Sherry Boschert

SAN FRANCISCO – Talking to patients after they start an antiresorptive drug for osteoporosis is better than laboratory testing to convince them to stay on therapy, according to Dr. Douglas C. Bauer.

Bone mineral density testing determines the need for antiresorptive medication, but it’s less helpful in monitoring the effects of treatment or adherence to therapy than is talking to patients. A test showing bone loss in the first year of treatment can confuse patients and doesn’t necessarily mean they are not responding to treatment, said Dr. Bauer, professor of medicine and of epidemiology and biostatistics at the University of California, San Francisco.

Besides, most of the patients who stop osteoporosis therapy within 3 years do so within the first few months of treatment, so annual bone density testing is unlikely to improve adherence, he added.

Biochemical markers of bone turnover eventually may become the standard for monitoring treatment, "but we’re not there yet," he said at a meeting on osteoporosis sponsored by the university.

Studies have shown that follow-up discussions after a patient starts antiresorptive medication is the factor that improves adherence, not measuring bone density or bone turnover markers.

Dr. Bauer said he tells patients not to expect routine follow-up bone density testing and asks about and encourages adherence at every patient visit. If a patient develops a fracture while on therapy or is considering a drug holiday after 5 years on alendronate, then he said he considers ordering follow-up bone mineral density testing.

"There’s a caveat: This may not be the right algorithm for tertiary care centers with severe or complex patients," said Dr. Bauer.

Although bone mineral density measurements are very precise, small differences in position or "noise" in the measures can produce apparent changes that are not clinically meaningful. To assess whether a change in bone density is "real," he recommended a useful equation called the "least significant change" equation: Multiply the coefficient of variations by three; if the sum is less than 4.5%, then the change may be due to chance.

For example, if the coefficient of variations in hip bone density is 1.5%, the least significant change is 4.5%. If a patient lost 3% in bone density, there is approximately a 10% chance that there was no change in bone density, he said.

"A somewhat more fundamental question is not just whether the measurements [are] real, but are they meaningful?" Dr. Bauer said.

Analyses of data from the Fracture Intervention Trial (FIT) show that patients on alendronate who lost up to 4% in total hip bone density in the 1-2 years of treatment still had 53% fewer vertebral fractures compared with their counterparts on placebo who lost similar amounts of bone density. Patients who lost up to 4% in spine density had 60% fewer vertebral fractures compared with their counterparts on placebo (Osteoporos. Int. 2005;16:842-8).

Then there’s the "regression to the mean" argument that patients who have an unusual response in the first year of antiresorptive therapy will develop a more typical response if treatment is continued, he said. A separate analysis of FIT data showed that 92% of patients who lost up to 4% of hip bone density in the first year of therapy gained an average of nearly 5% in bone density in the second year of treatment (JAMA 2000;283:1318-1321).

A more recent analysis of annual bone mineral density data in FIT showed that variation in the change in bone density over a 3-year period was mainly measurement-related, within-person variation. Treatment-related, between-person variation played a much smaller role (BMJ 2009;338:b2266).

That helps explain how patients can "lose" bone density but still have fewer fractures, Dr. Bauer said. "It’s reassuring that 98% on alendronate gained more than 0.02 g/cm²" in FIT.

Antiresorptive therapy decreases biochemical markers of bone turnover, but there is a lot of biologic variability and no clear threshold for efficacy. Biochemical marker measurements could be used to identify nonadherence to treatment, but "it’s cheaper just to ask," he said.

In a study of 2,382 osteoporotic women starting a year of risedronate therapy, the women were randomized to get bone turnover markers measured at weeks 13 and 25 or to routine visits without marker measurements. The results showed no difference in adherence rates between the groups (J. Clin. Endocrinol. Metab. 2007;92:1296-1304). In the marker measurement group, the adherence rate was 225% worse than in the control group if the marker results suggested a "bad" response to therapy (less than a 30% decrease in marker levels).

"That was unexpected," Dr. Bauer said. "Bone turnover markers by themselves are not helpful for increasing adherence" to therapy.

A separate randomized study of 75 women starting raloxifene treatment for low bone density randomized them to no monitoring; nurse visits at months 3, 6, and 9; or nurse visits plus bone turnover marker measurements. The nurse visits improved adherence to therapy compared with no monitoring, but biomarker measurements did not add anything to the nurse visits (J. Clin. Endocrinol. Metab. 2004;89:1117-1123).

In general, approximately 30%-40% of patients stop taking antiresorptive drugs within 1 year, he said.

Dr. Bauer said he has received research funding from Amgen, Novartis, and Proctor and Gamble.

SAN FRANCISCO – Talking to patients after they start an antiresorptive drug for osteoporosis is better than laboratory testing to convince them to stay on therapy, according to Dr. Douglas C. Bauer.

Bone mineral density testing determines the need for antiresorptive medication, but it’s less helpful in monitoring the effects of treatment or adherence to therapy than is talking to patients. A test showing bone loss in the first year of treatment can confuse patients and doesn’t necessarily mean they are not responding to treatment, said Dr. Bauer, professor of medicine and of epidemiology and biostatistics at the University of California, San Francisco.

Besides, most of the patients who stop osteoporosis therapy within 3 years do so within the first few months of treatment, so annual bone density testing is unlikely to improve adherence, he added.

Biochemical markers of bone turnover eventually may become the standard for monitoring treatment, "but we’re not there yet," he said at a meeting on osteoporosis sponsored by the university.

Studies have shown that follow-up discussions after a patient starts antiresorptive medication is the factor that improves adherence, not measuring bone density or bone turnover markers.

Dr. Bauer said he tells patients not to expect routine follow-up bone density testing and asks about and encourages adherence at every patient visit. If a patient develops a fracture while on therapy or is considering a drug holiday after 5 years on alendronate, then he said he considers ordering follow-up bone mineral density testing.

"There’s a caveat: This may not be the right algorithm for tertiary care centers with severe or complex patients," said Dr. Bauer.

Although bone mineral density measurements are very precise, small differences in position or "noise" in the measures can produce apparent changes that are not clinically meaningful. To assess whether a change in bone density is "real," he recommended a useful equation called the "least significant change" equation: Multiply the coefficient of variations by three; if the sum is less than 4.5%, then the change may be due to chance.

For example, if the coefficient of variations in hip bone density is 1.5%, the least significant change is 4.5%. If a patient lost 3% in bone density, there is approximately a 10% chance that there was no change in bone density, he said.

"A somewhat more fundamental question is not just whether the measurements [are] real, but are they meaningful?" Dr. Bauer said.

Analyses of data from the Fracture Intervention Trial (FIT) show that patients on alendronate who lost up to 4% in total hip bone density in the 1-2 years of treatment still had 53% fewer vertebral fractures compared with their counterparts on placebo who lost similar amounts of bone density. Patients who lost up to 4% in spine density had 60% fewer vertebral fractures compared with their counterparts on placebo (Osteoporos. Int. 2005;16:842-8).

Then there’s the "regression to the mean" argument that patients who have an unusual response in the first year of antiresorptive therapy will develop a more typical response if treatment is continued, he said. A separate analysis of FIT data showed that 92% of patients who lost up to 4% of hip bone density in the first year of therapy gained an average of nearly 5% in bone density in the second year of treatment (JAMA 2000;283:1318-1321).

A more recent analysis of annual bone mineral density data in FIT showed that variation in the change in bone density over a 3-year period was mainly measurement-related, within-person variation. Treatment-related, between-person variation played a much smaller role (BMJ 2009;338:b2266).

That helps explain how patients can "lose" bone density but still have fewer fractures, Dr. Bauer said. "It’s reassuring that 98% on alendronate gained more than 0.02 g/cm²" in FIT.

Antiresorptive therapy decreases biochemical markers of bone turnover, but there is a lot of biologic variability and no clear threshold for efficacy. Biochemical marker measurements could be used to identify nonadherence to treatment, but "it’s cheaper just to ask," he said.

In a study of 2,382 osteoporotic women starting a year of risedronate therapy, the women were randomized to get bone turnover markers measured at weeks 13 and 25 or to routine visits without marker measurements. The results showed no difference in adherence rates between the groups (J. Clin. Endocrinol. Metab. 2007;92:1296-1304). In the marker measurement group, the adherence rate was 225% worse than in the control group if the marker results suggested a "bad" response to therapy (less than a 30% decrease in marker levels).

"That was unexpected," Dr. Bauer said. "Bone turnover markers by themselves are not helpful for increasing adherence" to therapy.

A separate randomized study of 75 women starting raloxifene treatment for low bone density randomized them to no monitoring; nurse visits at months 3, 6, and 9; or nurse visits plus bone turnover marker measurements. The nurse visits improved adherence to therapy compared with no monitoring, but biomarker measurements did not add anything to the nurse visits (J. Clin. Endocrinol. Metab. 2004;89:1117-1123).

In general, approximately 30%-40% of patients stop taking antiresorptive drugs within 1 year, he said.

Dr. Bauer said he has received research funding from Amgen, Novartis, and Proctor and Gamble.

SAN FRANCISCO – Talking to patients after they start an antiresorptive drug for osteoporosis is better than laboratory testing to convince them to stay on therapy, according to Dr. Douglas C. Bauer.

Bone mineral density testing determines the need for antiresorptive medication, but it’s less helpful in monitoring the effects of treatment or adherence to therapy than is talking to patients. A test showing bone loss in the first year of treatment can confuse patients and doesn’t necessarily mean they are not responding to treatment, said Dr. Bauer, professor of medicine and of epidemiology and biostatistics at the University of California, San Francisco.

Besides, most of the patients who stop osteoporosis therapy within 3 years do so within the first few months of treatment, so annual bone density testing is unlikely to improve adherence, he added.

Biochemical markers of bone turnover eventually may become the standard for monitoring treatment, "but we’re not there yet," he said at a meeting on osteoporosis sponsored by the university.

Studies have shown that follow-up discussions after a patient starts antiresorptive medication is the factor that improves adherence, not measuring bone density or bone turnover markers.

Dr. Bauer said he tells patients not to expect routine follow-up bone density testing and asks about and encourages adherence at every patient visit. If a patient develops a fracture while on therapy or is considering a drug holiday after 5 years on alendronate, then he said he considers ordering follow-up bone mineral density testing.

"There’s a caveat: This may not be the right algorithm for tertiary care centers with severe or complex patients," said Dr. Bauer.

Although bone mineral density measurements are very precise, small differences in position or "noise" in the measures can produce apparent changes that are not clinically meaningful. To assess whether a change in bone density is "real," he recommended a useful equation called the "least significant change" equation: Multiply the coefficient of variations by three; if the sum is less than 4.5%, then the change may be due to chance.

For example, if the coefficient of variations in hip bone density is 1.5%, the least significant change is 4.5%. If a patient lost 3% in bone density, there is approximately a 10% chance that there was no change in bone density, he said.

"A somewhat more fundamental question is not just whether the measurements [are] real, but are they meaningful?" Dr. Bauer said.

Analyses of data from the Fracture Intervention Trial (FIT) show that patients on alendronate who lost up to 4% in total hip bone density in the 1-2 years of treatment still had 53% fewer vertebral fractures compared with their counterparts on placebo who lost similar amounts of bone density. Patients who lost up to 4% in spine density had 60% fewer vertebral fractures compared with their counterparts on placebo (Osteoporos. Int. 2005;16:842-8).

Then there’s the "regression to the mean" argument that patients who have an unusual response in the first year of antiresorptive therapy will develop a more typical response if treatment is continued, he said. A separate analysis of FIT data showed that 92% of patients who lost up to 4% of hip bone density in the first year of therapy gained an average of nearly 5% in bone density in the second year of treatment (JAMA 2000;283:1318-1321).

A more recent analysis of annual bone mineral density data in FIT showed that variation in the change in bone density over a 3-year period was mainly measurement-related, within-person variation. Treatment-related, between-person variation played a much smaller role (BMJ 2009;338:b2266).

That helps explain how patients can "lose" bone density but still have fewer fractures, Dr. Bauer said. "It’s reassuring that 98% on alendronate gained more than 0.02 g/cm²" in FIT.

Antiresorptive therapy decreases biochemical markers of bone turnover, but there is a lot of biologic variability and no clear threshold for efficacy. Biochemical marker measurements could be used to identify nonadherence to treatment, but "it’s cheaper just to ask," he said.

In a study of 2,382 osteoporotic women starting a year of risedronate therapy, the women were randomized to get bone turnover markers measured at weeks 13 and 25 or to routine visits without marker measurements. The results showed no difference in adherence rates between the groups (J. Clin. Endocrinol. Metab. 2007;92:1296-1304). In the marker measurement group, the adherence rate was 225% worse than in the control group if the marker results suggested a "bad" response to therapy (less than a 30% decrease in marker levels).

"That was unexpected," Dr. Bauer said. "Bone turnover markers by themselves are not helpful for increasing adherence" to therapy.

A separate randomized study of 75 women starting raloxifene treatment for low bone density randomized them to no monitoring; nurse visits at months 3, 6, and 9; or nurse visits plus bone turnover marker measurements. The nurse visits improved adherence to therapy compared with no monitoring, but biomarker measurements did not add anything to the nurse visits (J. Clin. Endocrinol. Metab. 2004;89:1117-1123).

In general, approximately 30%-40% of patients stop taking antiresorptive drugs within 1 year, he said.

Dr. Bauer said he has received research funding from Amgen, Novartis, and Proctor and Gamble.

SAN FRANCISCO – The pivotal clinical trial of denosumab showed a 20% decrease in nonvertebral fractures compared with placebo treatment, but a new subgroup analysis shows the protective effect is significantly higher in patients with femoral neck osteoporosis.

The preplanned subgroup analysis of data from the FREEDOM trial found that denosumab decreased nonvertebral fractures by 35% in patients with a femoral neck bone mineral density T score of -2.5 or lower and by only 3% in patients with higher femoral neck T scores, compared with patients in those subgroups who received placebo, Dr. Steven R. Cummings said.

The report of a 20% reduction in nonvertebral fractures in the overall trial for denosumab "underestimates its efficacy for those patients that we’re most interested in treating with this drug – those with osteoporosis," he said at a conference on osteoporosis sponsored by the University of California, San Francisco.

The findings have been submitted for publication. The analysis is one of several preplanned subgroup analyses being conducted, though this one is "the most interesting result for clinical care," said Dr. Cummings, emeritus professor of medicine and epidemiology and biostatistics at the university.

The original FREEDOM study (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive every 6 months either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements. All of the subjects had bone mineral density T scores that were less than -2.5 but not less than -4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The FREEDOM results were the basis of the Food and Drug Administration’s approval of denosumab in June 2010.

Data for 2,343 patients who continued denosumab for another 2 years and 2,207 patients who switched from placebo to denosumab in an ongoing extension of the trial suggest that the incidence of nonvertebral fractures continues to decline in the first 5 years of denosumab use. The 5-year results have been submitted for publication, he said.

For nonvertebral fractures, the incidence decreased from 2.6% in the denosumab group in the first year of the FREEDOM trial to 2.1% in year 2 and 2.2% in year 3. Nonvertebral fractures were seen in 1.4% of patients in year 4 and 1.1% of patients in year 5, extension study data show. Similar rates were seen for vertebral fractures.

The extension study did not include a placebo comparison, so "we did a pretty rigorous estimate of what the rates would be if the placebo group had continued out to 5 years," Dr. Cummings said. They estimated that nonvertebral or vertebral fracture rates would be 2.6% in the placebo group in years 4 and 5, more than twice that of patients on denosumab in the extension study.

A separate study highlighted another advantage of denosumab that it shares with zoledronic acid – greater adherence rates compared with oral therapies, he added. An open-label study of 250 women with untreated osteoporosis found an 87% adherence rate in the first year in patients randomized to get a denosumab injection every 6 months, compared with a 77% adherence rate for patients randomized to weekly oral alendronate therapy. Alendronate use was monitored by electronic bottle caps (Osteoporos. Int. 2011;22:1725-35).

The study’s 2-year results, which have not yet been published, show that the difference in adherence rates between groups continues to widen, Dr. Cummings said.

"Adherence difference really translates into difference in effectiveness of therapy. That’s the most important advantage over the oral drug," he added.

Dr. Cummings has been a consultant to Amgen Pharmaceuticals, which markets denosumab; to Merck, which markets alendronate; and to Eli Lilly and Company.

