg, accessing interface), and compatibility and integration between SMBG devices and electronic health record (EHR) systems.⁴

The Boise Veterans Affairs Medical Center (BVAMC) in Idaho serves more than 100,000 veterans. It includes a main site, community-based outpatient clinics, and a clinical resource hub that provides telehealth services to veterans residing in rural neighboring states. The BVAMC pharmacy department provides both inpatient and outpatient services. At the BVAMC, clinical pharmacist practitioners (CPPs) are independent practitioners who support their care teams in comprehensive medication management and have the ability to initiate, modify, and discontinue drug therapy for referred patients.⁵ A prominent role of CPPs in primary care teams is to manage patients with uncontrolled diabetes and intensive insulin regimens, in which SMBG data are vital to therapy optimization. As collecting SMBG data from patients is seen anecdotally as time intensive, we determined the mean time spent by CPPs collecting patient SMBG data and its potential implications.

Methods

Pharmacists at BVAMC were asked to estimate and record the following: SMBG data collection method, time spent collecting data, extra time spent documenting or formatting SMBG readings, total patient visit time, and visit type. Time was collected in minutes. Extra time spent documenting or formatting SMBG readings included any additional time formatting or entering data in the clinical note after talking to the patient; if this was done while multitasking and talking to the patient, it was not considered extra time. For total patient visit time, pharmacists were asked to estimate only time spent discussing diabetes care and collecting SMBG data. Visit types were categorized as in-person/face-to-face, telephone, and telehealth using clinical video telehealth (CVT)/VA Video Connect (VVC). Data were collected using a standardized spreadsheet. The spreadsheet was pilot tested by a CPP before distribution to all pharmacists.

CPPs were educated about the project in March 2021 and were asked to record data for a 1-week period between April 5, 2021, and April 30, 2021. One CPP also provided delayed data collected from May 17 to 21, 2021, and these data were included in our analysis.

Descriptive statistics were used to determine the mean time spent by CPPs collecting SMBG data. Unpaired t tests were used to compare time spent collecting SMBG data by different collection methods and patient visit types. A P value of ≤ .05 was considered statistically significant. Data were organized in Microsoft Excel, and statistics were completed with JMP Pro v15.

Results

Eight CPPs provided data from 120 patient encounters. For all patient encounter types, the mean time spent collecting SMBG data was 3.3 minutes, and completing additional documentation/formatting was 1.3 minutes (Table 1).

When compared by the SMBG collection method, the longest time spent collecting SMBG data was with patient report (3.7 minutes), and the longest time spent documenting/formatting time was with meter download/home telehealth (2 minutes). There was no statistically significant difference in the time to collect SMBG data between patient report and other methods (3.7 minutes vs 2.8 minutes; P = .07).

When compared by visit type, there was not a statistically significant difference between time spent collecting SMBG data (3.8 minutes vs 3.2 minutes; P = .39) (Table 2).

Discussion

We found that the mean amount of time spent collecting and documenting/formatting SMBG data was only 4.6 minutes; however, this still represented a substantial portion of visit time. For telephone and CVT/VVC appointments, this represented > 25% of total visit time. While CPPs make important contributions to interprofessional team management of patients with diabetes, their cost is not trivial.^6-8 It is worth exploring the most effective and efficient ways to use CPPs. Our results indicate that streamlining SMBG data collection may be beneficial.

Pharmacy technicians, licensed practical nurses/clinical associates, registered nurses/nurse care managers, or other team members could help improve SMBG data collection. Using other team members is also an opportunity for comanagement, for team collaboration, and for more patients to be seen. For example, if a CPP currently has 12 patient encounters that last 20 minutes each, this results in about 240 minutes of direct patient care. If patient encounters were 16 minutes, CPPS could have 15 patient encounters in 240 minutes. Saved time could be used for other clinical tasks involved in disease management or clinical reminder reviews. While there are benefits to CPPs collecting SMBG data, such as further inquiry about patient-reported values, other team members could also be trained to ask appropriate follow-up questions for abnormal blood glucose readings. In addition, leveraging current team members and optimizing their roles could prevent the need to acquire additional full-time equivalent employees.

Another opportunity to increase efficiency in SMBG data collection is with SMBG devices and EHR integration.^4,9 However, integration can be difficult with different types of SMBG devices and EHR platforms. Education for patients and practitioners could help to ensure accurate and reliable data uploads; patient internet availability; data protection, privacy, and sharing; workflow management; and clear patient-practitioner expectations.¹⁰ For example, if patient SMBG data are automatically uploaded to practitioners, patients’ expectations for practitioner review of data and follow-up need to be determined.

We found a subset of patient encounters (n = 23) where data collection and documenting/formatting represented more than half of the total visit time. In this subset, 13 SMBG reports were pulled from a log or meter, 8 were patient reported, and 3 were meter download or home telehealth.

Limitations

A potential reason for the lack of statistically significant differences in SMBG collection method or visit type in this study includes the small sample size. Participation in this work was voluntary, and all participating CPPs had ≥ 3 years of practice in their current setting, which includes a heavy workload of diabetes management. These pharmacists noted self-established procedures/systems for SMBG data collection, including the use of Excel spreadsheets with pregenerated formulas. For less experienced CPPs, SMBG data collection time may be even longer. Pharmacists also noted that they may limit time spent collecting SMBG data depending on the patient encounter and whether they have gathered sufficient data to guide clinical care. Other limitations of this work include data collection from a single institution and that the time documented represented estimates; there was no external monitor.

Conclusions

In this analysis, we found that CPPs spend about 3 minutes collecting SMBG data from patients, and about an additional 1 minute documenting and formatting data. While 4 to 5 minutes may not represent a substantial amount of time for one patient, it can be when multiplied by several patient encounters. The time spent collecting SMBG data did not significantly differ by collection method or visit type. Opportunities to increase efficiency in SMBG data collection, such as the use of nonpharmacist team members are worth exploring.

Acknowledgments

Thank you to the pharmacists at the Boise Veterans Affairs Medical Center for their time and support of this work: Danielle Ahlstrom, Paul Black, Robyn Cruz, Sarah Naidoo, Anthony Nelson, Laura Spoutz, Eileen Twomey, Donovan Victorine, and Michelle Wilkin.

Physicians may be missing opportunities to reduce harmful polypharmacy in elderly patients with newly diagnosed dementia, investigators for a large study of Medicare beneficiaries reported.

They found that those with an incident dementia diagnosis were somewhat more likely to initiate central nervous system–active medications and slightly more likely to discontinue cardiometabolic and anticholinergic medications, compared with controls.

According to the authors, time of diagnosis can be a potential inflexion point for deprescribing long-term medications with high safety risks, limited likelihood of benefit, or possible association with impaired cognition.

“Understanding the chronology of medication changes following a first dementia diagnosis may identify targets for deprescribing interventions to reduce preventable medication-related harms, said Timothy S. Anderson, MD, MAS, of the division of general medicine at Beth Israel Deaconess Medical Center, Boston, and colleagues in JAMA Internal Medicine.

“Our results provide a baseline to inform efforts to rethink the clinical approach to medication use at the time of a new dementia diagnosis.”

Hundreds of thousands of Americans are diagnosed annually with Alzheimer’s and related dementias, the authors pointed out, and the majority have multiple other chronic conditions. Worsening cognitive impairment may alter the risk-benefit balance of medications taken for these conditions.

Matched cohort study

The sample consisted of adults 67 years or older enrolled in traditional Medicare and Medicare Part D. Patients with an initial incident dementia diagnosis between January 2012 and December 2018 were matched with controls (as of last doctor’s office visit) based on demographics, geographic location, and baseline medication count. Data were analyzed from 2021 to June 2023.

The study included 266,675 adults with incident dementia and 266,675 controls. In both groups, 65.1% were 80 years or older (mean age, 82.2) and 67.8% were female. At baseline, patients with incident dementia were more likely than controls to use CNS-active medications (54.32% vs. 48.39%) and anticholinergic medications (17.79% vs. 15.96%) and less likely to use most cardiometabolic medications (for example, antidiabetics, 31.19% vs. 36.45%).

Immediately following the index diagnosis, the dementia cohort had greater increases in the mean number of medications used: 0.41 vs. –0.06 (95% confidence interval, 0.27-0.66) and in the proportion using CNS-active medications (absolute change, 3.44% vs. 0.79%; 95% CI, 0.85%-4.45%). The rise was because of an increased use of antipsychotics, antidepressants, and antiepileptics.

The affected cohort showed a modestly greater decline in anticholinergic medications: quarterly change in use: −0.53% vs. −0.21% (95% CI, −0.55% to −0.08%); and in most cardiometabolic medications: for example, quarterly change in antihypertensive use: –0.84% vs. –0.40% (95% CI, –0.64% to –0.25%). Still, a year post diagnosis, 75.2% of dementia patients were using five or more medications, for a 2.8% increase.

The drug classes with the steepest rate of discontinuation – such as lipid-lowering and antihypertensive medications – had low risks for adverse drug events, while higher-risk classes – such as insulins and antiplatelet and anticoagulant agents – had smaller or no reductions in use.

While the findings point to opportunities to reduce polypharmacy by deprescribing long-term medications of dubious benefit, interventions to reduce polypharmacy and inappropriate medications have been modestly successful for patients without dementia, the authors said. But the recent OPTIMIZE trial, an educational effort aimed at primary care clinicians and patients with cognitive impairment, reduced neither polypharmacy nor potentially inappropriate medications.

Luke D. Kim, MD, a geriatrician at the Cleveland Clinic in Ohio, agreed that seniors with dementia can benefit from reassessment of their pharmacologic therapies. “Older adults in general are more prone to have side effects from medications as their renal and hepatic clearance and metabolism are different and lower than those of younger individuals. But they tend to take multiple medications owing to more comorbidities,” said Dr. Kim, who was not involved in the study. “While all older adults need to be more careful about medication management, those with dementia need an even more careful approach as they have diminished cognitive reserve and risk more potential harm from medications.” 

The authors noted that since decision-making models aligned with patient priorities for older adults without dementia led to reductions in overall medication use, that may be a path forward in populations with dementia.

The study was supported by grants from the National Institute on Aging, National Institutes of Health. The authors had no competing interests to disclose. Dr. Kim disclosed no competing interests relevant to his comments.

Physicians may be missing opportunities to reduce harmful polypharmacy in elderly patients with newly diagnosed dementia, investigators for a large study of Medicare beneficiaries reported.

They found that those with an incident dementia diagnosis were somewhat more likely to initiate central nervous system–active medications and slightly more likely to discontinue cardiometabolic and anticholinergic medications, compared with controls.

According to the authors, time of diagnosis can be a potential inflexion point for deprescribing long-term medications with high safety risks, limited likelihood of benefit, or possible association with impaired cognition.

“Understanding the chronology of medication changes following a first dementia diagnosis may identify targets for deprescribing interventions to reduce preventable medication-related harms, said Timothy S. Anderson, MD, MAS, of the division of general medicine at Beth Israel Deaconess Medical Center, Boston, and colleagues in JAMA Internal Medicine.

“Our results provide a baseline to inform efforts to rethink the clinical approach to medication use at the time of a new dementia diagnosis.”

Hundreds of thousands of Americans are diagnosed annually with Alzheimer’s and related dementias, the authors pointed out, and the majority have multiple other chronic conditions. Worsening cognitive impairment may alter the risk-benefit balance of medications taken for these conditions.

Matched cohort study

The sample consisted of adults 67 years or older enrolled in traditional Medicare and Medicare Part D. Patients with an initial incident dementia diagnosis between January 2012 and December 2018 were matched with controls (as of last doctor’s office visit) based on demographics, geographic location, and baseline medication count. Data were analyzed from 2021 to June 2023.

The study included 266,675 adults with incident dementia and 266,675 controls. In both groups, 65.1% were 80 years or older (mean age, 82.2) and 67.8% were female. At baseline, patients with incident dementia were more likely than controls to use CNS-active medications (54.32% vs. 48.39%) and anticholinergic medications (17.79% vs. 15.96%) and less likely to use most cardiometabolic medications (for example, antidiabetics, 31.19% vs. 36.45%).

Immediately following the index diagnosis, the dementia cohort had greater increases in the mean number of medications used: 0.41 vs. –0.06 (95% confidence interval, 0.27-0.66) and in the proportion using CNS-active medications (absolute change, 3.44% vs. 0.79%; 95% CI, 0.85%-4.45%). The rise was because of an increased use of antipsychotics, antidepressants, and antiepileptics.

The affected cohort showed a modestly greater decline in anticholinergic medications: quarterly change in use: −0.53% vs. −0.21% (95% CI, −0.55% to −0.08%); and in most cardiometabolic medications: for example, quarterly change in antihypertensive use: –0.84% vs. –0.40% (95% CI, –0.64% to –0.25%). Still, a year post diagnosis, 75.2% of dementia patients were using five or more medications, for a 2.8% increase.

The drug classes with the steepest rate of discontinuation – such as lipid-lowering and antihypertensive medications – had low risks for adverse drug events, while higher-risk classes – such as insulins and antiplatelet and anticoagulant agents – had smaller or no reductions in use.

While the findings point to opportunities to reduce polypharmacy by deprescribing long-term medications of dubious benefit, interventions to reduce polypharmacy and inappropriate medications have been modestly successful for patients without dementia, the authors said. But the recent OPTIMIZE trial, an educational effort aimed at primary care clinicians and patients with cognitive impairment, reduced neither polypharmacy nor potentially inappropriate medications.

Luke D. Kim, MD, a geriatrician at the Cleveland Clinic in Ohio, agreed that seniors with dementia can benefit from reassessment of their pharmacologic therapies. “Older adults in general are more prone to have side effects from medications as their renal and hepatic clearance and metabolism are different and lower than those of younger individuals. But they tend to take multiple medications owing to more comorbidities,” said Dr. Kim, who was not involved in the study. “While all older adults need to be more careful about medication management, those with dementia need an even more careful approach as they have diminished cognitive reserve and risk more potential harm from medications.” 

The authors noted that since decision-making models aligned with patient priorities for older adults without dementia led to reductions in overall medication use, that may be a path forward in populations with dementia.

The study was supported by grants from the National Institute on Aging, National Institutes of Health. The authors had no competing interests to disclose. Dr. Kim disclosed no competing interests relevant to his comments.

