Diabetes

ORLANDO – It’s inevitable that hospitalists will soon be caring for patients who come in on insulin pumps, continuous glucose monitors, and even closed loop systems, if they haven’t done so already.

A third or more of patients with type 1 diabetes mellitus and growing numbers of patients with insulin-dependent type 2 diabetes mellitus patients are using pumps and sensor technology. The American Diabetes Association advocates allowing patients who are physically and mentally able to continue to use their pumps when hospitalized, and there’s general consensus that continuous glucose monitors (CGM) can be used in the hospital.

All in all, it’s a good thing, according to Guillermo E. Umpierrez, MD, professor of endocrinology at Emory University and chief of endocrinology at Grady Memorial Hospital, both in Atlanta.

In a talk at the annual scientific sessions of the American Diabetes Association, Dr. Umpierrez reviewed a number of studies showing that glycemic control with the new technology is no worse in the hospital – and sometimes even better – than with traditional point-of-care glucose testing and insulin administration. There is a lack of randomized, controlled trials to prove the point definitively, but what evidence does exist is promising.

“This technology is rapidly advancing, and I am very optimistic that we are going to see more and more of these devices in the hospital. If patients can manage themselves, allow them to use CGM, allow them to use their pumps,” he said.

As for closed loop systems – automated glucose sensing and insulin administration – emerging evidence suggests they “allow you to have very good glucose control and less glycemic variability,” both inside and outside of the ICU, he said. “I am very hopeful before I retire that there will be management of a significant number of patients with closed loop systems.”

To keep up, training for hospital providers on the new technology is now “mandatory at all levels,” Dr. Umpierrez said, and if they haven’t done so already, hospitals need to put policies and procedures in place for when, and when not, to allow patients to use their diabetes equipment, and how to integrate it into care.

Among many things to consider, patients must be well enough to use their pumps and monitors, be able to demonstrate their functions, and also want to participate in their own care.

Contraindications to inpatient pump use include impaired consciousness, critical illness, and hyperglycemic crises because insulin requirements change too rapidly and dramatically for pumps. Lack of trained providers and supplies is another hurdle. Pumps also need to come off for MRIs.

CGM, meanwhile, has been shown to improve glycemic control, detecting both hyperglycemia and hypoglycemia more readily than point-of-care testing. It’s good at picking up trends in glucose levels, and Dr. Umpierrez anticipates a time when readings will be transmitted to nurses’ stations automatically to track blood glucose trends. “I think that’s the future,” he said.

But, as with insulin pumps, there are caveats. Among them, it’s unclear how well CGM works during hypoxia, hypothermia, and hypotension. Thrombus formation and infections have been reported with intravascular monitors, and a number of agents can throw off some CGM devices, including acetaminophen, heparin, and dopamine.

Dr. Umpierrez disclosed relationships with AstraZeneca, Merck, Novo Nordisk, Sanofi, and other companies.

aotto@mdedge.com

ORLANDO – It’s inevitable that hospitalists will soon be caring for patients who come in on insulin pumps, continuous glucose monitors, and even closed loop systems, if they haven’t done so already.

A third or more of patients with type 1 diabetes mellitus and growing numbers of patients with insulin-dependent type 2 diabetes mellitus patients are using pumps and sensor technology. The American Diabetes Association advocates allowing patients who are physically and mentally able to continue to use their pumps when hospitalized, and there’s general consensus that continuous glucose monitors (CGM) can be used in the hospital.

All in all, it’s a good thing, according to Guillermo E. Umpierrez, MD, professor of endocrinology at Emory University and chief of endocrinology at Grady Memorial Hospital, both in Atlanta.

In a talk at the annual scientific sessions of the American Diabetes Association, Dr. Umpierrez reviewed a number of studies showing that glycemic control with the new technology is no worse in the hospital – and sometimes even better – than with traditional point-of-care glucose testing and insulin administration. There is a lack of randomized, controlled trials to prove the point definitively, but what evidence does exist is promising.

“This technology is rapidly advancing, and I am very optimistic that we are going to see more and more of these devices in the hospital. If patients can manage themselves, allow them to use CGM, allow them to use their pumps,” he said.

As for closed loop systems – automated glucose sensing and insulin administration – emerging evidence suggests they “allow you to have very good glucose control and less glycemic variability,” both inside and outside of the ICU, he said. “I am very hopeful before I retire that there will be management of a significant number of patients with closed loop systems.”

To keep up, training for hospital providers on the new technology is now “mandatory at all levels,” Dr. Umpierrez said, and if they haven’t done so already, hospitals need to put policies and procedures in place for when, and when not, to allow patients to use their diabetes equipment, and how to integrate it into care.

Among many things to consider, patients must be well enough to use their pumps and monitors, be able to demonstrate their functions, and also want to participate in their own care.

Contraindications to inpatient pump use include impaired consciousness, critical illness, and hyperglycemic crises because insulin requirements change too rapidly and dramatically for pumps. Lack of trained providers and supplies is another hurdle. Pumps also need to come off for MRIs.

CGM, meanwhile, has been shown to improve glycemic control, detecting both hyperglycemia and hypoglycemia more readily than point-of-care testing. It’s good at picking up trends in glucose levels, and Dr. Umpierrez anticipates a time when readings will be transmitted to nurses’ stations automatically to track blood glucose trends. “I think that’s the future,” he said.

But, as with insulin pumps, there are caveats. Among them, it’s unclear how well CGM works during hypoxia, hypothermia, and hypotension. Thrombus formation and infections have been reported with intravascular monitors, and a number of agents can throw off some CGM devices, including acetaminophen, heparin, and dopamine.

Dr. Umpierrez disclosed relationships with AstraZeneca, Merck, Novo Nordisk, Sanofi, and other companies.

aotto@mdedge.com

ORLANDO – It’s inevitable that hospitalists will soon be caring for patients who come in on insulin pumps, continuous glucose monitors, and even closed loop systems, if they haven’t done so already.

A third or more of patients with type 1 diabetes mellitus and growing numbers of patients with insulin-dependent type 2 diabetes mellitus patients are using pumps and sensor technology. The American Diabetes Association advocates allowing patients who are physically and mentally able to continue to use their pumps when hospitalized, and there’s general consensus that continuous glucose monitors (CGM) can be used in the hospital.

All in all, it’s a good thing, according to Guillermo E. Umpierrez, MD, professor of endocrinology at Emory University and chief of endocrinology at Grady Memorial Hospital, both in Atlanta.

In a talk at the annual scientific sessions of the American Diabetes Association, Dr. Umpierrez reviewed a number of studies showing that glycemic control with the new technology is no worse in the hospital – and sometimes even better – than with traditional point-of-care glucose testing and insulin administration. There is a lack of randomized, controlled trials to prove the point definitively, but what evidence does exist is promising.

“This technology is rapidly advancing, and I am very optimistic that we are going to see more and more of these devices in the hospital. If patients can manage themselves, allow them to use CGM, allow them to use their pumps,” he said.

As for closed loop systems – automated glucose sensing and insulin administration – emerging evidence suggests they “allow you to have very good glucose control and less glycemic variability,” both inside and outside of the ICU, he said. “I am very hopeful before I retire that there will be management of a significant number of patients with closed loop systems.”

To keep up, training for hospital providers on the new technology is now “mandatory at all levels,” Dr. Umpierrez said, and if they haven’t done so already, hospitals need to put policies and procedures in place for when, and when not, to allow patients to use their diabetes equipment, and how to integrate it into care.

Among many things to consider, patients must be well enough to use their pumps and monitors, be able to demonstrate their functions, and also want to participate in their own care.

Contraindications to inpatient pump use include impaired consciousness, critical illness, and hyperglycemic crises because insulin requirements change too rapidly and dramatically for pumps. Lack of trained providers and supplies is another hurdle. Pumps also need to come off for MRIs.

CGM, meanwhile, has been shown to improve glycemic control, detecting both hyperglycemia and hypoglycemia more readily than point-of-care testing. It’s good at picking up trends in glucose levels, and Dr. Umpierrez anticipates a time when readings will be transmitted to nurses’ stations automatically to track blood glucose trends. “I think that’s the future,” he said.

But, as with insulin pumps, there are caveats. Among them, it’s unclear how well CGM works during hypoxia, hypothermia, and hypotension. Thrombus formation and infections have been reported with intravascular monitors, and a number of agents can throw off some CGM devices, including acetaminophen, heparin, and dopamine.

Dr. Umpierrez disclosed relationships with AstraZeneca, Merck, Novo Nordisk, Sanofi, and other companies.

aotto@mdedge.com

Diabetic foot ulcers and infections can lead to osteomyelitis, a potentially devastating infection in the bone.

WILLSIE/Getty Images

How much of a difference can osteomyelitis make to a patient’s prognosis? A 2014 commentary by Benjamin A. Lipsky, MD, a prominent expert in problems associated with diabetic patients’ feet who’s with the University of Washington, Seattle, hints at the potential toll: “Overall, about 20% of patients with a diabetic foot infection (and over 60% of those with severe infections) have underlying osteomyelitis, which dramatically increases the risk of lower-extremity amputation” (Diabetes Care. 2014 Mar;37[3]:593-5).

Diagnosis of osteomyelitis, which relies on a bone biopsy, is clearly important. But there’s a big gap in diagnostic findings depending on whether doctors request culture or histology results, according to a new study released at the 2018 scientific meeting of the American Diabetes Association (Diabetes. 2018 Jul. doi: 10.2337/db18-110-OR).

In an interview, lead author and podiatrist Peter A. Crisologo, DPM, of University of Texas Southwestern Medical Center, Dallas, explained the study findings and offered guidance for requesting bone biopsies in possible cases of osteomyelitis.

Q: What makes diagnosis and treatment of osteomyelitis unique?

A: In the foot, there’s not a lot of soft tissue between the outside world and your bone. If the wounds on the feet go deep enough, they can spread a bacterial infection to the bone. This changes how foot infections are treated.
 

If you have a skin infection, it requires 11-12 days of antibiotics. Things start ramping up once you start getting into the bone. You’re talking potential surgery and 6 weeks of antibiotics through IV treatments. This is why it’s really important that you get your diagnosis right.

A lot of people say “I’m going to do the safe thing” and treat a bone infection with an extended course of antibiotics.

That’s not necessarily safe. If you’re overdiagnosing – for example, you identify bacteria that’s just a contaminant – you could put a patient through 6 weeks of IV treatment along with the risks of a PICC (peripherally inserted central catheter ) line infection, complications from IV placement, and complications from the antibiotic.

Also, acute kidney injury develops in at least a third of the patients who undergo 6 weeks of antibiotics. That’s not to mention the cost of the visits and the labs you have to draw. But we don’t want to underdiagnose either. If osteomyelitis is underdiagnosed and then not treated, the infection can smolder and continue to progress and worsen.

Q: Your study looks at the bone biopsy. How does it fit into care of osteomyelitis in the diabetic foot?

A: A bone biopsy is the standard for diagnosis under the guidelines of the Infectious Diseases Society of America/International Working Group on the Diabetic Foot (Clin Infect Dis. 2012;54[12]:e132-73 ).
 

But beyond that, nobody says anything. Everyone has an operational definition of how a bone biopsy is interpreted, and there’s a need for a consensus on how a bone biopsy can be used to diagnose osteomyelitis.

You’ll get different percentages of your patients diagnosed with osteomyelitis. For example, someone may say the biopsy is only positive if the histology is positive, while another says the histology doesn’t matter if the culture is positive.

Q: Your study looks at histology and culture analyses. What do these reveal?

A: A traditional culture helps you identify the bacteria, as well as guide your treatment when it’s tested against antibiotics.
 

A traditional histology allows the pathologist to look under a microscope for signs of osteomyelitis: Do they see the right inflammatory cells, white cells, lymphocytes, combinations of cells? Does this look like an acute or chronic osteomyelitis?

Q: Why might it be wise to combine culture and histology analyses?

A: If you have bacteria that’s difficult to culture via traditional methods, it may be a bacteria that doesn’t grow well or easily. If you combine culture with histology, pathologists can look and say, “Your culture was negative but we see these other signs, so we feel this is osteomyelitis.”



Q: Your study examined 35 consecutive patients aged at least 21 years who had moderate or severe infections bone infections in the foot linked with type 1 diabetes (n = 4) or type 2 diabetes (n = 31).

The samples were analyzed via culture, histology, and culture/histology examinations. You also performed genetic sequencing (quantitative polymerase chain reaction targeting 16S rRNA). How does this test fit in to bone biopsies in the clinic?

A: That’s a newer method and not a standard of care treatment for the diabetic foot. This analysis looks at DNA that’s present, bypassing the analysis of difficult-to-grow bacteria.



Q: What did you discover?

A: In this study, histology had the lowest incidence of positively detecting osteomyelitis. (45.7%). The level increases when a culture is taken (68.6% vs. histology; P = .02).
 

Then it goes up when DNA is used because it’s catching everything (82.9%, P = .001 vs. histology and P = .31 vs. culture).

[The study also found that adding histology to culture or to genetic sequencing did not change positive findings.]

Q: Does the study suggest one approach is better than the others?

A: This paper doesn’t provide enough evidence to use one method over another. The main purpose was to raise the concern that diagnosis can change dramatically depending on how the gold standard of bone biopsy is interpreted.



Q: What were the pros and cons of the genetic sequencing approach?

A: When we use this approach, our positive diagnostic rate significantly increases. But there are also downsides. We don’t know whether the bacteria we see is alive or dead. We just know it was there. So are the patients truly positive? That’s a question we can’t answer.
 

Genetic sequencing also doesn’t tell us about susceptibilities to antibiotics.

Q: What is the take-home message here for physicians who may order bone biopsies?

A: The thing to do is request both traditional culture and traditional histology.
 

As far as DNA sequencing, that not something I’d recommend as a standard of care.

Q: Can you comment on cost and insurance coverage for these approaches?

A: As far as I know, genetic sequencing is not covered as it is not standard of care in the diabetic foot and is used mainly for research at this time.
 

Pathology and culture are standard of care when evaluating for osteomyelitis and should be a covered service. However, a patient should call their insurance company first prior to having the procedure done to see whether it is covered.

Q: What’s next for research in this area?

A: From here, the next step is bigger numbers: Increase the study size and look at this again. Also, we may be able to identify susceptibilities by identifying resistance within the DNA.



Dr. Crisologo and two other study authors report no relevant disclosures. One study author reported various disclosures including research support, consulting, and service on speakers' bureaus.
 

Diabetic foot ulcers and infections can lead to osteomyelitis, a potentially devastating infection in the bone.

WILLSIE/Getty Images

How much of a difference can osteomyelitis make to a patient’s prognosis? A 2014 commentary by Benjamin A. Lipsky, MD, a prominent expert in problems associated with diabetic patients’ feet who’s with the University of Washington, Seattle, hints at the potential toll: “Overall, about 20% of patients with a diabetic foot infection (and over 60% of those with severe infections) have underlying osteomyelitis, which dramatically increases the risk of lower-extremity amputation” (Diabetes Care. 2014 Mar;37[3]:593-5).

Diagnosis of osteomyelitis, which relies on a bone biopsy, is clearly important. But there’s a big gap in diagnostic findings depending on whether doctors request culture or histology results, according to a new study released at the 2018 scientific meeting of the American Diabetes Association (Diabetes. 2018 Jul. doi: 10.2337/db18-110-OR).

In an interview, lead author and podiatrist Peter A. Crisologo, DPM, of University of Texas Southwestern Medical Center, Dallas, explained the study findings and offered guidance for requesting bone biopsies in possible cases of osteomyelitis.

Q: What makes diagnosis and treatment of osteomyelitis unique?

A: In the foot, there’s not a lot of soft tissue between the outside world and your bone. If the wounds on the feet go deep enough, they can spread a bacterial infection to the bone. This changes how foot infections are treated.
 

If you have a skin infection, it requires 11-12 days of antibiotics. Things start ramping up once you start getting into the bone. You’re talking potential surgery and 6 weeks of antibiotics through IV treatments. This is why it’s really important that you get your diagnosis right.

A lot of people say “I’m going to do the safe thing” and treat a bone infection with an extended course of antibiotics.

That’s not necessarily safe. If you’re overdiagnosing – for example, you identify bacteria that’s just a contaminant – you could put a patient through 6 weeks of IV treatment along with the risks of a PICC (peripherally inserted central catheter ) line infection, complications from IV placement, and complications from the antibiotic.

Also, acute kidney injury develops in at least a third of the patients who undergo 6 weeks of antibiotics. That’s not to mention the cost of the visits and the labs you have to draw. But we don’t want to underdiagnose either. If osteomyelitis is underdiagnosed and then not treated, the infection can smolder and continue to progress and worsen.

Q: Your study looks at the bone biopsy. How does it fit into care of osteomyelitis in the diabetic foot?

A: A bone biopsy is the standard for diagnosis under the guidelines of the Infectious Diseases Society of America/International Working Group on the Diabetic Foot (Clin Infect Dis. 2012;54[12]:e132-73 ).
 

But beyond that, nobody says anything. Everyone has an operational definition of how a bone biopsy is interpreted, and there’s a need for a consensus on how a bone biopsy can be used to diagnose osteomyelitis.

You’ll get different percentages of your patients diagnosed with osteomyelitis. For example, someone may say the biopsy is only positive if the histology is positive, while another says the histology doesn’t matter if the culture is positive.

Q: Your study looks at histology and culture analyses. What do these reveal?

A: A traditional culture helps you identify the bacteria, as well as guide your treatment when it’s tested against antibiotics.
 

A traditional histology allows the pathologist to look under a microscope for signs of osteomyelitis: Do they see the right inflammatory cells, white cells, lymphocytes, combinations of cells? Does this look like an acute or chronic osteomyelitis?

Q: Why might it be wise to combine culture and histology analyses?

A: If you have bacteria that’s difficult to culture via traditional methods, it may be a bacteria that doesn’t grow well or easily. If you combine culture with histology, pathologists can look and say, “Your culture was negative but we see these other signs, so we feel this is osteomyelitis.”



Q: Your study examined 35 consecutive patients aged at least 21 years who had moderate or severe infections bone infections in the foot linked with type 1 diabetes (n = 4) or type 2 diabetes (n = 31).

The samples were analyzed via culture, histology, and culture/histology examinations. You also performed genetic sequencing (quantitative polymerase chain reaction targeting 16S rRNA). How does this test fit in to bone biopsies in the clinic?

A: That’s a newer method and not a standard of care treatment for the diabetic foot. This analysis looks at DNA that’s present, bypassing the analysis of difficult-to-grow bacteria.



Q: What did you discover?

A: In this study, histology had the lowest incidence of positively detecting osteomyelitis. (45.7%). The level increases when a culture is taken (68.6% vs. histology; P = .02).
 

Then it goes up when DNA is used because it’s catching everything (82.9%, P = .001 vs. histology and P = .31 vs. culture).

[The study also found that adding histology to culture or to genetic sequencing did not change positive findings.]

Q: Does the study suggest one approach is better than the others?

A: This paper doesn’t provide enough evidence to use one method over another. The main purpose was to raise the concern that diagnosis can change dramatically depending on how the gold standard of bone biopsy is interpreted.



Q: What were the pros and cons of the genetic sequencing approach?

A: When we use this approach, our positive diagnostic rate significantly increases. But there are also downsides. We don’t know whether the bacteria we see is alive or dead. We just know it was there. So are the patients truly positive? That’s a question we can’t answer.
 

Genetic sequencing also doesn’t tell us about susceptibilities to antibiotics.

Q: What is the take-home message here for physicians who may order bone biopsies?

A: The thing to do is request both traditional culture and traditional histology.
 

As far as DNA sequencing, that not something I’d recommend as a standard of care.

Q: Can you comment on cost and insurance coverage for these approaches?