SAN FRANCISCO – The pivotal clinical trial of denosumab showed a 20% decrease in nonvertebral fractures compared with placebo treatment, but a new subgroup analysis shows the protective effect is significantly higher in patients with femoral neck osteoporosis.

The preplanned subgroup analysis of data from the FREEDOM trial found that denosumab decreased nonvertebral fractures by 35% in patients with a femoral neck bone mineral density T score of -2.5 or lower and by only 3% in patients with higher femoral neck T scores, compared with patients in those subgroups who received placebo, Dr. Steven R. Cummings said.

The report of a 20% reduction in nonvertebral fractures in the overall trial for denosumab "underestimates its efficacy for those patients that we’re most interested in treating with this drug – those with osteoporosis," he said at a conference on osteoporosis sponsored by the University of California, San Francisco.

The findings have been submitted for publication. The analysis is one of several preplanned subgroup analyses being conducted, though this one is "the most interesting result for clinical care," said Dr. Cummings, emeritus professor of medicine and epidemiology and biostatistics at the university.

The original FREEDOM study (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive every 6 months either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements. All of the subjects had bone mineral density T scores that were less than -2.5 but not less than -4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The FREEDOM results were the basis of the Food and Drug Administration’s approval of denosumab in June 2010.

Data for 2,343 patients who continued denosumab for another 2 years and 2,207 patients who switched from placebo to denosumab in an ongoing extension of the trial suggest that the incidence of nonvertebral fractures continues to decline in the first 5 years of denosumab use. The 5-year results have been submitted for publication, he said.

For nonvertebral fractures, the incidence decreased from 2.6% in the denosumab group in the first year of the FREEDOM trial to 2.1% in year 2 and 2.2% in year 3. Nonvertebral fractures were seen in 1.4% of patients in year 4 and 1.1% of patients in year 5, extension study data show. Similar rates were seen for vertebral fractures.

The extension study did not include a placebo comparison, so "we did a pretty rigorous estimate of what the rates would be if the placebo group had continued out to 5 years," Dr. Cummings said. They estimated that nonvertebral or vertebral fracture rates would be 2.6% in the placebo group in years 4 and 5, more than twice that of patients on denosumab in the extension study.

A separate study highlighted another advantage of denosumab that it shares with zoledronic acid – greater adherence rates compared with oral therapies, he added. An open-label study of 250 women with untreated osteoporosis found an 87% adherence rate in the first year in patients randomized to get a denosumab injection every 6 months, compared with a 77% adherence rate for patients randomized to weekly oral alendronate therapy. Alendronate use was monitored by electronic bottle caps (Osteoporos. Int. 2011;22:1725-35).

The study’s 2-year results, which have not yet been published, show that the difference in adherence rates between groups continues to widen, Dr. Cummings said.

"Adherence difference really translates into difference in effectiveness of therapy. That’s the most important advantage over the oral drug," he added.

Dr. Cummings has been a consultant to Amgen Pharmaceuticals, which markets denosumab; to Merck, which markets alendronate; and to Eli Lilly and Company.

SAN FRANCISCO – The pivotal clinical trial of denosumab showed a 20% decrease in nonvertebral fractures compared with placebo treatment, but a new subgroup analysis shows the protective effect is significantly higher in patients with femoral neck osteoporosis.

The preplanned subgroup analysis of data from the FREEDOM trial found that denosumab decreased nonvertebral fractures by 35% in patients with a femoral neck bone mineral density T score of -2.5 or lower and by only 3% in patients with higher femoral neck T scores, compared with patients in those subgroups who received placebo, Dr. Steven R. Cummings said.

The report of a 20% reduction in nonvertebral fractures in the overall trial for denosumab "underestimates its efficacy for those patients that we’re most interested in treating with this drug – those with osteoporosis," he said at a conference on osteoporosis sponsored by the University of California, San Francisco.

The findings have been submitted for publication. The analysis is one of several preplanned subgroup analyses being conducted, though this one is "the most interesting result for clinical care," said Dr. Cummings, emeritus professor of medicine and epidemiology and biostatistics at the university.

The original FREEDOM study (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive every 6 months either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements. All of the subjects had bone mineral density T scores that were less than -2.5 but not less than -4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The FREEDOM results were the basis of the Food and Drug Administration’s approval of denosumab in June 2010.

Data for 2,343 patients who continued denosumab for another 2 years and 2,207 patients who switched from placebo to denosumab in an ongoing extension of the trial suggest that the incidence of nonvertebral fractures continues to decline in the first 5 years of denosumab use. The 5-year results have been submitted for publication, he said.

For nonvertebral fractures, the incidence decreased from 2.6% in the denosumab group in the first year of the FREEDOM trial to 2.1% in year 2 and 2.2% in year 3. Nonvertebral fractures were seen in 1.4% of patients in year 4 and 1.1% of patients in year 5, extension study data show. Similar rates were seen for vertebral fractures.

The extension study did not include a placebo comparison, so "we did a pretty rigorous estimate of what the rates would be if the placebo group had continued out to 5 years," Dr. Cummings said. They estimated that nonvertebral or vertebral fracture rates would be 2.6% in the placebo group in years 4 and 5, more than twice that of patients on denosumab in the extension study.

A separate study highlighted another advantage of denosumab that it shares with zoledronic acid – greater adherence rates compared with oral therapies, he added. An open-label study of 250 women with untreated osteoporosis found an 87% adherence rate in the first year in patients randomized to get a denosumab injection every 6 months, compared with a 77% adherence rate for patients randomized to weekly oral alendronate therapy. Alendronate use was monitored by electronic bottle caps (Osteoporos. Int. 2011;22:1725-35).

The study’s 2-year results, which have not yet been published, show that the difference in adherence rates between groups continues to widen, Dr. Cummings said.

"Adherence difference really translates into difference in effectiveness of therapy. That’s the most important advantage over the oral drug," he added.

Dr. Cummings has been a consultant to Amgen Pharmaceuticals, which markets denosumab; to Merck, which markets alendronate; and to Eli Lilly and Company.

SAN FRANCISCO – Falls are the main cause of hip fractures, and proven prevention strategies should be in every clinician’s toolbox.

Physicians should ask patients aged 75 years or older if they’ve had any falls in the prior year or if they have balance or gait difficulties and observe them walking and getting into and out of a chair, said Dr. Edgar Pierluissi, medical director of the Acute Care for Elders Unit at San Francisco General Hospital.

A fall in the previous year increases the risk for a future fall three- to fourfold.

©bloodstone/iStockphoto.com

Studies suggest that approximately 30% of U.S. adults over 65 years of age who are living in the community and half of adults over age 80 years will fall in the next year. Falls in adults aged 65 years or older cause injury in approximately 31%. Among those injured, 56% go to an emergency department and 38% visit a medical clinic, he said at a conference on osteoporosis sponsored by the University of California, San Francisco.

An exercise program with balance and strength training might be appropriate for older patients who’ve had only one or no falls and who don’t have balance or gait difficulties, various guidelines suggest. If a patient reports two or more falls or has balance or gait difficulties, do a "falls evaluation," an assessment of predisposing or precipitating factors that can point to appropriate preventive interventions, he said.

"We can perhaps make a difference" in many of the most common risk factors for falls that have been identified in 16 studies, Dr. Pierluissi said.

Muscle weakness quadruples the risk for a fall. A gait deficit, balance deficit, or use of an assistive device nearly triples the risk for falling. A visual deficit, arthritis, depression, or impaired activities of daily living more than doubles the risk for a fall. Cognitive impairment, use of some types of medications, or age older than 80 years each nearly doubles the risk for falling.

To conduct a falls evaluation, get a good history of the patient’s falls and their circumstances. Do a cardiovascular examination, medication review, neurological examination, and assessment for cognitive impairment. Assess gait, balance and mobility, muscle weakness, visual impairment, home hazards that might precipitate a fall, and the patient’s perceived functional ability and fear related to falling (because many people who fear falling restrict their activity, which can lead to deconditioning and increased risk of falling).

How to Reduce the Risk of Falling

A Cochrane Review of 111 randomized, controlled trials with 55,303 participants identified effective interventions to reduce the risk of falling (Cochrane Database Syst. Rev. 2009 [doi:10.1002/14651858.CD007146.pub2]).

A number of forms of exercise reduced both the number of people who fell and the number of falls. Group tai chi exercise or individually prescribed exercise programs at home were effective. Multiple-component group exercise was effective if it targeted at least two of the following: strength, balance, flexibility, and endurance.

Conducting a multifactorial falls evaluation reduces the number of falls. In patients with visual impairment and a high risk of falling, assessing and modifying home hazards was effective.

Withdrawing psychotropic medications and educating primary care physicians about the risk of falls association with drug therapy reduced the number of falls, but not the number who fell. In patients with cardioinhibitory carotid sinus hypersensitivity, cardiac pacing reduced the number of falls.

Vitamin D supplementation may reduce falls in people with low vitamin D levels, but it’s unclear whether this helps people with adequate vitamin D levels. Other preventive strategies of unknown effectiveness include correction of visual deficiency, hormone replacement therapy, or modifying home hazards for people who have not fallen.

The Cochrane Review suggested that wearing hip protectors may provide some marginally significant benefit to frail, older adults in institutional care but not for older people who remain ambulant in the community, Dr. Pierluissi said.

One randomized, controlled trial of 1,042 residents in 37 nursing homes found a high rate of adherence to wearing hip protectors (74%) but these did not reduce the risk for hip fracture during the 20-month study. Residents served as their own controls by wearing hip protectors with padding on one hip but not the other. Investigators stopped the study early due to lack of efficacy, with hip fractures on 3.1% of the protected hips and 2.5% of unprotected hips, a statistically nonsignificant difference (JAMA 2007;298:413-22).

Dr. Pierluissi said he has no relevant conflicts of interest.

SAN FRANCISCO – Falls are the main cause of hip fractures, and proven prevention strategies should be in every clinician’s toolbox.

Physicians should ask patients aged 75 years or older if they’ve had any falls in the prior year or if they have balance or gait difficulties and observe them walking and getting into and out of a chair, said Dr. Edgar Pierluissi, medical director of the Acute Care for Elders Unit at San Francisco General Hospital.

A fall in the previous year increases the risk for a future fall three- to fourfold.

©bloodstone/iStockphoto.com

Studies suggest that approximately 30% of U.S. adults over 65 years of age who are living in the community and half of adults over age 80 years will fall in the next year. Falls in adults aged 65 years or older cause injury in approximately 31%. Among those injured, 56% go to an emergency department and 38% visit a medical clinic, he said at a conference on osteoporosis sponsored by the University of California, San Francisco.

An exercise program with balance and strength training might be appropriate for older patients who’ve had only one or no falls and who don’t have balance or gait difficulties, various guidelines suggest. If a patient reports two or more falls or has balance or gait difficulties, do a "falls evaluation," an assessment of predisposing or precipitating factors that can point to appropriate preventive interventions, he said.

"We can perhaps make a difference" in many of the most common risk factors for falls that have been identified in 16 studies, Dr. Pierluissi said.

Muscle weakness quadruples the risk for a fall. A gait deficit, balance deficit, or use of an assistive device nearly triples the risk for falling. A visual deficit, arthritis, depression, or impaired activities of daily living more than doubles the risk for a fall. Cognitive impairment, use of some types of medications, or age older than 80 years each nearly doubles the risk for falling.

To conduct a falls evaluation, get a good history of the patient’s falls and their circumstances. Do a cardiovascular examination, medication review, neurological examination, and assessment for cognitive impairment. Assess gait, balance and mobility, muscle weakness, visual impairment, home hazards that might precipitate a fall, and the patient’s perceived functional ability and fear related to falling (because many people who fear falling restrict their activity, which can lead to deconditioning and increased risk of falling).

How to Reduce the Risk of Falling

A Cochrane Review of 111 randomized, controlled trials with 55,303 participants identified effective interventions to reduce the risk of falling (Cochrane Database Syst. Rev. 2009 [doi:10.1002/14651858.CD007146.pub2]).

A number of forms of exercise reduced both the number of people who fell and the number of falls. Group tai chi exercise or individually prescribed exercise programs at home were effective. Multiple-component group exercise was effective if it targeted at least two of the following: strength, balance, flexibility, and endurance.

Conducting a multifactorial falls evaluation reduces the number of falls. In patients with visual impairment and a high risk of falling, assessing and modifying home hazards was effective.

Withdrawing psychotropic medications and educating primary care physicians about the risk of falls association with drug therapy reduced the number of falls, but not the number who fell. In patients with cardioinhibitory carotid sinus hypersensitivity, cardiac pacing reduced the number of falls.

Vitamin D supplementation may reduce falls in people with low vitamin D levels, but it’s unclear whether this helps people with adequate vitamin D levels. Other preventive strategies of unknown effectiveness include correction of visual deficiency, hormone replacement therapy, or modifying home hazards for people who have not fallen.

The Cochrane Review suggested that wearing hip protectors may provide some marginally significant benefit to frail, older adults in institutional care but not for older people who remain ambulant in the community, Dr. Pierluissi said.

One randomized, controlled trial of 1,042 residents in 37 nursing homes found a high rate of adherence to wearing hip protectors (74%) but these did not reduce the risk for hip fracture during the 20-month study. Residents served as their own controls by wearing hip protectors with padding on one hip but not the other. Investigators stopped the study early due to lack of efficacy, with hip fractures on 3.1% of the protected hips and 2.5% of unprotected hips, a statistically nonsignificant difference (JAMA 2007;298:413-22).

Dr. Pierluissi said he has no relevant conflicts of interest.

SAN FRANCISCO – Falls are the main cause of hip fractures, and proven prevention strategies should be in every clinician’s toolbox.

Physicians should ask patients aged 75 years or older if they’ve had any falls in the prior year or if they have balance or gait difficulties and observe them walking and getting into and out of a chair, said Dr. Edgar Pierluissi, medical director of the Acute Care for Elders Unit at San Francisco General Hospital.

A fall in the previous year increases the risk for a future fall three- to fourfold.

©bloodstone/iStockphoto.com

Studies suggest that approximately 30% of U.S. adults over 65 years of age who are living in the community and half of adults over age 80 years will fall in the next year. Falls in adults aged 65 years or older cause injury in approximately 31%. Among those injured, 56% go to an emergency department and 38% visit a medical clinic, he said at a conference on osteoporosis sponsored by the University of California, San Francisco.

An exercise program with balance and strength training might be appropriate for older patients who’ve had only one or no falls and who don’t have balance or gait difficulties, various guidelines suggest. If a patient reports two or more falls or has balance or gait difficulties, do a "falls evaluation," an assessment of predisposing or precipitating factors that can point to appropriate preventive interventions, he said.

"We can perhaps make a difference" in many of the most common risk factors for falls that have been identified in 16 studies, Dr. Pierluissi said.

Muscle weakness quadruples the risk for a fall. A gait deficit, balance deficit, or use of an assistive device nearly triples the risk for falling. A visual deficit, arthritis, depression, or impaired activities of daily living more than doubles the risk for a fall. Cognitive impairment, use of some types of medications, or age older than 80 years each nearly doubles the risk for falling.

To conduct a falls evaluation, get a good history of the patient’s falls and their circumstances. Do a cardiovascular examination, medication review, neurological examination, and assessment for cognitive impairment. Assess gait, balance and mobility, muscle weakness, visual impairment, home hazards that might precipitate a fall, and the patient’s perceived functional ability and fear related to falling (because many people who fear falling restrict their activity, which can lead to deconditioning and increased risk of falling).

How to Reduce the Risk of Falling

A Cochrane Review of 111 randomized, controlled trials with 55,303 participants identified effective interventions to reduce the risk of falling (Cochrane Database Syst. Rev. 2009 [doi:10.1002/14651858.CD007146.pub2]).

A number of forms of exercise reduced both the number of people who fell and the number of falls. Group tai chi exercise or individually prescribed exercise programs at home were effective. Multiple-component group exercise was effective if it targeted at least two of the following: strength, balance, flexibility, and endurance.

Conducting a multifactorial falls evaluation reduces the number of falls. In patients with visual impairment and a high risk of falling, assessing and modifying home hazards was effective.