Physicians may be missing opportunities to reduce harmful polypharmacy in elderly patients with newly diagnosed dementia, investigators for a large study of Medicare beneficiaries reported.

They found that those with an incident dementia diagnosis were somewhat more likely to initiate central nervous system–active medications and slightly more likely to discontinue cardiometabolic and anticholinergic medications, compared with controls.

According to the authors, time of diagnosis can be a potential inflexion point for deprescribing long-term medications with high safety risks, limited likelihood of benefit, or possible association with impaired cognition.

“Understanding the chronology of medication changes following a first dementia diagnosis may identify targets for deprescribing interventions to reduce preventable medication-related harms, said Timothy S. Anderson, MD, MAS, of the division of general medicine at Beth Israel Deaconess Medical Center, Boston, and colleagues in JAMA Internal Medicine.

“Our results provide a baseline to inform efforts to rethink the clinical approach to medication use at the time of a new dementia diagnosis.”

Hundreds of thousands of Americans are diagnosed annually with Alzheimer’s and related dementias, the authors pointed out, and the majority have multiple other chronic conditions. Worsening cognitive impairment may alter the risk-benefit balance of medications taken for these conditions.

Matched cohort study

The sample consisted of adults 67 years or older enrolled in traditional Medicare and Medicare Part D. Patients with an initial incident dementia diagnosis between January 2012 and December 2018 were matched with controls (as of last doctor’s office visit) based on demographics, geographic location, and baseline medication count. Data were analyzed from 2021 to June 2023.

The study included 266,675 adults with incident dementia and 266,675 controls. In both groups, 65.1% were 80 years or older (mean age, 82.2) and 67.8% were female. At baseline, patients with incident dementia were more likely than controls to use CNS-active medications (54.32% vs. 48.39%) and anticholinergic medications (17.79% vs. 15.96%) and less likely to use most cardiometabolic medications (for example, antidiabetics, 31.19% vs. 36.45%).

Immediately following the index diagnosis, the dementia cohort had greater increases in the mean number of medications used: 0.41 vs. –0.06 (95% confidence interval, 0.27-0.66) and in the proportion using CNS-active medications (absolute change, 3.44% vs. 0.79%; 95% CI, 0.85%-4.45%). The rise was because of an increased use of antipsychotics, antidepressants, and antiepileptics.

The affected cohort showed a modestly greater decline in anticholinergic medications: quarterly change in use: −0.53% vs. −0.21% (95% CI, −0.55% to −0.08%); and in most cardiometabolic medications: for example, quarterly change in antihypertensive use: –0.84% vs. –0.40% (95% CI, –0.64% to –0.25%). Still, a year post diagnosis, 75.2% of dementia patients were using five or more medications, for a 2.8% increase.

The drug classes with the steepest rate of discontinuation – such as lipid-lowering and antihypertensive medications – had low risks for adverse drug events, while higher-risk classes – such as insulins and antiplatelet and anticoagulant agents – had smaller or no reductions in use.

While the findings point to opportunities to reduce polypharmacy by deprescribing long-term medications of dubious benefit, interventions to reduce polypharmacy and inappropriate medications have been modestly successful for patients without dementia, the authors said. But the recent OPTIMIZE trial, an educational effort aimed at primary care clinicians and patients with cognitive impairment, reduced neither polypharmacy nor potentially inappropriate medications.

Luke D. Kim, MD, a geriatrician at the Cleveland Clinic in Ohio, agreed that seniors with dementia can benefit from reassessment of their pharmacologic therapies. “Older adults in general are more prone to have side effects from medications as their renal and hepatic clearance and metabolism are different and lower than those of younger individuals. But they tend to take multiple medications owing to more comorbidities,” said Dr. Kim, who was not involved in the study. “While all older adults need to be more careful about medication management, those with dementia need an even more careful approach as they have diminished cognitive reserve and risk more potential harm from medications.” 

The authors noted that since decision-making models aligned with patient priorities for older adults without dementia led to reductions in overall medication use, that may be a path forward in populations with dementia.

The study was supported by grants from the National Institute on Aging, National Institutes of Health. The authors had no competing interests to disclose. Dr. Kim disclosed no competing interests relevant to his comments.

Measuring four circulating biomarkers through a simple blood test in patients with type 2 diabetes and kidney disease may predict their risk of heart and kidney disease progression, suggests an analysis of the CREDENCE trial.

The research, published online in the journal Circulation, also revealed that patients treated with the sodium-glucose cotransporter-2 inhibitor canagliflozin (Invokana, Invokamet) had lower levels of the biomarkers after 1 year compared with those given placebo.

Examination of biomarker levels in more than 2,600 patients from CREDENCE showed that high baseline concentrations of the individual biomarkers were able to predict the future risk for a composite endpoint of renal and heart outcomes.

The combination of all four biomarkers into a single panel revealed that patients with the highest levels were more than four times as likely to experience the composite endpoint than were those with the lowest levels.

As two of the biomarkers used in the study have yet to have established prognostic thresholds, the results remain exploratory.

Lead author James L. Januzzi, MD, director of the Heart Failure and Biomarker Trials at the Baim Institute for Clinical Research, Boston, said that further study will help refine the predictive value of the panel.

“Given that the American Heart Association/American College of Cardiology and the American Diabetes Association now all recommend measurement of biomarkers to enhance the ability to predict risk in persons with type 2 diabetes, these results may considerably extend the reach of biomarker-based testing, refining accuracy even further,” he said in a press release.

In an interview, Dr. Januzzi said that “three out of the four biomarkers are already clinically and commercially available,” while the fourth, for insulin-like growth factor binding protein 7 (IGFBP7), is “on the near horizon.”

He stressed that the “future for multiple biomarker testing, however, will be less about ordering each individual test, and ultimately will revolve around panels of blood work that are ordered as a single test.”

Dr. Januzzi added that “rather than using the rather primitive approach that we took” of looking at the individual biomarkers in adjusted models, the next stage “will be to utilize algorithms to combine the results into a single value.

“A clinician will not have to struggle with looking at individual results but will just receive one aggregated test result that informs them whether a patient is at low, medium or higher risk,” he explained.

However, this will require determining the relative importance of each biomarker and weighting them in the final model.

Consequently, the current results “set the foundation for identifying some very powerful individual tests that may ultimately, in aggregate, help us to help our patients with diabetes avoid a major complication,” Dr. Januzzi said.

By revealing that some individuals with both type 2 diabetes and kidney disease are at higher risk than others, he also hopes the findings can be leveraged to treat patients with “varying degrees of intensity with proven therapies, including weight loss, dietary adjustment, and pharmacologic intervention.”

Dr. Januzzi added: “Diabetes affects a dramatic, and growing, percentage of our population, and this type of personalized strategy to reduce the major complications of this rather common disease is an important step forward.”

The authors noted that there is a “bidirectional relationship” between cardiovascular disease and chronic kidney disease (CKD), such that either diagnosis may increase the risk of, or exacerbate, the other. 

Individuals with type 2 diabetes and CKD albuminuria, they added, are at particularly high risk for major cardiovascular events, and studies have shown that several circulating cardiorenal stress biomarkers may predict the onset and progression of CKD in type 2 diabetes, as well as predict cardiovascular events.
 

Several biomarkers associated with myocardial stress and necrosis

The recent CANVAS trial revealed that, among individuals with type 2 diabetes with and without CKD, several biomarkers were associated with myocardial stress and necrosis, and renal tubular injury, predicting the progression of CKD with albuminuria, and the risk for heart failure events.

Taking inspiration from those findings, the current researchers studied a panel of similar cardiac and renal biomarkers among participants from the CREDENCE trial, for which 4,401 patients with type 2 diabetes and CKD at high risk of progression were randomly assigned to canagliflozin or placebo.

The current analysis involved 2,627 participants who had baseline plasma samples available for analysis of four circulating biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), and IGFBP7.

Among those, 2,385 participants also had year 1 plasma samples available for analysis, while year 3 plasma samples were available for 895 individuals.

The results showed that, in general, median baseline concentrations of each biomarker in both treatment groups were elevated compared with healthy reference populations.

Baseline log-transformed concentrations of each biomarker were also strongly predictive of cardiac and renal outcomes, including heart failure and progression of CKD.

For example, each unit increase in baseline NT-proBNP concentrations was associated with a hazard ratio of 1.35 for the primary composite endpoint of end-stage kidney disease, doubling of serum creatinine levels, renal death, or cardiovascular disease (P < .001).

For each unit increase in hs-cTnT levels, the hazard ratio for the primary composite was 1.73 (P < .001), for GDF-15 it was 1.84 (P < .0001), and for IGFBP7 the hazard ratio was 3.14 (P < .001).

Combining the four biomarkers into a single multimarker panel revealed that, compared with individuals with a low-risk score, those with a high-risk score had a hazard ratio for the primary outcome of 4.01, whereas those with a moderate risk score had a hazard ratio of 2.39 (P < .001 for both).

For the individual outcome of heart failure hospitalization, the effect was even greater. A high-risk score was associated with a hazard ratio vs. a low-risk score of 6.04 (P < .001), whereas patients with a moderate risk score had a hazard ratio of 2.45 (P = .04).

The researchers also reported that, between baseline and year 1, concentrations of all four biomarkers rose from 6% to 29% in the placebo group, but from 3% to just 10% in those treated with canagliflozin.

“It was reassuring to discover that canagliflozin helped reduce risks the most in people with the highest chances for complications,” said Dr. Januzzi.

The CREDENCE trial and the current analysis were funded by Janssen Research & Development LLC. NT-proBNP, hs-cTnT, GDF-15, and IGFBP7 reagents were provided by Roche Diagnostics. Dr. Januzzi is funded in part by the Hutter Family Professorship. Dr. Januzzi declared relationships with Imbria Pharmaceuticals, Jana Care, Abbott, Applied Therapeutics, HeartFlow, Innolife, Roche Diagnostics, Beckman, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, Pfizer, Siemens, Abbott, AbbVie, CVRx, Intercept, and Takeda.


 

A version of this article first appeared on Medscape.com.

Measuring four circulating biomarkers through a simple blood test in patients with type 2 diabetes and kidney disease may predict their risk of heart and kidney disease progression, suggests an analysis of the CREDENCE trial.

The research, published online in the journal Circulation, also revealed that patients treated with the sodium-glucose cotransporter-2 inhibitor canagliflozin (Invokana, Invokamet) had lower levels of the biomarkers after 1 year compared with those given placebo.

Examination of biomarker levels in more than 2,600 patients from CREDENCE showed that high baseline concentrations of the individual biomarkers were able to predict the future risk for a composite endpoint of renal and heart outcomes.

The combination of all four biomarkers into a single panel revealed that patients with the highest levels were more than four times as likely to experience the composite endpoint than were those with the lowest levels.

As two of the biomarkers used in the study have yet to have established prognostic thresholds, the results remain exploratory.

Lead author James L. Januzzi, MD, director of the Heart Failure and Biomarker Trials at the Baim Institute for Clinical Research, Boston, said that further study will help refine the predictive value of the panel.

“Given that the American Heart Association/American College of Cardiology and the American Diabetes Association now all recommend measurement of biomarkers to enhance the ability to predict risk in persons with type 2 diabetes, these results may considerably extend the reach of biomarker-based testing, refining accuracy even further,” he said in a press release.

In an interview, Dr. Januzzi said that “three out of the four biomarkers are already clinically and commercially available,” while the fourth, for insulin-like growth factor binding protein 7 (IGFBP7), is “on the near horizon.”

He stressed that the “future for multiple biomarker testing, however, will be less about ordering each individual test, and ultimately will revolve around panels of blood work that are ordered as a single test.”

Dr. Januzzi added that “rather than using the rather primitive approach that we took” of looking at the individual biomarkers in adjusted models, the next stage “will be to utilize algorithms to combine the results into a single value.

“A clinician will not have to struggle with looking at individual results but will just receive one aggregated test result that informs them whether a patient is at low, medium or higher risk,” he explained.

However, this will require determining the relative importance of each biomarker and weighting them in the final model.

Consequently, the current results “set the foundation for identifying some very powerful individual tests that may ultimately, in aggregate, help us to help our patients with diabetes avoid a major complication,” Dr. Januzzi said.

By revealing that some individuals with both type 2 diabetes and kidney disease are at higher risk than others, he also hopes the findings can be leveraged to treat patients with “varying degrees of intensity with proven therapies, including weight loss, dietary adjustment, and pharmacologic intervention.”

Dr. Januzzi added: “Diabetes affects a dramatic, and growing, percentage of our population, and this type of personalized strategy to reduce the major complications of this rather common disease is an important step forward.”

The authors noted that there is a “bidirectional relationship” between cardiovascular disease and chronic kidney disease (CKD), such that either diagnosis may increase the risk of, or exacerbate, the other. 

Individuals with type 2 diabetes and CKD albuminuria, they added, are at particularly high risk for major cardiovascular events, and studies have shown that several circulating cardiorenal stress biomarkers may predict the onset and progression of CKD in type 2 diabetes, as well as predict cardiovascular events.
 

Several biomarkers associated with myocardial stress and necrosis

The recent CANVAS trial revealed that, among individuals with type 2 diabetes with and without CKD, several biomarkers were associated with myocardial stress and necrosis, and renal tubular injury, predicting the progression of CKD with albuminuria, and the risk for heart failure events.

Taking inspiration from those findings, the current researchers studied a panel of similar cardiac and renal biomarkers among participants from the CREDENCE trial, for which 4,401 patients with type 2 diabetes and CKD at high risk of progression were randomly assigned to canagliflozin or placebo.

The current analysis involved 2,627 participants who had baseline plasma samples available for analysis of four circulating biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), and IGFBP7.

Among those, 2,385 participants also had year 1 plasma samples available for analysis, while year 3 plasma samples were available for 895 individuals.

The results showed that, in general, median baseline concentrations of each biomarker in both treatment groups were elevated compared with healthy reference populations.

Baseline log-transformed concentrations of each biomarker were also strongly predictive of cardiac and renal outcomes, including heart failure and progression of CKD.

For example, each unit increase in baseline NT-proBNP concentrations was associated with a hazard ratio of 1.35 for the primary composite endpoint of end-stage kidney disease, doubling of serum creatinine levels, renal death, or cardiovascular disease (P < .001).