A: As far as I know, genetic sequencing is not covered as it is not standard of care in the diabetic foot and is used mainly for research at this time.
 

Pathology and culture are standard of care when evaluating for osteomyelitis and should be a covered service. However, a patient should call their insurance company first prior to having the procedure done to see whether it is covered.

Q: What’s next for research in this area?

A: From here, the next step is bigger numbers: Increase the study size and look at this again. Also, we may be able to identify susceptibilities by identifying resistance within the DNA.



Dr. Crisologo and two other study authors report no relevant disclosures. One study author reported various disclosures including research support, consulting, and service on speakers' bureaus.
 

Diabetic foot ulcers and infections can lead to osteomyelitis, a potentially devastating infection in the bone.

WILLSIE/Getty Images

How much of a difference can osteomyelitis make to a patient’s prognosis? A 2014 commentary by Benjamin A. Lipsky, MD, a prominent expert in problems associated with diabetic patients’ feet who’s with the University of Washington, Seattle, hints at the potential toll: “Overall, about 20% of patients with a diabetic foot infection (and over 60% of those with severe infections) have underlying osteomyelitis, which dramatically increases the risk of lower-extremity amputation” (Diabetes Care. 2014 Mar;37[3]:593-5).

Diagnosis of osteomyelitis, which relies on a bone biopsy, is clearly important. But there’s a big gap in diagnostic findings depending on whether doctors request culture or histology results, according to a new study released at the 2018 scientific meeting of the American Diabetes Association (Diabetes. 2018 Jul. doi: 10.2337/db18-110-OR).

In an interview, lead author and podiatrist Peter A. Crisologo, DPM, of University of Texas Southwestern Medical Center, Dallas, explained the study findings and offered guidance for requesting bone biopsies in possible cases of osteomyelitis.

Q: What makes diagnosis and treatment of osteomyelitis unique?

A: In the foot, there’s not a lot of soft tissue between the outside world and your bone. If the wounds on the feet go deep enough, they can spread a bacterial infection to the bone. This changes how foot infections are treated.
 

If you have a skin infection, it requires 11-12 days of antibiotics. Things start ramping up once you start getting into the bone. You’re talking potential surgery and 6 weeks of antibiotics through IV treatments. This is why it’s really important that you get your diagnosis right.

A lot of people say “I’m going to do the safe thing” and treat a bone infection with an extended course of antibiotics.

That’s not necessarily safe. If you’re overdiagnosing – for example, you identify bacteria that’s just a contaminant – you could put a patient through 6 weeks of IV treatment along with the risks of a PICC (peripherally inserted central catheter ) line infection, complications from IV placement, and complications from the antibiotic.

Also, acute kidney injury develops in at least a third of the patients who undergo 6 weeks of antibiotics. That’s not to mention the cost of the visits and the labs you have to draw. But we don’t want to underdiagnose either. If osteomyelitis is underdiagnosed and then not treated, the infection can smolder and continue to progress and worsen.

Q: Your study looks at the bone biopsy. How does it fit into care of osteomyelitis in the diabetic foot?

A: A bone biopsy is the standard for diagnosis under the guidelines of the Infectious Diseases Society of America/International Working Group on the Diabetic Foot (Clin Infect Dis. 2012;54[12]:e132-73 ).
 

But beyond that, nobody says anything. Everyone has an operational definition of how a bone biopsy is interpreted, and there’s a need for a consensus on how a bone biopsy can be used to diagnose osteomyelitis.

You’ll get different percentages of your patients diagnosed with osteomyelitis. For example, someone may say the biopsy is only positive if the histology is positive, while another says the histology doesn’t matter if the culture is positive.

Q: Your study looks at histology and culture analyses. What do these reveal?

A: A traditional culture helps you identify the bacteria, as well as guide your treatment when it’s tested against antibiotics.
 

A traditional histology allows the pathologist to look under a microscope for signs of osteomyelitis: Do they see the right inflammatory cells, white cells, lymphocytes, combinations of cells? Does this look like an acute or chronic osteomyelitis?

Q: Why might it be wise to combine culture and histology analyses?

A: If you have bacteria that’s difficult to culture via traditional methods, it may be a bacteria that doesn’t grow well or easily. If you combine culture with histology, pathologists can look and say, “Your culture was negative but we see these other signs, so we feel this is osteomyelitis.”



Q: Your study examined 35 consecutive patients aged at least 21 years who had moderate or severe infections bone infections in the foot linked with type 1 diabetes (n = 4) or type 2 diabetes (n = 31).

The samples were analyzed via culture, histology, and culture/histology examinations. You also performed genetic sequencing (quantitative polymerase chain reaction targeting 16S rRNA). How does this test fit in to bone biopsies in the clinic?

A: That’s a newer method and not a standard of care treatment for the diabetic foot. This analysis looks at DNA that’s present, bypassing the analysis of difficult-to-grow bacteria.



Q: What did you discover?

A: In this study, histology had the lowest incidence of positively detecting osteomyelitis. (45.7%). The level increases when a culture is taken (68.6% vs. histology; P = .02).
 

Then it goes up when DNA is used because it’s catching everything (82.9%, P = .001 vs. histology and P = .31 vs. culture).

[The study also found that adding histology to culture or to genetic sequencing did not change positive findings.]

Q: Does the study suggest one approach is better than the others?

A: This paper doesn’t provide enough evidence to use one method over another. The main purpose was to raise the concern that diagnosis can change dramatically depending on how the gold standard of bone biopsy is interpreted.



Q: What were the pros and cons of the genetic sequencing approach?

A: When we use this approach, our positive diagnostic rate significantly increases. But there are also downsides. We don’t know whether the bacteria we see is alive or dead. We just know it was there. So are the patients truly positive? That’s a question we can’t answer.
 

Genetic sequencing also doesn’t tell us about susceptibilities to antibiotics.

Q: What is the take-home message here for physicians who may order bone biopsies?

A: The thing to do is request both traditional culture and traditional histology.
 

As far as DNA sequencing, that not something I’d recommend as a standard of care.

Q: Can you comment on cost and insurance coverage for these approaches?

A: As far as I know, genetic sequencing is not covered as it is not standard of care in the diabetic foot and is used mainly for research at this time.
 

Pathology and culture are standard of care when evaluating for osteomyelitis and should be a covered service. However, a patient should call their insurance company first prior to having the procedure done to see whether it is covered.

Q: What’s next for research in this area?

A: From here, the next step is bigger numbers: Increase the study size and look at this again. Also, we may be able to identify susceptibilities by identifying resistance within the DNA.



Dr. Crisologo and two other study authors report no relevant disclosures. One study author reported various disclosures including research support, consulting, and service on speakers' bureaus.
 

MUNICH – In a double blow to the current, widespread routine use of low-dose aspirin and fish oil supplements for primary cardiovascular prevention in patients with diabetes, neither treatment provided any net clinical benefit in the massive, long-term ASCEND study, investigators reported at the annual congress of the European Society of Cardiology.

And, in yet another bitter pill to swallow, low-dose aspirin failed to reduce the incidence of GI cancer or any other type of cancer, compared with placebo in the study. Earlier, nondefinitive meta-analyses of much smaller randomized trials had raised the possibility of a roughly 30% reduction in the incidence of colorectal cancer in long-time users, said Jane Armitage, MD, professor of clinical trials and epidemiology at the University of Oxford (England).

“We saw no suggestion of an anticancer effect emerging over time,” Dr. Armitage said. “We did see a significant reduction in the risk of vascular events but also an increase in major bleeding such that the absolute benefits from avoiding a serious vascular event were largely counterbalanced by increased risk of bleeding. And there was no subgroup in which we could clearly define that the benefit outweighs the risk,” she added in a video interview.

ASCEND (A Study of Cardiovascular Events in Diabetes) was a randomized, blinded trial in which 15,480 U.K. patients with diabetes and no known cardiovascular disease were placed on 100 mg/day of enteric-coated aspirin or placebo and 1 g/day of omega-3 fatty acids in capsule form or placebo in a 2 x 2 factorial design and followed prospectively for a mean of 7.4 years.

The study was undertaken because, even though the value of low-dose aspirin for secondary prevention is supported by strong evidence, the medication’s value for primary prevention in patients with diabetes has long been uncertain. American Diabetes Association guidelines give a Grade C recommendation to consideration of low-dose aspirin as a primary prevention strategy in patients with diabetes having a 10-year cardiovascular risk estimated at 10% or greater.

The primary efficacy endpoint in ASCEND was the occurrence of a first serious vascular event, defined as MI, stroke, transient ischemic attack, or death from any vascular cause other than intracranial hemorrhage. The rate was 8.5% in the aspirin group and 9.6% with placebo, for a statistically significant 12% relative risk reduction. However, the rate of the primary composite safety endpoint, comprising intracranial hemorrhage, GI bleeding, sight-threatening bleeding in the eye, or other bleeding serious enough to entail a trip to the hospital, was 4.1% in the aspirin group and 3.2% with placebo, a 29% increase in risk.

Aspirin reduced the absolute risk of a serious vascular event by 1.1%, compared with placebo, while boosting the risk of major bleeding by an absolute 0.9% – essentially a wash. The number needed to treat to avoid a serious vascular event was 91 patients, with 112 being the number needed to cause a major bleeding event. The risk of major bleeding rose with increasing baseline 5-year vascular event risk.

ASCEND provided no support for a recent report suggesting the benefit of low-dose aspirin for cardioprotection is largely confined to individuals weighing less than 70 kg (Lancet. 2018; 392:387-99); in fact, the opposite appeared to be true, according to Dr. Armitage.

The incidence of cancer of the GI tract was 2.0% in both study arms. The overall cancer rate was 11.6% in the aspirin arm and 11.5% with placebo. Additional follow-up focused on cancer is planned for 5 and 10 years after the end of ASCEND in order to examine the possibility of a delayed anticancer effect, she added.

Dr. Armitage said one reason aspirin may have failed to show a significant net benefit was the high rate of background cardioprotective medication usage, especially statins and antihypertensive drugs.

“I think if your diabetes is well managed and you’ve got your other risk factors under control, you have to consider very carefully whether or not, for you, the benefits of aspirin outweigh the risks,” she concluded.

Cardiologists respond

ASCEND’s two designated discussants, both cardiologists, took a more positive view of the results than Dr. Armitage, who isn’t a cardiologist.

Bruce Jancin/MDedge News

Sigrun Halvorsen, MD, professor of cardiology at the University of Oslo, noted that most ASCEND participants were at relatively low cardiovascular risk, with an event rate of about 1.3% per year. She indicated that she’d like to see more data on higher-risk individuals before excluding any role for aspirin in primary cardiovascular prevention in patients with diabetes.

“Serious vascular events and bleeding are not necessarily equally weighted,” she added. “Most major bleeds in ASCEND were GI bleeds, and these can be largely prevented by PPIs [proton pump inhibitors], in contrast to death and stroke, which are irreversible events.”

“I think this study could be interpreted more favorably,” agreed Christopher P. Cannon, MD, professor of medicine at Harvard Medical School, Boston. “Bleeds are reversible, but MIs and whatnot are not.”

Fish oil flounders in ASCEND

Bruce Jancin/MDedge News

Louise Bowman, MD, also at the University of Oxford, presented the ASCEND fish oil findings. Over an average of 7.4 years, omega-3 fatty acid supplementation had no effect on the rate of serious vascular events, no effect on cancer, no impact on all-cause or cause-specific mortality, and raised no safety issues in patients with diabetes. She argued that current guidelines recommending fish oil supplements for cardiovascular prevention should be reconsidered.

“Certainly there doesn’t seem to be any justification for the use of this dose of omega-3 fatty acids – 1 g/day – for the prevention of cardiovascular disease,” Dr. Bowman said.

However, Dr. Cannon saw a sliver of hope within the ASCEND findings. One component of the serious vascular event composite endpoint – vascular death – occurred in 2.4% of the fish oil group and 2.9% of placebo-treated controls, for a statistically significant 19% relative risk reduction. It could be a fluke, given that none of the other vascular endpoints followed suit. But physicians and patients won’t have to wait long to find out. Another randomized trial of low-dose fish oil supplements for primary cardiovascular prevention – the nearly 26,000-patient VITAL trial – is due to report later in 2018.

In addition, two major, randomized trials of higher-dose fish oil supplementation for secondary prevention are ongoing. The roughly 8,000-patient REDUCE-IT trial is expected to report results later this year, and the STRENGTH trial, featuring more than 13,000 patients, should be completed in 2020. Both studies are heavily loaded with diabetes patients, Dr. Cannon noted.

Simultaneous with presentation of the ASCEND results at the ESC congress, the study was published online at the New England Journal of Medicine website (doi: 10.1056/NEJMoa1804988 and doi: 10.1056/NEJMoa1804989).

The ASCEND study was funded by the British Heart Foundation and the U.K. Medical Research Council with support provided by Abbott Laboratories, Bayer, Mylan, and Solvay. Dr. Armitage and Dr. Bowman reported receiving research grants from the Medicines Company, Bayer, and Mylan. Dr. Halvorsen reported no financial conflicts. Dr. Cannon reported serving as a consultant to roughly a dozen pharmaceutical companies, including the Amarin Corporation, which markets a fish oil supplement and sponsored the REDUCE-IT trial.

bjancin@mdedge.com

MUNICH – In a double blow to the current, widespread routine use of low-dose aspirin and fish oil supplements for primary cardiovascular prevention in patients with diabetes, neither treatment provided any net clinical benefit in the massive, long-term ASCEND study, investigators reported at the annual congress of the European Society of Cardiology.

And, in yet another bitter pill to swallow, low-dose aspirin failed to reduce the incidence of GI cancer or any other type of cancer, compared with placebo in the study. Earlier, nondefinitive meta-analyses of much smaller randomized trials had raised the possibility of a roughly 30% reduction in the incidence of colorectal cancer in long-time users, said Jane Armitage, MD, professor of clinical trials and epidemiology at the University of Oxford (England).

“We saw no suggestion of an anticancer effect emerging over time,” Dr. Armitage said. “We did see a significant reduction in the risk of vascular events but also an increase in major bleeding such that the absolute benefits from avoiding a serious vascular event were largely counterbalanced by increased risk of bleeding. And there was no subgroup in which we could clearly define that the benefit outweighs the risk,” she added in a video interview.

ASCEND (A Study of Cardiovascular Events in Diabetes) was a randomized, blinded trial in which 15,480 U.K. patients with diabetes and no known cardiovascular disease were placed on 100 mg/day of enteric-coated aspirin or placebo and 1 g/day of omega-3 fatty acids in capsule form or placebo in a 2 x 2 factorial design and followed prospectively for a mean of 7.4 years.

The study was undertaken because, even though the value of low-dose aspirin for secondary prevention is supported by strong evidence, the medication’s value for primary prevention in patients with diabetes has long been uncertain. American Diabetes Association guidelines give a Grade C recommendation to consideration of low-dose aspirin as a primary prevention strategy in patients with diabetes having a 10-year cardiovascular risk estimated at 10% or greater.

The primary efficacy endpoint in ASCEND was the occurrence of a first serious vascular event, defined as MI, stroke, transient ischemic attack, or death from any vascular cause other than intracranial hemorrhage. The rate was 8.5% in the aspirin group and 9.6% with placebo, for a statistically significant 12% relative risk reduction. However, the rate of the primary composite safety endpoint, comprising intracranial hemorrhage, GI bleeding, sight-threatening bleeding in the eye, or other bleeding serious enough to entail a trip to the hospital, was 4.1% in the aspirin group and 3.2% with placebo, a 29% increase in risk.

Aspirin reduced the absolute risk of a serious vascular event by 1.1%, compared with placebo, while boosting the risk of major bleeding by an absolute 0.9% – essentially a wash. The number needed to treat to avoid a serious vascular event was 91 patients, with 112 being the number needed to cause a major bleeding event. The risk of major bleeding rose with increasing baseline 5-year vascular event risk.

ASCEND provided no support for a recent report suggesting the benefit of low-dose aspirin for cardioprotection is largely confined to individuals weighing less than 70 kg (Lancet. 2018; 392:387-99); in fact, the opposite appeared to be true, according to Dr. Armitage.

The incidence of cancer of the GI tract was 2.0% in both study arms. The overall cancer rate was 11.6% in the aspirin arm and 11.5% with placebo. Additional follow-up focused on cancer is planned for 5 and 10 years after the end of ASCEND in order to examine the possibility of a delayed anticancer effect, she added.

Dr. Armitage said one reason aspirin may have failed to show a significant net benefit was the high rate of background cardioprotective medication usage, especially statins and antihypertensive drugs.

“I think if your diabetes is well managed and you’ve got your other risk factors under control, you have to consider very carefully whether or not, for you, the benefits of aspirin outweigh the risks,” she concluded.

Cardiologists respond

ASCEND’s two designated discussants, both cardiologists, took a more positive view of the results than Dr. Armitage, who isn’t a cardiologist.

Bruce Jancin/MDedge News

Sigrun Halvorsen, MD, professor of cardiology at the University of Oslo, noted that most ASCEND participants were at relatively low cardiovascular risk, with an event rate of about 1.3% per year. She indicated that she’d like to see more data on higher-risk individuals before excluding any role for aspirin in primary cardiovascular prevention in patients with diabetes.

“Serious vascular events and bleeding are not necessarily equally weighted,” she added. “Most major bleeds in ASCEND were GI bleeds, and these can be largely prevented by PPIs [proton pump inhibitors], in contrast to death and stroke, which are irreversible events.”

“I think this study could be interpreted more favorably,” agreed Christopher P. Cannon, MD, professor of medicine at Harvard Medical School, Boston. “Bleeds are reversible, but MIs and whatnot are not.”

Fish oil flounders in ASCEND

Bruce Jancin/MDedge News

Louise Bowman, MD, also at the University of Oxford, presented the ASCEND fish oil findings. Over an average of 7.4 years, omega-3 fatty acid supplementation had no effect on the rate of serious vascular events, no effect on cancer, no impact on all-cause or cause-specific mortality, and raised no safety issues in patients with diabetes. She argued that current guidelines recommending fish oil supplements for cardiovascular prevention should be reconsidered.

“Certainly there doesn’t seem to be any justification for the use of this dose of omega-3 fatty acids – 1 g/day – for the prevention of cardiovascular disease,” Dr. Bowman said.

However, Dr. Cannon saw a sliver of hope within the ASCEND findings. One component of the serious vascular event composite endpoint – vascular death – occurred in 2.4% of the fish oil group and 2.9% of placebo-treated controls, for a statistically significant 19% relative risk reduction. It could be a fluke, given that none of the other vascular endpoints followed suit. But physicians and patients won’t have to wait long to find out. Another randomized trial of low-dose fish oil supplements for primary cardiovascular prevention – the nearly 26,000-patient VITAL trial – is due to report later in 2018.

In addition, two major, randomized trials of higher-dose fish oil supplementation for secondary prevention are ongoing. The roughly 8,000-patient REDUCE-IT trial is expected to report results later this year, and the STRENGTH trial, featuring more than 13,000 patients, should be completed in 2020. Both studies are heavily loaded with diabetes patients, Dr. Cannon noted.

Simultaneous with presentation of the ASCEND results at the ESC congress, the study was published online at the New England Journal of Medicine website (doi: 10.1056/NEJMoa1804988 and doi: 10.1056/NEJMoa1804989).

The ASCEND study was funded by the British Heart Foundation and the U.K. Medical Research Council with support provided by Abbott Laboratories, Bayer, Mylan, and Solvay. Dr. Armitage and Dr. Bowman reported receiving research grants from the Medicines Company, Bayer, and Mylan. Dr. Halvorsen reported no financial conflicts. Dr. Cannon reported serving as a consultant to roughly a dozen pharmaceutical companies, including the Amarin Corporation, which markets a fish oil supplement and sponsored the REDUCE-IT trial.

bjancin@mdedge.com

MUNICH – In a double blow to the current, widespread routine use of low-dose aspirin and fish oil supplements for primary cardiovascular prevention in patients with diabetes, neither treatment provided any net clinical benefit in the massive, long-term ASCEND study, investigators reported at the annual congress of the European Society of Cardiology.