Withdrawing psychotropic medications and educating primary care physicians about the risk of falls association with drug therapy reduced the number of falls, but not the number who fell. In patients with cardioinhibitory carotid sinus hypersensitivity, cardiac pacing reduced the number of falls.

Vitamin D supplementation may reduce falls in people with low vitamin D levels, but it’s unclear whether this helps people with adequate vitamin D levels. Other preventive strategies of unknown effectiveness include correction of visual deficiency, hormone replacement therapy, or modifying home hazards for people who have not fallen.

The Cochrane Review suggested that wearing hip protectors may provide some marginally significant benefit to frail, older adults in institutional care but not for older people who remain ambulant in the community, Dr. Pierluissi said.

One randomized, controlled trial of 1,042 residents in 37 nursing homes found a high rate of adherence to wearing hip protectors (74%) but these did not reduce the risk for hip fracture during the 20-month study. Residents served as their own controls by wearing hip protectors with padding on one hip but not the other. Investigators stopped the study early due to lack of efficacy, with hip fractures on 3.1% of the protected hips and 2.5% of unprotected hips, a statistically nonsignificant difference (JAMA 2007;298:413-22).

Dr. Pierluissi said he has no relevant conflicts of interest.

PARIS – Results of two randomized controlled trials appear to solidify the safety of remote monitoring of implantable cardioverter defibrillators, and one of the studies showed a significant decrease in the number of patients receiving inappropriate shocks in the remote-monitoring group.

Manufacturers of ICDs currently recommend in-clinic follow-up every 3 months to detect clinical events or device malfunctions. With increasing numbers of people receiving ICDs to prevent sudden cardiac death from rhythm disturbances, investigators are testing ways to avoid the time constraints of so many in-clinic visits by remotely transmitting information from the device via telephone from the patient’s home. Most ICDs now have this capability.

The two randomized controlled trials support findings from patient registries in Europe and in the United States, where remote monitoring is common.

In the yearlong Evaluation of Tele Follow-up (EVATEL) trial, 1,501 patients at 30 French centers were randomized to in-clinic follow-up at the implant center every 3 months or to remote transmission of data to the implant center every 3 months. The study included four types of ICDs.

Results showed no significant difference between groups in the time to first major cardiovascular event or in the rates of major cardiovascular events (death from all causes, cardiovascular-related hospitalization, or inappropriate or ineffective shocks), Dr. Philippe Mabo and his associates reported at the annual congress of the European Society of Cardiology .

Rates of this composite end point were 28% in the remote-monitoring group and 29% in the control group in an intent-to-treat analysis, showing that home monitoring was not inferior to in-office monitoring. In a per-protocol analysis, the primary end points were seen in 28% and 30% of the groups, respectively, but the confidence interval was too wide to claim that there was no significant difference between groups, said Dr. Mabo of Rennes (France) University Hospital.

The trial could not demonstrate an impact on preventing major clinical events, but it did reinforce the safety of remote monitoring, he said.

The study also found a significant 27% reduction in the number of inappropriate shocks delivered by the ICDs, from approximately 8% in the control group to 5% in the remote-monitoring group.

Among several weaknesses of the study, there were no interventions planned in response to monitoring, said Dr. Angelo Auricchio, who commented on the study in the presentation session. Using the data to intervene in problems with ICDs is "the greatest advantage" of the technology, so it is not surprising that the EVATEL study did not show a major impact on cardiovascular end points, said Dr. Auricchio of the Fondazione Cardiocentro Ticino, Lugano, Switzerland.

In addition, the number of patients in the study did not quite reach the calculated sample size required to demonstrate noninferiority of home ICD monitoring.

The separate Effectiveness and Cost of ICD Follow-up Schedule with Telecardiology (ECOST) study randomized 433 patients in 43 French centers to daily remote monitoring using the Biotronik Home Monitoring system or quarterly in-clinic follow-up for 27 months.

Rates of a combined end point of mortality, major cardiovascular events, or major device-related adverse events did not differ significantly between groups, affecting 38% of the remote-monitoring group and 42% of the control group, Dr. Salem Kacet and his associates reported.

Among secondary outcomes, the remote monitoring group showed a significant 52% reduction in the number of patients receiving inappropriate shocks (5% in the remote-monitoring group and 10% in the control group), said Dr. Kacet of the University of Lille, France.

The number of patients hospitalized because of inappropriate shocks also was significantly lower in the remote-monitoring group (3) compared with the control group (11).

A significant 76% decrease in the total number of charged shocks in the remote-monitoring group (499 shocks), compared with the control group (2,081 shocks) translated into a significant impact on battery longevity. Among patients with more than one charged shock during the study, ICD battery capacity depleted 0.07% per day in the remote-monitoring group and 0.18% per day in the control group, so that 3 patients in the remote-monitoring group and 11 in the control group had ICDs left with less than 50% of battery capacity.

The number of delivered shocks was significantly lower in the remote-monitoring group (193) than in the control group (657), a significant 71% difference.

Quality-of-life scores on the Short Form-36 were similar between groups.

The relatively long-term follow-up of the ECOST study supports the safety and noninferiority of remote monitoring of ICDs, and shows that home monitoring could reduce inappropriate shocks, charged shocks and delivered shocks, thus prolonging battery longevity and potentially delaying the need for battery replacement surgery, as well as decreasing associated risks.

"This is a very important observation," said Dr. Sidney Goldstein of Henry Ford Hospital, Detroit, who co-moderated a press briefing that included the two studies.

Dr. Kacet said the investigators will perform a secondary analysis of costs in the two monitoring groups soon. The cost analysis is important, because it is not known if the cost of resources to analyze the increased data from home monitoring outweighs potential financial benefits from reduced shocks and prolonged battery life, Dr. Gordon F. Tomaselli said in an interview.

U.S. patients with ICDs often have more than one doctor managing their care. If home monitoring can eliminate some visits to their primary care doctor, cardiologist, or electrophysiologist, this could make an important difference in convenience and costs, said Dr. Tomaselli, president of the American Heart Association and chief of cardiology at Johns Hopkins University, Baltimore.

"We use remote monitoring now for people who find it difficult to get back to our arrhythmia center to be evaluated. I don’t think [these studies] will change things too much in the way of what we do," he said. "For people who are very close, it’s oftentimes not inconvenient for them to come see us face-to-face."

The studies also add to evidence from two previous randomized controlled trials that relied on surrogate end points to evaluate remote ICD monitoring. One study of 1,339 patients reported a 45% reduction in in-office device evaluations among remotely monitored patients without affecting safety (Circulation 2010;122:325-32). A separate study of 1,997 patients found that remote monitoring reduced the time from an ICD-related event to a clinical decision from 22 days to 5 days, and reduced the length of cardiovascular-related hospital stays from an average of 4.0 days to 3.3 days (J. Am. Coll. Cardiol. 2011;57:1181-9).

Biotronik funded the ECOST study. Dr. Kacet has received research funding from Biotronik, Boston Scientific, Medtronic, Saint Jude Medical, Sorin Group, Bayer, Boehringer-Ingelheim, Meda, and Sanofi-Aventis. Dr. Mabo has been a speaker, consultant, or investigator for all five companies making implantable cardiac devices. Dr. Auricchio has been a consultant to all companies making implantable cardiac devices. Dr. Tomaselli said he has no conflicts of interest.

PARIS – Results of two randomized controlled trials appear to solidify the safety of remote monitoring of implantable cardioverter defibrillators, and one of the studies showed a significant decrease in the number of patients receiving inappropriate shocks in the remote-monitoring group.

Manufacturers of ICDs currently recommend in-clinic follow-up every 3 months to detect clinical events or device malfunctions. With increasing numbers of people receiving ICDs to prevent sudden cardiac death from rhythm disturbances, investigators are testing ways to avoid the time constraints of so many in-clinic visits by remotely transmitting information from the device via telephone from the patient’s home. Most ICDs now have this capability.

The two randomized controlled trials support findings from patient registries in Europe and in the United States, where remote monitoring is common.

In the yearlong Evaluation of Tele Follow-up (EVATEL) trial, 1,501 patients at 30 French centers were randomized to in-clinic follow-up at the implant center every 3 months or to remote transmission of data to the implant center every 3 months. The study included four types of ICDs.

Results showed no significant difference between groups in the time to first major cardiovascular event or in the rates of major cardiovascular events (death from all causes, cardiovascular-related hospitalization, or inappropriate or ineffective shocks), Dr. Philippe Mabo and his associates reported at the annual congress of the European Society of Cardiology .

Rates of this composite end point were 28% in the remote-monitoring group and 29% in the control group in an intent-to-treat analysis, showing that home monitoring was not inferior to in-office monitoring. In a per-protocol analysis, the primary end points were seen in 28% and 30% of the groups, respectively, but the confidence interval was too wide to claim that there was no significant difference between groups, said Dr. Mabo of Rennes (France) University Hospital.

The trial could not demonstrate an impact on preventing major clinical events, but it did reinforce the safety of remote monitoring, he said.

The study also found a significant 27% reduction in the number of inappropriate shocks delivered by the ICDs, from approximately 8% in the control group to 5% in the remote-monitoring group.

Among several weaknesses of the study, there were no interventions planned in response to monitoring, said Dr. Angelo Auricchio, who commented on the study in the presentation session. Using the data to intervene in problems with ICDs is "the greatest advantage" of the technology, so it is not surprising that the EVATEL study did not show a major impact on cardiovascular end points, said Dr. Auricchio of the Fondazione Cardiocentro Ticino, Lugano, Switzerland.

In addition, the number of patients in the study did not quite reach the calculated sample size required to demonstrate noninferiority of home ICD monitoring.

The separate Effectiveness and Cost of ICD Follow-up Schedule with Telecardiology (ECOST) study randomized 433 patients in 43 French centers to daily remote monitoring using the Biotronik Home Monitoring system or quarterly in-clinic follow-up for 27 months.

Rates of a combined end point of mortality, major cardiovascular events, or major device-related adverse events did not differ significantly between groups, affecting 38% of the remote-monitoring group and 42% of the control group, Dr. Salem Kacet and his associates reported.

Among secondary outcomes, the remote monitoring group showed a significant 52% reduction in the number of patients receiving inappropriate shocks (5% in the remote-monitoring group and 10% in the control group), said Dr. Kacet of the University of Lille, France.

The number of patients hospitalized because of inappropriate shocks also was significantly lower in the remote-monitoring group (3) compared with the control group (11).

A significant 76% decrease in the total number of charged shocks in the remote-monitoring group (499 shocks), compared with the control group (2,081 shocks) translated into a significant impact on battery longevity. Among patients with more than one charged shock during the study, ICD battery capacity depleted 0.07% per day in the remote-monitoring group and 0.18% per day in the control group, so that 3 patients in the remote-monitoring group and 11 in the control group had ICDs left with less than 50% of battery capacity.

The number of delivered shocks was significantly lower in the remote-monitoring group (193) than in the control group (657), a significant 71% difference.

Quality-of-life scores on the Short Form-36 were similar between groups.

The relatively long-term follow-up of the ECOST study supports the safety and noninferiority of remote monitoring of ICDs, and shows that home monitoring could reduce inappropriate shocks, charged shocks and delivered shocks, thus prolonging battery longevity and potentially delaying the need for battery replacement surgery, as well as decreasing associated risks.

"This is a very important observation," said Dr. Sidney Goldstein of Henry Ford Hospital, Detroit, who co-moderated a press briefing that included the two studies.

Dr. Kacet said the investigators will perform a secondary analysis of costs in the two monitoring groups soon. The cost analysis is important, because it is not known if the cost of resources to analyze the increased data from home monitoring outweighs potential financial benefits from reduced shocks and prolonged battery life, Dr. Gordon F. Tomaselli said in an interview.

U.S. patients with ICDs often have more than one doctor managing their care. If home monitoring can eliminate some visits to their primary care doctor, cardiologist, or electrophysiologist, this could make an important difference in convenience and costs, said Dr. Tomaselli, president of the American Heart Association and chief of cardiology at Johns Hopkins University, Baltimore.

"We use remote monitoring now for people who find it difficult to get back to our arrhythmia center to be evaluated. I don’t think [these studies] will change things too much in the way of what we do," he said. "For people who are very close, it’s oftentimes not inconvenient for them to come see us face-to-face."

The studies also add to evidence from two previous randomized controlled trials that relied on surrogate end points to evaluate remote ICD monitoring. One study of 1,339 patients reported a 45% reduction in in-office device evaluations among remotely monitored patients without affecting safety (Circulation 2010;122:325-32). A separate study of 1,997 patients found that remote monitoring reduced the time from an ICD-related event to a clinical decision from 22 days to 5 days, and reduced the length of cardiovascular-related hospital stays from an average of 4.0 days to 3.3 days (J. Am. Coll. Cardiol. 2011;57:1181-9).

Biotronik funded the ECOST study. Dr. Kacet has received research funding from Biotronik, Boston Scientific, Medtronic, Saint Jude Medical, Sorin Group, Bayer, Boehringer-Ingelheim, Meda, and Sanofi-Aventis. Dr. Mabo has been a speaker, consultant, or investigator for all five companies making implantable cardiac devices. Dr. Auricchio has been a consultant to all companies making implantable cardiac devices. Dr. Tomaselli said he has no conflicts of interest.

PARIS – Results of two randomized controlled trials appear to solidify the safety of remote monitoring of implantable cardioverter defibrillators, and one of the studies showed a significant decrease in the number of patients receiving inappropriate shocks in the remote-monitoring group.

Manufacturers of ICDs currently recommend in-clinic follow-up every 3 months to detect clinical events or device malfunctions. With increasing numbers of people receiving ICDs to prevent sudden cardiac death from rhythm disturbances, investigators are testing ways to avoid the time constraints of so many in-clinic visits by remotely transmitting information from the device via telephone from the patient’s home. Most ICDs now have this capability.

The two randomized controlled trials support findings from patient registries in Europe and in the United States, where remote monitoring is common.

In the yearlong Evaluation of Tele Follow-up (EVATEL) trial, 1,501 patients at 30 French centers were randomized to in-clinic follow-up at the implant center every 3 months or to remote transmission of data to the implant center every 3 months. The study included four types of ICDs.

Results showed no significant difference between groups in the time to first major cardiovascular event or in the rates of major cardiovascular events (death from all causes, cardiovascular-related hospitalization, or inappropriate or ineffective shocks), Dr. Philippe Mabo and his associates reported at the annual congress of the European Society of Cardiology .

Rates of this composite end point were 28% in the remote-monitoring group and 29% in the control group in an intent-to-treat analysis, showing that home monitoring was not inferior to in-office monitoring. In a per-protocol analysis, the primary end points were seen in 28% and 30% of the groups, respectively, but the confidence interval was too wide to claim that there was no significant difference between groups, said Dr. Mabo of Rennes (France) University Hospital.

The trial could not demonstrate an impact on preventing major clinical events, but it did reinforce the safety of remote monitoring, he said.

The study also found a significant 27% reduction in the number of inappropriate shocks delivered by the ICDs, from approximately 8% in the control group to 5% in the remote-monitoring group.

Among several weaknesses of the study, there were no interventions planned in response to monitoring, said Dr. Angelo Auricchio, who commented on the study in the presentation session. Using the data to intervene in problems with ICDs is "the greatest advantage" of the technology, so it is not surprising that the EVATEL study did not show a major impact on cardiovascular end points, said Dr. Auricchio of the Fondazione Cardiocentro Ticino, Lugano, Switzerland.

In addition, the number of patients in the study did not quite reach the calculated sample size required to demonstrate noninferiority of home ICD monitoring.

The separate Effectiveness and Cost of ICD Follow-up Schedule with Telecardiology (ECOST) study randomized 433 patients in 43 French centers to daily remote monitoring using the Biotronik Home Monitoring system or quarterly in-clinic follow-up for 27 months.

Rates of a combined end point of mortality, major cardiovascular events, or major device-related adverse events did not differ significantly between groups, affecting 38% of the remote-monitoring group and 42% of the control group, Dr. Salem Kacet and his associates reported.

Among secondary outcomes, the remote monitoring group showed a significant 52% reduction in the number of patients receiving inappropriate shocks (5% in the remote-monitoring group and 10% in the control group), said Dr. Kacet of the University of Lille, France.

The number of patients hospitalized because of inappropriate shocks also was significantly lower in the remote-monitoring group (3) compared with the control group (11).

