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| Medical Economics | Drug Topics | Formulary | Contemporary OB/GYN |
 Daily highlights from the American Diabetes Association 70th Scientific Sessions. From June 25-29, the editors of Medical Economics and Advanstar Communications' other primary care and pharmacy publications will bring you the latest news from Orlando. |
Welcome Greetings from the American Diabetes Association’s 70th Scientific Sessions June 29 – Orlando — The editorial staff of Medical Economics brings you daily coverage of breaking news, the latest research findings, and reports of interest to the readers of Medical Economics, Drug Topics, Formulary, and Contemporary OB/GYN. Our five-day coverage of this year’s American Diabetes Association’s 70th Scientific Sessions includes the results of major clinical trials and ongoing news and information of interest to clinicians who treat type 1 and 2 diabetes. EMERGING THERAPIES Will DPP-4 inhibitors replace sulfonylureas? Debaters make their case
Nauck, head of the Diabetes Centre, Diabeteszentrum Bad Lauterberg, Germany, made the case that the mode of action of sulfonylureas—no glucose dependence of insulinotropic effects—is dangerous, then supported this argument with clinical data from 4 studies in which DPP-4 inhibitors were compared with sulfonylureas. In each study, there was no difference between the drug classes in reduction of hemoglobin A1c levels. However, body-weight changes consistently favored the DPP-4 inhibitors, and superior effects on lipid profiles were observed in patients treated with DPP-4 inhibitors relative to those treated with sulfonylureas. Rates of hypoglycemia are also lower with DPP-4 inhibitors, Nauck said, and recovery of hypoglycemia is delayed with sulfonylureas. “I am not as concerned about hypoglycemia as I am about severe hypoglycemia,” he said, and on this endpoint, DPP-4 inhibitors are clearly superior. The rate of severe hypoglycemia is up to 1.5% over 2 years with sulfonylureas but is extremely rare with DPP-4 inhibitors, he said. “I am most concerned about hospitalization . . . and deaths due to severe hypoglycemia,” said Nauck, and again sulfonylureas show a “lethality” of 5.7%, which is the combined rate of hospitalizations and deaths caused by severe hypoglycemia. He calculated that 80 excess deaths occur per year in the United States because of sulfonylurea treatment. Going back to the 4 comparator trials between DPP-4 inhibitors and sulfonylureas, in the 2 trials in which cardiovascular events were reported, the rate was nearly half with the DPP-4 inhibitors, said Nauck.
“I am not saying that sulfonylureas are better than DPP-4 inhibitors. What I am saying is that there is no information about DPP-4 inhibitors as related to glycemic outcomes,” Matthews said. In contrast, clinical trial evidence is abundant with sulfonylureas. In the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial, intensive blood glucose control using gliclazide modified release resulted in a 14% relative risk reduction in major microvascular events compared with a conventional strategy. In the United Kingdom Prospective Diabetes Study (UKPDS), intensive blood glucose control with insulin and/or a sulfonylurea reduced the incidence of microvascular but not macrovascular complications compared with conventional treatment; however, insulin was the primary treatment in this study, and the use of multiple combination drug regimens in the intensive arm to maintain glycemic separation between the 2 arms preclude making definitive conclusions, Matthews said. Although there were more deaths in the tolbutamide recipients in the University Group Diabetes Program (UGDP), patients in this arm had a frequency of baseline electrocardiographic abnormalities that was 30% higher than the comparator arms. Hypoglycemia is not a true side effect of sulfonylureas, said Matthews, but rather too “much of the effect,” and the lesson to be learned is to use caution in dosing, as with many drugs. Part of the weight gain that occurs with sulfonylureas may be the result of the body defending against hypoglycemia, added Matthews, Finally, he said, cost is always a consideration in treatment, and sulfonylureas offer an inexpensive and safe therapy for a disease that is a worldwide pandemic. NEW RESEARCH Metformin associated with lower risk of mortality than other oral antidiabetic agents in patients with diabetes and heart failure In patients with diabetes and concomitant heart failure who are naive to oral antidiabetic drugs, the introduction of metformin use is associated with a lower risk of mortality than the introduction of other oral antidiabetic drugs, found Dean T Eurich, PhD. In a nested, case-control study, the records of patients 35 years or older who were newly diagnosed with both heart failure and diabetes after January 1988 and who died before October 2007 were selected from the UK General Practice Research Database. Controls were matched to cases on the basis of age, sex, clinic site, calendar year, and