And, in yet another bitter pill to swallow, low-dose aspirin failed to reduce the incidence of GI cancer or any other type of cancer, compared with placebo in the study. Earlier, nondefinitive meta-analyses of much smaller randomized trials had raised the possibility of a roughly 30% reduction in the incidence of colorectal cancer in long-time users, said Jane Armitage, MD, professor of clinical trials and epidemiology at the University of Oxford (England).

“We saw no suggestion of an anticancer effect emerging over time,” Dr. Armitage said. “We did see a significant reduction in the risk of vascular events but also an increase in major bleeding such that the absolute benefits from avoiding a serious vascular event were largely counterbalanced by increased risk of bleeding. And there was no subgroup in which we could clearly define that the benefit outweighs the risk,” she added in a video interview.

ASCEND (A Study of Cardiovascular Events in Diabetes) was a randomized, blinded trial in which 15,480 U.K. patients with diabetes and no known cardiovascular disease were placed on 100 mg/day of enteric-coated aspirin or placebo and 1 g/day of omega-3 fatty acids in capsule form or placebo in a 2 x 2 factorial design and followed prospectively for a mean of 7.4 years.

The study was undertaken because, even though the value of low-dose aspirin for secondary prevention is supported by strong evidence, the medication’s value for primary prevention in patients with diabetes has long been uncertain. American Diabetes Association guidelines give a Grade C recommendation to consideration of low-dose aspirin as a primary prevention strategy in patients with diabetes having a 10-year cardiovascular risk estimated at 10% or greater.

The primary efficacy endpoint in ASCEND was the occurrence of a first serious vascular event, defined as MI, stroke, transient ischemic attack, or death from any vascular cause other than intracranial hemorrhage. The rate was 8.5% in the aspirin group and 9.6% with placebo, for a statistically significant 12% relative risk reduction. However, the rate of the primary composite safety endpoint, comprising intracranial hemorrhage, GI bleeding, sight-threatening bleeding in the eye, or other bleeding serious enough to entail a trip to the hospital, was 4.1% in the aspirin group and 3.2% with placebo, a 29% increase in risk.

Aspirin reduced the absolute risk of a serious vascular event by 1.1%, compared with placebo, while boosting the risk of major bleeding by an absolute 0.9% – essentially a wash. The number needed to treat to avoid a serious vascular event was 91 patients, with 112 being the number needed to cause a major bleeding event. The risk of major bleeding rose with increasing baseline 5-year vascular event risk.

ASCEND provided no support for a recent report suggesting the benefit of low-dose aspirin for cardioprotection is largely confined to individuals weighing less than 70 kg (Lancet. 2018; 392:387-99); in fact, the opposite appeared to be true, according to Dr. Armitage.

The incidence of cancer of the GI tract was 2.0% in both study arms. The overall cancer rate was 11.6% in the aspirin arm and 11.5% with placebo. Additional follow-up focused on cancer is planned for 5 and 10 years after the end of ASCEND in order to examine the possibility of a delayed anticancer effect, she added.

Dr. Armitage said one reason aspirin may have failed to show a significant net benefit was the high rate of background cardioprotective medication usage, especially statins and antihypertensive drugs.

“I think if your diabetes is well managed and you’ve got your other risk factors under control, you have to consider very carefully whether or not, for you, the benefits of aspirin outweigh the risks,” she concluded.

Cardiologists respond

ASCEND’s two designated discussants, both cardiologists, took a more positive view of the results than Dr. Armitage, who isn’t a cardiologist.

Bruce Jancin/MDedge News

Sigrun Halvorsen, MD, professor of cardiology at the University of Oslo, noted that most ASCEND participants were at relatively low cardiovascular risk, with an event rate of about 1.3% per year. She indicated that she’d like to see more data on higher-risk individuals before excluding any role for aspirin in primary cardiovascular prevention in patients with diabetes.

“Serious vascular events and bleeding are not necessarily equally weighted,” she added. “Most major bleeds in ASCEND were GI bleeds, and these can be largely prevented by PPIs [proton pump inhibitors], in contrast to death and stroke, which are irreversible events.”

“I think this study could be interpreted more favorably,” agreed Christopher P. Cannon, MD, professor of medicine at Harvard Medical School, Boston. “Bleeds are reversible, but MIs and whatnot are not.”

Fish oil flounders in ASCEND

Bruce Jancin/MDedge News

Louise Bowman, MD, also at the University of Oxford, presented the ASCEND fish oil findings. Over an average of 7.4 years, omega-3 fatty acid supplementation had no effect on the rate of serious vascular events, no effect on cancer, no impact on all-cause or cause-specific mortality, and raised no safety issues in patients with diabetes. She argued that current guidelines recommending fish oil supplements for cardiovascular prevention should be reconsidered.

“Certainly there doesn’t seem to be any justification for the use of this dose of omega-3 fatty acids – 1 g/day – for the prevention of cardiovascular disease,” Dr. Bowman said.

However, Dr. Cannon saw a sliver of hope within the ASCEND findings. One component of the serious vascular event composite endpoint – vascular death – occurred in 2.4% of the fish oil group and 2.9% of placebo-treated controls, for a statistically significant 19% relative risk reduction. It could be a fluke, given that none of the other vascular endpoints followed suit. But physicians and patients won’t have to wait long to find out. Another randomized trial of low-dose fish oil supplements for primary cardiovascular prevention – the nearly 26,000-patient VITAL trial – is due to report later in 2018.

In addition, two major, randomized trials of higher-dose fish oil supplementation for secondary prevention are ongoing. The roughly 8,000-patient REDUCE-IT trial is expected to report results later this year, and the STRENGTH trial, featuring more than 13,000 patients, should be completed in 2020. Both studies are heavily loaded with diabetes patients, Dr. Cannon noted.

Simultaneous with presentation of the ASCEND results at the ESC congress, the study was published online at the New England Journal of Medicine website (doi: 10.1056/NEJMoa1804988 and doi: 10.1056/NEJMoa1804989).

The ASCEND study was funded by the British Heart Foundation and the U.K. Medical Research Council with support provided by Abbott Laboratories, Bayer, Mylan, and Solvay. Dr. Armitage and Dr. Bowman reported receiving research grants from the Medicines Company, Bayer, and Mylan. Dr. Halvorsen reported no financial conflicts. Dr. Cannon reported serving as a consultant to roughly a dozen pharmaceutical companies, including the Amarin Corporation, which markets a fish oil supplement and sponsored the REDUCE-IT trial.

bjancin@mdedge.com

MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.

Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.

In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.

In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”   

“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.

chackett@mdedge.com

MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.

Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.

In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.

In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”   

“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.

chackett@mdedge.com

MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.

Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.

In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.

In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”   

“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.

chackett@mdedge.com

MUNICH – Patients with hypercholesterolemia, atherosclerotic cardiovascular disease, and metabolic syndrome received a bigger benefit from treatment with a PCSK9 inhibitor than did otherwise similar patients without metabolic syndrome in a post hoc analysis of data collected from a placebo-controlled trial of a PCSK9 inhibitor with more than 27,000 total participants.

The analysis showed that patients with metabolic syndrome (MetS) treated with the proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor evolocumab in the FOURIER study had a statistically significant 17% relative risk reduction in the study’s primary efficacy endpoint compared with placebo, while those without MetS had an 11% relative risk reduction that did not reach statistical significance, Prakash Deedwania, MD, said at the annual congress of the European Society of Cardiology. “Given their higher baseline risk [for cardiovascular disease events], patients with metabolic syndrome had a larger absolute reduction in cardiovascular events,” said Dr. Deedwania, a professor of medicine at the University of California, San Francisco.

For the study’s secondary endpoint of the combined rate of cardiovascular disease death, nonfatal MI, and nonfatal stroke, patients with MetS treated with evolocumab had a statistically significant 24% relative risk reduction compared with placebo, while those without MetS had an insignificant 14% reduction. Dr. Deedwania and his associates calculated these relative risk reductions and those for the primary endpoint using adjustments for baseline differences between the MetS and non-MetS subgroups in age, race, sex, history of diabetes, history of MI, heart failure, smoking, renal function, LDL cholesterol levels, and use of a high-intensity dosage of a statin. Among the 27,342 patients enrolled in the trial 16,361 (60%) had MetS at entry into the study, which made this “the largest study ever reported for patients with metabolic syndrome,” he noted.

“Evolocumab was still effective in patients without metabolic syndrome, but it was of lesser magnitude, and that combined with the fewer patients in the non–metabolic syndrome subgroup meant the effect did not reach statistical significance,” Dr. Deedwania explained. “These data help identify the patients who benefit the most from treatment with an expensive drug,” a PCSK9 inhibitor. Based on list prices the annual cost for treatment with a PCSK9 inhibitor such as evolocumab (Repatha) or a second approved drug from this class, alirocumab (Praluent), is roughly $14,000 (JAMA Cardiol. 2017 Oct;2[10]:1066-8).

The analysis run by Dr. Deedwania used data collected in the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, which had showed an overall relative risk reduction of 15% compared with placebo during a median follow-up of 2.2 years for the primary endpoint of cardiovascular death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, or coronary revascularization (N Engl J Med. 2017 May 4;376[18]:1713-22). The study ran at 1,242 sites in 49 countries. He and his associates identified enrolled patients with MetS using the definition of the 2001 Third Report from the National Cholesterol Education Program: People with at least three of five criteria – fasting blood glucose of at least 100 mg/dL; waist circumference greater than 102 cm in men and 88 cm in women; systolic blood pressure of at least 135 mm Hg, diastolic blood pressure of at least 85 mm Hg, or a history of hypertension diagnosis; a triglyceride level greater than 150 mg/dL; and an HDL cholesterol level of less than 40 mg/dL in men and less than 50 mg/dL in women (JAMA. 2001 May 16;285[19]:2486-97).

The new analysis also showed that treatment with evolocumab led to an incremental, average reduction in LDL cholesterol of 58% in patients with MetS and 61% in patients without MetS at the time of enrollment. The patients with MetS in FOURIER overall had a significantly higher number of primary endpoint events, 15.8%, than enrolled patients without MetS, 12.9%, regardless of whether or not they received evolocumab, a relative risk of 21% more events after adjustment. The analysis also showed that treatment with evolocumab was equally safe and well tolerated by patients regardless of whether or not they had MetS, and that patients with MetS had no increased incidence of diabetes or elevations in fasting blood glucose or hemoglobin A1c while on treatment compared with those without MetS.

Dr. Deedwania has been a consultant to Amgen, the company that markets evolocumab, and to Sanofi, the company that markets a different PCSK9 inhibitor, alirocumab.

mzoler@mdedge.com

On Twitter @mitchelzoler

MUNICH – Patients with hypercholesterolemia, atherosclerotic cardiovascular disease, and metabolic syndrome received a bigger benefit from treatment with a PCSK9 inhibitor than did otherwise similar patients without metabolic syndrome in a post hoc analysis of data collected from a placebo-controlled trial of a PCSK9 inhibitor with more than 27,000 total participants.

The analysis showed that patients with metabolic syndrome (MetS) treated with the proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor evolocumab in the FOURIER study had a statistically significant 17% relative risk reduction in the study’s primary efficacy endpoint compared with placebo, while those without MetS had an 11% relative risk reduction that did not reach statistical significance, Prakash Deedwania, MD, said at the annual congress of the European Society of Cardiology. “Given their higher baseline risk [for cardiovascular disease events], patients with metabolic syndrome had a larger absolute reduction in cardiovascular events,” said Dr. Deedwania, a professor of medicine at the University of California, San Francisco.

For the study’s secondary endpoint of the combined rate of cardiovascular disease death, nonfatal MI, and nonfatal stroke, patients with MetS treated with evolocumab had a statistically significant 24% relative risk reduction compared with placebo, while those without MetS had an insignificant 14% reduction. Dr. Deedwania and his associates calculated these relative risk reductions and those for the primary endpoint using adjustments for baseline differences between the MetS and non-MetS subgroups in age, race, sex, history of diabetes, history of MI, heart failure, smoking, renal function, LDL cholesterol levels, and use of a high-intensity dosage of a statin. Among the 27,342 patients enrolled in the trial 16,361 (60%) had MetS at entry into the study, which made this “the largest study ever reported for patients with metabolic syndrome,” he noted.

“Evolocumab was still effective in patients without metabolic syndrome, but it was of lesser magnitude, and that combined with the fewer patients in the non–metabolic syndrome subgroup meant the effect did not reach statistical significance,” Dr. Deedwania explained. “These data help identify the patients who benefit the most from treatment with an expensive drug,” a PCSK9 inhibitor. Based on list prices the annual cost for treatment with a PCSK9 inhibitor such as evolocumab (Repatha) or a second approved drug from this class, alirocumab (Praluent), is roughly $14,000 (JAMA Cardiol. 2017 Oct;2[10]:1066-8).

The analysis run by Dr. Deedwania used data collected in the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, which had showed an overall relative risk reduction of 15% compared with placebo during a median follow-up of 2.2 years for the primary endpoint of cardiovascular death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, or coronary revascularization (N Engl J Med. 2017 May 4;376[18]:1713-22). The study ran at 1,242 sites in 49 countries. He and his associates identified enrolled patients with MetS using the definition of the 2001 Third Report from the National Cholesterol Education Program: People with at least three of five criteria – fasting blood glucose of at least 100 mg/dL; waist circumference greater than 102 cm in men and 88 cm in women; systolic blood pressure of at least 135 mm Hg, diastolic blood pressure of at least 85 mm Hg, or a history of hypertension diagnosis; a triglyceride level greater than 150 mg/dL; and an HDL cholesterol level of less than 40 mg/dL in men and less than 50 mg/dL in women (JAMA. 2001 May 16;285[19]:2486-97).

The new analysis also showed that treatment with evolocumab led to an incremental, average reduction in LDL cholesterol of 58% in patients with MetS and 61% in patients without MetS at the time of enrollment. The patients with MetS in FOURIER overall had a significantly higher number of primary endpoint events, 15.8%, than enrolled patients without MetS, 12.9%, regardless of whether or not they received evolocumab, a relative risk of 21% more events after adjustment. The analysis also showed that treatment with evolocumab was equally safe and well tolerated by patients regardless of whether or not they had MetS, and that patients with MetS had no increased incidence of diabetes or elevations in fasting blood glucose or hemoglobin A1c while on treatment compared with those without MetS.

Dr. Deedwania has been a consultant to Amgen, the company that markets evolocumab, and to Sanofi, the company that markets a different PCSK9 inhibitor, alirocumab.

mzoler@mdedge.com

On Twitter @mitchelzoler

MUNICH – Patients with hypercholesterolemia, atherosclerotic cardiovascular disease, and metabolic syndrome received a bigger benefit from treatment with a PCSK9 inhibitor than did otherwise similar patients without metabolic syndrome in a post hoc analysis of data collected from a placebo-controlled trial of a PCSK9 inhibitor with more than 27,000 total participants.

The analysis showed that patients with metabolic syndrome (MetS) treated with the proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor evolocumab in the FOURIER study had a statistically significant 17% relative risk reduction in the study’s primary efficacy endpoint compared with placebo, while those without MetS had an 11% relative risk reduction that did not reach statistical significance, Prakash Deedwania, MD, said at the annual congress of the European Society of Cardiology. “Given their higher baseline risk [for cardiovascular disease events], patients with metabolic syndrome had a larger absolute reduction in cardiovascular events,” said Dr. Deedwania, a professor of medicine at the University of California, San Francisco.

For the study’s secondary endpoint of the combined rate of cardiovascular disease death, nonfatal MI, and nonfatal stroke, patients with MetS treated with evolocumab had a statistically significant 24% relative risk reduction compared with placebo, while those without MetS had an insignificant 14% reduction. Dr. Deedwania and his associates calculated these relative risk reductions and those for the primary endpoint using adjustments for baseline differences between the MetS and non-MetS subgroups in age, race, sex, history of diabetes, history of MI, heart failure, smoking, renal function, LDL cholesterol levels, and use of a high-intensity dosage of a statin. Among the 27,342 patients enrolled in the trial 16,361 (60%) had MetS at entry into the study, which made this “the largest study ever reported for patients with metabolic syndrome,” he noted.

“Evolocumab was still effective in patients without metabolic syndrome, but it was of lesser magnitude, and that combined with the fewer patients in the non–metabolic syndrome subgroup meant the effect did not reach statistical significance,” Dr. Deedwania explained. “These data help identify the patients who benefit the most from treatment with an expensive drug,” a PCSK9 inhibitor. Based on list prices the annual cost for treatment with a PCSK9 inhibitor such as evolocumab (Repatha) or a second approved drug from this class, alirocumab (Praluent), is roughly $14,000 (JAMA Cardiol. 2017 Oct;2[10]:1066-8).

The analysis run by Dr. Deedwania used data collected in the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, which had showed an overall relative risk reduction of 15% compared with placebo during a median follow-up of 2.2 years for the primary endpoint of cardiovascular death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, or coronary revascularization (N Engl J Med. 2017 May 4;376[18]:1713-22). The study ran at 1,242 sites in 49 countries. He and his associates identified enrolled patients with MetS using the definition of the 2001 Third Report from the National Cholesterol Education Program: People with at least three of five criteria – fasting blood glucose of at least 100 mg/dL; waist circumference greater than 102 cm in men and 88 cm in women; systolic blood pressure of at least 135 mm Hg, diastolic blood pressure of at least 85 mm Hg, or a history of hypertension diagnosis; a triglyceride level greater than 150 mg/dL; and an HDL cholesterol level of less than 40 mg/dL in men and less than 50 mg/dL in women (JAMA. 2001 May 16;285[19]:2486-97).

The new analysis also showed that treatment with evolocumab led to an incremental, average reduction in LDL cholesterol of 58% in patients with MetS and 61% in patients without MetS at the time of enrollment. The patients with MetS in FOURIER overall had a significantly higher number of primary endpoint events, 15.8%, than enrolled patients without MetS, 12.9%, regardless of whether or not they received evolocumab, a relative risk of 21% more events after adjustment. The analysis also showed that treatment with evolocumab was equally safe and well tolerated by patients regardless of whether or not they had MetS, and that patients with MetS had no increased incidence of diabetes or elevations in fasting blood glucose or hemoglobin A1c while on treatment compared with those without MetS.

Dr. Deedwania has been a consultant to Amgen, the company that markets evolocumab, and to Sanofi, the company that markets a different PCSK9 inhibitor, alirocumab.

mzoler@mdedge.com

On Twitter @mitchelzoler

ORLANDO – In 42 states, emergency medical technicians aren’t allowed to administer glucagon to patients with severe hypoglycemia, and that’s a problem, according to investigators from the Joslin Diabetes Center, Boston.

Paramedics can administer the drug, but they’re only about a quarter of medical first-responders, so in many parts of the country, ambulance crews show up with only EMTs [emergency medical technicians] on board, and patients have to wait for the ED to get glucagon.

The delay increases the risk of coma, brain damage, and death. Just like in stroke, time is key with severe hypoglycemia. “The minutes really add up,” said lead investigator Nicole Wagner, a one-time researcher at Joslin and now a medical student at Thomas Jefferson Medical College, Philadelphia.

“Increasing the availability of glucagon in the prehospital setting will likely result in reduced cost burden and adverse consequences of severe hypoglycemia. All emergency persons should have access to glucagon along with the training to administer it,” she and her team concluded at the 2018 American Diabetes Association scientific sessions meeting.