A significant 76% decrease in the total number of charged shocks in the remote-monitoring group (499 shocks), compared with the control group (2,081 shocks) translated into a significant impact on battery longevity. Among patients with more than one charged shock during the study, ICD battery capacity depleted 0.07% per day in the remote-monitoring group and 0.18% per day in the control group, so that 3 patients in the remote-monitoring group and 11 in the control group had ICDs left with less than 50% of battery capacity.

The number of delivered shocks was significantly lower in the remote-monitoring group (193) than in the control group (657), a significant 71% difference.

Quality-of-life scores on the Short Form-36 were similar between groups.

The relatively long-term follow-up of the ECOST study supports the safety and noninferiority of remote monitoring of ICDs, and shows that home monitoring could reduce inappropriate shocks, charged shocks and delivered shocks, thus prolonging battery longevity and potentially delaying the need for battery replacement surgery, as well as decreasing associated risks.

"This is a very important observation," said Dr. Sidney Goldstein of Henry Ford Hospital, Detroit, who co-moderated a press briefing that included the two studies.

Dr. Kacet said the investigators will perform a secondary analysis of costs in the two monitoring groups soon. The cost analysis is important, because it is not known if the cost of resources to analyze the increased data from home monitoring outweighs potential financial benefits from reduced shocks and prolonged battery life, Dr. Gordon F. Tomaselli said in an interview.

U.S. patients with ICDs often have more than one doctor managing their care. If home monitoring can eliminate some visits to their primary care doctor, cardiologist, or electrophysiologist, this could make an important difference in convenience and costs, said Dr. Tomaselli, president of the American Heart Association and chief of cardiology at Johns Hopkins University, Baltimore.

"We use remote monitoring now for people who find it difficult to get back to our arrhythmia center to be evaluated. I don’t think [these studies] will change things too much in the way of what we do," he said. "For people who are very close, it’s oftentimes not inconvenient for them to come see us face-to-face."

The studies also add to evidence from two previous randomized controlled trials that relied on surrogate end points to evaluate remote ICD monitoring. One study of 1,339 patients reported a 45% reduction in in-office device evaluations among remotely monitored patients without affecting safety (Circulation 2010;122:325-32). A separate study of 1,997 patients found that remote monitoring reduced the time from an ICD-related event to a clinical decision from 22 days to 5 days, and reduced the length of cardiovascular-related hospital stays from an average of 4.0 days to 3.3 days (J. Am. Coll. Cardiol. 2011;57:1181-9).

Biotronik funded the ECOST study. Dr. Kacet has received research funding from Biotronik, Boston Scientific, Medtronic, Saint Jude Medical, Sorin Group, Bayer, Boehringer-Ingelheim, Meda, and Sanofi-Aventis. Dr. Mabo has been a speaker, consultant, or investigator for all five companies making implantable cardiac devices. Dr. Auricchio has been a consultant to all companies making implantable cardiac devices. Dr. Tomaselli said he has no conflicts of interest.

SAN FRANCISCO – Updated national guidelines on calcium and vitamin D intake should be followed only loosely, cautioned Dr. Deborah E. Sellmeyer, director of the Metabolic Bone Center at Johns Hopkins University, Baltimore.

There’s a lot of controversy surrounding the Institute of Medicine’s (IOM) November 2010 report, "Dietary Reference Intakes for Calcium and Vitamin D," which updated 1997 guidelines. Dr. Sellmeyer uses the latest IOM report as a starting point and then tailors the recommendations to meet the needs of her individual patients. And as a result, the amounts of vitamin D and calcium that her patients take usually vary from the guidelines, she said at a conference on osteoporosis sponsored by the University of California, San Francisco.

(c) Mary Hope/iStockphoto

There is uncertainty about the cutoff level of serum vitamin D that’s considered adequate and the potential side effects from ingesting too much calcium, she said.

The IOM recommends that adults take 600 IU/day through age 50 and 800 IU/day for those aged 51 years and older, with a suggested upper tolerability limit of 4,000 IU/day. Those are the intake amounts that generally would be needed to reach a serum level of 20 ng/mL.

Many experts, however, think that physiologic and fracture data suggest that a "sufficient" serum level should be in the 30-32 ng/mL range, she said. "It takes most people about 1,200 IU/day to reach that" serum level, said Dr. Sellmeyer, who advises her patients to get 1,200 IU/day of vitamin D.

A 2010 study of high-dose vitamin D and fracture risk caused "a lot of consternation," she noted. The double-blind trial randomized 2,256 older women to a once-yearly oral dose of 500,000 IU cholecalciferol or placebo, and found higher rates of falls and fractures in the vitamin D group (JAMA 2010;303:1815-22).

"It’s almost a moot point because you wouldn’t give 500,000 IU once a year, but it did raise the idea that there may be some administration techniques, some regimens that would not be beneficial," Dr. Sellmeyer said.

The IOM committee that compiled the 2010 report expressed a great deal of concern about a potentially higher mortality risk with excessively high vitamin D serum levels. The concern was sparked by the committee’s interpretation of an analysis of data from the Third National Health and Nutrition Examination Survey. Overall, that survey documented higher mortality rates in patients in the lowest quartile of serum vitamin D levels (Arch. Intern. Med. 2008;168:1629-37). However, the IOM committee noticed a statistically nonsignificant dip in mortality risk between the highest and second-highest quartiles of serum vitamin D before the mortality risk increased in each of the two lowest quartiles, constituting what some saw as a J-shaped curve to mortality risk.

Numerically, the lowest mortality was in patients with 24-32 ng/mL of serum vitamin D, but this was statistically not significantly different than in patients with a serum level greater than 32 ng/mL.

"I’m really not sure that there is a higher mortality," Dr. Sellmeyer said. "I think there is enough evidence to suggest that we probably ought to be a little more in the 30-40 ng/mL range."

The IOM recommends that adult males get 1,000 mg/day of calcium through age 70 years and 1,200 mg/day for those who are older. Adult women should get 1,000 mg/day through age 50 and 1,200 mg/day in older ages. The maximum tolerability limits were set at 2,500 mg/day for adults younger than 50 years or 2,000 mg/day for older adults.

It’s important to remember that the recommended level includes both dietary and supplemental sources of calcium, she emphasized. "We see a lot of women who are taking 1,200-1,500 mg/day in supplements and also drinking two glasses of milk a day," she said. "Those [are the patients who] can get into trouble."

There are no data to suggest that ingesting more than 1,200 mg/day is better for skeletal health, and high doses of calcium increase the risk of developing kidney stones, studies show.

The most controversial aspect of calcium supplementation in recent years has been some preliminary evidence of a possible increased risk for vascular calcification with higher doses of calcium.

Initially, an analysis of data on 36,282 participants in the Women’s Health Initiative (WHI) who were randomized to take 500 mg calcium carbonate with 200 IU vitamin D twice daily found no effect on risk of myocardial infarction (MI) or vascular calcification (Circulation 2007;115:846-54).

Then a randomized, controlled trial of 1,471 healthy women found that the group taking 1 g/day of calcium citrate showed a doubling in risk for MI and a trend toward higher risk of angina, compared with the placebo group (BMJ. 2008;336:262-6). The investigators in that study re-analyzed the WHI data and found a 22% increase in risk for MI in women who at baseline had no personal calcium use (BMJ 2011;19:342:d2040).

There were significant differences in the comparison groups in the re-analysis, including differences in personal history of MI, Dr. Sellmeyer noted. "Whether this truly represents an increased risk or not is unclear," she said.

Another study by some of the same investigators "got a ton of press" even though it was a relatively small meta-analysis, she added. The attempted meta-analysis of 190 trials of calcium supplementation yielded 15 eligible trials, but most of the data came from 5 trials. The meta-analysis reported a 31% increase in risk for MI in calcium supplement users, with possibly a higher risk in those taking more than 1,600 mg/day (BMJ 2010;341:c3691).

"It’s really hard to know at this point" whether the risk of vascular calcification from supplementation is significant, Dr. Sellmeyer said. "I think it does behoove us to be judicious with our calcium and not let people consume more calcium than we think is really beneficial."

Calcium citrate probably is a little better absorbed than calcium carbonate and may be a little less constipating, "but for a lot of people it doesn’t matter," she said.

As always, physicians should be alert for conditions in their patients that might warrant higher intakes of calcium or vitamin D, she said, including malabsorption (as in patients who underwent gastric bypass surgery), healing osteomalacia, fracture healing, anabolic therapy, postoperative hyperparathyroidism, hypoparathyroidism, or adolescence.

Dr. Sellmeyer said she has no relevant conflicts of interest.

SAN FRANCISCO – Updated national guidelines on calcium and vitamin D intake should be followed only loosely, cautioned Dr. Deborah E. Sellmeyer, director of the Metabolic Bone Center at Johns Hopkins University, Baltimore.

There’s a lot of controversy surrounding the Institute of Medicine’s (IOM) November 2010 report, "Dietary Reference Intakes for Calcium and Vitamin D," which updated 1997 guidelines. Dr. Sellmeyer uses the latest IOM report as a starting point and then tailors the recommendations to meet the needs of her individual patients. And as a result, the amounts of vitamin D and calcium that her patients take usually vary from the guidelines, she said at a conference on osteoporosis sponsored by the University of California, San Francisco.

(c) Mary Hope/iStockphoto

There is uncertainty about the cutoff level of serum vitamin D that’s considered adequate and the potential side effects from ingesting too much calcium, she said.

The IOM recommends that adults take 600 IU/day through age 50 and 800 IU/day for those aged 51 years and older, with a suggested upper tolerability limit of 4,000 IU/day. Those are the intake amounts that generally would be needed to reach a serum level of 20 ng/mL.

Many experts, however, think that physiologic and fracture data suggest that a "sufficient" serum level should be in the 30-32 ng/mL range, she said. "It takes most people about 1,200 IU/day to reach that" serum level, said Dr. Sellmeyer, who advises her patients to get 1,200 IU/day of vitamin D.

A 2010 study of high-dose vitamin D and fracture risk caused "a lot of consternation," she noted. The double-blind trial randomized 2,256 older women to a once-yearly oral dose of 500,000 IU cholecalciferol or placebo, and found higher rates of falls and fractures in the vitamin D group (JAMA 2010;303:1815-22).

"It’s almost a moot point because you wouldn’t give 500,000 IU once a year, but it did raise the idea that there may be some administration techniques, some regimens that would not be beneficial," Dr. Sellmeyer said.

The IOM committee that compiled the 2010 report expressed a great deal of concern about a potentially higher mortality risk with excessively high vitamin D serum levels. The concern was sparked by the committee’s interpretation of an analysis of data from the Third National Health and Nutrition Examination Survey. Overall, that survey documented higher mortality rates in patients in the lowest quartile of serum vitamin D levels (Arch. Intern. Med. 2008;168:1629-37). However, the IOM committee noticed a statistically nonsignificant dip in mortality risk between the highest and second-highest quartiles of serum vitamin D before the mortality risk increased in each of the two lowest quartiles, constituting what some saw as a J-shaped curve to mortality risk.

Numerically, the lowest mortality was in patients with 24-32 ng/mL of serum vitamin D, but this was statistically not significantly different than in patients with a serum level greater than 32 ng/mL.

"I’m really not sure that there is a higher mortality," Dr. Sellmeyer said. "I think there is enough evidence to suggest that we probably ought to be a little more in the 30-40 ng/mL range."

The IOM recommends that adult males get 1,000 mg/day of calcium through age 70 years and 1,200 mg/day for those who are older. Adult women should get 1,000 mg/day through age 50 and 1,200 mg/day in older ages. The maximum tolerability limits were set at 2,500 mg/day for adults younger than 50 years or 2,000 mg/day for older adults.

It’s important to remember that the recommended level includes both dietary and supplemental sources of calcium, she emphasized. "We see a lot of women who are taking 1,200-1,500 mg/day in supplements and also drinking two glasses of milk a day," she said. "Those [are the patients who] can get into trouble."

There are no data to suggest that ingesting more than 1,200 mg/day is better for skeletal health, and high doses of calcium increase the risk of developing kidney stones, studies show.

The most controversial aspect of calcium supplementation in recent years has been some preliminary evidence of a possible increased risk for vascular calcification with higher doses of calcium.

Initially, an analysis of data on 36,282 participants in the Women’s Health Initiative (WHI) who were randomized to take 500 mg calcium carbonate with 200 IU vitamin D twice daily found no effect on risk of myocardial infarction (MI) or vascular calcification (Circulation 2007;115:846-54).

Then a randomized, controlled trial of 1,471 healthy women found that the group taking 1 g/day of calcium citrate showed a doubling in risk for MI and a trend toward higher risk of angina, compared with the placebo group (BMJ. 2008;336:262-6). The investigators in that study re-analyzed the WHI data and found a 22% increase in risk for MI in women who at baseline had no personal calcium use (BMJ 2011;19:342:d2040).

There were significant differences in the comparison groups in the re-analysis, including differences in personal history of MI, Dr. Sellmeyer noted. "Whether this truly represents an increased risk or not is unclear," she said.

Another study by some of the same investigators "got a ton of press" even though it was a relatively small meta-analysis, she added. The attempted meta-analysis of 190 trials of calcium supplementation yielded 15 eligible trials, but most of the data came from 5 trials. The meta-analysis reported a 31% increase in risk for MI in calcium supplement users, with possibly a higher risk in those taking more than 1,600 mg/day (BMJ 2010;341:c3691).

"It’s really hard to know at this point" whether the risk of vascular calcification from supplementation is significant, Dr. Sellmeyer said. "I think it does behoove us to be judicious with our calcium and not let people consume more calcium than we think is really beneficial."

Calcium citrate probably is a little better absorbed than calcium carbonate and may be a little less constipating, "but for a lot of people it doesn’t matter," she said.

As always, physicians should be alert for conditions in their patients that might warrant higher intakes of calcium or vitamin D, she said, including malabsorption (as in patients who underwent gastric bypass surgery), healing osteomalacia, fracture healing, anabolic therapy, postoperative hyperparathyroidism, hypoparathyroidism, or adolescence.

Dr. Sellmeyer said she has no relevant conflicts of interest.

SAN FRANCISCO – Updated national guidelines on calcium and vitamin D intake should be followed only loosely, cautioned Dr. Deborah E. Sellmeyer, director of the Metabolic Bone Center at Johns Hopkins University, Baltimore.

There’s a lot of controversy surrounding the Institute of Medicine’s (IOM) November 2010 report, "Dietary Reference Intakes for Calcium and Vitamin D," which updated 1997 guidelines. Dr. Sellmeyer uses the latest IOM report as a starting point and then tailors the recommendations to meet the needs of her individual patients. And as a result, the amounts of vitamin D and calcium that her patients take usually vary from the guidelines, she said at a conference on osteoporosis sponsored by the University of California, San Francisco.

(c) Mary Hope/iStockphoto

There is uncertainty about the cutoff level of serum vitamin D that’s considered adequate and the potential side effects from ingesting too much calcium, she said.

The IOM recommends that adults take 600 IU/day through age 50 and 800 IU/day for those aged 51 years and older, with a suggested upper tolerability limit of 4,000 IU/day. Those are the intake amounts that generally would be needed to reach a serum level of 20 ng/mL.

Many experts, however, think that physiologic and fracture data suggest that a "sufficient" serum level should be in the 30-32 ng/mL range, she said. "It takes most people about 1,200 IU/day to reach that" serum level, said Dr. Sellmeyer, who advises her patients to get 1,200 IU/day of vitamin D.

A 2010 study of high-dose vitamin D and fracture risk caused "a lot of consternation," she noted. The double-blind trial randomized 2,256 older women to a once-yearly oral dose of 500,000 IU cholecalciferol or placebo, and found higher rates of falls and fractures in the vitamin D group (JAMA 2010;303:1815-22).

"It’s almost a moot point because you wouldn’t give 500,000 IU once a year, but it did raise the idea that there may be some administration techniques, some regimens that would not be beneficial," Dr. Sellmeyer said.