For each unit increase in hs-cTnT levels, the hazard ratio for the primary composite was 1.73 (P < .001), for GDF-15 it was 1.84 (P < .0001), and for IGFBP7 the hazard ratio was 3.14 (P < .001).

Combining the four biomarkers into a single multimarker panel revealed that, compared with individuals with a low-risk score, those with a high-risk score had a hazard ratio for the primary outcome of 4.01, whereas those with a moderate risk score had a hazard ratio of 2.39 (P < .001 for both).

For the individual outcome of heart failure hospitalization, the effect was even greater. A high-risk score was associated with a hazard ratio vs. a low-risk score of 6.04 (P < .001), whereas patients with a moderate risk score had a hazard ratio of 2.45 (P = .04).

The researchers also reported that, between baseline and year 1, concentrations of all four biomarkers rose from 6% to 29% in the placebo group, but from 3% to just 10% in those treated with canagliflozin.

“It was reassuring to discover that canagliflozin helped reduce risks the most in people with the highest chances for complications,” said Dr. Januzzi.

The CREDENCE trial and the current analysis were funded by Janssen Research & Development LLC. NT-proBNP, hs-cTnT, GDF-15, and IGFBP7 reagents were provided by Roche Diagnostics. Dr. Januzzi is funded in part by the Hutter Family Professorship. Dr. Januzzi declared relationships with Imbria Pharmaceuticals, Jana Care, Abbott, Applied Therapeutics, HeartFlow, Innolife, Roche Diagnostics, Beckman, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, Pfizer, Siemens, Abbott, AbbVie, CVRx, Intercept, and Takeda.


 

A version of this article first appeared on Medscape.com.

Measuring four circulating biomarkers through a simple blood test in patients with type 2 diabetes and kidney disease may predict their risk of heart and kidney disease progression, suggests an analysis of the CREDENCE trial.

The research, published online in the journal Circulation, also revealed that patients treated with the sodium-glucose cotransporter-2 inhibitor canagliflozin (Invokana, Invokamet) had lower levels of the biomarkers after 1 year compared with those given placebo.

Examination of biomarker levels in more than 2,600 patients from CREDENCE showed that high baseline concentrations of the individual biomarkers were able to predict the future risk for a composite endpoint of renal and heart outcomes.

The combination of all four biomarkers into a single panel revealed that patients with the highest levels were more than four times as likely to experience the composite endpoint than were those with the lowest levels.

As two of the biomarkers used in the study have yet to have established prognostic thresholds, the results remain exploratory.

Lead author James L. Januzzi, MD, director of the Heart Failure and Biomarker Trials at the Baim Institute for Clinical Research, Boston, said that further study will help refine the predictive value of the panel.

“Given that the American Heart Association/American College of Cardiology and the American Diabetes Association now all recommend measurement of biomarkers to enhance the ability to predict risk in persons with type 2 diabetes, these results may considerably extend the reach of biomarker-based testing, refining accuracy even further,” he said in a press release.

In an interview, Dr. Januzzi said that “three out of the four biomarkers are already clinically and commercially available,” while the fourth, for insulin-like growth factor binding protein 7 (IGFBP7), is “on the near horizon.”

He stressed that the “future for multiple biomarker testing, however, will be less about ordering each individual test, and ultimately will revolve around panels of blood work that are ordered as a single test.”

Dr. Januzzi added that “rather than using the rather primitive approach that we took” of looking at the individual biomarkers in adjusted models, the next stage “will be to utilize algorithms to combine the results into a single value.

“A clinician will not have to struggle with looking at individual results but will just receive one aggregated test result that informs them whether a patient is at low, medium or higher risk,” he explained.

However, this will require determining the relative importance of each biomarker and weighting them in the final model.

Consequently, the current results “set the foundation for identifying some very powerful individual tests that may ultimately, in aggregate, help us to help our patients with diabetes avoid a major complication,” Dr. Januzzi said.

By revealing that some individuals with both type 2 diabetes and kidney disease are at higher risk than others, he also hopes the findings can be leveraged to treat patients with “varying degrees of intensity with proven therapies, including weight loss, dietary adjustment, and pharmacologic intervention.”

Dr. Januzzi added: “Diabetes affects a dramatic, and growing, percentage of our population, and this type of personalized strategy to reduce the major complications of this rather common disease is an important step forward.”

The authors noted that there is a “bidirectional relationship” between cardiovascular disease and chronic kidney disease (CKD), such that either diagnosis may increase the risk of, or exacerbate, the other. 

Individuals with type 2 diabetes and CKD albuminuria, they added, are at particularly high risk for major cardiovascular events, and studies have shown that several circulating cardiorenal stress biomarkers may predict the onset and progression of CKD in type 2 diabetes, as well as predict cardiovascular events.
 

Several biomarkers associated with myocardial stress and necrosis

The recent CANVAS trial revealed that, among individuals with type 2 diabetes with and without CKD, several biomarkers were associated with myocardial stress and necrosis, and renal tubular injury, predicting the progression of CKD with albuminuria, and the risk for heart failure events.

Taking inspiration from those findings, the current researchers studied a panel of similar cardiac and renal biomarkers among participants from the CREDENCE trial, for which 4,401 patients with type 2 diabetes and CKD at high risk of progression were randomly assigned to canagliflozin or placebo.

The current analysis involved 2,627 participants who had baseline plasma samples available for analysis of four circulating biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), and IGFBP7.

Among those, 2,385 participants also had year 1 plasma samples available for analysis, while year 3 plasma samples were available for 895 individuals.

The results showed that, in general, median baseline concentrations of each biomarker in both treatment groups were elevated compared with healthy reference populations.

Baseline log-transformed concentrations of each biomarker were also strongly predictive of cardiac and renal outcomes, including heart failure and progression of CKD.

For example, each unit increase in baseline NT-proBNP concentrations was associated with a hazard ratio of 1.35 for the primary composite endpoint of end-stage kidney disease, doubling of serum creatinine levels, renal death, or cardiovascular disease (P < .001).

For each unit increase in hs-cTnT levels, the hazard ratio for the primary composite was 1.73 (P < .001), for GDF-15 it was 1.84 (P < .0001), and for IGFBP7 the hazard ratio was 3.14 (P < .001).

Combining the four biomarkers into a single multimarker panel revealed that, compared with individuals with a low-risk score, those with a high-risk score had a hazard ratio for the primary outcome of 4.01, whereas those with a moderate risk score had a hazard ratio of 2.39 (P < .001 for both).

For the individual outcome of heart failure hospitalization, the effect was even greater. A high-risk score was associated with a hazard ratio vs. a low-risk score of 6.04 (P < .001), whereas patients with a moderate risk score had a hazard ratio of 2.45 (P = .04).

The researchers also reported that, between baseline and year 1, concentrations of all four biomarkers rose from 6% to 29% in the placebo group, but from 3% to just 10% in those treated with canagliflozin.

“It was reassuring to discover that canagliflozin helped reduce risks the most in people with the highest chances for complications,” said Dr. Januzzi.

The CREDENCE trial and the current analysis were funded by Janssen Research & Development LLC. NT-proBNP, hs-cTnT, GDF-15, and IGFBP7 reagents were provided by Roche Diagnostics. Dr. Januzzi is funded in part by the Hutter Family Professorship. Dr. Januzzi declared relationships with Imbria Pharmaceuticals, Jana Care, Abbott, Applied Therapeutics, HeartFlow, Innolife, Roche Diagnostics, Beckman, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, Pfizer, Siemens, Abbott, AbbVie, CVRx, Intercept, and Takeda.


 

A version of this article first appeared on Medscape.com.

Men and women with prediabetes, undiagnosed diabetes, and, notably, diagnosed diabetes were at higher risk of incident cardiovascular disease (CVD), whereas those with low-normal A1c were at lower risk of this in a large, 12-year observational study of UK Biobank data.

The results highlight “the need for strategies to reduce risk of CVD across the [glycemic] spectrum,” Christopher T. Rentsch, MPH, PhD, and colleagues wrote in their study, which was published in the The Lancet Regional Health – Europe.

The findings suggest “that excess [CVD] risks in both men and women were largely explained by modifiable factors and could be ameliorated by attention to weight reduction strategies and greater use of antihypertensive and statin medications.

“Addressing these risk factors could reduce sex disparities in [glycemia]-related risks of CVD,” according to the researchers.

After the researchers accounted for age, the absolute rate of CVD events was higher among men than women (16.9 vs. 9.1 events per 1,000 person-years); however, the relative risk was higher among women than men.

Compared with men, women were more likely to have obesity (63% vs. 53%) and were less likely to be using antihypertensive medications (64% vs. 69%) or a statin (71% vs. 75%).

“This is the largest study to date to investigate sex differences in the risk of CVD across the glycemic spectrum,” the researchers noted.
 

“The lower the better”

“We uncovered compelling evidence that for blood sugar levels within the ‘normal’ range, it was a case of ‘the lower the better’ in protecting against heart disease,” Dr. Rentsch, assistant professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, told this news organization.

Compared with people with normal blood glucose levels, those with lower than normal levels were at 10% lower risk of developing any form of heart disease, he noted.

The study findings “support women being proactive in asking about medications like statins and antihypertensives as an option to help lower their [CVD] risk, if clinically appropriate,” Dr. Rentsch added.

“We found that men and women with diagnosed diabetes remained at elevated risk for three types of heart disease – coronary artery disease, stroke, and heart failure – even after accounting for a large number of sociodemographic, lifestyle, and clinical characteristics,” he pointed out.

However, “total cholesterol, family history of CVD, estimated glomerular filtration rate, and C-reactive protein had relatively little impact on explaining the risk of heart disease associated with blood sugar.”

“It is well established that being overweight can lead to higher blood sugar levels as well as higher blood pressure, these being factors that contribute to higher risk of heart attack and stroke,” Robert Storey, DM, professor of cardiology, University of Sheffield (England), told the UK Science Media Centre.

“This very large UK Biobank study,” he said, “shows that the higher heart risk associated with blood sugar can be detected at a very early stage along the path towards the abnormally high blood sugar levels associated with diabetes.

“The study provides support for a strategy of assessing cardiovascular risk in people who are overweight, including assessment of blood sugar, cholesterol, and blood pressure levels, all of which can be effectively managed to markedly reduce the risk of future heart attack and stroke,” according to Dr. Storey.
 

More than 400,000 men, women

The researchers enrolled men and women aged 40-69 between 2006 to 2010 who were living in England, Scotland, and Wales. After excluding people with type 1 diabetes or those whose A1c data were missing, the current study included 427,435 people (46% of whom were men).

The participants were classified as having low-normal A1c (< 35 mmol/mol or < 5.5%), normal A1c (35-41 mmol/mol or 5.5%-5.9%), prediabetes (42-47 mmol/mol or 6.0%-6.4%), undiagnosed diabetes (≥ 48 mmol/mol or ≥ 6.5%), or diagnosed type 2 diabetes (medical history and in receipt of glucose-lowering medication).

The researchers determined the incidence of six CVD outcomes during a median 11.8-year follow-up: coronary artery disease, atrial fibrillation, deep vein thrombosis, pulmonary embolism, stroke, and heart failure.

Few participants (5%) had any of these outcomes prior to study enrollment.

During the follow-up, there were 51,288 incident CVD events.

After adjustment for age, compared to having normal A1c, having prediabetes or undiagnosed diabetes was associated with an increased risk of CVD for women and men (hazard ratio [HR], 1.30-1.47).

Among individuals with diagnosed type 2 diabetes, the age-adjusted risk of CVD was greater for women (HR, 2.00) than for men (HR, 1.55).

After further adjustment for clinical and lifestyle factors, especially obesity and antihypertensive or statin use, the risk of CVD decreased and became similar among men and women. The fully adjusted HR for CVD was 1.17 for women and 1.06 for men with diagnosed diabetes.

Compared with having normal A1c, women and men with low-normal A1c were at decreased risk of CVD (HR, 0.86 for both).

The study was funded by Diabetes UK and the British Heart Foundation. Dr. Rentsch and Dr. Storey have disclosed no relevant financial relationships. The disclosures of the other study authors are listed in the original article.
 

A version of this article appeared on Medscape.com.

Men and women with prediabetes, undiagnosed diabetes, and, notably, diagnosed diabetes were at higher risk of incident cardiovascular disease (CVD), whereas those with low-normal A1c were at lower risk of this in a large, 12-year observational study of UK Biobank data.

The results highlight “the need for strategies to reduce risk of CVD across the [glycemic] spectrum,” Christopher T. Rentsch, MPH, PhD, and colleagues wrote in their study, which was published in the The Lancet Regional Health – Europe.

The findings suggest “that excess [CVD] risks in both men and women were largely explained by modifiable factors and could be ameliorated by attention to weight reduction strategies and greater use of antihypertensive and statin medications.

“Addressing these risk factors could reduce sex disparities in [glycemia]-related risks of CVD,” according to the researchers.

After the researchers accounted for age, the absolute rate of CVD events was higher among men than women (16.9 vs. 9.1 events per 1,000 person-years); however, the relative risk was higher among women than men.

Compared with men, women were more likely to have obesity (63% vs. 53%) and were less likely to be using antihypertensive medications (64% vs. 69%) or a statin (71% vs. 75%).

“This is the largest study to date to investigate sex differences in the risk of CVD across the glycemic spectrum,” the researchers noted.
 

“The lower the better”

“We uncovered compelling evidence that for blood sugar levels within the ‘normal’ range, it was a case of ‘the lower the better’ in protecting against heart disease,” Dr. Rentsch, assistant professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, told this news organization.

Compared with people with normal blood glucose levels, those with lower than normal levels were at 10% lower risk of developing any form of heart disease, he noted.

The study findings “support women being proactive in asking about medications like statins and antihypertensives as an option to help lower their [CVD] risk, if clinically appropriate,” Dr. Rentsch added.

“We found that men and women with diagnosed diabetes remained at elevated risk for three types of heart disease – coronary artery disease, stroke, and heart failure – even after accounting for a large number of sociodemographic, lifestyle, and clinical characteristics,” he pointed out.

However, “total cholesterol, family history of CVD, estimated glomerular filtration rate, and C-reactive protein had relatively little impact on explaining the risk of heart disease associated with blood sugar.”