The situation is puzzling because glucagon has a good safety profile – the main concern is nausea – and families of diabetics, at least at Joslin, are taught all the time how to mix and inject it.

aotto@mdedge.com

SOURCE: Wagner NE et al. 2018 American Diabetes Association scientific sessions abstract 387-P

ORLANDO – In 42 states, emergency medical technicians aren’t allowed to administer glucagon to patients with severe hypoglycemia, and that’s a problem, according to investigators from the Joslin Diabetes Center, Boston.

Paramedics can administer the drug, but they’re only about a quarter of medical first-responders, so in many parts of the country, ambulance crews show up with only EMTs [emergency medical technicians] on board, and patients have to wait for the ED to get glucagon.

The delay increases the risk of coma, brain damage, and death. Just like in stroke, time is key with severe hypoglycemia. “The minutes really add up,” said lead investigator Nicole Wagner, a one-time researcher at Joslin and now a medical student at Thomas Jefferson Medical College, Philadelphia.

“Increasing the availability of glucagon in the prehospital setting will likely result in reduced cost burden and adverse consequences of severe hypoglycemia. All emergency persons should have access to glucagon along with the training to administer it,” she and her team concluded at the 2018 American Diabetes Association scientific sessions meeting.

The situation is puzzling because glucagon has a good safety profile – the main concern is nausea – and families of diabetics, at least at Joslin, are taught all the time how to mix and inject it.

aotto@mdedge.com

SOURCE: Wagner NE et al. 2018 American Diabetes Association scientific sessions abstract 387-P

ORLANDO – In 42 states, emergency medical technicians aren’t allowed to administer glucagon to patients with severe hypoglycemia, and that’s a problem, according to investigators from the Joslin Diabetes Center, Boston.

Paramedics can administer the drug, but they’re only about a quarter of medical first-responders, so in many parts of the country, ambulance crews show up with only EMTs [emergency medical technicians] on board, and patients have to wait for the ED to get glucagon.

The delay increases the risk of coma, brain damage, and death. Just like in stroke, time is key with severe hypoglycemia. “The minutes really add up,” said lead investigator Nicole Wagner, a one-time researcher at Joslin and now a medical student at Thomas Jefferson Medical College, Philadelphia.

“Increasing the availability of glucagon in the prehospital setting will likely result in reduced cost burden and adverse consequences of severe hypoglycemia. All emergency persons should have access to glucagon along with the training to administer it,” she and her team concluded at the 2018 American Diabetes Association scientific sessions meeting.

The situation is puzzling because glucagon has a good safety profile – the main concern is nausea – and families of diabetics, at least at Joslin, are taught all the time how to mix and inject it.

aotto@mdedge.com

SOURCE: Wagner NE et al. 2018 American Diabetes Association scientific sessions abstract 387-P

Heightened first trimester hemoglobin A_1c levels may predict gestational diabetes mellitus (GDM), according to a case-control study drawn from the prospective NICHD Fetal Growth Studies-Singleton cohort.

Halfpoint/Thinkstock

Women who went on to develop GDM had higher HbA_1c levels, and measuring this factor improved prediction when added to traditional GDM risk factors, Stefanie N. Hinkle, PhD, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and her associates reported in Scientific Reports.

A previous report showed that GDM-associated fetal overgrowth begins before GDM diagnosis, which suggests a need to identify GDM earlier in pregnancy (Int J Epidemiol. 2018 Feb;47[1]:25–25l).

HbA_1c is already used to screen for type 2 diabetes mellitus outside of pregnancy. Previous studies that examined its potential utility for GDM have focused on high-risk patients, examined an HbA_1c threshold of 5.7%, used GDM during the first trimester only as the outcome, or had other limitations. There is little research on HbA_1c levels and GDM in population-based samples.

Dr. Hinkle and her associates conducted a secondary analysis of a case-control study that involved 2,334 low-risk pregnancies among nonobese women and 468 low-risk pregnancies among obese women (n = 2,802) at 12 U.S. centers. The women were recruited during gestational weeks 8-13 and then followed until the end of the pregnancy. The researchers did a nested GDM case-control study of 107 GDM cases and 214 matched non-GDM controls.

GDM cases had higher HbA_1c levels throughout their pregnancies (P less than .03). The researchers found a linear association between HbA_1c at enrollment and GDM risk (P = .001). Women with a first trimester HbA_1c level of 5.7% had an odds ratio of 2.73 for GDM, compared with women at the median level of 5.2%.

In the adjusted model, for each increment of 0.1% at enrollment, women had an OR of 1.22 for GDM (P less than .001). For every 0.1% difference between HbA_1c levels at enrollment and the second visit (24-29 weeks), the OR was 1.21 (P = .04). When the researchers excluded women who were obese, had smoked, had prior GDM, or had a hematologic disorder, the OR per 0.1% increase was similar (OR, 1.23; 95% confidence interval, 1.10-1.38).

A potential optimal cutoff point is 5.1%, which had a sensitivity of 47% (95% CI, 34%-60%) and a specificity of 79% (95% CI, 62%-88%). At 5.7%, which is used as the cutoff for prediabetes in nonpregnant women, the sensitivity was 21% (95% CI, 8%-36%) and the specificity was 95% (95% CI, 91%-99%).

When the model was added to conventional risk factors such as age, race/ethnicity, being overweight or obese before pregnancy, family history of diabetes, previous GDM, and nulliparity, the area under the curve of HbA_1c levels at enrollment increased from 0.59 to 0.65.

Robert Atlas, MD, chair of obstetrics and gynecology at Mercy Medical Center, Baltimore, said in an interview, “This is just the first study that needs to be replicated in different patient populations. No one has looked at a continuum of HbA_1c and what value above puts you at an increased risk. I think this is a very powerful study that sets the stage for further investigation into how to utilize HbA_1c in a better way than we’ve ever looked at it before.”

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural funding and by American Recovery and Reinvestment Act funding. Dr. Hinkle and her associates had no relevant financial disclosures. Dr. Atlas had no relevant financial disclosures.

SOURCE: Hinkle SN et al. Sci Rep. 2018 Aug 16;8(1):12249.

Heightened first trimester hemoglobin A_1c levels may predict gestational diabetes mellitus (GDM), according to a case-control study drawn from the prospective NICHD Fetal Growth Studies-Singleton cohort.

Halfpoint/Thinkstock

Women who went on to develop GDM had higher HbA_1c levels, and measuring this factor improved prediction when added to traditional GDM risk factors, Stefanie N. Hinkle, PhD, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and her associates reported in Scientific Reports.

A previous report showed that GDM-associated fetal overgrowth begins before GDM diagnosis, which suggests a need to identify GDM earlier in pregnancy (Int J Epidemiol. 2018 Feb;47[1]:25–25l).

HbA_1c is already used to screen for type 2 diabetes mellitus outside of pregnancy. Previous studies that examined its potential utility for GDM have focused on high-risk patients, examined an HbA_1c threshold of 5.7%, used GDM during the first trimester only as the outcome, or had other limitations. There is little research on HbA_1c levels and GDM in population-based samples.

Dr. Hinkle and her associates conducted a secondary analysis of a case-control study that involved 2,334 low-risk pregnancies among nonobese women and 468 low-risk pregnancies among obese women (n = 2,802) at 12 U.S. centers. The women were recruited during gestational weeks 8-13 and then followed until the end of the pregnancy. The researchers did a nested GDM case-control study of 107 GDM cases and 214 matched non-GDM controls.

GDM cases had higher HbA_1c levels throughout their pregnancies (P less than .03). The researchers found a linear association between HbA_1c at enrollment and GDM risk (P = .001). Women with a first trimester HbA_1c level of 5.7% had an odds ratio of 2.73 for GDM, compared with women at the median level of 5.2%.

In the adjusted model, for each increment of 0.1% at enrollment, women had an OR of 1.22 for GDM (P less than .001). For every 0.1% difference between HbA_1c levels at enrollment and the second visit (24-29 weeks), the OR was 1.21 (P = .04). When the researchers excluded women who were obese, had smoked, had prior GDM, or had a hematologic disorder, the OR per 0.1% increase was similar (OR, 1.23; 95% confidence interval, 1.10-1.38).

A potential optimal cutoff point is 5.1%, which had a sensitivity of 47% (95% CI, 34%-60%) and a specificity of 79% (95% CI, 62%-88%). At 5.7%, which is used as the cutoff for prediabetes in nonpregnant women, the sensitivity was 21% (95% CI, 8%-36%) and the specificity was 95% (95% CI, 91%-99%).

When the model was added to conventional risk factors such as age, race/ethnicity, being overweight or obese before pregnancy, family history of diabetes, previous GDM, and nulliparity, the area under the curve of HbA_1c levels at enrollment increased from 0.59 to 0.65.

Robert Atlas, MD, chair of obstetrics and gynecology at Mercy Medical Center, Baltimore, said in an interview, “This is just the first study that needs to be replicated in different patient populations. No one has looked at a continuum of HbA_1c and what value above puts you at an increased risk. I think this is a very powerful study that sets the stage for further investigation into how to utilize HbA_1c in a better way than we’ve ever looked at it before.”

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural funding and by American Recovery and Reinvestment Act funding. Dr. Hinkle and her associates had no relevant financial disclosures. Dr. Atlas had no relevant financial disclosures.

SOURCE: Hinkle SN et al. Sci Rep. 2018 Aug 16;8(1):12249.

Heightened first trimester hemoglobin A_1c levels may predict gestational diabetes mellitus (GDM), according to a case-control study drawn from the prospective NICHD Fetal Growth Studies-Singleton cohort.

Halfpoint/Thinkstock

Women who went on to develop GDM had higher HbA_1c levels, and measuring this factor improved prediction when added to traditional GDM risk factors, Stefanie N. Hinkle, PhD, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and her associates reported in Scientific Reports.

A previous report showed that GDM-associated fetal overgrowth begins before GDM diagnosis, which suggests a need to identify GDM earlier in pregnancy (Int J Epidemiol. 2018 Feb;47[1]:25–25l).

HbA_1c is already used to screen for type 2 diabetes mellitus outside of pregnancy. Previous studies that examined its potential utility for GDM have focused on high-risk patients, examined an HbA_1c threshold of 5.7%, used GDM during the first trimester only as the outcome, or had other limitations. There is little research on HbA_1c levels and GDM in population-based samples.

Dr. Hinkle and her associates conducted a secondary analysis of a case-control study that involved 2,334 low-risk pregnancies among nonobese women and 468 low-risk pregnancies among obese women (n = 2,802) at 12 U.S. centers. The women were recruited during gestational weeks 8-13 and then followed until the end of the pregnancy. The researchers did a nested GDM case-control study of 107 GDM cases and 214 matched non-GDM controls.

GDM cases had higher HbA_1c levels throughout their pregnancies (P less than .03). The researchers found a linear association between HbA_1c at enrollment and GDM risk (P = .001). Women with a first trimester HbA_1c level of 5.7% had an odds ratio of 2.73 for GDM, compared with women at the median level of 5.2%.

In the adjusted model, for each increment of 0.1% at enrollment, women had an OR of 1.22 for GDM (P less than .001). For every 0.1% difference between HbA_1c levels at enrollment and the second visit (24-29 weeks), the OR was 1.21 (P = .04). When the researchers excluded women who were obese, had smoked, had prior GDM, or had a hematologic disorder, the OR per 0.1% increase was similar (OR, 1.23; 95% confidence interval, 1.10-1.38).

A potential optimal cutoff point is 5.1%, which had a sensitivity of 47% (95% CI, 34%-60%) and a specificity of 79% (95% CI, 62%-88%). At 5.7%, which is used as the cutoff for prediabetes in nonpregnant women, the sensitivity was 21% (95% CI, 8%-36%) and the specificity was 95% (95% CI, 91%-99%).

When the model was added to conventional risk factors such as age, race/ethnicity, being overweight or obese before pregnancy, family history of diabetes, previous GDM, and nulliparity, the area under the curve of HbA_1c levels at enrollment increased from 0.59 to 0.65.

Robert Atlas, MD, chair of obstetrics and gynecology at Mercy Medical Center, Baltimore, said in an interview, “This is just the first study that needs to be replicated in different patient populations. No one has looked at a continuum of HbA_1c and what value above puts you at an increased risk. I think this is a very powerful study that sets the stage for further investigation into how to utilize HbA_1c in a better way than we’ve ever looked at it before.”

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural funding and by American Recovery and Reinvestment Act funding. Dr. Hinkle and her associates had no relevant financial disclosures. Dr. Atlas had no relevant financial disclosures.

SOURCE: Hinkle SN et al. Sci Rep. 2018 Aug 16;8(1):12249.

ORLANDO – Patient-centered decision making and support, along with improved diet and exercise, constitute the foundation of all glycemic management, according to a draft consensus report on the management of hyperglycemia in patients with type 2 diabetes mellitus (T2DM).

Patients with ASCVD or heart failure

Given new evidence from trials such as EMPA-REG and LEADER showing outcomes benefits with the use of specific antihyperglycemic medications in patients with established atherosclerotic cardiovascular disease (ASCVD), an important early step in the proposed approach is to consider the presence or absence of ASCVD and heart failure, said Dr. Wexler of Massachusetts General Hospital, Boston.

“The presence of cardiovascular disease is a compelling indication for the selection of certain glucose-lowering drugs,” she said.

The draft consensus recommendation in this regard – a new recommendation since the last consensus report in 2015 – differentiates between T2DM patients in whom ASCVD predominates and those in whom heart failure predominates.

“What’s new since 2015 is that we recommend that these comorbidities be considered first and foremost because they do influence the choice of a particular glucose-lowering medication, and the recommendation is that, among patients with type 2 diabetes with established ASCVD, sodium-glucose cotransporter 2 [SGLT2] inhibitors or glucagonlike peptide 1 [GLP-1] receptor agonists with proven cardiovascular benefit are recommended as part of glycemic management,” she said.

However, it is important to note that ASCVD is defined differently across trials, and patients considered in the development of these recommendations are those with much higher cardiovascular risk than the average patient with T2DM, she added.

“It’s also important to keep in mind that each cardiovascular outcomes trial, while large, is but a single experiment ... and we don’t have the benefit of replication,” she said, noting that it is not always clear whether differences in trial findings within a drug class are related to trial design or true differences in individual medications.

“So we try to read into them and interpret these data, but it’s just important to consider that ... and when evidence suggests a hierarchy, we noted that,” she said.

That said, if ASCVD predominates, the recommendation is for treatment with either a GLP-1 receptor agonist with proven cardiovascular benefit (favoring liraglutide over semaglutide and over long-acting exenatide) or an SGLT2 inhibitor with proven cardiovascular benefit if estimated glomerular filtration (eGFR) is adequate (favoring empagliflozin over canagliflozin).

These recommendations are based on the LEADER trial finding of significant improvement in the primary outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with liraglutide vs. placebo (hazard ratio, 0.87; number needed to treat [NNT], 52 over 3.8 years) and on the EMPA-REG trial finding of significant improvement in the same primary outcome with empagliflozin vs. placebo (HR, 0.86; NNT, 62 over 3.1 years).

Keep in mind that there is no evidence of cardiovascular benefit from these treatments in patients at lower risk and also that the “expensive and complicated” combination of an SGLT2 inhibitor and a GLP-1 receptor agonist has not been tested in cardiovascular outcomes trials and there is no evidence of additional benefit from a cardiovascular perspective with this combination, Dr. Wexler said.

If heart failure predominates, the recommendations call for consideration of an SGLT2 inhibitor as part of the treatment strategy because patients with T2DM are at increased risk for heart failure with reduced or preserved ejection fraction and because significant, consistent reduction in hospitalizations for heart failure were seen in SGLT2 inhibitor trials, writing group member Peter Rossing, MD, explained during the session; he noted, however, that the trials were not designed to adjudicate heart failure and that most patients did not have clinical heart failure at baseline.

In those in whom SGLT2 inhibitors are contraindicated – because of impaired renal function, for example – a GLP-1 receptor agonist with proven cardiovascular benefit is recommended.

“Then we suggest that if you are still not at [hemoglobin A_1c] target, you should avoid thiazolidinediones [TZD] because of the risk of fluid overload, and you could then consider, if needed, combining an SGLT2-inhibitor and a GLP-1 receptor agonist ... or you could use a [dipeptidyl peptidase–4 (DPP-4) inhibitor] if you are not on an GLP-1 receptor agonist. And we point out that saxagliptin has unfavorable data on heart failure,” Dr. Rossing of Steno Diabetes Center, Copenhagen, said, noting that basal insulin or sulfonylurea are other alternative options.

In EMPA-REG, hospitalization for heart failure was reduced by 35% with empagliflozin vs. placebo (HR, 0.65; NNT, 71 over 3 years), and similar findings were seen in the CANVAS trial. In LEADER, a nonsignificant 13% reduction was seen in hospitalization for heart failure with liraglutide vs. placebo (HR, 0.87). However, this was a secondary outcome; ongoing studies are addressing heart failure as a primary outcome, Dr. Rossing said.

The report also includes a recommendation that, for patients with chronic kidney disease and high cardiovascular risk, GLP-1 receptor agonists and SGLT2 inhibitors can be used but with dose reductions for some medications – several of which have demonstrated renal benefit and cardiovascular benefits in those populations and can be considered as part of treatment.
 

Lifestyle management and medication

With respect to lifestyle management and pharmacologic treatment, the proposed recommendations, which are based on several large trials, state that an individualized program of medical nutritional therapy should be offered to all patients and that all overweight and obese patients with diabetes should be advised of the health benefits of weight loss. They also should be encouraged to engage in a program of intensive lifestyle management, which may include food substitution, writing group member Walter Kernan, MD, said at the meeting.

In the DiRECT Trial, the average weight loss was about 10 kg in an intervention group that had complete food replacement for 3 months followed by gradual food reintroduction and ongoing counseling versus about 1 kg in controls, and the diabetes remission rate at 1 year was 46% versus 4%, respectively, said Dr. Kernan of Yale University, New Haven, Conn.

In addition, intentional physical activity is known to improve glycemic control and should be encouraged in all patients with T2DM, he said.

“The foundation of hyperglycemia treatment in type 2 diabetes is, for sure, lifestyle modification,” said group member Geltrude Mingrone, MD, of Catholic University of the Sacred Heart in Rome. “Those patients who are very well motivated and adherent to the [recommendations] can achieve very good results,” she added.

In those in whom lifestyle modification fails to lead to adequate improvement, “a pretty large medication portfolio is available,” she said, adding that the choice of treatment should be based on safety, efficacy, cost, and convenience, factors which are described in the statement.

The hope is that the final consensus statement will make it easier to navigate them, she said.

Finally, bariatric surgery can be considered a very effective salvage therapy, Dr. Mingrone said, noting that only lifestyle modification or bariatric surgery will lead to diabetes remission.

The draft consensus recommendation for bariatric surgery is to consider it in patients with T2DM and a body mass index of 40 kg/m² or greater (37.5 or greater in those of Asian ancestry), regardless of the level of glycemic control, and in those with BMI of 35-39.9 (32.5-37.4 in those of Asian ancestry) when hyperglycemia is inadequately controlled despite lifestyle and optimal medical therapy.

Decision making and injectable therapies

The statement includes decision-making strategies and algorithms for treatment and addresses issues such as choosing antihyperglycemic medications when weight is a concern (consider an SGLT2 inhibitor or a GLP-1 receptor agonist with good efficacy for weight loss to start – or a combination of both if HbA_1c is not on target), when minimizing hypoglycemia is the priority (consider adding an SGLT2 inhibitors, GLP-1 receptor agonist, a TZD, or a DPP-4 inhibitor to metformin therapy to start, followed by reintensification of lifestyle modifications and combination therapies if HbA_1c is above target), and when drug costs need to be minimized, as well as when and how to initiate injectable therapies, according to writing group members David D’Alessio, MD, of Duke University, Durham, N.C, and Chantal Mathieu, MD, of Katholieke Universteit Leuven (Belgium).