duration of follow-up. Analyses were adjusted for comorbidities, hemoglobin A1c values, renal function, body mass index, hemoglobin, blood pressure, and drug therapies known to affect outcomes in patients with diabetes and heart failure. There were 1,633 cases and 1,633 controls (mean age, 78 years). Compared with patients whose diabetes was controlled solely by diet and lifestyle, the use of metformin was associated with an adjusted 34% reduction in mortality on multivariate analyses (P=.006), whereas the use of other antidiabetic drugs or insulin was not associated with all-cause mortality. The use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs; 45% reduction) and beta-blockers (24% reduction) were also associated with lower mortality. By including only patients not previously exposed to antidiabetic drugs, “our results suggest that the apparent benefit of metformin over other antidiabetic agents is due to reduced mortality risk with metformin rather than harm with other agents,” according to Eurich, assistant professor, Department of Public Health Sciences, School of Public Health, University of Alberta, Edmonton, Alberta. “Until randomized trial evidence becomes available, we believe that our study and the extant published literature support the use of metformin-based strategies for glucose-lowering in patients with diabetes and heart failure," he said. He added that underuse of proven effective therapies in this group of patients is common, as evidenced by the low rate of the use of both ACE inhibitors or ARBs and beta blockers (18%) in the study population. Gut bacteria can affect obesity
“We should take into account microbes in the gut, diet, and other factors in considering energy balance and obesity,” said Peter Turnbaugh, PhD, Harvard FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts. “There is an interaction between host and microbes.” Turnbaugh explored the latest data on relationships between intestinal microbial communities and obesity during a Monday morning symposium, Nutrient-Gut-Brain Modulators. There are about 10 times more microbial cells than human cells in the typical individual, he noted, anywhere between 10 and 100 trillion cells. Most reside in the intestinal tract. The gut microflora is composed of about 10 major lineages, with Bacteroidetes, Fermicutes, and Actinobacteria accounting for more than 90% of the total population. Every individual hosts more than 1,000 distinct species of bacteria, Turnbaugh added, and the bacterial population living in each individual is unique. Mice raised in a sterile, germ-free environment eat more but weigh less than mice raised in a normal, bacteria-filled environment, but their weight quickly changes when bacterial communities are introduced. Genetically obese mice colonized with bacteria from obese humans become obese, whereas genetically identical mice colonized by bacteria from lean humans become lean. “There was no difference in the amount of chow these mice consumed before and after colonization,” Turnbaugh said. “The only difference was the relative population of Bacteroidetes and Fermicutes.” Using a broad-spectrum antibiotic to kill gut microbes reversed the weight gained by the obese mice that had been colonized with bacteria from obese humans, he continued. Changing the microbial balance can also attenuate the effects of type 1 diabetes and reverse metabolic syndrome in mice. Studies of obese and lean human twin pairs found 383 microbial genes associated with obesity, Turnbaugh continued. Many were associated with carbohydrate metabolism. That matches the findings that obese mice extract more calories from their diet than lean mice. Analysis of mice stools also found evidence of increased microbial fermentation in obese mice, a process that would provide additional calories. Among older diabetics, improvements in HbA1c levels with telemedicine is related to more frequent glucose checking
Weinstock and colleagues conducted a Medicare demonstration project to ascertain whether older adults living in underserved areas could better manage their diabetes through telemedicine. Medicare beneficiaries who lived in New York State, had diabetes, and lived in federally designated underserved areas were enrolled. The study population consisted of 265 ethnically diverse persons older than 70 years; approximately half were non-Hispanic white; 35% were Hispanic, and 15% were non-Hispanic black. They were randomized to receive a home telemedicine intervention or usual care. “The intervention group was given a home telemedicine unit that allowed them to videoconference with a nurse or dietitian at a diabetes center every 4 to 6 weeks, at which time they could also download and upload their blood glucose and blood pressure levels,” said Weinstock, chief of endocrinology, State University of New York. “They would discuss diabetes management issues and also blood glucose and blood pressure levels with a nurse case manager and dietitian. They remained within the care of their primary care physicians. We sent