“It is well established that being overweight can lead to higher blood sugar levels as well as higher blood pressure, these being factors that contribute to higher risk of heart attack and stroke,” Robert Storey, DM, professor of cardiology, University of Sheffield (England), told the UK Science Media Centre.

“This very large UK Biobank study,” he said, “shows that the higher heart risk associated with blood sugar can be detected at a very early stage along the path towards the abnormally high blood sugar levels associated with diabetes.

“The study provides support for a strategy of assessing cardiovascular risk in people who are overweight, including assessment of blood sugar, cholesterol, and blood pressure levels, all of which can be effectively managed to markedly reduce the risk of future heart attack and stroke,” according to Dr. Storey.
 

More than 400,000 men, women

The researchers enrolled men and women aged 40-69 between 2006 to 2010 who were living in England, Scotland, and Wales. After excluding people with type 1 diabetes or those whose A1c data were missing, the current study included 427,435 people (46% of whom were men).

The participants were classified as having low-normal A1c (< 35 mmol/mol or < 5.5%), normal A1c (35-41 mmol/mol or 5.5%-5.9%), prediabetes (42-47 mmol/mol or 6.0%-6.4%), undiagnosed diabetes (≥ 48 mmol/mol or ≥ 6.5%), or diagnosed type 2 diabetes (medical history and in receipt of glucose-lowering medication).

The researchers determined the incidence of six CVD outcomes during a median 11.8-year follow-up: coronary artery disease, atrial fibrillation, deep vein thrombosis, pulmonary embolism, stroke, and heart failure.

Few participants (5%) had any of these outcomes prior to study enrollment.

During the follow-up, there were 51,288 incident CVD events.

After adjustment for age, compared to having normal A1c, having prediabetes or undiagnosed diabetes was associated with an increased risk of CVD for women and men (hazard ratio [HR], 1.30-1.47).

Among individuals with diagnosed type 2 diabetes, the age-adjusted risk of CVD was greater for women (HR, 2.00) than for men (HR, 1.55).

After further adjustment for clinical and lifestyle factors, especially obesity and antihypertensive or statin use, the risk of CVD decreased and became similar among men and women. The fully adjusted HR for CVD was 1.17 for women and 1.06 for men with diagnosed diabetes.

Compared with having normal A1c, women and men with low-normal A1c were at decreased risk of CVD (HR, 0.86 for both).

The study was funded by Diabetes UK and the British Heart Foundation. Dr. Rentsch and Dr. Storey have disclosed no relevant financial relationships. The disclosures of the other study authors are listed in the original article.
 

A version of this article appeared on Medscape.com.

Men and women with prediabetes, undiagnosed diabetes, and, notably, diagnosed diabetes were at higher risk of incident cardiovascular disease (CVD), whereas those with low-normal A1c were at lower risk of this in a large, 12-year observational study of UK Biobank data.

The results highlight “the need for strategies to reduce risk of CVD across the [glycemic] spectrum,” Christopher T. Rentsch, MPH, PhD, and colleagues wrote in their study, which was published in the The Lancet Regional Health – Europe.

The findings suggest “that excess [CVD] risks in both men and women were largely explained by modifiable factors and could be ameliorated by attention to weight reduction strategies and greater use of antihypertensive and statin medications.

“Addressing these risk factors could reduce sex disparities in [glycemia]-related risks of CVD,” according to the researchers.

After the researchers accounted for age, the absolute rate of CVD events was higher among men than women (16.9 vs. 9.1 events per 1,000 person-years); however, the relative risk was higher among women than men.

Compared with men, women were more likely to have obesity (63% vs. 53%) and were less likely to be using antihypertensive medications (64% vs. 69%) or a statin (71% vs. 75%).

“This is the largest study to date to investigate sex differences in the risk of CVD across the glycemic spectrum,” the researchers noted.
 

“The lower the better”

“We uncovered compelling evidence that for blood sugar levels within the ‘normal’ range, it was a case of ‘the lower the better’ in protecting against heart disease,” Dr. Rentsch, assistant professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, told this news organization.

Compared with people with normal blood glucose levels, those with lower than normal levels were at 10% lower risk of developing any form of heart disease, he noted.

The study findings “support women being proactive in asking about medications like statins and antihypertensives as an option to help lower their [CVD] risk, if clinically appropriate,” Dr. Rentsch added.

“We found that men and women with diagnosed diabetes remained at elevated risk for three types of heart disease – coronary artery disease, stroke, and heart failure – even after accounting for a large number of sociodemographic, lifestyle, and clinical characteristics,” he pointed out.

However, “total cholesterol, family history of CVD, estimated glomerular filtration rate, and C-reactive protein had relatively little impact on explaining the risk of heart disease associated with blood sugar.”

“It is well established that being overweight can lead to higher blood sugar levels as well as higher blood pressure, these being factors that contribute to higher risk of heart attack and stroke,” Robert Storey, DM, professor of cardiology, University of Sheffield (England), told the UK Science Media Centre.

“This very large UK Biobank study,” he said, “shows that the higher heart risk associated with blood sugar can be detected at a very early stage along the path towards the abnormally high blood sugar levels associated with diabetes.

“The study provides support for a strategy of assessing cardiovascular risk in people who are overweight, including assessment of blood sugar, cholesterol, and blood pressure levels, all of which can be effectively managed to markedly reduce the risk of future heart attack and stroke,” according to Dr. Storey.
 

More than 400,000 men, women

The researchers enrolled men and women aged 40-69 between 2006 to 2010 who were living in England, Scotland, and Wales. After excluding people with type 1 diabetes or those whose A1c data were missing, the current study included 427,435 people (46% of whom were men).

The participants were classified as having low-normal A1c (< 35 mmol/mol or < 5.5%), normal A1c (35-41 mmol/mol or 5.5%-5.9%), prediabetes (42-47 mmol/mol or 6.0%-6.4%), undiagnosed diabetes (≥ 48 mmol/mol or ≥ 6.5%), or diagnosed type 2 diabetes (medical history and in receipt of glucose-lowering medication).

The researchers determined the incidence of six CVD outcomes during a median 11.8-year follow-up: coronary artery disease, atrial fibrillation, deep vein thrombosis, pulmonary embolism, stroke, and heart failure.

Few participants (5%) had any of these outcomes prior to study enrollment.

During the follow-up, there were 51,288 incident CVD events.

After adjustment for age, compared to having normal A1c, having prediabetes or undiagnosed diabetes was associated with an increased risk of CVD for women and men (hazard ratio [HR], 1.30-1.47).

Among individuals with diagnosed type 2 diabetes, the age-adjusted risk of CVD was greater for women (HR, 2.00) than for men (HR, 1.55).

After further adjustment for clinical and lifestyle factors, especially obesity and antihypertensive or statin use, the risk of CVD decreased and became similar among men and women. The fully adjusted HR for CVD was 1.17 for women and 1.06 for men with diagnosed diabetes.

Compared with having normal A1c, women and men with low-normal A1c were at decreased risk of CVD (HR, 0.86 for both).

The study was funded by Diabetes UK and the British Heart Foundation. Dr. Rentsch and Dr. Storey have disclosed no relevant financial relationships. The disclosures of the other study authors are listed in the original article.
 

A version of this article appeared on Medscape.com.

Every 4 years, an interprofessional panel of experts from the American Geriatrics Society provides updated guidelines on safe prescribing of medications in older adults, known as the Beers Criteria. A 2023 update was released in May 2023 after panel review of more 1,500 clinical trials and research studies published since the last update.

Anticoagulants

Notable changes to the 2023 guidelines include updated recommendations for anticoagulation. Warfarin should be avoided as initial therapy for venous thromboembolism or nonvalvular atrial fibrillation unless there are contraindications to direct oral anticoagulants (DOACs) or other substantial barriers to use.

Rivaroxaban should also be avoided, and dabigatran used with caution in favor of apixaban, which is felt to have a better safety profile in older adults. Rivaroxaban may be considered if once daily dosing is deemed to be more clinically appropriate. Financial barriers regarding drug coverage and formulary options were acknowledged as a significant barrier to equitable access to preferred direct oral anticoagulants in older adults.
 

Diabetes medication

Regarding diabetes management, short-acting sulfonylureas should be avoided in addition to long-acting sulfonylureas, because of the increased risk of hypoglycemia, and cardiovascular and all-cause mortality in older adults. Sodium-glucose cotransporter 2 inhibitors as an entire class are recommended to be used with caution, as older adults are at higher risk of euglycemic ketoacidosis and urogenital infections, particularly in women in the first month of initiating treatment.

Like DOACs, the panel acknowledged that financial considerations may lead to limited options for oral diabetic treatment. In circumstances where a sulfonylurea is used, short-acting forms are preferred over long acting to reduce the risk of prolonged hypoglycemia.
 

Aspirin for primary prevention

Alongside the U.S. Preventive Services Task Force guideline update in 2022 regarding aspirin for primary prevention of cardiovascular disease and stroke, the Beer’s Criteria recommend against initiation of aspirin for primary prevention in older adults. Ticagrelor and prasugrel should be used with caution because of the increased risk of major bleeding in older adults over the age of 75, compared with clopidogrel. If prasugrel is used, a lower dose of 5 mg is recommended, in line with guidelines by the American College of Cardiology and American Heart Association.

Pain medication

For pain management, the Beer’s Criteria updated recommendations to avoid NSAIDs, particularly when used in combination with steroids or anticoagulants. The panel highlights that even short-term use of NSAIDs is high risk when used in combination with steroids or anticoagulants. If no other alternatives are possible, patients should be placed on a proton pump inhibitor or misoprostol while taking NSAIDs.

Baclofen should be avoided in older adults with renal insufficiency (estimated glomerular filtration rate < 60 mL/min per 1.73 m²) because of the increased risk of encephalopathy, and when used, should be given at the lowest effective dose with close monitoring for mental status changes.
 

Androgen and estrogen replacement therapy

For androgen replacement therapy, the panel notes that testosterone supplementation should be avoided because of cardiovascular risks unless there is confirmed hypogonadism. The panel revised their recommendation on the basis of emerging data that a history of prostate cancer is not an absolute contraindication for exogenous testosterone. A risk versus benefit discussion about exogenous testosterone should be had with a medical oncologist or urologist in those with a history of prostate cancer.

Regarding estrogen, systemic formulations should not be initiated in women over the age of 60 because of increased risk of cardiovascular events, venous thromboembolism, and dementia. In women with a history of breast cancer, vaginal estrogens are generally felt to be safe to use at low doses, such as less than 25 mcg twice weekly.

Dr. Wang is a geriatrician and general internist at Harborview Medical Center, Seattle.

Every 4 years, an interprofessional panel of experts from the American Geriatrics Society provides updated guidelines on safe prescribing of medications in older adults, known as the Beers Criteria. A 2023 update was released in May 2023 after panel review of more 1,500 clinical trials and research studies published since the last update.

Anticoagulants

Notable changes to the 2023 guidelines include updated recommendations for anticoagulation. Warfarin should be avoided as initial therapy for venous thromboembolism or nonvalvular atrial fibrillation unless there are contraindications to direct oral anticoagulants (DOACs) or other substantial barriers to use.

Rivaroxaban should also be avoided, and dabigatran used with caution in favor of apixaban, which is felt to have a better safety profile in older adults. Rivaroxaban may be considered if once daily dosing is deemed to be more clinically appropriate. Financial barriers regarding drug coverage and formulary options were acknowledged as a significant barrier to equitable access to preferred direct oral anticoagulants in older adults.
 

Diabetes medication

Regarding diabetes management, short-acting sulfonylureas should be avoided in addition to long-acting sulfonylureas, because of the increased risk of hypoglycemia, and cardiovascular and all-cause mortality in older adults. Sodium-glucose cotransporter 2 inhibitors as an entire class are recommended to be used with caution, as older adults are at higher risk of euglycemic ketoacidosis and urogenital infections, particularly in women in the first month of initiating treatment.

Like DOACs, the panel acknowledged that financial considerations may lead to limited options for oral diabetic treatment. In circumstances where a sulfonylurea is used, short-acting forms are preferred over long acting to reduce the risk of prolonged hypoglycemia.
 

Aspirin for primary prevention

Alongside the U.S. Preventive Services Task Force guideline update in 2022 regarding aspirin for primary prevention of cardiovascular disease and stroke, the Beer’s Criteria recommend against initiation of aspirin for primary prevention in older adults. Ticagrelor and prasugrel should be used with caution because of the increased risk of major bleeding in older adults over the age of 75, compared with clopidogrel. If prasugrel is used, a lower dose of 5 mg is recommended, in line with guidelines by the American College of Cardiology and American Heart Association.

Pain medication

For pain management, the Beer’s Criteria updated recommendations to avoid NSAIDs, particularly when used in combination with steroids or anticoagulants. The panel highlights that even short-term use of NSAIDs is high risk when used in combination with steroids or anticoagulants. If no other alternatives are possible, patients should be placed on a proton pump inhibitor or misoprostol while taking NSAIDs.

Baclofen should be avoided in older adults with renal insufficiency (estimated glomerular filtration rate < 60 mL/min per 1.73 m²) because of the increased risk of encephalopathy, and when used, should be given at the lowest effective dose with close monitoring for mental status changes.
 

Androgen and estrogen replacement therapy

For androgen replacement therapy, the panel notes that testosterone supplementation should be avoided because of cardiovascular risks unless there is confirmed hypogonadism. The panel revised their recommendation on the basis of emerging data that a history of prostate cancer is not an absolute contraindication for exogenous testosterone. A risk versus benefit discussion about exogenous testosterone should be had with a medical oncologist or urologist in those with a history of prostate cancer.

Regarding estrogen, systemic formulations should not be initiated in women over the age of 60 because of increased risk of cardiovascular events, venous thromboembolism, and dementia. In women with a history of breast cancer, vaginal estrogens are generally felt to be safe to use at low doses, such as less than 25 mcg twice weekly.

Dr. Wang is a geriatrician and general internist at Harborview Medical Center, Seattle.

Every 4 years, an interprofessional panel of experts from the American Geriatrics Society provides updated guidelines on safe prescribing of medications in older adults, known as the Beers Criteria. A 2023 update was released in May 2023 after panel review of more 1,500 clinical trials and research studies published since the last update.

