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CONFERENCE COVERAGE
NEWS FROM THE 69TH ANNUAL SCIENTIFIC SESSIONS OF THE AMERICAN DIABETES ASSOCIATION (ADA) - NEW ORLEANS
JUNE 5–9, 2009
Overall Cardiovascular Safety of Rosiglitazone Confirmed in 5-Year Study
Results of the long-awaited RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) study were presented here and simultaneously published online in The Lancet.
"The RECORD study was designed to evaluate the long-term impact of rosiglitazone [Avandia, GlaxoSmithKline] on cardiovascular outcomes and blood glucose control, compared to the conventional medications metformin and sulfonylureas, and the results show that, provided known contraindications and cautions are observed, physicians should be comfortable prescribing rosiglitazone for their diabetes patients," said Philip D. Home, DM, DPhil, Chair of the study's Steering Committee and Professor of Diabetes Medicine, Newcastle University, UK, in an ADA news release.
"Overall, the cardiovascular safety of rosiglitazone has been confirmed in more than 4,000 participants. Indeed, on the composite outcomes of cardiovascular death, stroke, and [myocardial infarction {MI}]—an outcome used in many cardiovascular trials—the result was slightly but not statistically significantly in favor of rosiglitazone versus metformin and sulfonylureas," said Dr. Home.
The researchers concluded that when used in appropriately selected patients, rosiglitazone carries no overall increase in cardiovascular risk with regard to major morbidity or mortality.
"Further, at the end of the study, rosiglitazone was shown to be superior in controlling blood glucose levels compared with the older metformin and sulfonylurea therapies, thus demonstrating the longevity of its benefits," said Dr. Home.
For more information on RECORD, see the June 2008 issue of Review of Endocrinology.
Factors Affecting Benefit/Harm of Intensive Glucose Control in Type 2 Diabetes Elucidated
Factors affecting whether intensive glucose control is likely to reduce or increase the risk of cardiovascular events, including death, based on evidence in the VADT (VA Diabetes Trial), were reported in a symposium here.
"We found that initiation of intensive control in the first 15 years after a diagnosis of type 2 diabetes reduced the risk of cardiovascular events, including mortality, but initiation 16 to 20 years after diagnosis yielded no such benefit," said William C. Duckworth, MD, Director of Diabetes Research, Carl T. Hayden VA Medical Center in Phoenix, Professor of Clinical Medicine, University of Arizona, and Co-Chair of the VADT, in a news release from the ADA. "Further, initiation of intensive control 20 or more years after diagnosis increased the risk of cardiovascular events in the population studied in this trial," said Dr. Duckworth.
These duration effects were not affected by age, despite the fact that age itself is an independent risk for cardiovascular events. In contrast to the VADT report last year showing that intensive control did not have a statistically significant effect on reducing cardiovascular events, the subanalyses presented clearly showed which patients benefited from intensive glucose control and which patients did not.
The effect of duration impact was complex, however. According to the research, the risk of having a primary cardiovascular event among people who had diabetes for 10 to 15 years was reduced 40% if they were on intensive glucose control. But if diabetes had been present for >21 years, the risk of primary cardiovascular events in patients on intensive control more than doubled.
"Unless other factors are present that would contraindicate intensive treatment, such as hypoglycemia, intensive control is appropriate in the first 15 years after diagnosis," said Dr. Duckworth. "However, intensive treatment should not be initiated if the individual has already had diabetes for 20 years." He added that it is unknown whether a person who has already been on intensive treatment for many years can safely continue it beyond the 20-year mark.
For more information on the VADT, see the July 2008 issue of Review of Endocrinology.
Low Blood Glucose Levels Do Not Explain Excess Deaths in ACCORD
Low blood glucose levels do not explain the excess deaths seen in the intensive control group of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, according to a report here.
"After the original ACCORD report showed an increased mortality risk in the intensive strategy group aiming to lower A1C level <6%, concern arose that this approach might be dangerous," said Matthew C. Riddle, MD, Professor of Medicine, Oregon Health Science University and a member of the Glycemia Management Group of ACCORD, in an ADA news release. Dr. Riddle was a site principal investigator in the study. He confirmed the estimate reported last year of a 20% increased risk of death associated with ACCORD's intensive treatment strategy; however, new analyses did not confirm the proposed theory that low A1C levels might be the cause.
"An A1C <7% alone does not appear to explain the excess deaths in the ACCORD trial and is not necessarily a predictor of mortality risk," said Dr. Riddle. "Further, the rate of
1-year change in A1C showed that a greater decline in A1C was associated with a lower risk of death."
Analyses to identify the cause of the increased mortality, such as hypoglycemia, weight gain, or a particular drug or combination of drugs are continuing.
"We found a 20% higher risk of death for every 1% higher A1C level >6%, suggesting that lower blood glucose levels may be a worthy target in some patients," said Riddle.
That higher risk of death remained even after statistical adjustment for age, duration of diabetes, or prior cardiovascular events, he said. This analysis is also consistent with analyses from other epidemiologic studies showing a relationship between higher A1Cs and higher risk of death. The goal was for the intensive group to reach an A1C level of <6% and for the standard group goal to reach between 7% and 7.9%.