The IOM committee that compiled the 2010 report expressed a great deal of concern about a potentially higher mortality risk with excessively high vitamin D serum levels. The concern was sparked by the committee’s interpretation of an analysis of data from the Third National Health and Nutrition Examination Survey. Overall, that survey documented higher mortality rates in patients in the lowest quartile of serum vitamin D levels (Arch. Intern. Med. 2008;168:1629-37). However, the IOM committee noticed a statistically nonsignificant dip in mortality risk between the highest and second-highest quartiles of serum vitamin D before the mortality risk increased in each of the two lowest quartiles, constituting what some saw as a J-shaped curve to mortality risk.

Numerically, the lowest mortality was in patients with 24-32 ng/mL of serum vitamin D, but this was statistically not significantly different than in patients with a serum level greater than 32 ng/mL.

"I’m really not sure that there is a higher mortality," Dr. Sellmeyer said. "I think there is enough evidence to suggest that we probably ought to be a little more in the 30-40 ng/mL range."

The IOM recommends that adult males get 1,000 mg/day of calcium through age 70 years and 1,200 mg/day for those who are older. Adult women should get 1,000 mg/day through age 50 and 1,200 mg/day in older ages. The maximum tolerability limits were set at 2,500 mg/day for adults younger than 50 years or 2,000 mg/day for older adults.

It’s important to remember that the recommended level includes both dietary and supplemental sources of calcium, she emphasized. "We see a lot of women who are taking 1,200-1,500 mg/day in supplements and also drinking two glasses of milk a day," she said. "Those [are the patients who] can get into trouble."

There are no data to suggest that ingesting more than 1,200 mg/day is better for skeletal health, and high doses of calcium increase the risk of developing kidney stones, studies show.

The most controversial aspect of calcium supplementation in recent years has been some preliminary evidence of a possible increased risk for vascular calcification with higher doses of calcium.

Initially, an analysis of data on 36,282 participants in the Women’s Health Initiative (WHI) who were randomized to take 500 mg calcium carbonate with 200 IU vitamin D twice daily found no effect on risk of myocardial infarction (MI) or vascular calcification (Circulation 2007;115:846-54).

Then a randomized, controlled trial of 1,471 healthy women found that the group taking 1 g/day of calcium citrate showed a doubling in risk for MI and a trend toward higher risk of angina, compared with the placebo group (BMJ. 2008;336:262-6). The investigators in that study re-analyzed the WHI data and found a 22% increase in risk for MI in women who at baseline had no personal calcium use (BMJ 2011;19:342:d2040).

There were significant differences in the comparison groups in the re-analysis, including differences in personal history of MI, Dr. Sellmeyer noted. "Whether this truly represents an increased risk or not is unclear," she said.

Another study by some of the same investigators "got a ton of press" even though it was a relatively small meta-analysis, she added. The attempted meta-analysis of 190 trials of calcium supplementation yielded 15 eligible trials, but most of the data came from 5 trials. The meta-analysis reported a 31% increase in risk for MI in calcium supplement users, with possibly a higher risk in those taking more than 1,600 mg/day (BMJ 2010;341:c3691).

"It’s really hard to know at this point" whether the risk of vascular calcification from supplementation is significant, Dr. Sellmeyer said. "I think it does behoove us to be judicious with our calcium and not let people consume more calcium than we think is really beneficial."

Calcium citrate probably is a little better absorbed than calcium carbonate and may be a little less constipating, "but for a lot of people it doesn’t matter," she said.

As always, physicians should be alert for conditions in their patients that might warrant higher intakes of calcium or vitamin D, she said, including malabsorption (as in patients who underwent gastric bypass surgery), healing osteomalacia, fracture healing, anabolic therapy, postoperative hyperparathyroidism, hypoparathyroidism, or adolescence.

Dr. Sellmeyer said she has no relevant conflicts of interest.

PARIS – Postprandial triglyceride levels helped assess cardiovascular risk in patients with normal glucose tolerance but provided no extra prognostic information in those with impaired glucose tolerance or diabetes in a prospective study of 514 consecutive patients with stable coronary artery disease.

In the Homburg Cream and Sugar Study participants who were undergoing coronary angiography ate a standardized dinner at 6 p.m., fasted overnight, and at 8 a.m. drank 250 ml of cream containing 75 g of fat. Three hours later those who were not receiving treatment for diabetes also drank 250 ml of water containing 75 g of glucose.

Photo credit: Sherry Boschert/Elsevier Global Medical News

Investigators then measured fasting and postprandial triglyceride concentrations, followed by insulin concentrations and glucose tolerance. Follow-up 12 and 18 months later identified cardiovascular events.

Diabetes was present in 46% of patients, and only 25% had completely normal glucose tolerance. Patient characteristics were typical of those with coronary artery disease, Dr. Ulrich Laufs and his associates reported at the annual congress of the European Society of Cardiology.

For the cohort as a whole, postprandial triglyceride levels did not correlate with the primary outcome, a composite of cardiovascular deaths or hospitalizations for cardiovascular events. A weak correlation between fasting triglycerides and the primary outcome became non-significant in multivariate analysis.

Fasting triglyceride levels, and to an even greater extent postprandial triglyceride levels, were independent markers for the primary cardiovascular outcomes, said Dr. Laufs of Saarland University Hospital, Homburg, Germany. In patients with diabetes and impaired fasting glucose, however, absolute fasting and postprandial triglyceride levels were high but did not independently predict risk of cardiovascular death or hospitalization.

The highest tertile of triglyceride concentrations – levels above 150 mg/dL – in patients with normal glucose tolerance predicted a tripling in risk for the cardiovascular endpoints, compared with the middle and lowest tertiles. The highest tertile of postprandial triglyceride levels predicted a four-fold increased risk in patients with normal glucose tolerance. The study controlled for the effects of other risk factors, including other lipids, age, and sex.

These findings were "a little bit surprising," he said.

The study was designed to help address ongoing debate about whether triglyceride levels add to other measures of cardiovascular risk. "There is evidence from primary prevention studies and from mechanistic basic science studies that maybe the triglyceride-rich lipoproteins that are increased after a meal may be especially atherogenic," Dr. Laufs said.

Triglycerides are regulated not only by the time and type of meal but other factors as well. Importantly, glucose metabolism influences triglyceride kinetics, the study showed. Compared to patients with diabetes, those without diabetes had lower concentrations of fasting and absolute triglycerides and increased postprandial triglycerides. The relative increase, however, was similar between these two groups, he said.

"For the majority of patients, the primary consequence of this analysis is that we have to look very carefully at glucose metabolism," he said. "We may have to focus more on patients with normal glucose tolerance. If those patients have high fasting triglycerides, they have increased risk. It may be interesting in the future to look at whether these patients may benefit from intervention."

The study was limited by looking at only the first 5 hours after a meal, statin therapy in 95% of patients, the absence of genetic testing, and a predominantly Caucasian cohort, he said.

Dr. Laufs has been a speaker for nearly all pharmaceutical companies dealing with lipids.

PARIS – Postprandial triglyceride levels helped assess cardiovascular risk in patients with normal glucose tolerance but provided no extra prognostic information in those with impaired glucose tolerance or diabetes in a prospective study of 514 consecutive patients with stable coronary artery disease.

In the Homburg Cream and Sugar Study participants who were undergoing coronary angiography ate a standardized dinner at 6 p.m., fasted overnight, and at 8 a.m. drank 250 ml of cream containing 75 g of fat. Three hours later those who were not receiving treatment for diabetes also drank 250 ml of water containing 75 g of glucose.

Photo credit: Sherry Boschert/Elsevier Global Medical News

Investigators then measured fasting and postprandial triglyceride concentrations, followed by insulin concentrations and glucose tolerance. Follow-up 12 and 18 months later identified cardiovascular events.

Diabetes was present in 46% of patients, and only 25% had completely normal glucose tolerance. Patient characteristics were typical of those with coronary artery disease, Dr. Ulrich Laufs and his associates reported at the annual congress of the European Society of Cardiology.

For the cohort as a whole, postprandial triglyceride levels did not correlate with the primary outcome, a composite of cardiovascular deaths or hospitalizations for cardiovascular events. A weak correlation between fasting triglycerides and the primary outcome became non-significant in multivariate analysis.

Fasting triglyceride levels, and to an even greater extent postprandial triglyceride levels, were independent markers for the primary cardiovascular outcomes, said Dr. Laufs of Saarland University Hospital, Homburg, Germany. In patients with diabetes and impaired fasting glucose, however, absolute fasting and postprandial triglyceride levels were high but did not independently predict risk of cardiovascular death or hospitalization.

The highest tertile of triglyceride concentrations – levels above 150 mg/dL – in patients with normal glucose tolerance predicted a tripling in risk for the cardiovascular endpoints, compared with the middle and lowest tertiles. The highest tertile of postprandial triglyceride levels predicted a four-fold increased risk in patients with normal glucose tolerance. The study controlled for the effects of other risk factors, including other lipids, age, and sex.

These findings were "a little bit surprising," he said.

The study was designed to help address ongoing debate about whether triglyceride levels add to other measures of cardiovascular risk. "There is evidence from primary prevention studies and from mechanistic basic science studies that maybe the triglyceride-rich lipoproteins that are increased after a meal may be especially atherogenic," Dr. Laufs said.

Triglycerides are regulated not only by the time and type of meal but other factors as well. Importantly, glucose metabolism influences triglyceride kinetics, the study showed. Compared to patients with diabetes, those without diabetes had lower concentrations of fasting and absolute triglycerides and increased postprandial triglycerides. The relative increase, however, was similar between these two groups, he said.

"For the majority of patients, the primary consequence of this analysis is that we have to look very carefully at glucose metabolism," he said. "We may have to focus more on patients with normal glucose tolerance. If those patients have high fasting triglycerides, they have increased risk. It may be interesting in the future to look at whether these patients may benefit from intervention."

The study was limited by looking at only the first 5 hours after a meal, statin therapy in 95% of patients, the absence of genetic testing, and a predominantly Caucasian cohort, he said.

Dr. Laufs has been a speaker for nearly all pharmaceutical companies dealing with lipids.

PARIS – Postprandial triglyceride levels helped assess cardiovascular risk in patients with normal glucose tolerance but provided no extra prognostic information in those with impaired glucose tolerance or diabetes in a prospective study of 514 consecutive patients with stable coronary artery disease.

In the Homburg Cream and Sugar Study participants who were undergoing coronary angiography ate a standardized dinner at 6 p.m., fasted overnight, and at 8 a.m. drank 250 ml of cream containing 75 g of fat. Three hours later those who were not receiving treatment for diabetes also drank 250 ml of water containing 75 g of glucose.

Photo credit: Sherry Boschert/Elsevier Global Medical News

Investigators then measured fasting and postprandial triglyceride concentrations, followed by insulin concentrations and glucose tolerance. Follow-up 12 and 18 months later identified cardiovascular events.

Diabetes was present in 46% of patients, and only 25% had completely normal glucose tolerance. Patient characteristics were typical of those with coronary artery disease, Dr. Ulrich Laufs and his associates reported at the annual congress of the European Society of Cardiology.

For the cohort as a whole, postprandial triglyceride levels did not correlate with the primary outcome, a composite of cardiovascular deaths or hospitalizations for cardiovascular events. A weak correlation between fasting triglycerides and the primary outcome became non-significant in multivariate analysis.

Fasting triglyceride levels, and to an even greater extent postprandial triglyceride levels, were independent markers for the primary cardiovascular outcomes, said Dr. Laufs of Saarland University Hospital, Homburg, Germany. In patients with diabetes and impaired fasting glucose, however, absolute fasting and postprandial triglyceride levels were high but did not independently predict risk of cardiovascular death or hospitalization.

The highest tertile of triglyceride concentrations – levels above 150 mg/dL – in patients with normal glucose tolerance predicted a tripling in risk for the cardiovascular endpoints, compared with the middle and lowest tertiles. The highest tertile of postprandial triglyceride levels predicted a four-fold increased risk in patients with normal glucose tolerance. The study controlled for the effects of other risk factors, including other lipids, age, and sex.

These findings were "a little bit surprising," he said.

The study was designed to help address ongoing debate about whether triglyceride levels add to other measures of cardiovascular risk. "There is evidence from primary prevention studies and from mechanistic basic science studies that maybe the triglyceride-rich lipoproteins that are increased after a meal may be especially atherogenic," Dr. Laufs said.

Triglycerides are regulated not only by the time and type of meal but other factors as well. Importantly, glucose metabolism influences triglyceride kinetics, the study showed. Compared to patients with diabetes, those without diabetes had lower concentrations of fasting and absolute triglycerides and increased postprandial triglycerides. The relative increase, however, was similar between these two groups, he said.

"For the majority of patients, the primary consequence of this analysis is that we have to look very carefully at glucose metabolism," he said. "We may have to focus more on patients with normal glucose tolerance. If those patients have high fasting triglycerides, they have increased risk. It may be interesting in the future to look at whether these patients may benefit from intervention."

The study was limited by looking at only the first 5 hours after a meal, statin therapy in 95% of patients, the absence of genetic testing, and a predominantly Caucasian cohort, he said.

Dr. Laufs has been a speaker for nearly all pharmaceutical companies dealing with lipids.

SAN FRANCISCO – Three experimental therapies may improve bone mass more than do existing treatments for osteoporosis.

One of them, anti-sclerostin antibodies, "may be the most potent agent yet for formation of bone," Dr. Steven R. Cummings said at a meeting on osteoporosis sponsored by the University of California, San Francisco.

Anti-sclerostin monoclonal antibodies are in phase II clinical trials. "It will probably be 3-4 years before we see results in terms of risk of fracture," said Dr. Cummings, professor of medicine and epidemiology and biostatistics at the university.

A phase III trial that will assess impact on fracture risk is underway for a different drug, the cathepsin K inhibitor odanacatib, which appears to improve bone mineral density, compared with placebo, he said. Data on whether odanacatib reduces the risk of nonvertebral fractures more than current therapies should be available in approximately 2 years.

The third promising agent is a well-known drug used off label: nitroglycerin. A preliminary study suggests it increases bone mineral density and bone strength, but the fact that nitrates are generic and widely available makes it unlikely that a pharmaceutical company will sponsor clinical trials for this indication.

"We’d like to do a phase II study to compare several doses" of nitroglycerin in patients with low bone density, "but we can’t get the funding from the National Institutes of Health," Dr. Cummings said.

These promising agents might strengthen a weak spot in osteoporosis treatment by helping to reduce nonvertebral fractures, he said. Current treatments can produce a 10%-30% reduction in nonvertebral fractures, which account for approximately 90% of days of disability due to fractures.

"We need more effective treatments," he said.

Anti-Sclerostin Antibodies

Sclerostin is produced by mature osteocytes in response to decreased loading, and is found in no other cells. It inhibits the formation of osteoblasts.

An initial trial of various doses in 48 healthy postmenopausal women found a 5%-6% increase in spine bone mineral density and a 3%-4% increase in total hip bone mineral density in less than 3 months in the 6 women randomized to a single 10-mg/kg injection.

"These are breathtaking increases in bone mineral density, but this is very early, preliminary data," Dr. Cummings said.

Although osteoblasts usually form bone where it has been reabsorbed, anti-sclerostin antibodies induce formation of bone on "quiet" surfaces such as the periosteum, which increases the diameter and bending strength of long bones, he said.

Odanacatib

Osteoclasts produce cathepsin K, which is released during bone resorption and degrades collagen. Blocking cathepsin K blocks the resorption of proteins and limits bone resorption to shallower pits than usual. This might decrease resorption a little yet allow full bone formation, theoretically.

Unpublished data from a 48-month trial suggest that a weekly 50-mg dose of the cathepsin K inhibitor odanacatib produced an 11% increase in lumbar spine bone mineral density, compared with less than a 1% increase on placebo, and a 9% increase in femoral neck bone mineral density on odanacatib, compared with nearly a 2% decrease on placebo.

"These increases over a 4-year span are impressive," said Dr. Cummings, who said he looks forward to results of the fracture end point trial.

Nitroglycerin

Nitroglycerin prevented bone loss due to ovariectomy in rodent studies. A preliminary study in 243 postmenopausal women randomized them to apply ointment containing 15 mg nitroglycerin or placebo every night, and 93% completed a 2-year evaluation.

Femoral neck bone density increased by approximately 6% on nitroglycerin and decreased by approximately 1% on placebo. In general, bisphosphonates increase femoral neck bone density about 4%-5%, he said. Nitroglycerin increased lumbar spine density by nearly 8%, compared with approximately a 1% increase on placebo.