Anticoagulants

Notable changes to the 2023 guidelines include updated recommendations for anticoagulation. Warfarin should be avoided as initial therapy for venous thromboembolism or nonvalvular atrial fibrillation unless there are contraindications to direct oral anticoagulants (DOACs) or other substantial barriers to use.

Rivaroxaban should also be avoided, and dabigatran used with caution in favor of apixaban, which is felt to have a better safety profile in older adults. Rivaroxaban may be considered if once daily dosing is deemed to be more clinically appropriate. Financial barriers regarding drug coverage and formulary options were acknowledged as a significant barrier to equitable access to preferred direct oral anticoagulants in older adults.
 

Diabetes medication

Regarding diabetes management, short-acting sulfonylureas should be avoided in addition to long-acting sulfonylureas, because of the increased risk of hypoglycemia, and cardiovascular and all-cause mortality in older adults. Sodium-glucose cotransporter 2 inhibitors as an entire class are recommended to be used with caution, as older adults are at higher risk of euglycemic ketoacidosis and urogenital infections, particularly in women in the first month of initiating treatment.

Like DOACs, the panel acknowledged that financial considerations may lead to limited options for oral diabetic treatment. In circumstances where a sulfonylurea is used, short-acting forms are preferred over long acting to reduce the risk of prolonged hypoglycemia.
 

Aspirin for primary prevention

Alongside the U.S. Preventive Services Task Force guideline update in 2022 regarding aspirin for primary prevention of cardiovascular disease and stroke, the Beer’s Criteria recommend against initiation of aspirin for primary prevention in older adults. Ticagrelor and prasugrel should be used with caution because of the increased risk of major bleeding in older adults over the age of 75, compared with clopidogrel. If prasugrel is used, a lower dose of 5 mg is recommended, in line with guidelines by the American College of Cardiology and American Heart Association.

Pain medication

For pain management, the Beer’s Criteria updated recommendations to avoid NSAIDs, particularly when used in combination with steroids or anticoagulants. The panel highlights that even short-term use of NSAIDs is high risk when used in combination with steroids or anticoagulants. If no other alternatives are possible, patients should be placed on a proton pump inhibitor or misoprostol while taking NSAIDs.

Baclofen should be avoided in older adults with renal insufficiency (estimated glomerular filtration rate < 60 mL/min per 1.73 m²) because of the increased risk of encephalopathy, and when used, should be given at the lowest effective dose with close monitoring for mental status changes.
 

Androgen and estrogen replacement therapy

For androgen replacement therapy, the panel notes that testosterone supplementation should be avoided because of cardiovascular risks unless there is confirmed hypogonadism. The panel revised their recommendation on the basis of emerging data that a history of prostate cancer is not an absolute contraindication for exogenous testosterone. A risk versus benefit discussion about exogenous testosterone should be had with a medical oncologist or urologist in those with a history of prostate cancer.

Regarding estrogen, systemic formulations should not be initiated in women over the age of 60 because of increased risk of cardiovascular events, venous thromboembolism, and dementia. In women with a history of breast cancer, vaginal estrogens are generally felt to be safe to use at low doses, such as less than 25 mcg twice weekly.

Dr. Wang is a geriatrician and general internist at Harborview Medical Center, Seattle.

Should we be exercising in the morning or afternoon? Before a meal or after a meal?

Popular media outlets, researchers, and clinicians seem to love these debates. I hate them. For me, it’s a false dichotomy. A false dichotomy is when people argue two sides as if only one option exists. A winner must be crowned, and a loser exists. But in reality, a gray zone exists, and/or a number of options are available. For me, exercise at any point of the day is a win.

Some but not all research suggests that morning fasted exercise may be the best time of day and condition to work out for weight control and training adaptations. Morning exercise may be a bit better for logistical reasons if you like to get up early. Some of us are indeed early chronotypes who rise early, get as much done as we can, including all our fitness and work-related activities, and then head to bed early (for me that is about 10 PM). Getting an early morning workout seems to fit with our schedules as morning larks.

But if you are a late-day chronotype, early exercise may not be in sync with your low morning energy levels or your preference for leisure-time activities later in the day. And lots of people with diabetes prefer to eat and then exercise. Late chronotypes are less physically active in general, compared with early chronotypes, and those who train in the morning tend to have better training adherence and expend more energy overall throughout the day. According to Dr. Normand Boulé from the University of Alberta, Edmonton, who presented on the topic of exercise time of day at the recent scientific sessions of the American Diabetes Association in San Diego, morning exercise in the fasted state tends to be associated with higher rates of fat oxidation, better weight control, and better skeletal muscle adaptations over time, compared with exercise performed later in the day. Dr Boulé also proposed that fasted exercise might be superior for training adaptations and long-term glycemia if you have type 2 diabetes.

But the argument for morning-only exercise falls short when we look specifically at postmeal glycemia, according to Dr. Jenna Gillen from the University of Toronto, who faced off against Dr. Boulé at a debate at the meeting and also publishes on the topic. She pointed out that mild to moderate intensity exercising done soon after meals typically results in fewer glucose spikes after meals in people with diabetes, and her argument is supported by at least one recent meta-analysis where postmeal walking was best for improving glycemia in those with prediabetes and type 2 diabetes.

The notion that postmeal or afternoon exercise is best for people with type 2 diabetes is also supported by a recent reexamination of the original Look AHEAD Trial of over 2,400 adults with type 2 diabetes, wherein the role of lifestyle intervention on cardiovascular outcomes was the original goal. In this recent secondary analysis of the Look AHEAD Trial, those most active in the afternoon (between 1:43 p.m. and 5:00 p.m.) had the greatest improvements in their overall glucose control after 1 year of the intensive lifestyle intervention, compared with exercise at other times of day. Afternoon exercisers were also more likely to have complete “remission” of their diabetes, as defined by no longer needing any glucose-lowering agents to control their glucose levels. But this was not a study that was designed for determining whether exercise time of day matters for glycemia because the participants were not randomly assigned to a set time of day for their activity, and glycemic control was not the primary endpoint (cardiovascular events were).

But hold on a minute. I said this was a false-dichotomy argument. It is. Just because it may or may not be “better” for your glucose to exercise in the morning vs. afternoon, if you have diabetes, it doesn’t mean you have to choose one or the other. You could choose neither (okay, that’s bad), both, or you could alternate between the two. For me this argument is like saying; “There only one time of day to save money”; “to tell a joke”; “to eat a meal” (okay, that’s another useless debate); or “do my laundry” (my mother once told me it’s technically cheaper after 6 p.m.!).

I live with diabetes, and I take insulin. I like how morning exercise in the form of a run with my dog wakes me up, sets me up for the day with positive thoughts, helps generate lots of creative ideas, and perhaps more importantly for me, it tends not to result in hypoglycemia because my insulin on board is lowest then.

Exercise later in the day is tricky when taking insulin because it tends to result in a higher insulin “potency effect” with prandial insulins. However, I still like midday activity and late-day exercise. For example, taking an activity break after lunch blunts the rise in my glucose and breaks up my prolonged sitting time in the office. After-dinner exercise allows me to spend a little more time with my wife, dog, or friends outdoors as the hot summer day begins to cool off. On Monday nights, I play basketball because that’s the only time we can book the gymnasium and that may not end until 9:45 p.m. (15 minutes before I want to go to bed; if you remember, I am a lark). That can result in two frustrating things related to my diabetes: It can cause an immediate rise in my glucose because of a competitive stress response and then a drop in my glucose overnight when I’m sleeping. But I still do it. I know that the training I’m doing at any point of the day will benefit me in lots of little ways, and I think we all need to take as many opportunities to be physically active as we possibly can. My kids and I coin this our daily “fitness opportunities,” and it does not matter to me if its morning, noon, or night!

It’s time to make the headlines and arguments stop. There is no wrong time of day to exercise. At least not in my opinion.
 

Dr. Riddle is a full professor in the school of kinesiology and health science at York University and senior scientist at LMC Diabetes & Endocrinology, both in Toronto. He has disclosed financial relationships with Dexcom, Eli Lilly, Indigo Diabetes, Insulet, Novo Nordisk, Sanofi, Supersapiens, and Zucara Therapeutics.

A version of this article first appeared on Medscape.com.

Should we be exercising in the morning or afternoon? Before a meal or after a meal?

Popular media outlets, researchers, and clinicians seem to love these debates. I hate them. For me, it’s a false dichotomy. A false dichotomy is when people argue two sides as if only one option exists. A winner must be crowned, and a loser exists. But in reality, a gray zone exists, and/or a number of options are available. For me, exercise at any point of the day is a win.

Some but not all research suggests that morning fasted exercise may be the best time of day and condition to work out for weight control and training adaptations. Morning exercise may be a bit better for logistical reasons if you like to get up early. Some of us are indeed early chronotypes who rise early, get as much done as we can, including all our fitness and work-related activities, and then head to bed early (for me that is about 10 PM). Getting an early morning workout seems to fit with our schedules as morning larks.

But if you are a late-day chronotype, early exercise may not be in sync with your low morning energy levels or your preference for leisure-time activities later in the day. And lots of people with diabetes prefer to eat and then exercise. Late chronotypes are less physically active in general, compared with early chronotypes, and those who train in the morning tend to have better training adherence and expend more energy overall throughout the day. According to Dr. Normand Boulé from the University of Alberta, Edmonton, who presented on the topic of exercise time of day at the recent scientific sessions of the American Diabetes Association in San Diego, morning exercise in the fasted state tends to be associated with higher rates of fat oxidation, better weight control, and better skeletal muscle adaptations over time, compared with exercise performed later in the day. Dr Boulé also proposed that fasted exercise might be superior for training adaptations and long-term glycemia if you have type 2 diabetes.

But the argument for morning-only exercise falls short when we look specifically at postmeal glycemia, according to Dr. Jenna Gillen from the University of Toronto, who faced off against Dr. Boulé at a debate at the meeting and also publishes on the topic. She pointed out that mild to moderate intensity exercising done soon after meals typically results in fewer glucose spikes after meals in people with diabetes, and her argument is supported by at least one recent meta-analysis where postmeal walking was best for improving glycemia in those with prediabetes and type 2 diabetes.

The notion that postmeal or afternoon exercise is best for people with type 2 diabetes is also supported by a recent reexamination of the original Look AHEAD Trial of over 2,400 adults with type 2 diabetes, wherein the role of lifestyle intervention on cardiovascular outcomes was the original goal. In this recent secondary analysis of the Look AHEAD Trial, those most active in the afternoon (between 1:43 p.m. and 5:00 p.m.) had the greatest improvements in their overall glucose control after 1 year of the intensive lifestyle intervention, compared with exercise at other times of day. Afternoon exercisers were also more likely to have complete “remission” of their diabetes, as defined by no longer needing any glucose-lowering agents to control their glucose levels. But this was not a study that was designed for determining whether exercise time of day matters for glycemia because the participants were not randomly assigned to a set time of day for their activity, and glycemic control was not the primary endpoint (cardiovascular events were).

But hold on a minute. I said this was a false-dichotomy argument. It is. Just because it may or may not be “better” for your glucose to exercise in the morning vs. afternoon, if you have diabetes, it doesn’t mean you have to choose one or the other. You could choose neither (okay, that’s bad), both, or you could alternate between the two. For me this argument is like saying; “There only one time of day to save money”; “to tell a joke”; “to eat a meal” (okay, that’s another useless debate); or “do my laundry” (my mother once told me it’s technically cheaper after 6 p.m.!).

I live with diabetes, and I take insulin. I like how morning exercise in the form of a run with my dog wakes me up, sets me up for the day with positive thoughts, helps generate lots of creative ideas, and perhaps more importantly for me, it tends not to result in hypoglycemia because my insulin on board is lowest then.

Exercise later in the day is tricky when taking insulin because it tends to result in a higher insulin “potency effect” with prandial insulins. However, I still like midday activity and late-day exercise. For example, taking an activity break after lunch blunts the rise in my glucose and breaks up my prolonged sitting time in the office. After-dinner exercise allows me to spend a little more time with my wife, dog, or friends outdoors as the hot summer day begins to cool off. On Monday nights, I play basketball because that’s the only time we can book the gymnasium and that may not end until 9:45 p.m. (15 minutes before I want to go to bed; if you remember, I am a lark). That can result in two frustrating things related to my diabetes: It can cause an immediate rise in my glucose because of a competitive stress response and then a drop in my glucose overnight when I’m sleeping. But I still do it. I know that the training I’m doing at any point of the day will benefit me in lots of little ways, and I think we all need to take as many opportunities to be physically active as we possibly can. My kids and I coin this our daily “fitness opportunities,” and it does not matter to me if its morning, noon, or night!

It’s time to make the headlines and arguments stop. There is no wrong time of day to exercise. At least not in my opinion.
 

Dr. Riddle is a full professor in the school of kinesiology and health science at York University and senior scientist at LMC Diabetes & Endocrinology, both in Toronto. He has disclosed financial relationships with Dexcom, Eli Lilly, Indigo Diabetes, Insulet, Novo Nordisk, Sanofi, Supersapiens, and Zucara Therapeutics.

A version of this article first appeared on Medscape.com.

Should we be exercising in the morning or afternoon? Before a meal or after a meal?

Popular media outlets, researchers, and clinicians seem to love these debates. I hate them. For me, it’s a false dichotomy. A false dichotomy is when people argue two sides as if only one option exists. A winner must be crowned, and a loser exists. But in reality, a gray zone exists, and/or a number of options are available. For me, exercise at any point of the day is a win.

Some but not all research suggests that morning fasted exercise may be the best time of day and condition to work out for weight control and training adaptations. Morning exercise may be a bit better for logistical reasons if you like to get up early. Some of us are indeed early chronotypes who rise early, get as much done as we can, including all our fitness and work-related activities, and then head to bed early (for me that is about 10 PM). Getting an early morning workout seems to fit with our schedules as morning larks.

But if you are a late-day chronotype, early exercise may not be in sync with your low morning energy levels or your preference for leisure-time activities later in the day. And lots of people with diabetes prefer to eat and then exercise. Late chronotypes are less physically active in general, compared with early chronotypes, and those who train in the morning tend to have better training adherence and expend more energy overall throughout the day. According to Dr. Normand Boulé from the University of Alberta, Edmonton, who presented on the topic of exercise time of day at the recent scientific sessions of the American Diabetes Association in San Diego, morning exercise in the fasted state tends to be associated with higher rates of fat oxidation, better weight control, and better skeletal muscle adaptations over time, compared with exercise performed later in the day. Dr Boulé also proposed that fasted exercise might be superior for training adaptations and long-term glycemia if you have type 2 diabetes.