The draft consensus recommendation regarding the latter is that, in patients who need the greater glucose-lowering effect of an injectable medication, GLP-1 receptor agonists should be considered as the first choice and that, when insulin is the medication of choice on the basis of clinical characteristics, basal insulin is preferred. Additionally, in patients who are unable to maintain glycemic targets on basal insulin in combination with oral medication, intensification with a GLP-1 receptor agonist, SGLT2 inhibitor, or prandial insulin can be considered.

This recommendation is based on “overwhelming evidence that GLP-1 receptor agonists give you HbA_1c lowering in the same range as basal insulin but can do so without hypoglycemia and with weight loss, in contrast to weight gain with most insulin preparations,” Dr. Mathieu noted.

The bottom line, however, is that “the patient is at the center of everything and ... should become an integral part of the team treating this patient,” Dr. Mathieu said.
 

Knowledge gaps

In a review of remaining knowledge gaps regarding glycemic control in T2DM, Dr. Buse said that, while the tools available to treat and prevent diabetes are vastly improved, implementation of effective innovation has lagged behind and “requires fundamental changes in health care policy and societal approaches to wellness.”

Additionally, the management of overweight and obesity is clearly inadequate and requires much greater emphasis on lifestyle techniques, behavioral approaches, medication, and surgery, said Dr. Buse, who is the Verne S. Caviness distinguished professor and chief of the division of endocrinology, as well as director of the Diabetes Center, at the University of North Carolina, Chapel Hill.

These and numerous other knowledge gaps (with respect to preserving and enhancing beta-cell function, incorporating personalized medicine, the value of combinations for additive benefit, the identification of biomarkers, the use of early intensive therapy, metabolic surgery decision making, the value of self-monitoring of blood glucose, and the need for better drugs – including those for the primary prevention of cardiovascular disease) need to be addressed and “require additional investment in basic, translational, clinical, and implementation research,” he said.

“More time- and cost-efficient research paradigms to address patient-centered endpoints are needed through regulatory reform and leveraging informatics and coordinated learning health care systems. Additionally, the increasing burden of cardiometabolic disease is an existential threat to society,” he said, stressing that “urgent attention to improve prevention and treatment is of the essence.”
 

Consensus statement development

The draft consensus statement is the work of group members selected by the ADA and EASD to ensure regional representation (five each from the United States and Europe). The group had two face-to-face meetings, as well as regular teleconferences; the members also conducted a “robust evidence review, which informed the content,” said group cochair Melanie J. Davies, MD, of the University of Leicester (U.K.).

The group reviewed randomized controlled trials, systematic reviews, and meta-analyses published from Jan. 1, 2014, (to capture research that may have been missed during development of the 2015 statement) through Feb. 28, 2018.

The process was based on consensus among members; areas of disagreement were voted on and the group proceeded according to 60% supermajority votes.

The updates were mainly based on research generated over the past 2 years, Dr. Davies said.

The final draft will be submitted for publication to Diabetes Care and Diabetologia.

Dr. Buse reported relationships (research support, stock ownership, and/or advisory roles) with Adocia, AstraZeneca, Boehringer Ingelheim, Dexcom, Elcelyx Therapeutics, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon Pharmaceuticals, Mellitus Health, Metavention, NovaTarg Therapeutics, Novo Nordisk, PhaseBio Pharmaceuticals, Sanofi, Senseonics, Theracos, and vTv Therapeutics; Dr. Wexler reported having no disclosures; Dr. Rossing reported relationships (consultancy and/or speaking fees, research grants, stock ownership) with AbbVie, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MDS Medical, Novo Nordisk, and Sanofi; Dr. Kernan reported having no disclosures; Dr. Mingrone is a consultant for Novo Nordisk, Fractyl, and Johnson & Johnson; Dr. D’Alessio reported advisory board membership with and/or research support from Eli Lilly, Intarcia Therapeutics, Merck, and Novo Nordisk; Dr. Mathieu reported relationships (advisory board membership, speaker’s bureau, and/or research support) with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Hanmi Pharmaceuticals, Intrexon, Janssen Pharmaceuticals, MannKind, Medtronic, Merck Sharp & Dohme (MSD), Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, Sanofi, and UCB; Dr. Davies reported relationships (advisory panel, consulting, research support, and/or speaker’s bureau) with AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, MSD, Mitsubishi Tanabi Pharma, Novo Nordisk, Sanofi, and Servier.

sworcester@frontlinemedcom.com

ORLANDO – Patient-centered decision making and support, along with improved diet and exercise, constitute the foundation of all glycemic management, according to a draft consensus report on the management of hyperglycemia in patients with type 2 diabetes mellitus (T2DM).

Patients with ASCVD or heart failure

Given new evidence from trials such as EMPA-REG and LEADER showing outcomes benefits with the use of specific antihyperglycemic medications in patients with established atherosclerotic cardiovascular disease (ASCVD), an important early step in the proposed approach is to consider the presence or absence of ASCVD and heart failure, said Dr. Wexler of Massachusetts General Hospital, Boston.

“The presence of cardiovascular disease is a compelling indication for the selection of certain glucose-lowering drugs,” she said.

The draft consensus recommendation in this regard – a new recommendation since the last consensus report in 2015 – differentiates between T2DM patients in whom ASCVD predominates and those in whom heart failure predominates.

“What’s new since 2015 is that we recommend that these comorbidities be considered first and foremost because they do influence the choice of a particular glucose-lowering medication, and the recommendation is that, among patients with type 2 diabetes with established ASCVD, sodium-glucose cotransporter 2 [SGLT2] inhibitors or glucagonlike peptide 1 [GLP-1] receptor agonists with proven cardiovascular benefit are recommended as part of glycemic management,” she said.

However, it is important to note that ASCVD is defined differently across trials, and patients considered in the development of these recommendations are those with much higher cardiovascular risk than the average patient with T2DM, she added.

“It’s also important to keep in mind that each cardiovascular outcomes trial, while large, is but a single experiment ... and we don’t have the benefit of replication,” she said, noting that it is not always clear whether differences in trial findings within a drug class are related to trial design or true differences in individual medications.

“So we try to read into them and interpret these data, but it’s just important to consider that ... and when evidence suggests a hierarchy, we noted that,” she said.

That said, if ASCVD predominates, the recommendation is for treatment with either a GLP-1 receptor agonist with proven cardiovascular benefit (favoring liraglutide over semaglutide and over long-acting exenatide) or an SGLT2 inhibitor with proven cardiovascular benefit if estimated glomerular filtration (eGFR) is adequate (favoring empagliflozin over canagliflozin).

These recommendations are based on the LEADER trial finding of significant improvement in the primary outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with liraglutide vs. placebo (hazard ratio, 0.87; number needed to treat [NNT], 52 over 3.8 years) and on the EMPA-REG trial finding of significant improvement in the same primary outcome with empagliflozin vs. placebo (HR, 0.86; NNT, 62 over 3.1 years).

Keep in mind that there is no evidence of cardiovascular benefit from these treatments in patients at lower risk and also that the “expensive and complicated” combination of an SGLT2 inhibitor and a GLP-1 receptor agonist has not been tested in cardiovascular outcomes trials and there is no evidence of additional benefit from a cardiovascular perspective with this combination, Dr. Wexler said.

If heart failure predominates, the recommendations call for consideration of an SGLT2 inhibitor as part of the treatment strategy because patients with T2DM are at increased risk for heart failure with reduced or preserved ejection fraction and because significant, consistent reduction in hospitalizations for heart failure were seen in SGLT2 inhibitor trials, writing group member Peter Rossing, MD, explained during the session; he noted, however, that the trials were not designed to adjudicate heart failure and that most patients did not have clinical heart failure at baseline.

In those in whom SGLT2 inhibitors are contraindicated – because of impaired renal function, for example – a GLP-1 receptor agonist with proven cardiovascular benefit is recommended.

“Then we suggest that if you are still not at [hemoglobin A_1c] target, you should avoid thiazolidinediones [TZD] because of the risk of fluid overload, and you could then consider, if needed, combining an SGLT2-inhibitor and a GLP-1 receptor agonist ... or you could use a [dipeptidyl peptidase–4 (DPP-4) inhibitor] if you are not on an GLP-1 receptor agonist. And we point out that saxagliptin has unfavorable data on heart failure,” Dr. Rossing of Steno Diabetes Center, Copenhagen, said, noting that basal insulin or sulfonylurea are other alternative options.

In EMPA-REG, hospitalization for heart failure was reduced by 35% with empagliflozin vs. placebo (HR, 0.65; NNT, 71 over 3 years), and similar findings were seen in the CANVAS trial. In LEADER, a nonsignificant 13% reduction was seen in hospitalization for heart failure with liraglutide vs. placebo (HR, 0.87). However, this was a secondary outcome; ongoing studies are addressing heart failure as a primary outcome, Dr. Rossing said.

The report also includes a recommendation that, for patients with chronic kidney disease and high cardiovascular risk, GLP-1 receptor agonists and SGLT2 inhibitors can be used but with dose reductions for some medications – several of which have demonstrated renal benefit and cardiovascular benefits in those populations and can be considered as part of treatment.
 

Lifestyle management and medication

With respect to lifestyle management and pharmacologic treatment, the proposed recommendations, which are based on several large trials, state that an individualized program of medical nutritional therapy should be offered to all patients and that all overweight and obese patients with diabetes should be advised of the health benefits of weight loss. They also should be encouraged to engage in a program of intensive lifestyle management, which may include food substitution, writing group member Walter Kernan, MD, said at the meeting.

In the DiRECT Trial, the average weight loss was about 10 kg in an intervention group that had complete food replacement for 3 months followed by gradual food reintroduction and ongoing counseling versus about 1 kg in controls, and the diabetes remission rate at 1 year was 46% versus 4%, respectively, said Dr. Kernan of Yale University, New Haven, Conn.

In addition, intentional physical activity is known to improve glycemic control and should be encouraged in all patients with T2DM, he said.

“The foundation of hyperglycemia treatment in type 2 diabetes is, for sure, lifestyle modification,” said group member Geltrude Mingrone, MD, of Catholic University of the Sacred Heart in Rome. “Those patients who are very well motivated and adherent to the [recommendations] can achieve very good results,” she added.

In those in whom lifestyle modification fails to lead to adequate improvement, “a pretty large medication portfolio is available,” she said, adding that the choice of treatment should be based on safety, efficacy, cost, and convenience, factors which are described in the statement.

The hope is that the final consensus statement will make it easier to navigate them, she said.

Finally, bariatric surgery can be considered a very effective salvage therapy, Dr. Mingrone said, noting that only lifestyle modification or bariatric surgery will lead to diabetes remission.

The draft consensus recommendation for bariatric surgery is to consider it in patients with T2DM and a body mass index of 40 kg/m² or greater (37.5 or greater in those of Asian ancestry), regardless of the level of glycemic control, and in those with BMI of 35-39.9 (32.5-37.4 in those of Asian ancestry) when hyperglycemia is inadequately controlled despite lifestyle and optimal medical therapy.

Decision making and injectable therapies

The statement includes decision-making strategies and algorithms for treatment and addresses issues such as choosing antihyperglycemic medications when weight is a concern (consider an SGLT2 inhibitor or a GLP-1 receptor agonist with good efficacy for weight loss to start – or a combination of both if HbA_1c is not on target), when minimizing hypoglycemia is the priority (consider adding an SGLT2 inhibitors, GLP-1 receptor agonist, a TZD, or a DPP-4 inhibitor to metformin therapy to start, followed by reintensification of lifestyle modifications and combination therapies if HbA_1c is above target), and when drug costs need to be minimized, as well as when and how to initiate injectable therapies, according to writing group members David D’Alessio, MD, of Duke University, Durham, N.C, and Chantal Mathieu, MD, of Katholieke Universteit Leuven (Belgium).

The draft consensus recommendation regarding the latter is that, in patients who need the greater glucose-lowering effect of an injectable medication, GLP-1 receptor agonists should be considered as the first choice and that, when insulin is the medication of choice on the basis of clinical characteristics, basal insulin is preferred. Additionally, in patients who are unable to maintain glycemic targets on basal insulin in combination with oral medication, intensification with a GLP-1 receptor agonist, SGLT2 inhibitor, or prandial insulin can be considered.

This recommendation is based on “overwhelming evidence that GLP-1 receptor agonists give you HbA_1c lowering in the same range as basal insulin but can do so without hypoglycemia and with weight loss, in contrast to weight gain with most insulin preparations,” Dr. Mathieu noted.

The bottom line, however, is that “the patient is at the center of everything and ... should become an integral part of the team treating this patient,” Dr. Mathieu said.
 

Knowledge gaps

In a review of remaining knowledge gaps regarding glycemic control in T2DM, Dr. Buse said that, while the tools available to treat and prevent diabetes are vastly improved, implementation of effective innovation has lagged behind and “requires fundamental changes in health care policy and societal approaches to wellness.”

Additionally, the management of overweight and obesity is clearly inadequate and requires much greater emphasis on lifestyle techniques, behavioral approaches, medication, and surgery, said Dr. Buse, who is the Verne S. Caviness distinguished professor and chief of the division of endocrinology, as well as director of the Diabetes Center, at the University of North Carolina, Chapel Hill.

These and numerous other knowledge gaps (with respect to preserving and enhancing beta-cell function, incorporating personalized medicine, the value of combinations for additive benefit, the identification of biomarkers, the use of early intensive therapy, metabolic surgery decision making, the value of self-monitoring of blood glucose, and the need for better drugs – including those for the primary prevention of cardiovascular disease) need to be addressed and “require additional investment in basic, translational, clinical, and implementation research,” he said.

“More time- and cost-efficient research paradigms to address patient-centered endpoints are needed through regulatory reform and leveraging informatics and coordinated learning health care systems. Additionally, the increasing burden of cardiometabolic disease is an existential threat to society,” he said, stressing that “urgent attention to improve prevention and treatment is of the essence.”
 

Consensus statement development

The draft consensus statement is the work of group members selected by the ADA and EASD to ensure regional representation (five each from the United States and Europe). The group had two face-to-face meetings, as well as regular teleconferences; the members also conducted a “robust evidence review, which informed the content,” said group cochair Melanie J. Davies, MD, of the University of Leicester (U.K.).

The group reviewed randomized controlled trials, systematic reviews, and meta-analyses published from Jan. 1, 2014, (to capture research that may have been missed during development of the 2015 statement) through Feb. 28, 2018.

The process was based on consensus among members; areas of disagreement were voted on and the group proceeded according to 60% supermajority votes.

The updates were mainly based on research generated over the past 2 years, Dr. Davies said.

The final draft will be submitted for publication to Diabetes Care and Diabetologia.

Dr. Buse reported relationships (research support, stock ownership, and/or advisory roles) with Adocia, AstraZeneca, Boehringer Ingelheim, Dexcom, Elcelyx Therapeutics, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon Pharmaceuticals, Mellitus Health, Metavention, NovaTarg Therapeutics, Novo Nordisk, PhaseBio Pharmaceuticals, Sanofi, Senseonics, Theracos, and vTv Therapeutics; Dr. Wexler reported having no disclosures; Dr. Rossing reported relationships (consultancy and/or speaking fees, research grants, stock ownership) with AbbVie, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MDS Medical, Novo Nordisk, and Sanofi; Dr. Kernan reported having no disclosures; Dr. Mingrone is a consultant for Novo Nordisk, Fractyl, and Johnson & Johnson; Dr. D’Alessio reported advisory board membership with and/or research support from Eli Lilly, Intarcia Therapeutics, Merck, and Novo Nordisk; Dr. Mathieu reported relationships (advisory board membership, speaker’s bureau, and/or research support) with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Hanmi Pharmaceuticals, Intrexon, Janssen Pharmaceuticals, MannKind, Medtronic, Merck Sharp & Dohme (MSD), Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, Sanofi, and UCB; Dr. Davies reported relationships (advisory panel, consulting, research support, and/or speaker’s bureau) with AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, MSD, Mitsubishi Tanabi Pharma, Novo Nordisk, Sanofi, and Servier.

sworcester@frontlinemedcom.com

ORLANDO – Patient-centered decision making and support, along with improved diet and exercise, constitute the foundation of all glycemic management, according to a draft consensus report on the management of hyperglycemia in patients with type 2 diabetes mellitus (T2DM).

Patients with ASCVD or heart failure

Given new evidence from trials such as EMPA-REG and LEADER showing outcomes benefits with the use of specific antihyperglycemic medications in patients with established atherosclerotic cardiovascular disease (ASCVD), an important early step in the proposed approach is to consider the presence or absence of ASCVD and heart failure, said Dr. Wexler of Massachusetts General Hospital, Boston.

“The presence of cardiovascular disease is a compelling indication for the selection of certain glucose-lowering drugs,” she said.

The draft consensus recommendation in this regard – a new recommendation since the last consensus report in 2015 – differentiates between T2DM patients in whom ASCVD predominates and those in whom heart failure predominates.

“What’s new since 2015 is that we recommend that these comorbidities be considered first and foremost because they do influence the choice of a particular glucose-lowering medication, and the recommendation is that, among patients with type 2 diabetes with established ASCVD, sodium-glucose cotransporter 2 [SGLT2] inhibitors or glucagonlike peptide 1 [GLP-1] receptor agonists with proven cardiovascular benefit are recommended as part of glycemic management,” she said.

However, it is important to note that ASCVD is defined differently across trials, and patients considered in the development of these recommendations are those with much higher cardiovascular risk than the average patient with T2DM, she added.

“It’s also important to keep in mind that each cardiovascular outcomes trial, while large, is but a single experiment ... and we don’t have the benefit of replication,” she said, noting that it is not always clear whether differences in trial findings within a drug class are related to trial design or true differences in individual medications.

“So we try to read into them and interpret these data, but it’s just important to consider that ... and when evidence suggests a hierarchy, we noted that,” she said.

That said, if ASCVD predominates, the recommendation is for treatment with either a GLP-1 receptor agonist with proven cardiovascular benefit (favoring liraglutide over semaglutide and over long-acting exenatide) or an SGLT2 inhibitor with proven cardiovascular benefit if estimated glomerular filtration (eGFR) is adequate (favoring empagliflozin over canagliflozin).

These recommendations are based on the LEADER trial finding of significant improvement in the primary outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with liraglutide vs. placebo (hazard ratio, 0.87; number needed to treat [NNT], 52 over 3.8 years) and on the EMPA-REG trial finding of significant improvement in the same primary outcome with empagliflozin vs. placebo (HR, 0.86; NNT, 62 over 3.1 years).

Keep in mind that there is no evidence of cardiovascular benefit from these treatments in patients at lower risk and also that the “expensive and complicated” combination of an SGLT2 inhibitor and a GLP-1 receptor agonist has not been tested in cardiovascular outcomes trials and there is no evidence of additional benefit from a cardiovascular perspective with this combination, Dr. Wexler said.

If heart failure predominates, the recommendations call for consideration of an SGLT2 inhibitor as part of the treatment strategy because patients with T2DM are at increased risk for heart failure with reduced or preserved ejection fraction and because significant, consistent reduction in hospitalizations for heart failure were seen in SGLT2 inhibitor trials, writing group member Peter Rossing, MD, explained during the session; he noted, however, that the trials were not designed to adjudicate heart failure and that most patients did not have clinical heart failure at baseline.

In those in whom SGLT2 inhibitors are contraindicated – because of impaired renal function, for example – a GLP-1 receptor agonist with proven cardiovascular benefit is recommended.