Measures of bone geometry suggested increases in bone size and strength on nitroglycerin. For the radius, cortical thickness increased 14%, periosteal circumference increased 7%, and the polar moment of inertial increased 7% in the nitroglycerin group, compared with placebo. For the tibia, cortical thickness increased 25%, periosteal circumference increased 3%, and the polar moment of inertia increased 10% in the nitroglycerin group, compared with placebo.

Measurements of markers of bone formation and resorption suggest that nitroglycerin "uncouples" bone formation and resorption, he added.

Headaches were common but decreased with time. In a run-in phase of the study, 25% of women stopped treatment due to headache. One year into the study, 6% on nitroglycerin and 2% on placebo had stopped treatment due to headache. After 1 year, only two women in the nitroglycerin group reported headache.

Dr. Cummings has been a consultant to Amgen, which is developing an anti-sclerostin antibody drug, as well as for Merck, which is developing odanacatib, and Eli Lilly.

SAN FRANCISCO – Three experimental therapies may improve bone mass more than do existing treatments for osteoporosis.

One of them, anti-sclerostin antibodies, "may be the most potent agent yet for formation of bone," Dr. Steven R. Cummings said at a meeting on osteoporosis sponsored by the University of California, San Francisco.

Anti-sclerostin monoclonal antibodies are in phase II clinical trials. "It will probably be 3-4 years before we see results in terms of risk of fracture," said Dr. Cummings, professor of medicine and epidemiology and biostatistics at the university.

A phase III trial that will assess impact on fracture risk is underway for a different drug, the cathepsin K inhibitor odanacatib, which appears to improve bone mineral density, compared with placebo, he said. Data on whether odanacatib reduces the risk of nonvertebral fractures more than current therapies should be available in approximately 2 years.

The third promising agent is a well-known drug used off label: nitroglycerin. A preliminary study suggests it increases bone mineral density and bone strength, but the fact that nitrates are generic and widely available makes it unlikely that a pharmaceutical company will sponsor clinical trials for this indication.

"We’d like to do a phase II study to compare several doses" of nitroglycerin in patients with low bone density, "but we can’t get the funding from the National Institutes of Health," Dr. Cummings said.

These promising agents might strengthen a weak spot in osteoporosis treatment by helping to reduce nonvertebral fractures, he said. Current treatments can produce a 10%-30% reduction in nonvertebral fractures, which account for approximately 90% of days of disability due to fractures.

"We need more effective treatments," he said.

Anti-Sclerostin Antibodies

Sclerostin is produced by mature osteocytes in response to decreased loading, and is found in no other cells. It inhibits the formation of osteoblasts.

An initial trial of various doses in 48 healthy postmenopausal women found a 5%-6% increase in spine bone mineral density and a 3%-4% increase in total hip bone mineral density in less than 3 months in the 6 women randomized to a single 10-mg/kg injection.

"These are breathtaking increases in bone mineral density, but this is very early, preliminary data," Dr. Cummings said.

Although osteoblasts usually form bone where it has been reabsorbed, anti-sclerostin antibodies induce formation of bone on "quiet" surfaces such as the periosteum, which increases the diameter and bending strength of long bones, he said.

Odanacatib

Osteoclasts produce cathepsin K, which is released during bone resorption and degrades collagen. Blocking cathepsin K blocks the resorption of proteins and limits bone resorption to shallower pits than usual. This might decrease resorption a little yet allow full bone formation, theoretically.

Unpublished data from a 48-month trial suggest that a weekly 50-mg dose of the cathepsin K inhibitor odanacatib produced an 11% increase in lumbar spine bone mineral density, compared with less than a 1% increase on placebo, and a 9% increase in femoral neck bone mineral density on odanacatib, compared with nearly a 2% decrease on placebo.

"These increases over a 4-year span are impressive," said Dr. Cummings, who said he looks forward to results of the fracture end point trial.

Nitroglycerin

Nitroglycerin prevented bone loss due to ovariectomy in rodent studies. A preliminary study in 243 postmenopausal women randomized them to apply ointment containing 15 mg nitroglycerin or placebo every night, and 93% completed a 2-year evaluation.

Femoral neck bone density increased by approximately 6% on nitroglycerin and decreased by approximately 1% on placebo. In general, bisphosphonates increase femoral neck bone density about 4%-5%, he said. Nitroglycerin increased lumbar spine density by nearly 8%, compared with approximately a 1% increase on placebo.

Measures of bone geometry suggested increases in bone size and strength on nitroglycerin. For the radius, cortical thickness increased 14%, periosteal circumference increased 7%, and the polar moment of inertial increased 7% in the nitroglycerin group, compared with placebo. For the tibia, cortical thickness increased 25%, periosteal circumference increased 3%, and the polar moment of inertia increased 10% in the nitroglycerin group, compared with placebo.

Measurements of markers of bone formation and resorption suggest that nitroglycerin "uncouples" bone formation and resorption, he added.

Headaches were common but decreased with time. In a run-in phase of the study, 25% of women stopped treatment due to headache. One year into the study, 6% on nitroglycerin and 2% on placebo had stopped treatment due to headache. After 1 year, only two women in the nitroglycerin group reported headache.

Dr. Cummings has been a consultant to Amgen, which is developing an anti-sclerostin antibody drug, as well as for Merck, which is developing odanacatib, and Eli Lilly.

SAN FRANCISCO – Three experimental therapies may improve bone mass more than do existing treatments for osteoporosis.

One of them, anti-sclerostin antibodies, "may be the most potent agent yet for formation of bone," Dr. Steven R. Cummings said at a meeting on osteoporosis sponsored by the University of California, San Francisco.

Anti-sclerostin monoclonal antibodies are in phase II clinical trials. "It will probably be 3-4 years before we see results in terms of risk of fracture," said Dr. Cummings, professor of medicine and epidemiology and biostatistics at the university.

A phase III trial that will assess impact on fracture risk is underway for a different drug, the cathepsin K inhibitor odanacatib, which appears to improve bone mineral density, compared with placebo, he said. Data on whether odanacatib reduces the risk of nonvertebral fractures more than current therapies should be available in approximately 2 years.

The third promising agent is a well-known drug used off label: nitroglycerin. A preliminary study suggests it increases bone mineral density and bone strength, but the fact that nitrates are generic and widely available makes it unlikely that a pharmaceutical company will sponsor clinical trials for this indication.

"We’d like to do a phase II study to compare several doses" of nitroglycerin in patients with low bone density, "but we can’t get the funding from the National Institutes of Health," Dr. Cummings said.

These promising agents might strengthen a weak spot in osteoporosis treatment by helping to reduce nonvertebral fractures, he said. Current treatments can produce a 10%-30% reduction in nonvertebral fractures, which account for approximately 90% of days of disability due to fractures.

"We need more effective treatments," he said.

Anti-Sclerostin Antibodies

Sclerostin is produced by mature osteocytes in response to decreased loading, and is found in no other cells. It inhibits the formation of osteoblasts.

An initial trial of various doses in 48 healthy postmenopausal women found a 5%-6% increase in spine bone mineral density and a 3%-4% increase in total hip bone mineral density in less than 3 months in the 6 women randomized to a single 10-mg/kg injection.

"These are breathtaking increases in bone mineral density, but this is very early, preliminary data," Dr. Cummings said.

Although osteoblasts usually form bone where it has been reabsorbed, anti-sclerostin antibodies induce formation of bone on "quiet" surfaces such as the periosteum, which increases the diameter and bending strength of long bones, he said.

Odanacatib

Osteoclasts produce cathepsin K, which is released during bone resorption and degrades collagen. Blocking cathepsin K blocks the resorption of proteins and limits bone resorption to shallower pits than usual. This might decrease resorption a little yet allow full bone formation, theoretically.

Unpublished data from a 48-month trial suggest that a weekly 50-mg dose of the cathepsin K inhibitor odanacatib produced an 11% increase in lumbar spine bone mineral density, compared with less than a 1% increase on placebo, and a 9% increase in femoral neck bone mineral density on odanacatib, compared with nearly a 2% decrease on placebo.

"These increases over a 4-year span are impressive," said Dr. Cummings, who said he looks forward to results of the fracture end point trial.

Nitroglycerin

Nitroglycerin prevented bone loss due to ovariectomy in rodent studies. A preliminary study in 243 postmenopausal women randomized them to apply ointment containing 15 mg nitroglycerin or placebo every night, and 93% completed a 2-year evaluation.

Femoral neck bone density increased by approximately 6% on nitroglycerin and decreased by approximately 1% on placebo. In general, bisphosphonates increase femoral neck bone density about 4%-5%, he said. Nitroglycerin increased lumbar spine density by nearly 8%, compared with approximately a 1% increase on placebo.

Measures of bone geometry suggested increases in bone size and strength on nitroglycerin. For the radius, cortical thickness increased 14%, periosteal circumference increased 7%, and the polar moment of inertial increased 7% in the nitroglycerin group, compared with placebo. For the tibia, cortical thickness increased 25%, periosteal circumference increased 3%, and the polar moment of inertia increased 10% in the nitroglycerin group, compared with placebo.

Measurements of markers of bone formation and resorption suggest that nitroglycerin "uncouples" bone formation and resorption, he added.

Headaches were common but decreased with time. In a run-in phase of the study, 25% of women stopped treatment due to headache. One year into the study, 6% on nitroglycerin and 2% on placebo had stopped treatment due to headache. After 1 year, only two women in the nitroglycerin group reported headache.

Dr. Cummings has been a consultant to Amgen, which is developing an anti-sclerostin antibody drug, as well as for Merck, which is developing odanacatib, and Eli Lilly.

SAN FRANCISCO – Vertebroplasty worked no better than sham surgery to reduce pain and disability from vertebral fracture, according to data from recent randomized, controlled trials that put nonsurgical therapies firmly in the first line of treatment.

Osteoporotic vertebral fractures should be treated aggressively with antiresorptive or anabolic therapy for at least 6-12 weeks before considering surgery, Dr. Douglas C. Bauer said at a meeting on osteoporosis sponsored by the University of California, San Francisco. Optimize medical therapy, physical therapy, and other options that might be appropriate such as adding calcitonin or referring the patient for a facet joint injection, he said.

Even after all that, clinicians should consider kyphoplasty before resorting to vertebroplasty, said Dr. Bauer, who is professor of medicine and of epidemiology and biostatistics at the university.

Findings from one unblinded, randomized trial suggests that kyphoplasty may reduce pain and disability, compared with conservative care initially, though the difference in results is less apparent 1 year after surgery.

Despite data from numerous uncontrolled studies suggesting that vertebroplasty also lessens pain and improves function, findings from two well-designed controlled trials "raised a brouhaha" and surprised investigators by showing vertebroplasty to have no benefit, "suggesting that a very commonly done procedure is not helpful," he said. It’s unclear whether the uncontrolled trial results were due to an extended placebo effect or some other factor.

In kyphoplasty, surgeons insert a balloon device to reduce the cervical fracture, remove the balloon, and replace it with cement. Vertebroplasty injects cement only, without the balloon, and does not attempt to increase vertebral height. Both are minimally invasive surgeries that usually are performed under general anesthesia but can be done using local anesthesia, often with conscious sedation.

The unblinded trial of kyphoplasty randomized 149 patients to kyphoplasty and 151 to usual nonsurgical care. "The patients were typical of who we see with vertebral fracture," Dr. Bauer noted. The primary results showed that 1 month after surgery, scores on the Short Form-36 (SF-36) Physical Component Summary had increased from 26 at baseline in both groups to 27 in the kyphoplasty group and 33 in the control group, a significant difference between groups (Lancet 2009;373:1016-24).

Follow-up continued out to 3, 6, and 12 months after surgery, and results were significantly better in the kyphoplasty group at all time points for the SF-36 Physical Component, patient-reported Visual Analog Scale (VAS) scores for back pain, and the number of days of limited activity in the previous 2 weeks.

Although statistically significant, some of the differences between groups were more clinically significant than others. The self-reported VAS pain scores, for example, differed between groups by only 1 point on a 10-point scale at 12 months. The kyphoplasty group, however, enjoyed an average of 60 fewer days of limited activity during those 12 months, compared with the control group, which "patients may be most interested in," he said.

At 24 months, only the difference in pain scores remained statistically significant between groups (J. Bone Miner. Res. 2011;26:1627-37).

More trials of kyphoplasty are needed before the surgery becomes widespread, Dr. Bauer said.

A separate uncontrolled trial that randomized 202 patients to vertebroplasty or usual care similarly found statistically greater improvements in the vertebroplasty group in VAS pain scores at 1 month (a decrease of 5 points) and 1 year (a 6-point drop), compared with usual care (a 3- and 4-point drop, respectively). Patients in the surgery arm also reported less narcotic use (Lancet 2010;376:1085-92).

The two well-designed controlled trials of vertebroplasty contradict other findings, however. Patients were taken to the operating room before randomization. The control group received sham surgery that included needle insertions in their backs and the breaking of a vial of chemicals to disperse a chemical smell. Outcomes assessors were blinded to randomization.

In one study of 71 patients, scores for back pain decreased significantly in both the real and sham surgery groups, but outcomes did not differ significantly between groups at any time point out to 6 months (New Engl. J. Med. 2009;361:557-68).

In the other study of 131 patients, both groups showed immediate improvements in disability and pain scores but no outcomes differed significantly between groups at 1 month (New Engl. J. Med. 2009;361:569-79).

While it’s conceivable that the benefits reported for vertebroplasty and kyphoplasty in uncontrolled studies are due to an extended placebo effect, the likelihood that the placebo effect would last for as much as 24 months of follow-up is unclear, Dr. Bauer said.

Some have suggested that the sham-surgery studies included a harder-to-treat population by accepting patients with vertebral fractures up to 1 year in duration, but a subsequent analysis of data limited to fractures of less than 6 weeks duration found no change in the overall results.

Case series have shown that anesthetic or steroid injections alone can reduce vertebral fracture pain, which may explain the improvement in pain scores in both the real and sham-surgery groups in the vertebroplasty trials, he suggested.

There also may be a difference between the two surgeries that produce different results from kyphoplasty or vertebroplasty. Randomized, controlled trials comparing the two are underway.

Further research is needed on optimal patient selection, on whether the surgeries prevent kyphosis, and on long-term outcomes, Dr. Bauer said.

The 700,000 vertebral compression fractures in the United States each year hospitalize more than 150,000 people.

Dr. Bauer has received research funding from Amgen and Novartis.

SAN FRANCISCO – Vertebroplasty worked no better than sham surgery to reduce pain and disability from vertebral fracture, according to data from recent randomized, controlled trials that put nonsurgical therapies firmly in the first line of treatment.

Osteoporotic vertebral fractures should be treated aggressively with antiresorptive or anabolic therapy for at least 6-12 weeks before considering surgery, Dr. Douglas C. Bauer said at a meeting on osteoporosis sponsored by the University of California, San Francisco. Optimize medical therapy, physical therapy, and other options that might be appropriate such as adding calcitonin or referring the patient for a facet joint injection, he said.

Even after all that, clinicians should consider kyphoplasty before resorting to vertebroplasty, said Dr. Bauer, who is professor of medicine and of epidemiology and biostatistics at the university.

Findings from one unblinded, randomized trial suggests that kyphoplasty may reduce pain and disability, compared with conservative care initially, though the difference in results is less apparent 1 year after surgery.

Despite data from numerous uncontrolled studies suggesting that vertebroplasty also lessens pain and improves function, findings from two well-designed controlled trials "raised a brouhaha" and surprised investigators by showing vertebroplasty to have no benefit, "suggesting that a very commonly done procedure is not helpful," he said. It’s unclear whether the uncontrolled trial results were due to an extended placebo effect or some other factor.

In kyphoplasty, surgeons insert a balloon device to reduce the cervical fracture, remove the balloon, and replace it with cement. Vertebroplasty injects cement only, without the balloon, and does not attempt to increase vertebral height. Both are minimally invasive surgeries that usually are performed under general anesthesia but can be done using local anesthesia, often with conscious sedation.

The unblinded trial of kyphoplasty randomized 149 patients to kyphoplasty and 151 to usual nonsurgical care. "The patients were typical of who we see with vertebral fracture," Dr. Bauer noted. The primary results showed that 1 month after surgery, scores on the Short Form-36 (SF-36) Physical Component Summary had increased from 26 at baseline in both groups to 27 in the kyphoplasty group and 33 in the control group, a significant difference between groups (Lancet 2009;373:1016-24).