But the argument for morning-only exercise falls short when we look specifically at postmeal glycemia, according to Dr. Jenna Gillen from the University of Toronto, who faced off against Dr. Boulé at a debate at the meeting and also publishes on the topic. She pointed out that mild to moderate intensity exercising done soon after meals typically results in fewer glucose spikes after meals in people with diabetes, and her argument is supported by at least one recent meta-analysis where postmeal walking was best for improving glycemia in those with prediabetes and type 2 diabetes.

The notion that postmeal or afternoon exercise is best for people with type 2 diabetes is also supported by a recent reexamination of the original Look AHEAD Trial of over 2,400 adults with type 2 diabetes, wherein the role of lifestyle intervention on cardiovascular outcomes was the original goal. In this recent secondary analysis of the Look AHEAD Trial, those most active in the afternoon (between 1:43 p.m. and 5:00 p.m.) had the greatest improvements in their overall glucose control after 1 year of the intensive lifestyle intervention, compared with exercise at other times of day. Afternoon exercisers were also more likely to have complete “remission” of their diabetes, as defined by no longer needing any glucose-lowering agents to control their glucose levels. But this was not a study that was designed for determining whether exercise time of day matters for glycemia because the participants were not randomly assigned to a set time of day for their activity, and glycemic control was not the primary endpoint (cardiovascular events were).

But hold on a minute. I said this was a false-dichotomy argument. It is. Just because it may or may not be “better” for your glucose to exercise in the morning vs. afternoon, if you have diabetes, it doesn’t mean you have to choose one or the other. You could choose neither (okay, that’s bad), both, or you could alternate between the two. For me this argument is like saying; “There only one time of day to save money”; “to tell a joke”; “to eat a meal” (okay, that’s another useless debate); or “do my laundry” (my mother once told me it’s technically cheaper after 6 p.m.!).

I live with diabetes, and I take insulin. I like how morning exercise in the form of a run with my dog wakes me up, sets me up for the day with positive thoughts, helps generate lots of creative ideas, and perhaps more importantly for me, it tends not to result in hypoglycemia because my insulin on board is lowest then.

Exercise later in the day is tricky when taking insulin because it tends to result in a higher insulin “potency effect” with prandial insulins. However, I still like midday activity and late-day exercise. For example, taking an activity break after lunch blunts the rise in my glucose and breaks up my prolonged sitting time in the office. After-dinner exercise allows me to spend a little more time with my wife, dog, or friends outdoors as the hot summer day begins to cool off. On Monday nights, I play basketball because that’s the only time we can book the gymnasium and that may not end until 9:45 p.m. (15 minutes before I want to go to bed; if you remember, I am a lark). That can result in two frustrating things related to my diabetes: It can cause an immediate rise in my glucose because of a competitive stress response and then a drop in my glucose overnight when I’m sleeping. But I still do it. I know that the training I’m doing at any point of the day will benefit me in lots of little ways, and I think we all need to take as many opportunities to be physically active as we possibly can. My kids and I coin this our daily “fitness opportunities,” and it does not matter to me if its morning, noon, or night!

It’s time to make the headlines and arguments stop. There is no wrong time of day to exercise. At least not in my opinion.
 

Dr. Riddle is a full professor in the school of kinesiology and health science at York University and senior scientist at LMC Diabetes & Endocrinology, both in Toronto. He has disclosed financial relationships with Dexcom, Eli Lilly, Indigo Diabetes, Insulet, Novo Nordisk, Sanofi, Supersapiens, and Zucara Therapeutics.

A version of this article first appeared on Medscape.com.

Initially approved by the U.S. Food and Drug Administration (FDA) in 1994, metformin has been the preferred first-line glucose-lowering agent for patients with type 2 diabetes (T2D) owing to its effectiveness, low hypoglycemia risk, weight neutrality, long clinical track record of safety, and affordability. However, the advent of newer glucose-lowering agents with evidence-based cardiovascular (CV) and renal benefits calls into question whether metformin should continue to be the initial pharmacotherapy for all patients with T2D. To help determine whether metformin has been “dethroned” as first-line treatment for T2D, here is a brief review of recent evidence and current guideline recommendations.

Cardiovascular outcome trials transform standard of care

In 2008, the FDA issued guidance to industry to ensure that CV risk is more thoroughly addressed during development of T2D therapies. This guidance document required dedicated trials to establish CV safety of new glucose-lowering therapies. Findings from subsequent cardiovascular outcome trials (CVOTs) and subsequent large renal and heart failure (HF) outcome trials have since prompted frequent and substantial updates to major guidelines. On the basis of recent evidence from CVOT and renal trials, contemporary clinical practice guidelines have transitioned from a traditional glucocentric treatment approach to a holistic management approach that emphasizes organ protection through heart-kidney-metabolic risk reduction.

Per the 2008 FDA guidance, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagonlike peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT2) inhibitors were evaluated in large dedicated CVOTs. Findings from several CVOTs established GLP-1 receptor agonist and SGLT2 inhibitor CV safety, and unexpectedly demonstrated reduced rates of major adverse cardiovascular events (MACE) relative to placebo. The LEADER and EMPA-REG OUTCOME trials were the first CVOTs to report cardioprotective benefits of the GLP-1 receptor agonist liraglutide and the SGLT2 inhibitor empagliflozin, respectively. The LEADER trial reported a 13% significant relative risk reduction for its primary composite MACE outcome, and the EMPA-REG OUTCOME trial similarly reported a 14% relative risk reduction for MACE. After CVOTs on other GLP-1 receptor agonists and SGLT2 inhibitors reported CV benefit, clinical practice guidelines began to recommend use of these agents in at-risk patients to mitigate CV risk.

During the period when most CVOTs were designed and conducted, a majority of trial participants were receiving metformin at baseline. Inclusion of a small subset of metformin-naive participants in these trials allowed for several post hoc and meta-analyses investigating the impact of background metformin use on the overall CV benefits reported. Depending on the trial, baseline metformin use in large GLP-1 receptor agonist CVOTs ranged from 66% to 81%. For instance, 76% of participants in the LEADER trial were receiving metformin at baseline, but a post hoc analysis found no heterogeneity for the observed CV benefit based on background metformin use. Similarly, a subgroup analysis of pooled data from the SUSTAIN-6 and PIONEER 6 trials of injectable and oral formulations of semaglutide, respectively, reported similar CV outcomes for participants, regardless of concomitant metformin use. When looking at the GLP-1 receptor agonist class overall, a meta-analysis of seven CVOTs, which included participants with established atherosclerotic cardiovascular disease (ASCVD) and those with multiple ASCVD risk factors, concluded that GLP-1 receptor agonist therapy reduced the overall incidence of MACE in participants not receiving concomitant metformin at baseline.

Similar analyses have examined the impact of background metformin use on CV outcomes with SGLT2 inhibitors. An analysis of EMPA-REG OUTCOME found that empagliflozin improved CV outcomes and reduced mortality irrespective of background metformin, sulfonylurea, or insulin use. Of note, this analysis suggested a greater risk reduction for incident or worsening nephropathy in patients not on concomitant metformin (hazard ratio, 0.47; 95% confidence interval, 0.37-0.59; P = .01), when compared with those taking metformin at baseline (HR, 0.68; 95% CI, 0.58-0.79; P = .01). In addition, a meta-analysis of six large outcome trials found consistent benefits of SGLT2 inhibition on CV, kidney, and mortality outcomes regardless of background metformin treatment. Therefore, although CVOTs on GLP-1 receptor agonists and SGLT2 inhibitors were not designed to assess the impact of background metformin use on CV outcomes, available evidence supports the CV benefits of these agents independent of metformin use.
 

Individualizing care to attain cardiorenal-metabolic goals

Three dedicated SGLT2 inhibitor renal outcome trials have been published to date: CREDENCE, DAPA-CKD, and EMPA-KIDNEY. All three studies confirmed the positive secondary renal outcomes observed in SGLT2 inhibitor CVOTs: reduced progression of kidney disease, HF-associated hospital admissions, and CV-related death. The observed renal and CV benefits from the CREDENCE trial were consistent across different levels of kidney function. Similarly, a meta-analysis of five SGLT2 inhibitor trials of patients with HF demonstrated a decreased risk for CV-related death and admission for HF, irrespective of baseline heart function. The ongoing FLOW is the first dedicated kidney-outcome trial to evaluate the effectiveness of a GLP-1 receptor agonist (semaglutide) in slowing the progression and worsening of chronic kidney disease (CKD) in patients with T2D.

As previously noted, findings from the LEADER and EMPA-REG OUTCOME trials demonstrated the beneficial effects of GLP-1 receptor agonists and SGLT2 inhibitors not only on MACE but also on secondary HF and kidney disease outcomes. These findings have supported a series of dedicated HF and kidney outcome trials further informing the standard of care for patients with these key comorbidities. Indeed, the American Diabetes Association’s 2023 Standards of Care in Diabetes updated its recommendations and algorithm for the use of glucose-lowering medications in the management of T2D. The current ADA recommendations stress cardiorenal risk reduction while concurrently achieving and maintaining glycemic and weight management goals. On the basis of evolving outcome trial data, GLP-1 receptor agonists and SGLT2 inhibitors with evidence of benefit are recommended for patients with established or at high risk for ASCVD. Further, the Standards preferentially recommend SGLT2 inhibitors for patients with HF and/or CKD. Because evidence suggests no heterogeneity of benefit based on hemoglobin A1c for MACE outcomes with GLP-1 receptor agonists and no heterogeneity of benefit for HF or CKD benefits with SGLT2 inhibitors, these agents are recommended for cardiorenal risk reduction regardless of the need to lower glucose.

The 2023 update to the American Association of Clinical Endocrinology Consensus Statement: Type 2 Diabetes Management Algorithm similarly recommends the use of GLP-1 receptor agonists and SGLT2 inhibitors to improve cardiorenal outcomes. To further emphasize the importance of prescribing agents with proven organ-protective benefits, the AACE consensus statement provides a complications-centric algorithm to guide therapeutic decisions for risk reduction in patients with key comorbidities (for instance, ASCVD, HF, CKD) and a separate glucocentric algorithm to guide selection and intensification of glucose-lowering agents in patients without key comorbidities to meet individualized glycemic targets. Within the complications-centric algorithm, AACE recommends GLP-1 receptor agonists and SGLT2 inhibitors as first-line treatment for cardiorenal risk reduction regardless of background metformin use or A1c level.

In addition to the emphasis on the use of GLP-1 receptor agonists and SGLT2 inhibitors for organ protection, guidelines now recommend SGLT2 inhibitors as the standard-of-care therapy in patients with T2D and CKD with an estimated glomerular filtration rate ≥ 20 mL/min per 1.73 m², and irrespective of ejection fraction or a diagnosis of diabetes in the setting of HF. Overall, a common thread within current guidelines is the importance of individualized therapy based on patient- and medication-specific factors.
 

Optimizing guideline-directed medical therapy

Results from the DISCOVER trial found that GLP-1 receptor agonist and SGLT2 inhibitor use was less likely in the key patient subgroups most likely to benefit from therapy, including patients with peripheral artery disease and CKD. Factors contributing to underutilization of newer cardiorenal protective glucose-lowering therapies range from cost and access barriers to clinician-level barriers (for example, lack of knowledge on CKD, lack of familiarity with CKD practice guidelines). Addressing these issues and helping patients work through financial and other access barriers is essential to optimize the utilization of these therapies and improve cardiorenal and metabolic outcomes.

So, has metformin been “dethroned” as a first-line therapy for T2D? As is often the case in medicine, the answer depends on the individual patient and clinical situation. Metformin remains an important first-line treatment in combination with lifestyle interventions to help patients with T2D without key cardiorenal comorbidities achieve individualized glycemic targets. However, based on evidence demonstrating cardiorenal protective benefits and improved glycemia and weight loss, GLP-1 agonists and SGLT2 inhibitors may be considered as first-line treatment for patients with T2D with or at high risk for ASCVD, HF, or CKD, regardless of the need for additional glucose-lowering agents and independent of background metformin. Ultimately, the choice of first-line therapy for patients with T2D should be informed by individualized treatment goals, preferences, and cost-related access. Continued efforts to increase patient access to GLP-1 receptor agonists and SGLT2 inhibitors as first-line treatment when indicated are essential to ensure optimal treatment and outcomes.

Dr. Neumiller is professor, department of pharmacotherapy, Washington State University, Spokane. He disclosed ties with Bayer, Boehringer Ingelheim, and Eli Lilly. Dr. Alicic is clinical professor, department of medicine, University of Washington; and associate director of research, Inland Northwest Washington, Providence St. Joseph Health, Spokane. She disclosed ties with Providence St. Joseph Health, Boehringer Ingelheim/Lilly, and Bayer.

A version of this article appeared on Medscape.com.

Initially approved by the U.S. Food and Drug Administration (FDA) in 1994, metformin has been the preferred first-line glucose-lowering agent for patients with type 2 diabetes (T2D) owing to its effectiveness, low hypoglycemia risk, weight neutrality, long clinical track record of safety, and affordability. However, the advent of newer glucose-lowering agents with evidence-based cardiovascular (CV) and renal benefits calls into question whether metformin should continue to be the initial pharmacotherapy for all patients with T2D. To help determine whether metformin has been “dethroned” as first-line treatment for T2D, here is a brief review of recent evidence and current guideline recommendations.

Cardiovascular outcome trials transform standard of care

In 2008, the FDA issued guidance to industry to ensure that CV risk is more thoroughly addressed during development of T2D therapies. This guidance document required dedicated trials to establish CV safety of new glucose-lowering therapies. Findings from subsequent cardiovascular outcome trials (CVOTs) and subsequent large renal and heart failure (HF) outcome trials have since prompted frequent and substantial updates to major guidelines. On the basis of recent evidence from CVOT and renal trials, contemporary clinical practice guidelines have transitioned from a traditional glucocentric treatment approach to a holistic management approach that emphasizes organ protection through heart-kidney-metabolic risk reduction.