“Then we suggest that if you are still not at [hemoglobin A_1c] target, you should avoid thiazolidinediones [TZD] because of the risk of fluid overload, and you could then consider, if needed, combining an SGLT2-inhibitor and a GLP-1 receptor agonist ... or you could use a [dipeptidyl peptidase–4 (DPP-4) inhibitor] if you are not on an GLP-1 receptor agonist. And we point out that saxagliptin has unfavorable data on heart failure,” Dr. Rossing of Steno Diabetes Center, Copenhagen, said, noting that basal insulin or sulfonylurea are other alternative options.

In EMPA-REG, hospitalization for heart failure was reduced by 35% with empagliflozin vs. placebo (HR, 0.65; NNT, 71 over 3 years), and similar findings were seen in the CANVAS trial. In LEADER, a nonsignificant 13% reduction was seen in hospitalization for heart failure with liraglutide vs. placebo (HR, 0.87). However, this was a secondary outcome; ongoing studies are addressing heart failure as a primary outcome, Dr. Rossing said.

The report also includes a recommendation that, for patients with chronic kidney disease and high cardiovascular risk, GLP-1 receptor agonists and SGLT2 inhibitors can be used but with dose reductions for some medications – several of which have demonstrated renal benefit and cardiovascular benefits in those populations and can be considered as part of treatment.
 

Lifestyle management and medication

With respect to lifestyle management and pharmacologic treatment, the proposed recommendations, which are based on several large trials, state that an individualized program of medical nutritional therapy should be offered to all patients and that all overweight and obese patients with diabetes should be advised of the health benefits of weight loss. They also should be encouraged to engage in a program of intensive lifestyle management, which may include food substitution, writing group member Walter Kernan, MD, said at the meeting.

In the DiRECT Trial, the average weight loss was about 10 kg in an intervention group that had complete food replacement for 3 months followed by gradual food reintroduction and ongoing counseling versus about 1 kg in controls, and the diabetes remission rate at 1 year was 46% versus 4%, respectively, said Dr. Kernan of Yale University, New Haven, Conn.

In addition, intentional physical activity is known to improve glycemic control and should be encouraged in all patients with T2DM, he said.

“The foundation of hyperglycemia treatment in type 2 diabetes is, for sure, lifestyle modification,” said group member Geltrude Mingrone, MD, of Catholic University of the Sacred Heart in Rome. “Those patients who are very well motivated and adherent to the [recommendations] can achieve very good results,” she added.

In those in whom lifestyle modification fails to lead to adequate improvement, “a pretty large medication portfolio is available,” she said, adding that the choice of treatment should be based on safety, efficacy, cost, and convenience, factors which are described in the statement.

The hope is that the final consensus statement will make it easier to navigate them, she said.

Finally, bariatric surgery can be considered a very effective salvage therapy, Dr. Mingrone said, noting that only lifestyle modification or bariatric surgery will lead to diabetes remission.

The draft consensus recommendation for bariatric surgery is to consider it in patients with T2DM and a body mass index of 40 kg/m² or greater (37.5 or greater in those of Asian ancestry), regardless of the level of glycemic control, and in those with BMI of 35-39.9 (32.5-37.4 in those of Asian ancestry) when hyperglycemia is inadequately controlled despite lifestyle and optimal medical therapy.

Decision making and injectable therapies

The statement includes decision-making strategies and algorithms for treatment and addresses issues such as choosing antihyperglycemic medications when weight is a concern (consider an SGLT2 inhibitor or a GLP-1 receptor agonist with good efficacy for weight loss to start – or a combination of both if HbA_1c is not on target), when minimizing hypoglycemia is the priority (consider adding an SGLT2 inhibitors, GLP-1 receptor agonist, a TZD, or a DPP-4 inhibitor to metformin therapy to start, followed by reintensification of lifestyle modifications and combination therapies if HbA_1c is above target), and when drug costs need to be minimized, as well as when and how to initiate injectable therapies, according to writing group members David D’Alessio, MD, of Duke University, Durham, N.C, and Chantal Mathieu, MD, of Katholieke Universteit Leuven (Belgium).

The draft consensus recommendation regarding the latter is that, in patients who need the greater glucose-lowering effect of an injectable medication, GLP-1 receptor agonists should be considered as the first choice and that, when insulin is the medication of choice on the basis of clinical characteristics, basal insulin is preferred. Additionally, in patients who are unable to maintain glycemic targets on basal insulin in combination with oral medication, intensification with a GLP-1 receptor agonist, SGLT2 inhibitor, or prandial insulin can be considered.

This recommendation is based on “overwhelming evidence that GLP-1 receptor agonists give you HbA_1c lowering in the same range as basal insulin but can do so without hypoglycemia and with weight loss, in contrast to weight gain with most insulin preparations,” Dr. Mathieu noted.

The bottom line, however, is that “the patient is at the center of everything and ... should become an integral part of the team treating this patient,” Dr. Mathieu said.
 

Knowledge gaps

In a review of remaining knowledge gaps regarding glycemic control in T2DM, Dr. Buse said that, while the tools available to treat and prevent diabetes are vastly improved, implementation of effective innovation has lagged behind and “requires fundamental changes in health care policy and societal approaches to wellness.”

Additionally, the management of overweight and obesity is clearly inadequate and requires much greater emphasis on lifestyle techniques, behavioral approaches, medication, and surgery, said Dr. Buse, who is the Verne S. Caviness distinguished professor and chief of the division of endocrinology, as well as director of the Diabetes Center, at the University of North Carolina, Chapel Hill.

These and numerous other knowledge gaps (with respect to preserving and enhancing beta-cell function, incorporating personalized medicine, the value of combinations for additive benefit, the identification of biomarkers, the use of early intensive therapy, metabolic surgery decision making, the value of self-monitoring of blood glucose, and the need for better drugs – including those for the primary prevention of cardiovascular disease) need to be addressed and “require additional investment in basic, translational, clinical, and implementation research,” he said.

“More time- and cost-efficient research paradigms to address patient-centered endpoints are needed through regulatory reform and leveraging informatics and coordinated learning health care systems. Additionally, the increasing burden of cardiometabolic disease is an existential threat to society,” he said, stressing that “urgent attention to improve prevention and treatment is of the essence.”
 

Consensus statement development

The draft consensus statement is the work of group members selected by the ADA and EASD to ensure regional representation (five each from the United States and Europe). The group had two face-to-face meetings, as well as regular teleconferences; the members also conducted a “robust evidence review, which informed the content,” said group cochair Melanie J. Davies, MD, of the University of Leicester (U.K.).

The group reviewed randomized controlled trials, systematic reviews, and meta-analyses published from Jan. 1, 2014, (to capture research that may have been missed during development of the 2015 statement) through Feb. 28, 2018.

The process was based on consensus among members; areas of disagreement were voted on and the group proceeded according to 60% supermajority votes.

The updates were mainly based on research generated over the past 2 years, Dr. Davies said.

The final draft will be submitted for publication to Diabetes Care and Diabetologia.

Dr. Buse reported relationships (research support, stock ownership, and/or advisory roles) with Adocia, AstraZeneca, Boehringer Ingelheim, Dexcom, Elcelyx Therapeutics, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon Pharmaceuticals, Mellitus Health, Metavention, NovaTarg Therapeutics, Novo Nordisk, PhaseBio Pharmaceuticals, Sanofi, Senseonics, Theracos, and vTv Therapeutics; Dr. Wexler reported having no disclosures; Dr. Rossing reported relationships (consultancy and/or speaking fees, research grants, stock ownership) with AbbVie, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MDS Medical, Novo Nordisk, and Sanofi; Dr. Kernan reported having no disclosures; Dr. Mingrone is a consultant for Novo Nordisk, Fractyl, and Johnson & Johnson; Dr. D’Alessio reported advisory board membership with and/or research support from Eli Lilly, Intarcia Therapeutics, Merck, and Novo Nordisk; Dr. Mathieu reported relationships (advisory board membership, speaker’s bureau, and/or research support) with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Hanmi Pharmaceuticals, Intrexon, Janssen Pharmaceuticals, MannKind, Medtronic, Merck Sharp & Dohme (MSD), Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, Sanofi, and UCB; Dr. Davies reported relationships (advisory panel, consulting, research support, and/or speaker’s bureau) with AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, MSD, Mitsubishi Tanabi Pharma, Novo Nordisk, Sanofi, and Servier.

sworcester@frontlinemedcom.com

ORLANDO – Improvements in cardiovascular and renal outcomes seen after nearly 10 years of improved glucose control among participants in the Veterans Affairs Diabetes Trial (VADT) who received intensive glucose-lowering therapy dissipated by year 15, according to final results from the VADT follow-up study (VADT-F).

Participants in the randomized, controlled VADT, which compared the effects of intensive versus standard glucose control in more than 1,700 patients with type 2 diabetes mellitus (T2DM), did not experience a significant improvement in the primary cardiovascular disease (CVD) outcome – a composite of myocardial infarction, stroke, cardiovascular death, new congestive heart failure, cardiovascular surgery or inoperable coronary artery disease, and ischemic amputation – after a median of 5.6 years of active treatment (hazard ratio, 0.88; P = .14). Nor did they experience significant improvement in secondary cardiovascular outcomes, including cardiovascular death and death from any cause (HRs, 1.32 and 1.07, respectively), or in a renal composite outcome (HR, 0.85), according to the findings published in 2009 (N Engl J Med. 2009 Jan 8;360[2]:129-39).

This was despite a rapid and statistically significant separation of hemoglobin A_1c (HbA_1c) levels between the treatment groups, Peter Reaven, MD, noted during a presentation of the final follow-up data at the annual scientific sessions of the American Diabetes Association.

Approximately 6 months after the start of the VADT, median HbA_1c levels decreased from more than 9% in both groups to 6.9% and 8.4% in intensive and standard treatment groups, respectively (a median separation of 1.5%), said Dr. Reaven, director of the diabetes research program at the Phoenix VA Health Care System and a professor of clinical medicine at the University of Arizona in Phoenix.

“This was maintained throughout the study period,” he said. “All other risk factors during this period of time were equal between the two treatment groups.”
 

10-year outcomes

However, 10-year interim data from VADT-F, published in the New England Journal of Medicine (2015 Jun 4;372[23]:2197-206), showed a delayed benefit in these outcomes among those in the intensive control group: The incidence of the primary CVD composite outcome was reduced by 17% (HR, 0.83; P = .04) in favor of the intensive therapy at that time, Dr. Reaven said.

The incidence of the renal composite outcome, which included estimated glomerular filtration rate less than 54 mL/min per 1.73m², sustained macroalbuminuria, and end-stage renal disease, was reduced by 32% (HR, 0.68; P = .008), said Nicholas Emanuele, MD, who presented the VADT-F renal and microvascular outcomes at the ADA meeting.

At that 10-year follow-up, HbA_1c levels in the intensive and standard treatment groups had nearly equalized (although they remained slightly better in the intensive treatment group), and eventually, the levels stabilized at about 8.2% in both groups through the end of the 15-year follow-up, the investigators said.

“So it was still lower by nearly 1.2 hemoglobin percent units, compared to baseline values nearly 15 years earlier, and despite ending the study in very good control, after we released these patients to the primary care providers for their diabetes care, there was a substantial rise in HbA_1c levels over time ... illustrating the difficulty of controlling HbA_1c values to this level in this advanced diabetes population,” Dr. Reaven said.
 

15-year outcomes

At the final 15-year follow up, with the HbA_1c levels similar in the groups, nearly all benefits seen at 10 years were lost. Event rates for the CVD primary composite outcome were 51.8 and 47.3 per 1,000 patient-years in the intensive care and standard care groups, respectively (HR, 0.91; P = .23), and event rates for the renal composite outcome were 88 and 85 per 1,000 patient-years (HR, 0.90; P = .55).

Similarly, no differences were seen at 15 years in the secondary VADT-F outcomes of any major diabetes outcome, (HR, 0.90; P = .16), cardiovascular death (HR, 0.94; P = .61), or death from any cause (HR 1.02; P = .81), and no differences were seen in the individual components of the composite outcomes, the investigators said.

The same was true for other outcomes, including hospitalizations and health-related quality of life, Dr. Reaven said.

Ocular events studied in the VADT-F included cataract extraction, laster photocoagulation, vitrectomy, and intravitreal injections, with the latter three constituting a retinal event composite for which there was a difference of “very borderline significance (HR, 0.84; P = .053),” said Dr. Emanuele of Hines (Ill.) VA Hospital and Loyola University of Chicago.

There was no difference between groups for cataract extraction. (HR, 1.16; P = .30) or in participants’ self reported vision at 15 years, he added.

Additional analyses showed that there were no treatment interactions for results based on baseline differences in diabetes duration, prior CV events, or risk scores.

In essence, there was no evidence of a legacy effect, Dr. Reaven said, noting that the findings are “relatively consistent” with those from other recent glucose-lowering trials, including ACCORDION and ADVANCE-ON, which also showed no legacy benefits of intensive glucose lowering.

Dr. Emanuele also concluded that no prolonged legacy effect was apparent for renal and other microvascular outcomes.

The lack of a legacy effect at 15 years, however, shouldn’t discount the benefits seen at the 10-year follow-up because there are other ways to look at “legacy,” Hertzel C. Gerstein, MD, said during an independent “clinical perspective” commentary on the VADT and VADT-F findings.

“Another way to define ‘legacy’ is what happens after the active clinical trial ends, and if you think of it that way, there is a legacy,” said Dr. Gerstein, a professor and Population Health Institute chair in diabetes research at McMaster University and Hamilton Health Sciences, Ontario, Canada.

That is, the intensive glycemic control led to significant improvements at 10-year follow-up. While he acknowledged “that’s just semantics,” he stressed that a number of important lessons have been learned from the VADT and VADT-F – not the least of which relate to mediation analyses that showed the benefit seen at 10 years can be explained, at least statistically, by the differences in HbA_1c levels achieved during those intervening 10 years of follow-up.

For example, the 10-year cardiovascular outcome hazard ratios changed from 0.83 with a P value of .04 to 0.86 with a P value of .12 (after controlling for time-varying HbA_1c levels) and to 0.94 with a P value of .53 (after controlling for time-varying cumulative mean HbA_1c), he said, noting that similar findings have been reported from prior trials.

The VADT was designed to evaluate whether an intensive glycemic control regimen could reduce the incidence of major cardiovascular events compared with standard care in patients with T2DM; secondary objectives included differences in additional cardiovascular, renal, and other outcomes.

Subjects, who were enrolled from 20 VA medical centers beginning in December 2000, were aged 41 years or older (mean of about 60 years) and had failed to respond to a maximum dose of at least one oral agent and/or daily insulin. Patients were excluded if they had HbA_1c less than 7.5%, had had a cardiovascular event in the previous 6 months, had advanced congestive heart failure, had severe angina, had a life expectancy of less than 7 years, had a body mass index over 40 kg/m², had serum creatinine less than 1.6 mg/dL, or had an alanine transaminase level greater than 3 times the upper limit of normal, according to Wyndy L. Wiitala, PhD, of the VA Center for Clinical Management Research in Ann Arbor, Michigan.

A total of 818 patients in the standard care group and 837 in the intensive treatment group completed the study with up to 7.5 years of total follow-up (median, 5.6 years). The groups were similar in age; both were mostly male, which is expected for a VA population; and the average HbA_1c level was 9.4% in both groups. Other clinical measures, including lipids, blood pressure, and estimated cardiovascular risk were also similar between the two groups.

“The VADT was designed so that the only planned difference between the treatment groups was the level of glycemic control,” Dr. Wiitala said.

All patients with a BMI of 27 kg/m² or greater were started on metformin plus rosiglitazone, and those with a BMI less than 27 kg/m² were started on glimepiride plus rosiglitazone. Those in the intensive therapy arm were started on maximal doses, and those in the standard therapy arm were started on half the maximal doses. Insulin was added for patients in the intensive-therapy group who did not achieve HbA_1c below 6%, as well as for those in the standard-therapy group with a level of less than 9%.

Any subsequent medication changes were determined according to protocol guidelines and local assessment, and investigators were allowed to use any approved drug at their discretion.

“The use of medications between the two groups was similar, with differences in dose and insulin intensity only,” Dr. Wiitala said, adding that all other aspects of treatment, including blood pressure control, lipid control, aspirin therapy, diet, and nutrition, were “nearly identical” in the two groups.



The VADT-F design

The negative findings from the VADT raised “a number of questions, which really provided the rationale for the VADT follow-up study,” Dr. Reaven said.

“Would the post-VADT follow-up reveal an emerging cardiovascular benefit? This was particularly relevant as there was an indication that the group differences were increasing toward the end of the study, and benefits in cardiovascular outcomes, as we know, take a fair amount of time,” he said, adding that since the glucose separation seen in the treatment groups was greater than that seen in other recent studies involving patients with advanced T2DM and remained that way for an extended period of time, the follow-up study provided an excellent opportunity to examine whether there was a legacy or other effects.

The VADT-F continued to follow the VADT patients after the intervention ended in 2008; at that time, patients returned to normal care with no further intervention by the research team, Dr. Wiitala said, noting that participants were followed using national data sources, annual mail surveys, and targeted chart reviews.

The 10-year interim analysis was reported in 2015, and the 15-year final analysis, which is currently under review, represents the longest follow-up of patients with advanced T2DM with high risk for cardiovascular disease, she said.

“These results suggest that there are modest long-term cardiovascular disease benefits of therapies directed toward bringing glucose control to near-normal range in high-risk type 2 diabetes and that substantial and continuous glucose separation may be required to maintain these improvements,” Dr. Reaven concluded, adding that “recent studies demonstrating cardiovascular benefit with diabetes agents that only achieve modest improvements in glycemic control highlight the importance of also considering nonglycemic approaches to reducing cardiovascular disease events and mortality in these patients.”

Similarly, Dr. Emanuele concluded that there is a delayed beneficial effect of intensive glycemic control on kidney outcomes but that the effect dissipates as glycemic separation wanes.

However, in his commentary at the meeting, Dr. Gerstein stressed that the findings add value; in addition to showing, via mediation analyses, that HbA_1c levels statistically explain the differences seen between the intensive and standard therapy arms at 10 years, the VADT and VADT-F findings also underscore the veracity of the ADA’s recommended target of HbA_1c less than 7%, albeit “with all sorts of caveats.”

“But one point to make is that clinical trials do not tell you how to treat the patient in front of you. [They] just tell you what works on average for the average patient. ... You have to take the information you get from randomized trials and put it into your brain as a doctor and treat the patient,” he said.

He and several colleagues further explained this concept in a recent editorial (Diabetes Care. 2018 Jun;41[6]:1121-4) penned in response to new guidance statements published by the American College of Physicians advocating for relaxation of HbA_1c control goals in patients with T2DM.

“The ACP proposal may encourage a step backward at a time when accumulating evidence from randomized, controlled trials calls for movement forward in the treatment of diabetes,” they wrote in the editorial entitled “A_1c targets should be personalized to maximize benefits while limiting risks.”

Findings from those trials, including the VADT and VADT-F, continue to increase diabetes insights and inform care, and while there is not yet a statin-like “prescribe-and-go” treatment for diabetes, the findings represent a step in the right direction, Dr Gerstein said.

“All you have to do is look at all the clinical trials that are happening. We’re going to get there. ... This is not the end of the end, this is the beginning of the next phase,” he said.

The VADT and VADT-F were funded by the VA Cooperative Studies Program, the ADA, and the National Institutes of Health/National Eye Institute. Medication and additional support were provided by Aventis, GlaxoSmithKline, and Novo Nordisk Pharmaceuticals, which provided funding and supplies, and by Abbott Laboratory, Amylin, Eli Lily, Kos, Roche, and the University of Chicago, which also provided supplies. Dr. Reaven is an advisory panel member for Sanofi and has received research support from AstraZeneca and Novo Nordisk. Dr. Gerstein has received grants or other research support, honoraria, and/or consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Novo Nordisk, and Sanofi. Dr. Wiitala and Dr. Emanuele reported having no disclosures.

sworcester@mdedge.com

ORLANDO – Improvements in cardiovascular and renal outcomes seen after nearly 10 years of improved glucose control among participants in the Veterans Affairs Diabetes Trial (VADT) who received intensive glucose-lowering therapy dissipated by year 15, according to final results from the VADT follow-up study (VADT-F).