Follow-up continued out to 3, 6, and 12 months after surgery, and results were significantly better in the kyphoplasty group at all time points for the SF-36 Physical Component, patient-reported Visual Analog Scale (VAS) scores for back pain, and the number of days of limited activity in the previous 2 weeks.

Although statistically significant, some of the differences between groups were more clinically significant than others. The self-reported VAS pain scores, for example, differed between groups by only 1 point on a 10-point scale at 12 months. The kyphoplasty group, however, enjoyed an average of 60 fewer days of limited activity during those 12 months, compared with the control group, which "patients may be most interested in," he said.

At 24 months, only the difference in pain scores remained statistically significant between groups (J. Bone Miner. Res. 2011;26:1627-37).

More trials of kyphoplasty are needed before the surgery becomes widespread, Dr. Bauer said.

A separate uncontrolled trial that randomized 202 patients to vertebroplasty or usual care similarly found statistically greater improvements in the vertebroplasty group in VAS pain scores at 1 month (a decrease of 5 points) and 1 year (a 6-point drop), compared with usual care (a 3- and 4-point drop, respectively). Patients in the surgery arm also reported less narcotic use (Lancet 2010;376:1085-92).

The two well-designed controlled trials of vertebroplasty contradict other findings, however. Patients were taken to the operating room before randomization. The control group received sham surgery that included needle insertions in their backs and the breaking of a vial of chemicals to disperse a chemical smell. Outcomes assessors were blinded to randomization.

In one study of 71 patients, scores for back pain decreased significantly in both the real and sham surgery groups, but outcomes did not differ significantly between groups at any time point out to 6 months (New Engl. J. Med. 2009;361:557-68).

In the other study of 131 patients, both groups showed immediate improvements in disability and pain scores but no outcomes differed significantly between groups at 1 month (New Engl. J. Med. 2009;361:569-79).

While it’s conceivable that the benefits reported for vertebroplasty and kyphoplasty in uncontrolled studies are due to an extended placebo effect, the likelihood that the placebo effect would last for as much as 24 months of follow-up is unclear, Dr. Bauer said.

Some have suggested that the sham-surgery studies included a harder-to-treat population by accepting patients with vertebral fractures up to 1 year in duration, but a subsequent analysis of data limited to fractures of less than 6 weeks duration found no change in the overall results.

Case series have shown that anesthetic or steroid injections alone can reduce vertebral fracture pain, which may explain the improvement in pain scores in both the real and sham-surgery groups in the vertebroplasty trials, he suggested.

There also may be a difference between the two surgeries that produce different results from kyphoplasty or vertebroplasty. Randomized, controlled trials comparing the two are underway.

Further research is needed on optimal patient selection, on whether the surgeries prevent kyphosis, and on long-term outcomes, Dr. Bauer said.

The 700,000 vertebral compression fractures in the United States each year hospitalize more than 150,000 people.

Dr. Bauer has received research funding from Amgen and Novartis.

SAN FRANCISCO – Vertebroplasty worked no better than sham surgery to reduce pain and disability from vertebral fracture, according to data from recent randomized, controlled trials that put nonsurgical therapies firmly in the first line of treatment.

Osteoporotic vertebral fractures should be treated aggressively with antiresorptive or anabolic therapy for at least 6-12 weeks before considering surgery, Dr. Douglas C. Bauer said at a meeting on osteoporosis sponsored by the University of California, San Francisco. Optimize medical therapy, physical therapy, and other options that might be appropriate such as adding calcitonin or referring the patient for a facet joint injection, he said.

Even after all that, clinicians should consider kyphoplasty before resorting to vertebroplasty, said Dr. Bauer, who is professor of medicine and of epidemiology and biostatistics at the university.

Findings from one unblinded, randomized trial suggests that kyphoplasty may reduce pain and disability, compared with conservative care initially, though the difference in results is less apparent 1 year after surgery.

Despite data from numerous uncontrolled studies suggesting that vertebroplasty also lessens pain and improves function, findings from two well-designed controlled trials "raised a brouhaha" and surprised investigators by showing vertebroplasty to have no benefit, "suggesting that a very commonly done procedure is not helpful," he said. It’s unclear whether the uncontrolled trial results were due to an extended placebo effect or some other factor.

In kyphoplasty, surgeons insert a balloon device to reduce the cervical fracture, remove the balloon, and replace it with cement. Vertebroplasty injects cement only, without the balloon, and does not attempt to increase vertebral height. Both are minimally invasive surgeries that usually are performed under general anesthesia but can be done using local anesthesia, often with conscious sedation.

The unblinded trial of kyphoplasty randomized 149 patients to kyphoplasty and 151 to usual nonsurgical care. "The patients were typical of who we see with vertebral fracture," Dr. Bauer noted. The primary results showed that 1 month after surgery, scores on the Short Form-36 (SF-36) Physical Component Summary had increased from 26 at baseline in both groups to 27 in the kyphoplasty group and 33 in the control group, a significant difference between groups (Lancet 2009;373:1016-24).

Follow-up continued out to 3, 6, and 12 months after surgery, and results were significantly better in the kyphoplasty group at all time points for the SF-36 Physical Component, patient-reported Visual Analog Scale (VAS) scores for back pain, and the number of days of limited activity in the previous 2 weeks.

Although statistically significant, some of the differences between groups were more clinically significant than others. The self-reported VAS pain scores, for example, differed between groups by only 1 point on a 10-point scale at 12 months. The kyphoplasty group, however, enjoyed an average of 60 fewer days of limited activity during those 12 months, compared with the control group, which "patients may be most interested in," he said.

At 24 months, only the difference in pain scores remained statistically significant between groups (J. Bone Miner. Res. 2011;26:1627-37).

More trials of kyphoplasty are needed before the surgery becomes widespread, Dr. Bauer said.

A separate uncontrolled trial that randomized 202 patients to vertebroplasty or usual care similarly found statistically greater improvements in the vertebroplasty group in VAS pain scores at 1 month (a decrease of 5 points) and 1 year (a 6-point drop), compared with usual care (a 3- and 4-point drop, respectively). Patients in the surgery arm also reported less narcotic use (Lancet 2010;376:1085-92).

The two well-designed controlled trials of vertebroplasty contradict other findings, however. Patients were taken to the operating room before randomization. The control group received sham surgery that included needle insertions in their backs and the breaking of a vial of chemicals to disperse a chemical smell. Outcomes assessors were blinded to randomization.

In one study of 71 patients, scores for back pain decreased significantly in both the real and sham surgery groups, but outcomes did not differ significantly between groups at any time point out to 6 months (New Engl. J. Med. 2009;361:557-68).

In the other study of 131 patients, both groups showed immediate improvements in disability and pain scores but no outcomes differed significantly between groups at 1 month (New Engl. J. Med. 2009;361:569-79).

While it’s conceivable that the benefits reported for vertebroplasty and kyphoplasty in uncontrolled studies are due to an extended placebo effect, the likelihood that the placebo effect would last for as much as 24 months of follow-up is unclear, Dr. Bauer said.

Some have suggested that the sham-surgery studies included a harder-to-treat population by accepting patients with vertebral fractures up to 1 year in duration, but a subsequent analysis of data limited to fractures of less than 6 weeks duration found no change in the overall results.

Case series have shown that anesthetic or steroid injections alone can reduce vertebral fracture pain, which may explain the improvement in pain scores in both the real and sham-surgery groups in the vertebroplasty trials, he suggested.

There also may be a difference between the two surgeries that produce different results from kyphoplasty or vertebroplasty. Randomized, controlled trials comparing the two are underway.

Further research is needed on optimal patient selection, on whether the surgeries prevent kyphosis, and on long-term outcomes, Dr. Bauer said.

The 700,000 vertebral compression fractures in the United States each year hospitalize more than 150,000 people.

Dr. Bauer has received research funding from Amgen and Novartis.

SAN FRANCISCO – Evidence continues to mount that thiazolidinediones decrease bone density and increase fracture risk in patients with diabetes, but so far there are no randomized studies to show that adding an antiresorptive drug would protect bone health in this setting.

Bisphosphonates, denosumab, and parathyroid hormone have not been tested in human studies to see if they could reduce fracture risk in patients with diabetes who are taking thiazolidinediones, but randomized studies in mice suggest significant bone benefits from adding a bisphosphonate, Dr. Jonathan Graf said at a conference on osteoporosis sponsored by the University of California, San Francisco.

For now, however, recommendations call for avoiding thiazolidinediones in patients with diabetes who have a high risk of fracture. A patient’s risk should be assessed by using the online FRAX tool and assessing the history for other risk factors for fracture that are not covered by FRAX, said Dr. Graf, a rheumatologist at San Francisco General Hospital.

If you do decide to use a thiazolidinedione to treat diabetes in someone at high risk for fracture, the detrimental effects on bone might be mitigated by using a lower dose. At least two thiazolidinediones – rosiglitazone and pioglitazone – are available in lower-dose formulations in combination with metformin, and the combinations provide the same level of diabetes control as higher-dose glitazone monotherapy, he said.

Preliminary data also suggest that combining lower doses of thiazolidinediones with an incretin drug may provide diabetes control while mitigating adverse effects on bone, he added. Incretins may even promote bone formation, some evidence suggests.

"There is not a lot of evidence out there to steer you one way or the other" in these management choices, but the evidence of damaging effects of thiazolidinediones on bone is becoming nearly overwhelming, he said.

In a prospective cohort study of 84,339 men and women with diabetes, the risk of fracture was 28% higher in patients on thiazolidinediones than in patients taking sulfonylureas, and the risk increased with cumulative exposure to thiazolidinediones. In men, pioglitazone increased fracture risk but rosiglitazone did not (Arch. Intern. Med. 2009;169:1395-1402).

A separate cohort study of 20,964 Medicare beneficiaries over age 65 years with diabetes found a statistical trend toward higher risk of peripheral fractures in both men and women on thiazolidinedione monotherapy compared with treatment with sulfonylureas or metformin (J. Clin. Endocrinol. Metab. 2009;94:2792-98).

Previous trials have suggested that the fracture risk is higher in women than in men. A meta-analysis of 10 trials and 2 observational studies containing a total of 45,484 patients with diabetes reported a doubling of fracture risk in women but not in men on thiazolidinediones, compared with controls (Can. Med. Assoc. J. 2009;180:32-9). In a separate analysis of a claims database, thiazolidinedione therapy doubled the risk of limb fracture in women (Am. J. Manag. Care 2009;15:491-6).

Thiazolidinedione therapy and the duration of therapy in older patients were associated with significant increases in nonvertebral fractures, including more than a fourfold increased risk of hip or femur fracture, a tripling in risk of forearm fracture, and a doubling in risk of humerus fracture, an observational study found (Arch. Intern. Med. 2008;168:820-5).

The 4-year fracture rate in patients on rosiglitazone doubled in both pre- and postmenopausal women but not in men compared with other diabetes treatments in A Diabetes Outcome Progression Trial (ADOPT), a randomized, double-blind study of about 3,600 patients. The fracture rate was 15% on rosiglitazone, 8% on glyburide, and 7% on metformin (Diab. Care 2008;31:845-51). At least three separate studies found significantly increased bone loss in women within weeks of starting thiazolidinediones, especially in postmenopausal women.

Thiazolidinediones are agonists to peroxisome proliferator-activated receptor gamma, which helps regulate bone formation. Thiazolidinediones decrease insulin-like growth factor 1 expression (which decreases bone formation), decrease osteoblastogenesis, and promote osteoblast differentiation.

"Just like glucocorticoids, they have several mechanisms that affect bone," he said.

Dr. Graf reported that he has no conflicts of interest.

SAN FRANCISCO – Evidence continues to mount that thiazolidinediones decrease bone density and increase fracture risk in patients with diabetes, but so far there are no randomized studies to show that adding an antiresorptive drug would protect bone health in this setting.

Bisphosphonates, denosumab, and parathyroid hormone have not been tested in human studies to see if they could reduce fracture risk in patients with diabetes who are taking thiazolidinediones, but randomized studies in mice suggest significant bone benefits from adding a bisphosphonate, Dr. Jonathan Graf said at a conference on osteoporosis sponsored by the University of California, San Francisco.

For now, however, recommendations call for avoiding thiazolidinediones in patients with diabetes who have a high risk of fracture. A patient’s risk should be assessed by using the online FRAX tool and assessing the history for other risk factors for fracture that are not covered by FRAX, said Dr. Graf, a rheumatologist at San Francisco General Hospital.

If you do decide to use a thiazolidinedione to treat diabetes in someone at high risk for fracture, the detrimental effects on bone might be mitigated by using a lower dose. At least two thiazolidinediones – rosiglitazone and pioglitazone – are available in lower-dose formulations in combination with metformin, and the combinations provide the same level of diabetes control as higher-dose glitazone monotherapy, he said.

Preliminary data also suggest that combining lower doses of thiazolidinediones with an incretin drug may provide diabetes control while mitigating adverse effects on bone, he added. Incretins may even promote bone formation, some evidence suggests.

"There is not a lot of evidence out there to steer you one way or the other" in these management choices, but the evidence of damaging effects of thiazolidinediones on bone is becoming nearly overwhelming, he said.

In a prospective cohort study of 84,339 men and women with diabetes, the risk of fracture was 28% higher in patients on thiazolidinediones than in patients taking sulfonylureas, and the risk increased with cumulative exposure to thiazolidinediones. In men, pioglitazone increased fracture risk but rosiglitazone did not (Arch. Intern. Med. 2009;169:1395-1402).

A separate cohort study of 20,964 Medicare beneficiaries over age 65 years with diabetes found a statistical trend toward higher risk of peripheral fractures in both men and women on thiazolidinedione monotherapy compared with treatment with sulfonylureas or metformin (J. Clin. Endocrinol. Metab. 2009;94:2792-98).

Previous trials have suggested that the fracture risk is higher in women than in men. A meta-analysis of 10 trials and 2 observational studies containing a total of 45,484 patients with diabetes reported a doubling of fracture risk in women but not in men on thiazolidinediones, compared with controls (Can. Med. Assoc. J. 2009;180:32-9). In a separate analysis of a claims database, thiazolidinedione therapy doubled the risk of limb fracture in women (Am. J. Manag. Care 2009;15:491-6).

Thiazolidinedione therapy and the duration of therapy in older patients were associated with significant increases in nonvertebral fractures, including more than a fourfold increased risk of hip or femur fracture, a tripling in risk of forearm fracture, and a doubling in risk of humerus fracture, an observational study found (Arch. Intern. Med. 2008;168:820-5).

The 4-year fracture rate in patients on rosiglitazone doubled in both pre- and postmenopausal women but not in men compared with other diabetes treatments in A Diabetes Outcome Progression Trial (ADOPT), a randomized, double-blind study of about 3,600 patients. The fracture rate was 15% on rosiglitazone, 8% on glyburide, and 7% on metformin (Diab. Care 2008;31:845-51). At least three separate studies found significantly increased bone loss in women within weeks of starting thiazolidinediones, especially in postmenopausal women.

Thiazolidinediones are agonists to peroxisome proliferator-activated receptor gamma, which helps regulate bone formation. Thiazolidinediones decrease insulin-like growth factor 1 expression (which decreases bone formation), decrease osteoblastogenesis, and promote osteoblast differentiation.

"Just like glucocorticoids, they have several mechanisms that affect bone," he said.

Dr. Graf reported that he has no conflicts of interest.

SAN FRANCISCO – Evidence continues to mount that thiazolidinediones decrease bone density and increase fracture risk in patients with diabetes, but so far there are no randomized studies to show that adding an antiresorptive drug would protect bone health in this setting.

Bisphosphonates, denosumab, and parathyroid hormone have not been tested in human studies to see if they could reduce fracture risk in patients with diabetes who are taking thiazolidinediones, but randomized studies in mice suggest significant bone benefits from adding a bisphosphonate, Dr. Jonathan Graf said at a conference on osteoporosis sponsored by the University of California, San Francisco.

For now, however, recommendations call for avoiding thiazolidinediones in patients with diabetes who have a high risk of fracture. A patient’s risk should be assessed by using the online FRAX tool and assessing the history for other risk factors for fracture that are not covered by FRAX, said Dr. Graf, a rheumatologist at San Francisco General Hospital.