Per the 2008 FDA guidance, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagonlike peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT2) inhibitors were evaluated in large dedicated CVOTs. Findings from several CVOTs established GLP-1 receptor agonist and SGLT2 inhibitor CV safety, and unexpectedly demonstrated reduced rates of major adverse cardiovascular events (MACE) relative to placebo. The LEADER and EMPA-REG OUTCOME trials were the first CVOTs to report cardioprotective benefits of the GLP-1 receptor agonist liraglutide and the SGLT2 inhibitor empagliflozin, respectively. The LEADER trial reported a 13% significant relative risk reduction for its primary composite MACE outcome, and the EMPA-REG OUTCOME trial similarly reported a 14% relative risk reduction for MACE. After CVOTs on other GLP-1 receptor agonists and SGLT2 inhibitors reported CV benefit, clinical practice guidelines began to recommend use of these agents in at-risk patients to mitigate CV risk.

During the period when most CVOTs were designed and conducted, a majority of trial participants were receiving metformin at baseline. Inclusion of a small subset of metformin-naive participants in these trials allowed for several post hoc and meta-analyses investigating the impact of background metformin use on the overall CV benefits reported. Depending on the trial, baseline metformin use in large GLP-1 receptor agonist CVOTs ranged from 66% to 81%. For instance, 76% of participants in the LEADER trial were receiving metformin at baseline, but a post hoc analysis found no heterogeneity for the observed CV benefit based on background metformin use. Similarly, a subgroup analysis of pooled data from the SUSTAIN-6 and PIONEER 6 trials of injectable and oral formulations of semaglutide, respectively, reported similar CV outcomes for participants, regardless of concomitant metformin use. When looking at the GLP-1 receptor agonist class overall, a meta-analysis of seven CVOTs, which included participants with established atherosclerotic cardiovascular disease (ASCVD) and those with multiple ASCVD risk factors, concluded that GLP-1 receptor agonist therapy reduced the overall incidence of MACE in participants not receiving concomitant metformin at baseline.

Similar analyses have examined the impact of background metformin use on CV outcomes with SGLT2 inhibitors. An analysis of EMPA-REG OUTCOME found that empagliflozin improved CV outcomes and reduced mortality irrespective of background metformin, sulfonylurea, or insulin use. Of note, this analysis suggested a greater risk reduction for incident or worsening nephropathy in patients not on concomitant metformin (hazard ratio, 0.47; 95% confidence interval, 0.37-0.59; P = .01), when compared with those taking metformin at baseline (HR, 0.68; 95% CI, 0.58-0.79; P = .01). In addition, a meta-analysis of six large outcome trials found consistent benefits of SGLT2 inhibition on CV, kidney, and mortality outcomes regardless of background metformin treatment. Therefore, although CVOTs on GLP-1 receptor agonists and SGLT2 inhibitors were not designed to assess the impact of background metformin use on CV outcomes, available evidence supports the CV benefits of these agents independent of metformin use.
 

Individualizing care to attain cardiorenal-metabolic goals

Three dedicated SGLT2 inhibitor renal outcome trials have been published to date: CREDENCE, DAPA-CKD, and EMPA-KIDNEY. All three studies confirmed the positive secondary renal outcomes observed in SGLT2 inhibitor CVOTs: reduced progression of kidney disease, HF-associated hospital admissions, and CV-related death. The observed renal and CV benefits from the CREDENCE trial were consistent across different levels of kidney function. Similarly, a meta-analysis of five SGLT2 inhibitor trials of patients with HF demonstrated a decreased risk for CV-related death and admission for HF, irrespective of baseline heart function. The ongoing FLOW is the first dedicated kidney-outcome trial to evaluate the effectiveness of a GLP-1 receptor agonist (semaglutide) in slowing the progression and worsening of chronic kidney disease (CKD) in patients with T2D.

As previously noted, findings from the LEADER and EMPA-REG OUTCOME trials demonstrated the beneficial effects of GLP-1 receptor agonists and SGLT2 inhibitors not only on MACE but also on secondary HF and kidney disease outcomes. These findings have supported a series of dedicated HF and kidney outcome trials further informing the standard of care for patients with these key comorbidities. Indeed, the American Diabetes Association’s 2023 Standards of Care in Diabetes updated its recommendations and algorithm for the use of glucose-lowering medications in the management of T2D. The current ADA recommendations stress cardiorenal risk reduction while concurrently achieving and maintaining glycemic and weight management goals. On the basis of evolving outcome trial data, GLP-1 receptor agonists and SGLT2 inhibitors with evidence of benefit are recommended for patients with established or at high risk for ASCVD. Further, the Standards preferentially recommend SGLT2 inhibitors for patients with HF and/or CKD. Because evidence suggests no heterogeneity of benefit based on hemoglobin A1c for MACE outcomes with GLP-1 receptor agonists and no heterogeneity of benefit for HF or CKD benefits with SGLT2 inhibitors, these agents are recommended for cardiorenal risk reduction regardless of the need to lower glucose.

The 2023 update to the American Association of Clinical Endocrinology Consensus Statement: Type 2 Diabetes Management Algorithm similarly recommends the use of GLP-1 receptor agonists and SGLT2 inhibitors to improve cardiorenal outcomes. To further emphasize the importance of prescribing agents with proven organ-protective benefits, the AACE consensus statement provides a complications-centric algorithm to guide therapeutic decisions for risk reduction in patients with key comorbidities (for instance, ASCVD, HF, CKD) and a separate glucocentric algorithm to guide selection and intensification of glucose-lowering agents in patients without key comorbidities to meet individualized glycemic targets. Within the complications-centric algorithm, AACE recommends GLP-1 receptor agonists and SGLT2 inhibitors as first-line treatment for cardiorenal risk reduction regardless of background metformin use or A1c level.

In addition to the emphasis on the use of GLP-1 receptor agonists and SGLT2 inhibitors for organ protection, guidelines now recommend SGLT2 inhibitors as the standard-of-care therapy in patients with T2D and CKD with an estimated glomerular filtration rate ≥ 20 mL/min per 1.73 m², and irrespective of ejection fraction or a diagnosis of diabetes in the setting of HF. Overall, a common thread within current guidelines is the importance of individualized therapy based on patient- and medication-specific factors.
 

Optimizing guideline-directed medical therapy

Results from the DISCOVER trial found that GLP-1 receptor agonist and SGLT2 inhibitor use was less likely in the key patient subgroups most likely to benefit from therapy, including patients with peripheral artery disease and CKD. Factors contributing to underutilization of newer cardiorenal protective glucose-lowering therapies range from cost and access barriers to clinician-level barriers (for example, lack of knowledge on CKD, lack of familiarity with CKD practice guidelines). Addressing these issues and helping patients work through financial and other access barriers is essential to optimize the utilization of these therapies and improve cardiorenal and metabolic outcomes.

So, has metformin been “dethroned” as a first-line therapy for T2D? As is often the case in medicine, the answer depends on the individual patient and clinical situation. Metformin remains an important first-line treatment in combination with lifestyle interventions to help patients with T2D without key cardiorenal comorbidities achieve individualized glycemic targets. However, based on evidence demonstrating cardiorenal protective benefits and improved glycemia and weight loss, GLP-1 agonists and SGLT2 inhibitors may be considered as first-line treatment for patients with T2D with or at high risk for ASCVD, HF, or CKD, regardless of the need for additional glucose-lowering agents and independent of background metformin. Ultimately, the choice of first-line therapy for patients with T2D should be informed by individualized treatment goals, preferences, and cost-related access. Continued efforts to increase patient access to GLP-1 receptor agonists and SGLT2 inhibitors as first-line treatment when indicated are essential to ensure optimal treatment and outcomes.

Dr. Neumiller is professor, department of pharmacotherapy, Washington State University, Spokane. He disclosed ties with Bayer, Boehringer Ingelheim, and Eli Lilly. Dr. Alicic is clinical professor, department of medicine, University of Washington; and associate director of research, Inland Northwest Washington, Providence St. Joseph Health, Spokane. She disclosed ties with Providence St. Joseph Health, Boehringer Ingelheim/Lilly, and Bayer.

A version of this article appeared on Medscape.com.

Initially approved by the U.S. Food and Drug Administration (FDA) in 1994, metformin has been the preferred first-line glucose-lowering agent for patients with type 2 diabetes (T2D) owing to its effectiveness, low hypoglycemia risk, weight neutrality, long clinical track record of safety, and affordability. However, the advent of newer glucose-lowering agents with evidence-based cardiovascular (CV) and renal benefits calls into question whether metformin should continue to be the initial pharmacotherapy for all patients with T2D. To help determine whether metformin has been “dethroned” as first-line treatment for T2D, here is a brief review of recent evidence and current guideline recommendations.

Cardiovascular outcome trials transform standard of care

In 2008, the FDA issued guidance to industry to ensure that CV risk is more thoroughly addressed during development of T2D therapies. This guidance document required dedicated trials to establish CV safety of new glucose-lowering therapies. Findings from subsequent cardiovascular outcome trials (CVOTs) and subsequent large renal and heart failure (HF) outcome trials have since prompted frequent and substantial updates to major guidelines. On the basis of recent evidence from CVOT and renal trials, contemporary clinical practice guidelines have transitioned from a traditional glucocentric treatment approach to a holistic management approach that emphasizes organ protection through heart-kidney-metabolic risk reduction.

Per the 2008 FDA guidance, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagonlike peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT2) inhibitors were evaluated in large dedicated CVOTs. Findings from several CVOTs established GLP-1 receptor agonist and SGLT2 inhibitor CV safety, and unexpectedly demonstrated reduced rates of major adverse cardiovascular events (MACE) relative to placebo. The LEADER and EMPA-REG OUTCOME trials were the first CVOTs to report cardioprotective benefits of the GLP-1 receptor agonist liraglutide and the SGLT2 inhibitor empagliflozin, respectively. The LEADER trial reported a 13% significant relative risk reduction for its primary composite MACE outcome, and the EMPA-REG OUTCOME trial similarly reported a 14% relative risk reduction for MACE. After CVOTs on other GLP-1 receptor agonists and SGLT2 inhibitors reported CV benefit, clinical practice guidelines began to recommend use of these agents in at-risk patients to mitigate CV risk.

During the period when most CVOTs were designed and conducted, a majority of trial participants were receiving metformin at baseline. Inclusion of a small subset of metformin-naive participants in these trials allowed for several post hoc and meta-analyses investigating the impact of background metformin use on the overall CV benefits reported. Depending on the trial, baseline metformin use in large GLP-1 receptor agonist CVOTs ranged from 66% to 81%. For instance, 76% of participants in the LEADER trial were receiving metformin at baseline, but a post hoc analysis found no heterogeneity for the observed CV benefit based on background metformin use. Similarly, a subgroup analysis of pooled data from the SUSTAIN-6 and PIONEER 6 trials of injectable and oral formulations of semaglutide, respectively, reported similar CV outcomes for participants, regardless of concomitant metformin use. When looking at the GLP-1 receptor agonist class overall, a meta-analysis of seven CVOTs, which included participants with established atherosclerotic cardiovascular disease (ASCVD) and those with multiple ASCVD risk factors, concluded that GLP-1 receptor agonist therapy reduced the overall incidence of MACE in participants not receiving concomitant metformin at baseline.

Similar analyses have examined the impact of background metformin use on CV outcomes with SGLT2 inhibitors. An analysis of EMPA-REG OUTCOME found that empagliflozin improved CV outcomes and reduced mortality irrespective of background metformin, sulfonylurea, or insulin use. Of note, this analysis suggested a greater risk reduction for incident or worsening nephropathy in patients not on concomitant metformin (hazard ratio, 0.47; 95% confidence interval, 0.37-0.59; P = .01), when compared with those taking metformin at baseline (HR, 0.68; 95% CI, 0.58-0.79; P = .01). In addition, a meta-analysis of six large outcome trials found consistent benefits of SGLT2 inhibition on CV, kidney, and mortality outcomes regardless of background metformin treatment. Therefore, although CVOTs on GLP-1 receptor agonists and SGLT2 inhibitors were not designed to assess the impact of background metformin use on CV outcomes, available evidence supports the CV benefits of these agents independent of metformin use.
 

Individualizing care to attain cardiorenal-metabolic goals

Three dedicated SGLT2 inhibitor renal outcome trials have been published to date: CREDENCE, DAPA-CKD, and EMPA-KIDNEY. All three studies confirmed the positive secondary renal outcomes observed in SGLT2 inhibitor CVOTs: reduced progression of kidney disease, HF-associated hospital admissions, and CV-related death. The observed renal and CV benefits from the CREDENCE trial were consistent across different levels of kidney function. Similarly, a meta-analysis of five SGLT2 inhibitor trials of patients with HF demonstrated a decreased risk for CV-related death and admission for HF, irrespective of baseline heart function. The ongoing FLOW is the first dedicated kidney-outcome trial to evaluate the effectiveness of a GLP-1 receptor agonist (semaglutide) in slowing the progression and worsening of chronic kidney disease (CKD) in patients with T2D.

As previously noted, findings from the LEADER and EMPA-REG OUTCOME trials demonstrated the beneficial effects of GLP-1 receptor agonists and SGLT2 inhibitors not only on MACE but also on secondary HF and kidney disease outcomes. These findings have supported a series of dedicated HF and kidney outcome trials further informing the standard of care for patients with these key comorbidities. Indeed, the American Diabetes Association’s 2023 Standards of Care in Diabetes updated its recommendations and algorithm for the use of glucose-lowering medications in the management of T2D. The current ADA recommendations stress cardiorenal risk reduction while concurrently achieving and maintaining glycemic and weight management goals. On the basis of evolving outcome trial data, GLP-1 receptor agonists and SGLT2 inhibitors with evidence of benefit are recommended for patients with established or at high risk for ASCVD. Further, the Standards preferentially recommend SGLT2 inhibitors for patients with HF and/or CKD. Because evidence suggests no heterogeneity of benefit based on hemoglobin A1c for MACE outcomes with GLP-1 receptor agonists and no heterogeneity of benefit for HF or CKD benefits with SGLT2 inhibitors, these agents are recommended for cardiorenal risk reduction regardless of the need to lower glucose.