Participants in the randomized, controlled VADT, which compared the effects of intensive versus standard glucose control in more than 1,700 patients with type 2 diabetes mellitus (T2DM), did not experience a significant improvement in the primary cardiovascular disease (CVD) outcome – a composite of myocardial infarction, stroke, cardiovascular death, new congestive heart failure, cardiovascular surgery or inoperable coronary artery disease, and ischemic amputation – after a median of 5.6 years of active treatment (hazard ratio, 0.88; P = .14). Nor did they experience significant improvement in secondary cardiovascular outcomes, including cardiovascular death and death from any cause (HRs, 1.32 and 1.07, respectively), or in a renal composite outcome (HR, 0.85), according to the findings published in 2009 (N Engl J Med. 2009 Jan 8;360[2]:129-39).

This was despite a rapid and statistically significant separation of hemoglobin A_1c (HbA_1c) levels between the treatment groups, Peter Reaven, MD, noted during a presentation of the final follow-up data at the annual scientific sessions of the American Diabetes Association.

Approximately 6 months after the start of the VADT, median HbA_1c levels decreased from more than 9% in both groups to 6.9% and 8.4% in intensive and standard treatment groups, respectively (a median separation of 1.5%), said Dr. Reaven, director of the diabetes research program at the Phoenix VA Health Care System and a professor of clinical medicine at the University of Arizona in Phoenix.

“This was maintained throughout the study period,” he said. “All other risk factors during this period of time were equal between the two treatment groups.”
 

10-year outcomes

However, 10-year interim data from VADT-F, published in the New England Journal of Medicine (2015 Jun 4;372[23]:2197-206), showed a delayed benefit in these outcomes among those in the intensive control group: The incidence of the primary CVD composite outcome was reduced by 17% (HR, 0.83; P = .04) in favor of the intensive therapy at that time, Dr. Reaven said.

The incidence of the renal composite outcome, which included estimated glomerular filtration rate less than 54 mL/min per 1.73m², sustained macroalbuminuria, and end-stage renal disease, was reduced by 32% (HR, 0.68; P = .008), said Nicholas Emanuele, MD, who presented the VADT-F renal and microvascular outcomes at the ADA meeting.

At that 10-year follow-up, HbA_1c levels in the intensive and standard treatment groups had nearly equalized (although they remained slightly better in the intensive treatment group), and eventually, the levels stabilized at about 8.2% in both groups through the end of the 15-year follow-up, the investigators said.

“So it was still lower by nearly 1.2 hemoglobin percent units, compared to baseline values nearly 15 years earlier, and despite ending the study in very good control, after we released these patients to the primary care providers for their diabetes care, there was a substantial rise in HbA_1c levels over time ... illustrating the difficulty of controlling HbA_1c values to this level in this advanced diabetes population,” Dr. Reaven said.
 

15-year outcomes

At the final 15-year follow up, with the HbA_1c levels similar in the groups, nearly all benefits seen at 10 years were lost. Event rates for the CVD primary composite outcome were 51.8 and 47.3 per 1,000 patient-years in the intensive care and standard care groups, respectively (HR, 0.91; P = .23), and event rates for the renal composite outcome were 88 and 85 per 1,000 patient-years (HR, 0.90; P = .55).

Similarly, no differences were seen at 15 years in the secondary VADT-F outcomes of any major diabetes outcome, (HR, 0.90; P = .16), cardiovascular death (HR, 0.94; P = .61), or death from any cause (HR 1.02; P = .81), and no differences were seen in the individual components of the composite outcomes, the investigators said.

The same was true for other outcomes, including hospitalizations and health-related quality of life, Dr. Reaven said.

Ocular events studied in the VADT-F included cataract extraction, laster photocoagulation, vitrectomy, and intravitreal injections, with the latter three constituting a retinal event composite for which there was a difference of “very borderline significance (HR, 0.84; P = .053),” said Dr. Emanuele of Hines (Ill.) VA Hospital and Loyola University of Chicago.

There was no difference between groups for cataract extraction. (HR, 1.16; P = .30) or in participants’ self reported vision at 15 years, he added.

Additional analyses showed that there were no treatment interactions for results based on baseline differences in diabetes duration, prior CV events, or risk scores.

In essence, there was no evidence of a legacy effect, Dr. Reaven said, noting that the findings are “relatively consistent” with those from other recent glucose-lowering trials, including ACCORDION and ADVANCE-ON, which also showed no legacy benefits of intensive glucose lowering.

Dr. Emanuele also concluded that no prolonged legacy effect was apparent for renal and other microvascular outcomes.

The lack of a legacy effect at 15 years, however, shouldn’t discount the benefits seen at the 10-year follow-up because there are other ways to look at “legacy,” Hertzel C. Gerstein, MD, said during an independent “clinical perspective” commentary on the VADT and VADT-F findings.

“Another way to define ‘legacy’ is what happens after the active clinical trial ends, and if you think of it that way, there is a legacy,” said Dr. Gerstein, a professor and Population Health Institute chair in diabetes research at McMaster University and Hamilton Health Sciences, Ontario, Canada.

That is, the intensive glycemic control led to significant improvements at 10-year follow-up. While he acknowledged “that’s just semantics,” he stressed that a number of important lessons have been learned from the VADT and VADT-F – not the least of which relate to mediation analyses that showed the benefit seen at 10 years can be explained, at least statistically, by the differences in HbA_1c levels achieved during those intervening 10 years of follow-up.

For example, the 10-year cardiovascular outcome hazard ratios changed from 0.83 with a P value of .04 to 0.86 with a P value of .12 (after controlling for time-varying HbA_1c levels) and to 0.94 with a P value of .53 (after controlling for time-varying cumulative mean HbA_1c), he said, noting that similar findings have been reported from prior trials.

The VADT was designed to evaluate whether an intensive glycemic control regimen could reduce the incidence of major cardiovascular events compared with standard care in patients with T2DM; secondary objectives included differences in additional cardiovascular, renal, and other outcomes.

Subjects, who were enrolled from 20 VA medical centers beginning in December 2000, were aged 41 years or older (mean of about 60 years) and had failed to respond to a maximum dose of at least one oral agent and/or daily insulin. Patients were excluded if they had HbA_1c less than 7.5%, had had a cardiovascular event in the previous 6 months, had advanced congestive heart failure, had severe angina, had a life expectancy of less than 7 years, had a body mass index over 40 kg/m², had serum creatinine less than 1.6 mg/dL, or had an alanine transaminase level greater than 3 times the upper limit of normal, according to Wyndy L. Wiitala, PhD, of the VA Center for Clinical Management Research in Ann Arbor, Michigan.

A total of 818 patients in the standard care group and 837 in the intensive treatment group completed the study with up to 7.5 years of total follow-up (median, 5.6 years). The groups were similar in age; both were mostly male, which is expected for a VA population; and the average HbA_1c level was 9.4% in both groups. Other clinical measures, including lipids, blood pressure, and estimated cardiovascular risk were also similar between the two groups.

“The VADT was designed so that the only planned difference between the treatment groups was the level of glycemic control,” Dr. Wiitala said.

All patients with a BMI of 27 kg/m² or greater were started on metformin plus rosiglitazone, and those with a BMI less than 27 kg/m² were started on glimepiride plus rosiglitazone. Those in the intensive therapy arm were started on maximal doses, and those in the standard therapy arm were started on half the maximal doses. Insulin was added for patients in the intensive-therapy group who did not achieve HbA_1c below 6%, as well as for those in the standard-therapy group with a level of less than 9%.

Any subsequent medication changes were determined according to protocol guidelines and local assessment, and investigators were allowed to use any approved drug at their discretion.

“The use of medications between the two groups was similar, with differences in dose and insulin intensity only,” Dr. Wiitala said, adding that all other aspects of treatment, including blood pressure control, lipid control, aspirin therapy, diet, and nutrition, were “nearly identical” in the two groups.



The VADT-F design

The negative findings from the VADT raised “a number of questions, which really provided the rationale for the VADT follow-up study,” Dr. Reaven said.

“Would the post-VADT follow-up reveal an emerging cardiovascular benefit? This was particularly relevant as there was an indication that the group differences were increasing toward the end of the study, and benefits in cardiovascular outcomes, as we know, take a fair amount of time,” he said, adding that since the glucose separation seen in the treatment groups was greater than that seen in other recent studies involving patients with advanced T2DM and remained that way for an extended period of time, the follow-up study provided an excellent opportunity to examine whether there was a legacy or other effects.

The VADT-F continued to follow the VADT patients after the intervention ended in 2008; at that time, patients returned to normal care with no further intervention by the research team, Dr. Wiitala said, noting that participants were followed using national data sources, annual mail surveys, and targeted chart reviews.

The 10-year interim analysis was reported in 2015, and the 15-year final analysis, which is currently under review, represents the longest follow-up of patients with advanced T2DM with high risk for cardiovascular disease, she said.

“These results suggest that there are modest long-term cardiovascular disease benefits of therapies directed toward bringing glucose control to near-normal range in high-risk type 2 diabetes and that substantial and continuous glucose separation may be required to maintain these improvements,” Dr. Reaven concluded, adding that “recent studies demonstrating cardiovascular benefit with diabetes agents that only achieve modest improvements in glycemic control highlight the importance of also considering nonglycemic approaches to reducing cardiovascular disease events and mortality in these patients.”

Similarly, Dr. Emanuele concluded that there is a delayed beneficial effect of intensive glycemic control on kidney outcomes but that the effect dissipates as glycemic separation wanes.

However, in his commentary at the meeting, Dr. Gerstein stressed that the findings add value; in addition to showing, via mediation analyses, that HbA_1c levels statistically explain the differences seen between the intensive and standard therapy arms at 10 years, the VADT and VADT-F findings also underscore the veracity of the ADA’s recommended target of HbA_1c less than 7%, albeit “with all sorts of caveats.”

“But one point to make is that clinical trials do not tell you how to treat the patient in front of you. [They] just tell you what works on average for the average patient. ... You have to take the information you get from randomized trials and put it into your brain as a doctor and treat the patient,” he said.

He and several colleagues further explained this concept in a recent editorial (Diabetes Care. 2018 Jun;41[6]:1121-4) penned in response to new guidance statements published by the American College of Physicians advocating for relaxation of HbA_1c control goals in patients with T2DM.

“The ACP proposal may encourage a step backward at a time when accumulating evidence from randomized, controlled trials calls for movement forward in the treatment of diabetes,” they wrote in the editorial entitled “A_1c targets should be personalized to maximize benefits while limiting risks.”

Findings from those trials, including the VADT and VADT-F, continue to increase diabetes insights and inform care, and while there is not yet a statin-like “prescribe-and-go” treatment for diabetes, the findings represent a step in the right direction, Dr Gerstein said.

“All you have to do is look at all the clinical trials that are happening. We’re going to get there. ... This is not the end of the end, this is the beginning of the next phase,” he said.

The VADT and VADT-F were funded by the VA Cooperative Studies Program, the ADA, and the National Institutes of Health/National Eye Institute. Medication and additional support were provided by Aventis, GlaxoSmithKline, and Novo Nordisk Pharmaceuticals, which provided funding and supplies, and by Abbott Laboratory, Amylin, Eli Lily, Kos, Roche, and the University of Chicago, which also provided supplies. Dr. Reaven is an advisory panel member for Sanofi and has received research support from AstraZeneca and Novo Nordisk. Dr. Gerstein has received grants or other research support, honoraria, and/or consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Novo Nordisk, and Sanofi. Dr. Wiitala and Dr. Emanuele reported having no disclosures.

sworcester@mdedge.com

ORLANDO – Improvements in cardiovascular and renal outcomes seen after nearly 10 years of improved glucose control among participants in the Veterans Affairs Diabetes Trial (VADT) who received intensive glucose-lowering therapy dissipated by year 15, according to final results from the VADT follow-up study (VADT-F).

Participants in the randomized, controlled VADT, which compared the effects of intensive versus standard glucose control in more than 1,700 patients with type 2 diabetes mellitus (T2DM), did not experience a significant improvement in the primary cardiovascular disease (CVD) outcome – a composite of myocardial infarction, stroke, cardiovascular death, new congestive heart failure, cardiovascular surgery or inoperable coronary artery disease, and ischemic amputation – after a median of 5.6 years of active treatment (hazard ratio, 0.88; P = .14). Nor did they experience significant improvement in secondary cardiovascular outcomes, including cardiovascular death and death from any cause (HRs, 1.32 and 1.07, respectively), or in a renal composite outcome (HR, 0.85), according to the findings published in 2009 (N Engl J Med. 2009 Jan 8;360[2]:129-39).

This was despite a rapid and statistically significant separation of hemoglobin A_1c (HbA_1c) levels between the treatment groups, Peter Reaven, MD, noted during a presentation of the final follow-up data at the annual scientific sessions of the American Diabetes Association.

Approximately 6 months after the start of the VADT, median HbA_1c levels decreased from more than 9% in both groups to 6.9% and 8.4% in intensive and standard treatment groups, respectively (a median separation of 1.5%), said Dr. Reaven, director of the diabetes research program at the Phoenix VA Health Care System and a professor of clinical medicine at the University of Arizona in Phoenix.

“This was maintained throughout the study period,” he said. “All other risk factors during this period of time were equal between the two treatment groups.”
 

10-year outcomes

However, 10-year interim data from VADT-F, published in the New England Journal of Medicine (2015 Jun 4;372[23]:2197-206), showed a delayed benefit in these outcomes among those in the intensive control group: The incidence of the primary CVD composite outcome was reduced by 17% (HR, 0.83; P = .04) in favor of the intensive therapy at that time, Dr. Reaven said.

The incidence of the renal composite outcome, which included estimated glomerular filtration rate less than 54 mL/min per 1.73m², sustained macroalbuminuria, and end-stage renal disease, was reduced by 32% (HR, 0.68; P = .008), said Nicholas Emanuele, MD, who presented the VADT-F renal and microvascular outcomes at the ADA meeting.

At that 10-year follow-up, HbA_1c levels in the intensive and standard treatment groups had nearly equalized (although they remained slightly better in the intensive treatment group), and eventually, the levels stabilized at about 8.2% in both groups through the end of the 15-year follow-up, the investigators said.

“So it was still lower by nearly 1.2 hemoglobin percent units, compared to baseline values nearly 15 years earlier, and despite ending the study in very good control, after we released these patients to the primary care providers for their diabetes care, there was a substantial rise in HbA_1c levels over time ... illustrating the difficulty of controlling HbA_1c values to this level in this advanced diabetes population,” Dr. Reaven said.
 

15-year outcomes

At the final 15-year follow up, with the HbA_1c levels similar in the groups, nearly all benefits seen at 10 years were lost. Event rates for the CVD primary composite outcome were 51.8 and 47.3 per 1,000 patient-years in the intensive care and standard care groups, respectively (HR, 0.91; P = .23), and event rates for the renal composite outcome were 88 and 85 per 1,000 patient-years (HR, 0.90; P = .55).

Similarly, no differences were seen at 15 years in the secondary VADT-F outcomes of any major diabetes outcome, (HR, 0.90; P = .16), cardiovascular death (HR, 0.94; P = .61), or death from any cause (HR 1.02; P = .81), and no differences were seen in the individual components of the composite outcomes, the investigators said.

The same was true for other outcomes, including hospitalizations and health-related quality of life, Dr. Reaven said.

Ocular events studied in the VADT-F included cataract extraction, laster photocoagulation, vitrectomy, and intravitreal injections, with the latter three constituting a retinal event composite for which there was a difference of “very borderline significance (HR, 0.84; P = .053),” said Dr. Emanuele of Hines (Ill.) VA Hospital and Loyola University of Chicago.

There was no difference between groups for cataract extraction. (HR, 1.16; P = .30) or in participants’ self reported vision at 15 years, he added.

Additional analyses showed that there were no treatment interactions for results based on baseline differences in diabetes duration, prior CV events, or risk scores.

In essence, there was no evidence of a legacy effect, Dr. Reaven said, noting that the findings are “relatively consistent” with those from other recent glucose-lowering trials, including ACCORDION and ADVANCE-ON, which also showed no legacy benefits of intensive glucose lowering.

Dr. Emanuele also concluded that no prolonged legacy effect was apparent for renal and other microvascular outcomes.

The lack of a legacy effect at 15 years, however, shouldn’t discount the benefits seen at the 10-year follow-up because there are other ways to look at “legacy,” Hertzel C. Gerstein, MD, said during an independent “clinical perspective” commentary on the VADT and VADT-F findings.

“Another way to define ‘legacy’ is what happens after the active clinical trial ends, and if you think of it that way, there is a legacy,” said Dr. Gerstein, a professor and Population Health Institute chair in diabetes research at McMaster University and Hamilton Health Sciences, Ontario, Canada.

That is, the intensive glycemic control led to significant improvements at 10-year follow-up. While he acknowledged “that’s just semantics,” he stressed that a number of important lessons have been learned from the VADT and VADT-F – not the least of which relate to mediation analyses that showed the benefit seen at 10 years can be explained, at least statistically, by the differences in HbA_1c levels achieved during those intervening 10 years of follow-up.

For example, the 10-year cardiovascular outcome hazard ratios changed from 0.83 with a P value of .04 to 0.86 with a P value of .12 (after controlling for time-varying HbA_1c levels) and to 0.94 with a P value of .53 (after controlling for time-varying cumulative mean HbA_1c), he said, noting that similar findings have been reported from prior trials.

The VADT was designed to evaluate whether an intensive glycemic control regimen could reduce the incidence of major cardiovascular events compared with standard care in patients with T2DM; secondary objectives included differences in additional cardiovascular, renal, and other outcomes.

Subjects, who were enrolled from 20 VA medical centers beginning in December 2000, were aged 41 years or older (mean of about 60 years) and had failed to respond to a maximum dose of at least one oral agent and/or daily insulin. Patients were excluded if they had HbA_1c less than 7.5%, had had a cardiovascular event in the previous 6 months, had advanced congestive heart failure, had severe angina, had a life expectancy of less than 7 years, had a body mass index over 40 kg/m², had serum creatinine less than 1.6 mg/dL, or had an alanine transaminase level greater than 3 times the upper limit of normal, according to Wyndy L. Wiitala, PhD, of the VA Center for Clinical Management Research in Ann Arbor, Michigan.

A total of 818 patients in the standard care group and 837 in the intensive treatment group completed the study with up to 7.5 years of total follow-up (median, 5.6 years). The groups were similar in age; both were mostly male, which is expected for a VA population; and the average HbA_1c level was 9.4% in both groups. Other clinical measures, including lipids, blood pressure, and estimated cardiovascular risk were also similar between the two groups.

“The VADT was designed so that the only planned difference between the treatment groups was the level of glycemic control,” Dr. Wiitala said.

All patients with a BMI of 27 kg/m² or greater were started on metformin plus rosiglitazone, and those with a BMI less than 27 kg/m² were started on glimepiride plus rosiglitazone. Those in the intensive therapy arm were started on maximal doses, and those in the standard therapy arm were started on half the maximal doses. Insulin was added for patients in the intensive-therapy group who did not achieve HbA_1c below 6%, as well as for those in the standard-therapy group with a level of less than 9%.

Any subsequent medication changes were determined according to protocol guidelines and local assessment, and investigators were allowed to use any approved drug at their discretion.