If you do decide to use a thiazolidinedione to treat diabetes in someone at high risk for fracture, the detrimental effects on bone might be mitigated by using a lower dose. At least two thiazolidinediones – rosiglitazone and pioglitazone – are available in lower-dose formulations in combination with metformin, and the combinations provide the same level of diabetes control as higher-dose glitazone monotherapy, he said.

Preliminary data also suggest that combining lower doses of thiazolidinediones with an incretin drug may provide diabetes control while mitigating adverse effects on bone, he added. Incretins may even promote bone formation, some evidence suggests.

"There is not a lot of evidence out there to steer you one way or the other" in these management choices, but the evidence of damaging effects of thiazolidinediones on bone is becoming nearly overwhelming, he said.

In a prospective cohort study of 84,339 men and women with diabetes, the risk of fracture was 28% higher in patients on thiazolidinediones than in patients taking sulfonylureas, and the risk increased with cumulative exposure to thiazolidinediones. In men, pioglitazone increased fracture risk but rosiglitazone did not (Arch. Intern. Med. 2009;169:1395-1402).

A separate cohort study of 20,964 Medicare beneficiaries over age 65 years with diabetes found a statistical trend toward higher risk of peripheral fractures in both men and women on thiazolidinedione monotherapy compared with treatment with sulfonylureas or metformin (J. Clin. Endocrinol. Metab. 2009;94:2792-98).

Previous trials have suggested that the fracture risk is higher in women than in men. A meta-analysis of 10 trials and 2 observational studies containing a total of 45,484 patients with diabetes reported a doubling of fracture risk in women but not in men on thiazolidinediones, compared with controls (Can. Med. Assoc. J. 2009;180:32-9). In a separate analysis of a claims database, thiazolidinedione therapy doubled the risk of limb fracture in women (Am. J. Manag. Care 2009;15:491-6).

Thiazolidinedione therapy and the duration of therapy in older patients were associated with significant increases in nonvertebral fractures, including more than a fourfold increased risk of hip or femur fracture, a tripling in risk of forearm fracture, and a doubling in risk of humerus fracture, an observational study found (Arch. Intern. Med. 2008;168:820-5).

The 4-year fracture rate in patients on rosiglitazone doubled in both pre- and postmenopausal women but not in men compared with other diabetes treatments in A Diabetes Outcome Progression Trial (ADOPT), a randomized, double-blind study of about 3,600 patients. The fracture rate was 15% on rosiglitazone, 8% on glyburide, and 7% on metformin (Diab. Care 2008;31:845-51). At least three separate studies found significantly increased bone loss in women within weeks of starting thiazolidinediones, especially in postmenopausal women.

Thiazolidinediones are agonists to peroxisome proliferator-activated receptor gamma, which helps regulate bone formation. Thiazolidinediones decrease insulin-like growth factor 1 expression (which decreases bone formation), decrease osteoblastogenesis, and promote osteoblast differentiation.

"Just like glucocorticoids, they have several mechanisms that affect bone," he said.

Dr. Graf reported that he has no conflicts of interest.

SAN DIEGO – Intravenous exenatide appeared to be as effective and safe as IV insulin to treat hyperglycemia patients in the cardiac ICU, but caused nausea in a fifth of patients in a small study.

The prospective, open-label study included 40 adults admitted to the cardiac ICU primarily for cardiac reasons who were treated with IV exenatide for fasting blood glucose levels of 140-400 mg/dL. They were compared with two historical control groups: 39 patients who were admitted to a cardiac ICU in 2009-2010 and treated with IV insulin for blood glucose levels greater than 180 mg/dL, and 94 patients in the cardiac ICU before 2009 who were treated under prior protocols for stricter glycemic control that started insulin for blood glucose levels greater than 140 mg/dL.

The exenatide and recent control groups aimed to maintain glucose levels at 100-140 mg/dL. The pre-2009 control group aimed to maintain glucose levels at 90-119 mg/dL.

Mean glucose levels at admission to the cardiac ICU were 199 mg/dL in the exenatide group, significantly lower than mean levels at admission of 240 mg/dL in the recent control group and 218 mg/dL in the pre-2009 control group.

Exenatide was infused at a fixed dose of 0.05 mcg/min for a 30-minute bolus, then 0.025 mcg/min continuously for 24-48 hours.

It took a mean of 3.9 hours for patients in the exenatide group to achieve a first glucose value of 140 mg/dL or lower, significantly faster than the 9.3 hours required in the recent control group and similar to the 3.5 hours required in the pre-2009 control group, Dr. Steven P. Marso and his associates reported at the annual scientific sessions of the American Diabetes Association.

Mean steady state glucose values were 139 mg/dL in the exenatide group, 147 mg/dL in the recent control group, and 115 mg/dL in the pre-2009 control group, said Dr. Marso of St. Luke’s Cardiovascular Consultants, Kansas City, Mo.

Eight patients developed exenatide-related nausea, and six of these discontinued the drug.

The exenatide group had a lower rate of hypoglycemic events and severe hypoglycemic episodes than the other groups, though the differences were not statistically significant.

Blood glucose levels below 70 mg/dL were seen in 0.9% of 668 measurements in the exenatide group, 1.2% of 745 measurements in the recent control group, and 1.6% of 1,651 measurements in the pre-2009 control group. No patients on exenatide developed severe hypoglycemia (blood glucose less than 50 mg/dL), but this was seen in 0.3% of measurements in the recent control group and in 0.06% in the pre-2009 control group.

The findings show that it’s feasible to treat hyperglycemia in the cardiac ICU with fixed-dose IV exenatide and that results are comparable to those with IV insulin without the risk for severe hypoglycemia, Dr. Marso said. The disadvantage of IV exenatide is the risk for treatment-limited nausea.

He cautioned, however, that this is a small, nonrandomized, proof-of-concept study with no active control group and no long-term clinical follow-up.

A significantly greater proportion of patients in the exenatide group had diabetes (75%), compared with patients in the recent control group (67%).

The study included two historical control groups because recommendations for glycemic control in the ICU setting have changed in recent years. Initial clinical trials showed clinical benefit from intensive glucose control for patients with hyperglycemia in the ICU, but later studies reported higher risks for severe hypoglycemia and death with intensive glucose control in these patients, Dr. Marso said. Updated consensus guidelines subsequently called for less tight glycemic control.

A 2009 consensus statement on inpatient glycemic control from the American Diabetes Association and American Association of Clinical Endocrinologists calls for insulin therapy to be initiated in critically ill patients when blood glucose values drop below 180 mg/dL. Glucose should be maintained between 140-180 mg/dL, and targets less than 100 mg/dL are not recommended (Endocr. Pract. 2009;15:353-69).

The statement says that IV insulin is the preferred treatment and that noninsulin antihyperglycemic agents are not appropriate in most hospitalized patients who require therapy for hyperglycemia. But the potential risks with insulin therapy prompted the current study of IV exenatide.

The study excluded patients who were dependent on a ventilator, unconscious on sedation, who had type 1 diabetes, were pregnant, were post-orthotopic heart transplant, had a creatinine clearance less than 30 mL/min, had a history of pancreatitis, or who were being treated with insulin monotherapy other than long-acting basal insulin (glargine or detemir).

The study was funded by Amylin Pharmaceuticals, which markets exenatide with Lilly. Dr. Marso has been a consultant to, or received research support from, Amylin, Abbott Vascular, The Medicines Company, Novo Nordisk, Volcano, Boston Scientific, and Terumo Medical.

SAN DIEGO – Intravenous exenatide appeared to be as effective and safe as IV insulin to treat hyperglycemia patients in the cardiac ICU, but caused nausea in a fifth of patients in a small study.

The prospective, open-label study included 40 adults admitted to the cardiac ICU primarily for cardiac reasons who were treated with IV exenatide for fasting blood glucose levels of 140-400 mg/dL. They were compared with two historical control groups: 39 patients who were admitted to a cardiac ICU in 2009-2010 and treated with IV insulin for blood glucose levels greater than 180 mg/dL, and 94 patients in the cardiac ICU before 2009 who were treated under prior protocols for stricter glycemic control that started insulin for blood glucose levels greater than 140 mg/dL.

The exenatide and recent control groups aimed to maintain glucose levels at 100-140 mg/dL. The pre-2009 control group aimed to maintain glucose levels at 90-119 mg/dL.

Mean glucose levels at admission to the cardiac ICU were 199 mg/dL in the exenatide group, significantly lower than mean levels at admission of 240 mg/dL in the recent control group and 218 mg/dL in the pre-2009 control group.

Exenatide was infused at a fixed dose of 0.05 mcg/min for a 30-minute bolus, then 0.025 mcg/min continuously for 24-48 hours.

It took a mean of 3.9 hours for patients in the exenatide group to achieve a first glucose value of 140 mg/dL or lower, significantly faster than the 9.3 hours required in the recent control group and similar to the 3.5 hours required in the pre-2009 control group, Dr. Steven P. Marso and his associates reported at the annual scientific sessions of the American Diabetes Association.

Mean steady state glucose values were 139 mg/dL in the exenatide group, 147 mg/dL in the recent control group, and 115 mg/dL in the pre-2009 control group, said Dr. Marso of St. Luke’s Cardiovascular Consultants, Kansas City, Mo.

Eight patients developed exenatide-related nausea, and six of these discontinued the drug.

The exenatide group had a lower rate of hypoglycemic events and severe hypoglycemic episodes than the other groups, though the differences were not statistically significant.

Blood glucose levels below 70 mg/dL were seen in 0.9% of 668 measurements in the exenatide group, 1.2% of 745 measurements in the recent control group, and 1.6% of 1,651 measurements in the pre-2009 control group. No patients on exenatide developed severe hypoglycemia (blood glucose less than 50 mg/dL), but this was seen in 0.3% of measurements in the recent control group and in 0.06% in the pre-2009 control group.

The findings show that it’s feasible to treat hyperglycemia in the cardiac ICU with fixed-dose IV exenatide and that results are comparable to those with IV insulin without the risk for severe hypoglycemia, Dr. Marso said. The disadvantage of IV exenatide is the risk for treatment-limited nausea.

He cautioned, however, that this is a small, nonrandomized, proof-of-concept study with no active control group and no long-term clinical follow-up.

A significantly greater proportion of patients in the exenatide group had diabetes (75%), compared with patients in the recent control group (67%).

The study included two historical control groups because recommendations for glycemic control in the ICU setting have changed in recent years. Initial clinical trials showed clinical benefit from intensive glucose control for patients with hyperglycemia in the ICU, but later studies reported higher risks for severe hypoglycemia and death with intensive glucose control in these patients, Dr. Marso said. Updated consensus guidelines subsequently called for less tight glycemic control.

A 2009 consensus statement on inpatient glycemic control from the American Diabetes Association and American Association of Clinical Endocrinologists calls for insulin therapy to be initiated in critically ill patients when blood glucose values drop below 180 mg/dL. Glucose should be maintained between 140-180 mg/dL, and targets less than 100 mg/dL are not recommended (Endocr. Pract. 2009;15:353-69).

The statement says that IV insulin is the preferred treatment and that noninsulin antihyperglycemic agents are not appropriate in most hospitalized patients who require therapy for hyperglycemia. But the potential risks with insulin therapy prompted the current study of IV exenatide.

The study excluded patients who were dependent on a ventilator, unconscious on sedation, who had type 1 diabetes, were pregnant, were post-orthotopic heart transplant, had a creatinine clearance less than 30 mL/min, had a history of pancreatitis, or who were being treated with insulin monotherapy other than long-acting basal insulin (glargine or detemir).

The study was funded by Amylin Pharmaceuticals, which markets exenatide with Lilly. Dr. Marso has been a consultant to, or received research support from, Amylin, Abbott Vascular, The Medicines Company, Novo Nordisk, Volcano, Boston Scientific, and Terumo Medical.

SAN DIEGO – Intravenous exenatide appeared to be as effective and safe as IV insulin to treat hyperglycemia patients in the cardiac ICU, but caused nausea in a fifth of patients in a small study.

The prospective, open-label study included 40 adults admitted to the cardiac ICU primarily for cardiac reasons who were treated with IV exenatide for fasting blood glucose levels of 140-400 mg/dL. They were compared with two historical control groups: 39 patients who were admitted to a cardiac ICU in 2009-2010 and treated with IV insulin for blood glucose levels greater than 180 mg/dL, and 94 patients in the cardiac ICU before 2009 who were treated under prior protocols for stricter glycemic control that started insulin for blood glucose levels greater than 140 mg/dL.

The exenatide and recent control groups aimed to maintain glucose levels at 100-140 mg/dL. The pre-2009 control group aimed to maintain glucose levels at 90-119 mg/dL.

Mean glucose levels at admission to the cardiac ICU were 199 mg/dL in the exenatide group, significantly lower than mean levels at admission of 240 mg/dL in the recent control group and 218 mg/dL in the pre-2009 control group.

Exenatide was infused at a fixed dose of 0.05 mcg/min for a 30-minute bolus, then 0.025 mcg/min continuously for 24-48 hours.

It took a mean of 3.9 hours for patients in the exenatide group to achieve a first glucose value of 140 mg/dL or lower, significantly faster than the 9.3 hours required in the recent control group and similar to the 3.5 hours required in the pre-2009 control group, Dr. Steven P. Marso and his associates reported at the annual scientific sessions of the American Diabetes Association.

Mean steady state glucose values were 139 mg/dL in the exenatide group, 147 mg/dL in the recent control group, and 115 mg/dL in the pre-2009 control group, said Dr. Marso of St. Luke’s Cardiovascular Consultants, Kansas City, Mo.

Eight patients developed exenatide-related nausea, and six of these discontinued the drug.

The exenatide group had a lower rate of hypoglycemic events and severe hypoglycemic episodes than the other groups, though the differences were not statistically significant.

Blood glucose levels below 70 mg/dL were seen in 0.9% of 668 measurements in the exenatide group, 1.2% of 745 measurements in the recent control group, and 1.6% of 1,651 measurements in the pre-2009 control group. No patients on exenatide developed severe hypoglycemia (blood glucose less than 50 mg/dL), but this was seen in 0.3% of measurements in the recent control group and in 0.06% in the pre-2009 control group.

The findings show that it’s feasible to treat hyperglycemia in the cardiac ICU with fixed-dose IV exenatide and that results are comparable to those with IV insulin without the risk for severe hypoglycemia, Dr. Marso said. The disadvantage of IV exenatide is the risk for treatment-limited nausea.

He cautioned, however, that this is a small, nonrandomized, proof-of-concept study with no active control group and no long-term clinical follow-up.

A significantly greater proportion of patients in the exenatide group had diabetes (75%), compared with patients in the recent control group (67%).

The study included two historical control groups because recommendations for glycemic control in the ICU setting have changed in recent years. Initial clinical trials showed clinical benefit from intensive glucose control for patients with hyperglycemia in the ICU, but later studies reported higher risks for severe hypoglycemia and death with intensive glucose control in these patients, Dr. Marso said. Updated consensus guidelines subsequently called for less tight glycemic control.

A 2009 consensus statement on inpatient glycemic control from the American Diabetes Association and American Association of Clinical Endocrinologists calls for insulin therapy to be initiated in critically ill patients when blood glucose values drop below 180 mg/dL. Glucose should be maintained between 140-180 mg/dL, and targets less than 100 mg/dL are not recommended (Endocr. Pract. 2009;15:353-69).

The statement says that IV insulin is the preferred treatment and that noninsulin antihyperglycemic agents are not appropriate in most hospitalized patients who require therapy for hyperglycemia. But the potential risks with insulin therapy prompted the current study of IV exenatide.

The study excluded patients who were dependent on a ventilator, unconscious on sedation, who had type 1 diabetes, were pregnant, were post-orthotopic heart transplant, had a creatinine clearance less than 30 mL/min, had a history of pancreatitis, or who were being treated with insulin monotherapy other than long-acting basal insulin (glargine or detemir).

The study was funded by Amylin Pharmaceuticals, which markets exenatide with Lilly. Dr. Marso has been a consultant to, or received research support from, Amylin, Abbott Vascular, The Medicines Company, Novo Nordisk, Volcano, Boston Scientific, and Terumo Medical.