recommendations to primary care physicians to change pharmacologic therapy if we thought it was indicated.” As reported previously, after 5 years, HbA1c levels, blood pressure levels, and low-density lipoprotein cholesterol levels were significantly improved in the participants in the telemedicine group compared to the usual-care group. At baseline, the Hispanic participants had the highest HbA1c levels, and the non-Hispanic whites had the lowest HbA1c values. “The Hispanics had the greatest fall in HbA1cs, but they still didn’t end up quite as low as the non-Hispanic white participants,” said Weinstock. In another presentation here, the same authors found that telemedicine participants had smaller declines in physical activity over time and a lower rate of physical impairment than the usual-care group. “The concept should work wherever there’s a need,” Weinstock said. “We found that physicians in upstate New York don’t have access to dietitians, so they found this very valuable to be able to provide education to their patients.” Promising pilot study of resveratrol A pilot study of resveratrol in 10 older adults suggests that the compound may be beneficial for patients with impaired glucose tolerance. At doses of 1 to 2 grams daily for 4 weeks, resveratrol significantly increased insulin resistance and lowered postprandial glucose levels. “The results of this pilot study are preliminary and need to be confirmed in larger numbers of patients,” said lead author Jill Crandall, MD, associate professor of medicine, Albert Einstein College of Medicine, New York, in a prepared statement. “We are encouraged by these findings and plan to conduct additional studies to further explore the potential utility of resveratrol in improving glucose metabolism.” Resveratrol is found in red grapes, red wine, nuts, berries, and some plants. Preclinical trials have shown that it increases life span in yeast, worms, fruit flies, and rodents, but there is little human data. The substance is thought to activate sirtuin-1, an NADH-dependent histone deacylase and AMP kinase. It may affect glucose uptake, mitochondrial biogenesis and oxidation, and nitric oxide production. Researchers gave resveratrol to 10 patients between the ages of 60 and 80 with prediabetes (2-hour fasting glucose 140-199). Outcomes were 3-hour glucose and insulin area under the curve (AUC) following a standard meal, the calculated Matsuda index of insulin sensitivity, and insulin secretion. The resveratrol dose was given with the meal. Glucose and insulin were measured at 0, 30, 60, 120, and 180 minutes after the meal. Endothelial function was assessed using peripheral arterial tonometry before and 90 minutes after eating. The results did not differ by dose. Fasting glucose was unchanged after 4 weeks of resveratrol, but postprandial glucose AUC fell from a mean of 469 to 428 (P=.001). The Matsuda index improved from 3.1 to 3.8 (P=.03) and insulin secretion was unchanged, indicating that the major effect was on insulin resistance. There was a trend to increased postprandial reactive hyperemia index, suggesting improved microvascular endothelial function, but the change was not statistically significant. Weight, blood pressure, and lipids were unchanged, and there were no changes in safety parameters, including chemistries, complete blood count, urinalysis, and electrocardiogram. Hypoglycemic episodes linked to oral antidiabetic drug discontinuation, higher costs
The Ingenix Impact database, a large administrative database of managed care plans, was used to identify 212,061 patients with type 2 diabetes receiving 1 or more oral antidiabetic drug. Of these, 4,860 (2.29%) had at least 1 hypoglycemic episode during the first year after the index date. The risk of hypoglycemia varied among the treatments. In the 6-month interval after the index date, use of a sulfonylurea or insulin was associated with the largest increase in the risk of hypoglycemia, followed by other oral antidiabetic drugs and thiazolidinediones, said lead investigator Morgan Bron, PharmD, associate director of global health outcomes at Takeda Pharmaceuticals International, Deerfield, Illinois. The use of metformin had no effect on the risk of hypoglycemia, and dipeptidyl peptidase-4 (DPP-4) inhibitors were associated with a decreased risk. On multivariate analysis, the use of sulfonylureas as an index drug increased the risk of hypoglycemia by 58% (P<.0001), and insulins increased the risk by 77% (P<.0001) in the following 6-month interval. Use of DPP-4 inhibitors was associated with a 21% decrease in the risk of hypoglycemia (P=.0141). A diagnosis of hypoglycemia in a given 6-month interval significantly increased the likelihood of treatment discontinuation, with an odds ratio (OR) of 1.27 within the same 6-month interval and an OR of 1.14 in the next 6-month interval. “Cost differences [associated with hypoglycemic episodes] were a lot higher than we thought they would be,” said Bron. “Instead of the $2,000 range, they were more in the range of $4,000 to $5,000.” After adjusting for confounding factors, incremental annual total costs and diabetes-related total costs were $5,031 higher and $3,751 higher, respectively (both P<.0001), in patients with a hypoglycemic episode compared with those without a hypoglycemic episode. PATIENT MANAGEMENT Cardiac disease in diabetes still a black box