“The use of medications between the two groups was similar, with differences in dose and insulin intensity only,” Dr. Wiitala said, adding that all other aspects of treatment, including blood pressure control, lipid control, aspirin therapy, diet, and nutrition, were “nearly identical” in the two groups.



The VADT-F design

The negative findings from the VADT raised “a number of questions, which really provided the rationale for the VADT follow-up study,” Dr. Reaven said.

“Would the post-VADT follow-up reveal an emerging cardiovascular benefit? This was particularly relevant as there was an indication that the group differences were increasing toward the end of the study, and benefits in cardiovascular outcomes, as we know, take a fair amount of time,” he said, adding that since the glucose separation seen in the treatment groups was greater than that seen in other recent studies involving patients with advanced T2DM and remained that way for an extended period of time, the follow-up study provided an excellent opportunity to examine whether there was a legacy or other effects.

The VADT-F continued to follow the VADT patients after the intervention ended in 2008; at that time, patients returned to normal care with no further intervention by the research team, Dr. Wiitala said, noting that participants were followed using national data sources, annual mail surveys, and targeted chart reviews.

The 10-year interim analysis was reported in 2015, and the 15-year final analysis, which is currently under review, represents the longest follow-up of patients with advanced T2DM with high risk for cardiovascular disease, she said.

“These results suggest that there are modest long-term cardiovascular disease benefits of therapies directed toward bringing glucose control to near-normal range in high-risk type 2 diabetes and that substantial and continuous glucose separation may be required to maintain these improvements,” Dr. Reaven concluded, adding that “recent studies demonstrating cardiovascular benefit with diabetes agents that only achieve modest improvements in glycemic control highlight the importance of also considering nonglycemic approaches to reducing cardiovascular disease events and mortality in these patients.”

Similarly, Dr. Emanuele concluded that there is a delayed beneficial effect of intensive glycemic control on kidney outcomes but that the effect dissipates as glycemic separation wanes.

However, in his commentary at the meeting, Dr. Gerstein stressed that the findings add value; in addition to showing, via mediation analyses, that HbA_1c levels statistically explain the differences seen between the intensive and standard therapy arms at 10 years, the VADT and VADT-F findings also underscore the veracity of the ADA’s recommended target of HbA_1c less than 7%, albeit “with all sorts of caveats.”

“But one point to make is that clinical trials do not tell you how to treat the patient in front of you. [They] just tell you what works on average for the average patient. ... You have to take the information you get from randomized trials and put it into your brain as a doctor and treat the patient,” he said.

He and several colleagues further explained this concept in a recent editorial (Diabetes Care. 2018 Jun;41[6]:1121-4) penned in response to new guidance statements published by the American College of Physicians advocating for relaxation of HbA_1c control goals in patients with T2DM.

“The ACP proposal may encourage a step backward at a time when accumulating evidence from randomized, controlled trials calls for movement forward in the treatment of diabetes,” they wrote in the editorial entitled “A_1c targets should be personalized to maximize benefits while limiting risks.”

Findings from those trials, including the VADT and VADT-F, continue to increase diabetes insights and inform care, and while there is not yet a statin-like “prescribe-and-go” treatment for diabetes, the findings represent a step in the right direction, Dr Gerstein said.

“All you have to do is look at all the clinical trials that are happening. We’re going to get there. ... This is not the end of the end, this is the beginning of the next phase,” he said.

The VADT and VADT-F were funded by the VA Cooperative Studies Program, the ADA, and the National Institutes of Health/National Eye Institute. Medication and additional support were provided by Aventis, GlaxoSmithKline, and Novo Nordisk Pharmaceuticals, which provided funding and supplies, and by Abbott Laboratory, Amylin, Eli Lily, Kos, Roche, and the University of Chicago, which also provided supplies. Dr. Reaven is an advisory panel member for Sanofi and has received research support from AstraZeneca and Novo Nordisk. Dr. Gerstein has received grants or other research support, honoraria, and/or consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Novo Nordisk, and Sanofi. Dr. Wiitala and Dr. Emanuele reported having no disclosures.

sworcester@mdedge.com

Taking steps to manage cardiovascular risk can help improve long-term outcomes for type 2 diabetes mellitus, according to two new studies published Aug. 16 in the New England Journal of Medicine.

The first study, which examined weight gain after smoking cessation, found that despite a temporary increase in T2DM risk, post-cessation weight gain did not diminish the long-term benefits of reduced cardiovascular and all-cause mortality.

The analysis included three cohort studies: the Nurses’ Health Study (NHS), Nurses’ Health Study II (NHS II), and the Health Professionals Follow-Up Study (HPFS), with follow-up questionnaires every 2 years. After exclusions, a total of 162,807 patients were included in the diabetes analysis and 170,723 in the mortality analysis, reported Yang Hu of the department of nutrition at Harvard T.H. Chan School of Public Health, Boston, and his coauthors (N Engl J Med. 2018 Aug 16. doi: 10.1056/NEJMoa1803626).

In each follow-up cycle, participants who reported being smokers in the previous cycle but “past” smokers in the current cycle were identified. Quitters were defined as either transient quitters (past smokers in the current cycle but current smokers in previous and next cycles), recent quitters (2-6 consecutive years since smoking cessation), and long-term quitters (6 or more consecutive years since cessation). Weight change was observed for the first 6 years after quitting.

Overall, 12,384 cases of T2DM were confirmed. Diabetes risk was higher for recent quitters than for current smokers (hazard ratio, 1.22; 95% confidence interval, 1.12-1.32); this risk peaked 5-7 years after quitting and then gradually decreased. In analysis of patients with the longest follow-up time, diabetes risk dropped after 30 years of cessation to that of participants who had never smoked, the authors reported.

Compared with current smokers, hazard ratios for T2DM in recent quitters were 1.08 (95% CI, 0.93-1.26) for those without weight gain, 1.15 (95% CI, 0.99-1.33) for those with weight gain of 0.1-5.0 kg, 1.36 (95% CI, 1.16-1.58) for those with weight gain of 5.1-10 kg, and 1.59 (95% CI, 1.36-1.85) in those with weight gain of more than 10 kg.

In the mortality analysis, 23,867 deaths occurred, of which 5,492 were due to cardiovascular disease. Compared with current smokers, hazard ratios for death from cardiovascular disease in recent quitters were 0.69 (95% CI, 0.54-0.88) in those without weight gain; 0.47 (95% CI, 0.35-0.63) in those with weight gain of 0.1-5 kg; 0.25 (95% CI, 0.15-0.42) in those with weight gain of 5.1-10 kg; 0.33 (95% CI, 0.18-0.60) in those with weight gain of more than 10 kg; and 0.50 (95% CI, 0.46-0.55) for longer term quitters. The corresponding hazard ratios for all-cause deaths in the same weight gain groups were 0.81 (95% CI, 0.73-0.90); 0.52 (95% CI, 0.46-0.59); 0.46 (95% CI, 0.38-0.55); 0.50 (95% CI, 0.40-0.63); and 0.57 (95% CI, 0.54-0.59).

The findings suggest that weight gain after quitting smoking “did not attenuate the apparent benefits of smoking cessation on reducing cardiovascular mortality or extending longevity,” the authors said. “However, preventing excessive weight gain may maximize the health benefits of smoking cessation through reducing the short-term risk of diabetes and further lowering the long-term risk of death.”

The second study, which included 271,174 patients with T2DM from the Swedish National Diabetes Register and 1,355,870 controls, examined five risk factors: elevated glycated hemoglobin level, elevated low-density lipoprotein cholesterol level, albuminuria, smoking, and elevated blood pressure.

All-cause mortality, myocardial infarction, stroke, and hospitalization for heart failure were evaluated. The risk of each outcome among patients with T2DM was estimated according to the number of risk-factor variables within guideline-recommended target ranges, compared with matched controls, wrote Aidin Rawshani, MD, of the department of molecular and clinical medicine at the University of Gothenburg (Sweden), and his coauthors (N Engl J Med. 2018 Aug 16. doi: 10.1056/NEJMoa1800256).

Among the T2DM patients, the excess risk of outcomes was reduced with each risk factor variable within the recommended target range. A total of 37,825 patients with T2DM (13.9%) and 137,520 controls (10.1%) died during the study period.

Among T2DM patients with all variables within target range, the hazard ratio was 1.06 for all-cause death (95% CI, 1.00-1.12); 0.84 for acute myocardial infarction (95% CI, 0.75-0.93); and 0.95 for stroke (95% CI, 0.84-1.07). Smoking was the strongest predictor of death, followed by physical activity, marital status, glycated hemoglobin level, and use of statins.

The study results “indicate that having all five risk-factor variables within the target ranges could theoretically eliminate the excess risk of acute myocardial infarction,” Dr. Rawshani and his colleagues wrote. “Patients with type 2 diabetes who had five risk-factor variables within target ranges appeared to have little or no excess risks of death, myocardial infarction, and stroke as compared with the general population.”

Dr. Hu and his coauthors did not report any disclosures. Dr. Rawshani’s coauthors disclosed relationships with numerous companies including Amgen, Astra Zeneca, and Boehringer Ingelheim.

SOURCE: Hu Y et al. N Engl J Med. 2018 Aug 16. doi: 10.1056/NEJMoa1803626. Rawshani A et al. N Engl J Med. 2018 Aug 16. doi: 10.1056/NEJMoa1800256.

Taking steps to manage cardiovascular risk can help improve long-term outcomes for type 2 diabetes mellitus, according to two new studies published Aug. 16 in the New England Journal of Medicine.

The first study, which examined weight gain after smoking cessation, found that despite a temporary increase in T2DM risk, post-cessation weight gain did not diminish the long-term benefits of reduced cardiovascular and all-cause mortality.

The analysis included three cohort studies: the Nurses’ Health Study (NHS), Nurses’ Health Study II (NHS II), and the Health Professionals Follow-Up Study (HPFS), with follow-up questionnaires every 2 years. After exclusions, a total of 162,807 patients were included in the diabetes analysis and 170,723 in the mortality analysis, reported Yang Hu of the department of nutrition at Harvard T.H. Chan School of Public Health, Boston, and his coauthors (N Engl J Med. 2018 Aug 16. doi: 10.1056/NEJMoa1803626).

In each follow-up cycle, participants who reported being smokers in the previous cycle but “past” smokers in the current cycle were identified. Quitters were defined as either transient quitters (past smokers in the current cycle but current smokers in previous and next cycles), recent quitters (2-6 consecutive years since smoking cessation), and long-term quitters (6 or more consecutive years since cessation). Weight change was observed for the first 6 years after quitting.

Overall, 12,384 cases of T2DM were confirmed. Diabetes risk was higher for recent quitters than for current smokers (hazard ratio, 1.22; 95% confidence interval, 1.12-1.32); this risk peaked 5-7 years after quitting and then gradually decreased. In analysis of patients with the longest follow-up time, diabetes risk dropped after 30 years of cessation to that of participants who had never smoked, the authors reported.

Compared with current smokers, hazard ratios for T2DM in recent quitters were 1.08 (95% CI, 0.93-1.26) for those without weight gain, 1.15 (95% CI, 0.99-1.33) for those with weight gain of 0.1-5.0 kg, 1.36 (95% CI, 1.16-1.58) for those with weight gain of 5.1-10 kg, and 1.59 (95% CI, 1.36-1.85) in those with weight gain of more than 10 kg.

In the mortality analysis, 23,867 deaths occurred, of which 5,492 were due to cardiovascular disease. Compared with current smokers, hazard ratios for death from cardiovascular disease in recent quitters were 0.69 (95% CI, 0.54-0.88) in those without weight gain; 0.47 (95% CI, 0.35-0.63) in those with weight gain of 0.1-5 kg; 0.25 (95% CI, 0.15-0.42) in those with weight gain of 5.1-10 kg; 0.33 (95% CI, 0.18-0.60) in those with weight gain of more than 10 kg; and 0.50 (95% CI, 0.46-0.55) for longer term quitters. The corresponding hazard ratios for all-cause deaths in the same weight gain groups were 0.81 (95% CI, 0.73-0.90); 0.52 (95% CI, 0.46-0.59); 0.46 (95% CI, 0.38-0.55); 0.50 (95% CI, 0.40-0.63); and 0.57 (95% CI, 0.54-0.59).

The findings suggest that weight gain after quitting smoking “did not attenuate the apparent benefits of smoking cessation on reducing cardiovascular mortality or extending longevity,” the authors said. “However, preventing excessive weight gain may maximize the health benefits of smoking cessation through reducing the short-term risk of diabetes and further lowering the long-term risk of death.”

The second study, which included 271,174 patients with T2DM from the Swedish National Diabetes Register and 1,355,870 controls, examined five risk factors: elevated glycated hemoglobin level, elevated low-density lipoprotein cholesterol level, albuminuria, smoking, and elevated blood pressure.

All-cause mortality, myocardial infarction, stroke, and hospitalization for heart failure were evaluated. The risk of each outcome among patients with T2DM was estimated according to the number of risk-factor variables within guideline-recommended target ranges, compared with matched controls, wrote Aidin Rawshani, MD, of the department of molecular and clinical medicine at the University of Gothenburg (Sweden), and his coauthors (N Engl J Med. 2018 Aug 16. doi: 10.1056/NEJMoa1800256).

Among the T2DM patients, the excess risk of outcomes was reduced with each risk factor variable within the recommended target range. A total of 37,825 patients with T2DM (13.9%) and 137,520 controls (10.1%) died during the study period.

Among T2DM patients with all variables within target range, the hazard ratio was 1.06 for all-cause death (95% CI, 1.00-1.12); 0.84 for acute myocardial infarction (95% CI, 0.75-0.93); and 0.95 for stroke (95% CI, 0.84-1.07). Smoking was the strongest predictor of death, followed by physical activity, marital status, glycated hemoglobin level, and use of statins.

The study results “indicate that having all five risk-factor variables within the target ranges could theoretically eliminate the excess risk of acute myocardial infarction,” Dr. Rawshani and his colleagues wrote. “Patients with type 2 diabetes who had five risk-factor variables within target ranges appeared to have little or no excess risks of death, myocardial infarction, and stroke as compared with the general population.”

Dr. Hu and his coauthors did not report any disclosures. Dr. Rawshani’s coauthors disclosed relationships with numerous companies including Amgen, Astra Zeneca, and Boehringer Ingelheim.

SOURCE: Hu Y et al. N Engl J Med. 2018 Aug 16. doi: 10.1056/NEJMoa1803626. Rawshani A et al. N Engl J Med. 2018 Aug 16. doi: 10.1056/NEJMoa1800256.

Taking steps to manage cardiovascular risk can help improve long-term outcomes for type 2 diabetes mellitus, according to two new studies published Aug. 16 in the New England Journal of Medicine.

The first study, which examined weight gain after smoking cessation, found that despite a temporary increase in T2DM risk, post-cessation weight gain did not diminish the long-term benefits of reduced cardiovascular and all-cause mortality.

The analysis included three cohort studies: the Nurses’ Health Study (NHS), Nurses’ Health Study II (NHS II), and the Health Professionals Follow-Up Study (HPFS), with follow-up questionnaires every 2 years. After exclusions, a total of 162,807 patients were included in the diabetes analysis and 170,723 in the mortality analysis, reported Yang Hu of the department of nutrition at Harvard T.H. Chan School of Public Health, Boston, and his coauthors (N Engl J Med. 2018 Aug 16. doi: 10.1056/NEJMoa1803626).

In each follow-up cycle, participants who reported being smokers in the previous cycle but “past” smokers in the current cycle were identified. Quitters were defined as either transient quitters (past smokers in the current cycle but current smokers in previous and next cycles), recent quitters (2-6 consecutive years since smoking cessation), and long-term quitters (6 or more consecutive years since cessation). Weight change was observed for the first 6 years after quitting.

Overall, 12,384 cases of T2DM were confirmed. Diabetes risk was higher for recent quitters than for current smokers (hazard ratio, 1.22; 95% confidence interval, 1.12-1.32); this risk peaked 5-7 years after quitting and then gradually decreased. In analysis of patients with the longest follow-up time, diabetes risk dropped after 30 years of cessation to that of participants who had never smoked, the authors reported.

Compared with current smokers, hazard ratios for T2DM in recent quitters were 1.08 (95% CI, 0.93-1.26) for those without weight gain, 1.15 (95% CI, 0.99-1.33) for those with weight gain of 0.1-5.0 kg, 1.36 (95% CI, 1.16-1.58) for those with weight gain of 5.1-10 kg, and 1.59 (95% CI, 1.36-1.85) in those with weight gain of more than 10 kg.

In the mortality analysis, 23,867 deaths occurred, of which 5,492 were due to cardiovascular disease. Compared with current smokers, hazard ratios for death from cardiovascular disease in recent quitters were 0.69 (95% CI, 0.54-0.88) in those without weight gain; 0.47 (95% CI, 0.35-0.63) in those with weight gain of 0.1-5 kg; 0.25 (95% CI, 0.15-0.42) in those with weight gain of 5.1-10 kg; 0.33 (95% CI, 0.18-0.60) in those with weight gain of more than 10 kg; and 0.50 (95% CI, 0.46-0.55) for longer term quitters. The corresponding hazard ratios for all-cause deaths in the same weight gain groups were 0.81 (95% CI, 0.73-0.90); 0.52 (95% CI, 0.46-0.59); 0.46 (95% CI, 0.38-0.55); 0.50 (95% CI, 0.40-0.63); and 0.57 (95% CI, 0.54-0.59).

The findings suggest that weight gain after quitting smoking “did not attenuate the apparent benefits of smoking cessation on reducing cardiovascular mortality or extending longevity,” the authors said. “However, preventing excessive weight gain may maximize the health benefits of smoking cessation through reducing the short-term risk of diabetes and further lowering the long-term risk of death.”

The second study, which included 271,174 patients with T2DM from the Swedish National Diabetes Register and 1,355,870 controls, examined five risk factors: elevated glycated hemoglobin level, elevated low-density lipoprotein cholesterol level, albuminuria, smoking, and elevated blood pressure.

All-cause mortality, myocardial infarction, stroke, and hospitalization for heart failure were evaluated. The risk of each outcome among patients with T2DM was estimated according to the number of risk-factor variables within guideline-recommended target ranges, compared with matched controls, wrote Aidin Rawshani, MD, of the department of molecular and clinical medicine at the University of Gothenburg (Sweden), and his coauthors (N Engl J Med. 2018 Aug 16. doi: 10.1056/NEJMoa1800256).

Among the T2DM patients, the excess risk of outcomes was reduced with each risk factor variable within the recommended target range. A total of 37,825 patients with T2DM (13.9%) and 137,520 controls (10.1%) died during the study period.

Among T2DM patients with all variables within target range, the hazard ratio was 1.06 for all-cause death (95% CI, 1.00-1.12); 0.84 for acute myocardial infarction (95% CI, 0.75-0.93); and 0.95 for stroke (95% CI, 0.84-1.07). Smoking was the strongest predictor of death, followed by physical activity, marital status, glycated hemoglobin level, and use of statins.

The study results “indicate that having all five risk-factor variables within the target ranges could theoretically eliminate the excess risk of acute myocardial infarction,” Dr. Rawshani and his colleagues wrote. “Patients with type 2 diabetes who had five risk-factor variables within target ranges appeared to have little or no excess risks of death, myocardial infarction, and stroke as compared with the general population.”

Dr. Hu and his coauthors did not report any disclosures. Dr. Rawshani’s coauthors disclosed relationships with numerous companies including Amgen, Astra Zeneca, and Boehringer Ingelheim.

SOURCE: Hu Y et al. N Engl J Med. 2018 Aug 16. doi: 10.1056/NEJMoa1803626. Rawshani A et al. N Engl J Med. 2018 Aug 16. doi: 10.1056/NEJMoa1800256.