The 2023 update to the American Association of Clinical Endocrinology Consensus Statement: Type 2 Diabetes Management Algorithm similarly recommends the use of GLP-1 receptor agonists and SGLT2 inhibitors to improve cardiorenal outcomes. To further emphasize the importance of prescribing agents with proven organ-protective benefits, the AACE consensus statement provides a complications-centric algorithm to guide therapeutic decisions for risk reduction in patients with key comorbidities (for instance, ASCVD, HF, CKD) and a separate glucocentric algorithm to guide selection and intensification of glucose-lowering agents in patients without key comorbidities to meet individualized glycemic targets. Within the complications-centric algorithm, AACE recommends GLP-1 receptor agonists and SGLT2 inhibitors as first-line treatment for cardiorenal risk reduction regardless of background metformin use or A1c level.

In addition to the emphasis on the use of GLP-1 receptor agonists and SGLT2 inhibitors for organ protection, guidelines now recommend SGLT2 inhibitors as the standard-of-care therapy in patients with T2D and CKD with an estimated glomerular filtration rate ≥ 20 mL/min per 1.73 m², and irrespective of ejection fraction or a diagnosis of diabetes in the setting of HF. Overall, a common thread within current guidelines is the importance of individualized therapy based on patient- and medication-specific factors.
 

Optimizing guideline-directed medical therapy

Results from the DISCOVER trial found that GLP-1 receptor agonist and SGLT2 inhibitor use was less likely in the key patient subgroups most likely to benefit from therapy, including patients with peripheral artery disease and CKD. Factors contributing to underutilization of newer cardiorenal protective glucose-lowering therapies range from cost and access barriers to clinician-level barriers (for example, lack of knowledge on CKD, lack of familiarity with CKD practice guidelines). Addressing these issues and helping patients work through financial and other access barriers is essential to optimize the utilization of these therapies and improve cardiorenal and metabolic outcomes.

So, has metformin been “dethroned” as a first-line therapy for T2D? As is often the case in medicine, the answer depends on the individual patient and clinical situation. Metformin remains an important first-line treatment in combination with lifestyle interventions to help patients with T2D without key cardiorenal comorbidities achieve individualized glycemic targets. However, based on evidence demonstrating cardiorenal protective benefits and improved glycemia and weight loss, GLP-1 agonists and SGLT2 inhibitors may be considered as first-line treatment for patients with T2D with or at high risk for ASCVD, HF, or CKD, regardless of the need for additional glucose-lowering agents and independent of background metformin. Ultimately, the choice of first-line therapy for patients with T2D should be informed by individualized treatment goals, preferences, and cost-related access. Continued efforts to increase patient access to GLP-1 receptor agonists and SGLT2 inhibitors as first-line treatment when indicated are essential to ensure optimal treatment and outcomes.

Dr. Neumiller is professor, department of pharmacotherapy, Washington State University, Spokane. He disclosed ties with Bayer, Boehringer Ingelheim, and Eli Lilly. Dr. Alicic is clinical professor, department of medicine, University of Washington; and associate director of research, Inland Northwest Washington, Providence St. Joseph Health, Spokane. She disclosed ties with Providence St. Joseph Health, Boehringer Ingelheim/Lilly, and Bayer.

A version of this article appeared on Medscape.com.

Health benefits of prolonged “water fasting” (zero calories) or Buchinger fasting (200-300 calories/day) don’t last, according to authors of a review of eight studies.

Five days of fasting lowered weight by about 6%, but this weight was regained after 3 months of regular eating, the investigators found. The article was published in Nutrition Reviews.

“Water fasting led to improvements in blood pressure, cholesterol, and blood sugar levels, but these were short-lived,” senior author Krista A. Varady, PhD, told this news organization.

“Levels returned to baseline ... quickly after participants started eating. Most benefits disappeared in 3-4 months,” said Dr. Varady, professor of nutrition at the University of Illinois, Chicago.

“My overall conclusion,” she said, “is that I guess you could try it, but it just seems like a lot of work, and all those metabolic benefits disappear. I would encourage someone hoping to lose weight to try intermittent fasting instead of water fasting, because there’s a lot more data to show it can help with weight management.

“People should consult their doctor if they have diabetes or any other major obesity-related conditions before doing water fasting,” Dr. Varady cautioned.

“Healthy people with obesity can probably fast safely for 5 days on their own (if they don’t have any other conditions). However, no one should undertake one of these fasts for more than 5 days without medical supervision,” she stressed.
 

Eight studies of water and Buchinger fasting

Although several favorable effects of prolonged fasting have been observed, benefits must be weighed against risks, Dr. Varady and her coauthors wrote.

Most medically supervised fasting programs have reported only minor adverse events, which included hunger, headaches, nausea, vomiting, dry mouth, and fatigue. However, more severe events have been documented, including edema, abnormal results on liver function tests, decreased bone density, and metabolic acidosis.

The researchers aimed to determine the effect of prolonged fasting on weight, blood pressure, lipid levels, and glycemic control, as well as safety and the effects of refeeding.

They examined two types of prolonged fasting: water fasting and Buchinger fasting, which involves consuming 250 mL of fruit or vegetable juice for lunch and 250 mL of soup for dinner every day of the 5- to 20-day fast.

Buchinger fasting is popular in Central Europe. Water fasting “institutes” exist in the United States, such as one in California, Dr. Varady noted.

The researchers excluded fasting during Ramadan or fasting practiced by Seventh Day Adventists.

They identified four studies of water fasting and four studies of Buchinger fasting (of which one study of 1,422 participants assessed fasting for 5, 10, 15, and 20 days).

The review showed that prolonged fasting for 5-20 days produced large increases in circulating ketones, weight loss of 2%-10%, and decreases in systolic and diastolic blood pressure.

People who fasted 5 days typically lost 4%-6% of their weight; those who fasted 7-10 days lost 2%-10% of their weight; and those who fasted 15-20 days lost 7%-10% of their weight.

LDL cholesterol and triglyceride levels decreased in some trials.

Fasting glucose levels, fasting insulin levels, insulin resistance, and A1c decreased in adults without diabetes but remained unchanged in patients with type 1 or type 2 diabetes.

Some participants experienced metabolic acidosis, headaches, insomnia, or hunger.

About two-thirds of the weight lost was of lean mass, and one-third was of fat mass. The loss of lean mass loss suggests that prolonged fasting may increase the breakdown of muscle proteins, which is a concern, the researchers noted.

Few of the trials examined the effects of refeeding. In one study, normal-weight adults lost 6% of their weight after 5 days of water-only fasting but then gained it all back after 3 months of eating regularly.

In three trials, participants regained 1%-2% of their weight 2-4 months after fasting; however, those trials instructed participants to follow a calorie-restricted diet during the refeeding period.

Three to 4 months after the fast was completed, none of the metabolic benefits were maintained, even when weight loss was maintained.

The study did not receive external funding. Dr. Varady has received author fees from Hachette Book Group for “The Every Other Day Diet” and from Pan Macmillan Press for “The Fastest Diet.” The other authors have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Health benefits of prolonged “water fasting” (zero calories) or Buchinger fasting (200-300 calories/day) don’t last, according to authors of a review of eight studies.

Five days of fasting lowered weight by about 6%, but this weight was regained after 3 months of regular eating, the investigators found. The article was published in Nutrition Reviews.

“Water fasting led to improvements in blood pressure, cholesterol, and blood sugar levels, but these were short-lived,” senior author Krista A. Varady, PhD, told this news organization.

“Levels returned to baseline ... quickly after participants started eating. Most benefits disappeared in 3-4 months,” said Dr. Varady, professor of nutrition at the University of Illinois, Chicago.

“My overall conclusion,” she said, “is that I guess you could try it, but it just seems like a lot of work, and all those metabolic benefits disappear. I would encourage someone hoping to lose weight to try intermittent fasting instead of water fasting, because there’s a lot more data to show it can help with weight management.

“People should consult their doctor if they have diabetes or any other major obesity-related conditions before doing water fasting,” Dr. Varady cautioned.

“Healthy people with obesity can probably fast safely for 5 days on their own (if they don’t have any other conditions). However, no one should undertake one of these fasts for more than 5 days without medical supervision,” she stressed.
 

Eight studies of water and Buchinger fasting

Although several favorable effects of prolonged fasting have been observed, benefits must be weighed against risks, Dr. Varady and her coauthors wrote.

Most medically supervised fasting programs have reported only minor adverse events, which included hunger, headaches, nausea, vomiting, dry mouth, and fatigue. However, more severe events have been documented, including edema, abnormal results on liver function tests, decreased bone density, and metabolic acidosis.

The researchers aimed to determine the effect of prolonged fasting on weight, blood pressure, lipid levels, and glycemic control, as well as safety and the effects of refeeding.

They examined two types of prolonged fasting: water fasting and Buchinger fasting, which involves consuming 250 mL of fruit or vegetable juice for lunch and 250 mL of soup for dinner every day of the 5- to 20-day fast.

Buchinger fasting is popular in Central Europe. Water fasting “institutes” exist in the United States, such as one in California, Dr. Varady noted.

The researchers excluded fasting during Ramadan or fasting practiced by Seventh Day Adventists.

They identified four studies of water fasting and four studies of Buchinger fasting (of which one study of 1,422 participants assessed fasting for 5, 10, 15, and 20 days).

The review showed that prolonged fasting for 5-20 days produced large increases in circulating ketones, weight loss of 2%-10%, and decreases in systolic and diastolic blood pressure.

People who fasted 5 days typically lost 4%-6% of their weight; those who fasted 7-10 days lost 2%-10% of their weight; and those who fasted 15-20 days lost 7%-10% of their weight.

LDL cholesterol and triglyceride levels decreased in some trials.

Fasting glucose levels, fasting insulin levels, insulin resistance, and A1c decreased in adults without diabetes but remained unchanged in patients with type 1 or type 2 diabetes.

Some participants experienced metabolic acidosis, headaches, insomnia, or hunger.

About two-thirds of the weight lost was of lean mass, and one-third was of fat mass. The loss of lean mass loss suggests that prolonged fasting may increase the breakdown of muscle proteins, which is a concern, the researchers noted.

Few of the trials examined the effects of refeeding. In one study, normal-weight adults lost 6% of their weight after 5 days of water-only fasting but then gained it all back after 3 months of eating regularly.

In three trials, participants regained 1%-2% of their weight 2-4 months after fasting; however, those trials instructed participants to follow a calorie-restricted diet during the refeeding period.

Three to 4 months after the fast was completed, none of the metabolic benefits were maintained, even when weight loss was maintained.

The study did not receive external funding. Dr. Varady has received author fees from Hachette Book Group for “The Every Other Day Diet” and from Pan Macmillan Press for “The Fastest Diet.” The other authors have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Health benefits of prolonged “water fasting” (zero calories) or Buchinger fasting (200-300 calories/day) don’t last, according to authors of a review of eight studies.

Five days of fasting lowered weight by about 6%, but this weight was regained after 3 months of regular eating, the investigators found. The article was published in Nutrition Reviews.

“Water fasting led to improvements in blood pressure, cholesterol, and blood sugar levels, but these were short-lived,” senior author Krista A. Varady, PhD, told this news organization.

“Levels returned to baseline ... quickly after participants started eating. Most benefits disappeared in 3-4 months,” said Dr. Varady, professor of nutrition at the University of Illinois, Chicago.

“My overall conclusion,” she said, “is that I guess you could try it, but it just seems like a lot of work, and all those metabolic benefits disappear. I would encourage someone hoping to lose weight to try intermittent fasting instead of water fasting, because there’s a lot more data to show it can help with weight management.

“People should consult their doctor if they have diabetes or any other major obesity-related conditions before doing water fasting,” Dr. Varady cautioned.

“Healthy people with obesity can probably fast safely for 5 days on their own (if they don’t have any other conditions). However, no one should undertake one of these fasts for more than 5 days without medical supervision,” she stressed.
 

Eight studies of water and Buchinger fasting

Although several favorable effects of prolonged fasting have been observed, benefits must be weighed against risks, Dr. Varady and her coauthors wrote.

Most medically supervised fasting programs have reported only minor adverse events, which included hunger, headaches, nausea, vomiting, dry mouth, and fatigue. However, more severe events have been documented, including edema, abnormal results on liver function tests, decreased bone density, and metabolic acidosis.

The researchers aimed to determine the effect of prolonged fasting on weight, blood pressure, lipid levels, and glycemic control, as well as safety and the effects of refeeding.

They examined two types of prolonged fasting: water fasting and Buchinger fasting, which involves consuming 250 mL of fruit or vegetable juice for lunch and 250 mL of soup for dinner every day of the 5- to 20-day fast.

Buchinger fasting is popular in Central Europe. Water fasting “institutes” exist in the United States, such as one in California, Dr. Varady noted.

The researchers excluded fasting during Ramadan or fasting practiced by Seventh Day Adventists.

They identified four studies of water fasting and four studies of Buchinger fasting (of which one study of 1,422 participants assessed fasting for 5, 10, 15, and 20 days).

The review showed that prolonged fasting for 5-20 days produced large increases in circulating ketones, weight loss of 2%-10%, and decreases in systolic and diastolic blood pressure.

People who fasted 5 days typically lost 4%-6% of their weight; those who fasted 7-10 days lost 2%-10% of their weight; and those who fasted 15-20 days lost 7%-10% of their weight.

LDL cholesterol and triglyceride levels decreased in some trials.

Fasting glucose levels, fasting insulin levels, insulin resistance, and A1c decreased in adults without diabetes but remained unchanged in patients with type 1 or type 2 diabetes.

Some participants experienced metabolic acidosis, headaches, insomnia, or hunger.

About two-thirds of the weight lost was of lean mass, and one-third was of fat mass. The loss of lean mass loss suggests that prolonged fasting may increase the breakdown of muscle proteins, which is a concern, the researchers noted.

Few of the trials examined the effects of refeeding. In one study, normal-weight adults lost 6% of their weight after 5 days of water-only fasting but then gained it all back after 3 months of eating regularly.

In three trials, participants regained 1%-2% of their weight 2-4 months after fasting; however, those trials instructed participants to follow a calorie-restricted diet during the refeeding period.

Three to 4 months after the fast was completed, none of the metabolic benefits were maintained, even when weight loss was maintained.

The study did not receive external funding. Dr. Varady has received author fees from Hachette Book Group for “The Every Other Day Diet” and from Pan Macmillan Press for “The Fastest Diet.” The other authors have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.