“Atherosclerosis is the major cause of morbidity and mortality in all of our patients with diabetes, whether it is type 1 or type 2,” said Ira Goldberg, MD, professor of medicine, Columbia University Medical Center. “Why does diabetes cause atherosclerosis? I don’t know.” Goldberg examined the state of diabetic cardiovascular disease research during the annual Edwin Bierman Lecture Monday morning. There is growing evidence that hyperglycemia and hyperlipidemia play key roles in the development of coronary artery disease. There is just as much evidence supporting key roles for hypertension and lipid abnormalities. One of the basic conundrums is the effect of lowering hemoglobin (Hb) A1c. Reducing HbA1c has a dramatic and linear effect on microvascular disease, but reduction in macrovascular disease is far less dramatic. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial raised more questions. Intensive treatment to lower glucose produced an increase a fatal cardiac events but an ever-larger decline in nonfatal events. At the same time, altering risk factors by lowering blood pressure and low-density lipoproteins have protective effects on both coronary artery disease and glucose control. Plaque stability and regression are open questions. In the presence of diabetes, arterial plaque becomes less stable. Diabetes also inhibits the regression of plaque that normally occurs when cholesterol levels fall. Glucose and insulin play roles in atherosclerosis. Insulin alters lipoproteins, mediates inflammation, decreases the size of necrotic cores, and more. Glucose encourages inflammation, among other effects, possibly by altering the balance between Ly-6C hi, which are proinflammatory, and Ly-6C lo monocytes, which are less inflammatory. Injecting hyperglycemic mice with phlorizin, an antiglucose agent, normalizes glucose levels and restores the normal monocyte balance. “Glucose itself is toxic,” Goldberg said. “We are still sorting out the role of diabetes versus risk factors and still studying alterations in plaque. But atherosclerosis is still a black box. I don’t know why diabetes increases atherosclerosis.” Herbals helpful for diabetes care, but there’s little evidence
“The evidence for herbals in diabetes is quite limited,” said Benjamin Kligler, MD, MPH, vice chair of integrative medicine, Beth Israel Medical Center, New York. “There may be promising agents, but none have reached the level of large, multicenter trials.” Kligler discussed the pros and cons of herbals and supplements for diabetes during an afternoon presentation, Herbal Remedies for Diabetes—Show Me the Evidence. The reality, he said, is that there may never be randomized, controlled trials. “These are not patentable substances,” Kligler explained. “They are all in the public domain. There is very little incentive for manufacturers to research their products. So where is that large trial going to come from? It would have to be funded by NIH or some other organization.” What little evidence there is suggests that herbals have no effect on glycemic control, Kligler continued. But there is evidence that selected herbals can improve lipid profiles, hepatic function, and other forms of metabolic disarray associated with diabetes. There is a significant body of data showing that silymarin helps hepatic cells regenerate more quickly. That makes it a useful agent for patients with elevated liver enzymes associated with statins, HIV medications, and other agents. “We all know how often you have to take a patient off a med due to elevated liver enzymes,” Kligler explained. “Silymarin can bring those enzymes back to normal, and you can continue your otherwise effective treatment.” Fish oil is another useful supplement, as well as fish consumption. Omega-3 fatty acids have no effect on glycemic control, but have a positive effect on triglycerides. Red yeast rice, a common ingredient in Chinese medicine, has been shown to reduce low-density lipoproteins by 10% to 20% without affecting hepatic function. A key problem, Kligler noted, is selecting a product. Herbals and dietary supplements are not required to prove efficacy, and quality control varies dramatically among manufacturers. Reliable information on herbals is also in short supply. He recommended online information from the Memorial Sloan-Kettering Cancer Center Integrative Medicine Service (www.mskcc.org/mskcc/html/11570.cfm). Useful product analysis and comparisons can be found at ConsumerLab.com, a subscription service. “It is buyer beware in the herbal marketplace,” Kligler cautioned. “There are good products and good brands out there, but you have to be a little suspicious.” DISCLAIMER: |
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