A closer look at the role of hypoglycemia in ACCORD was presented by Denise Bonds, MD, MPH, an investigator at ACCORD's Coordinating Center who is now a medical officer for the trial at the National Heart, Lung, and Blood Institute at the National Institutes of Health. The study defined severe hypoglycemia as a blood glucose level
<50 mg/dL or symptoms consistent with hypoglycemia and recovery with glucagon or an oral carbohydrate. It was further divided into those who required any assistance versus those who required emergency medical assistance at home or in a hospital.
According to the ADA news release, the ACCORD group also adjudicated each death for the potential role of hypoglycemia. Of the 451 deaths, they were only able to identify one case where it was concluded that severe hypoglycemia definitely played a role. There cannot be complete certainty, however, because glucose measures are not available near or at the times of deaths. Continuous glucose monitoring was rarely done during the trial.
For more on the ACCORD trial, see the July 2008 issue of Review of Endocrinology
Prompt Bypass, Angioplasty Does Not Lower Mortality Risk Vs Drug Therapy in Patients With Type 2 Diabetes
The long-awaited results of the BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes) study, a multicenter trial led by the University of Pittsburgh Graduate School of Public Health, were reported here.
"In combining the two revascularization approaches, we found that prompt revascularization did not hold any advantage over intensive medical therapy alone with regard to total mortality," said Trevor Orchard, MD, Professor of Epidemiology, University of Pittsburgh Graduate School of Public Health and Director of the Lipid Management Center of BARI 2D. He added, "Prompt coronary artery bypass [graft] surgery [CABG], compared with intensive medical therapy alone, had significantly better outcomes when cardiovascular events were considered in addition to death."
A large part of this benefit consisted of a reduction in nonfatal MIs never before shown with CABG, the investigators noted.
According to an ADA news release, the landmark study evaluated both a cardiovascular treatment approach as well as a diabetes control approach in 2,368 patients with type 2 diabetes and stable coronary artery disease (CAD) to reduce deaths or deaths and cardiovascular events combined.
The first component compared intensive medical treatment with prompt coronary revascularization by either CABG or angioplasty with intensive medical treatment alone. The two coronary revascularization procedures were not compared with each other; rather, each treatment group was independently compared to its own control group receiving intensive medical therapy alone. The second component compared whether controlling diabetes with insulin sensitization had an advantage for heart health or survival compared to using a strategy emphasizing insulin provision.
"BARI 2D results further inform the clinical management of type 2 diabetes in patients with stable [CAD] and ischemia and strengthen the choice of early CABG over medical therapy alone in those who are appropriate candidates for bypass surgery," said Saul M. Genuth, MD, Professor of Medicine, Case Western Reserve University and Director of the Diabetes Management Center of BARI 2D.Ê"Some of the observations also support the concurrent use of glycemic management aimed at reducing insulin resistance."
Liraglutide More Effective at Blood Glucose Lowering Than Glimepiride: LEAD-3
Once-daily liraglutide (Victoza, Novo Nordisk), taken as monotherapy, leads to statistically significant and sustained reductions in blood glucose and weight after 2 years of treatment.
"The fact that liraglutide continues to effectively lower blood sugar after 2 years of treatment is consistent with its other long-term clinical benefits such as continued reductions in fasting blood sugar and weight," said Alan Garber, MD, Baylor College of Medicine, Houston, a principal study investigator. "Even with available treatments, many type 2 diabetes patients still struggle to control their blood sugar, while losing weight. Liraglutide represents an important advance for these patients," he said in a Novo Nordisk news release.
Dr. Garber and colleagues found that 58% of patients treated with liraglutide 1.8 mg/day reached and maintained the ADA A1C goal of <7% compared with 37% of patients treated with glimepiride 8 mg once daily.
The extension study—LEAD 3 (Liraglutide Effect and Action in Diabetes)—also documented that treatment with liraglutide leads to early and lasting weight loss. Specifically, after 2-year treatment, mean body weight decreased significantly (-2.7 kg) compared to overall weight increase in the glimepiride group (+1.1 kg). Minor hypoglycemia was more than six times less frequent in the liraglutide treatment groups compared with the glimepiride group.
Type 2 diabetes patients enrolled in the 1-year LEAD 3 extension study were assigned liraglutide (1.8 mg and
1.2 mg, once daily) or glimepiride (8 mg, once daily). Included patients were treated previously with diet/exercise or low doses of one oral antidiabetic drug. The trial had a 52-week randomized, double-blind period followed by the 1-year extension; 59% entered the extension period of the trial, and 43% of these patients completed the full 2-year study period, according to Novo Nordisk.
A regulatory decision in the United States regarding liraglutide is pending.
Alogliptin Safe, Effective in Elderly With Type 2 Diabetes
A pooled analysis of alogliptin (Takeda) phase 2 and 3 data found the treatment to be safe and effective in elderly patients with type 2 diabetes.
Richard E. Pratley, MD, Professor of Medicine and Director of the Diabetes and Metabolism Translational Medicine Unit at the University of Vermont reported the results from six phase 2 and 3 double-blind, placebo-controlled randomized studies evaluating the efficacy and safety of alogliptin 12.5 or 25 mg daily for up to 26 weeks.
Among the subset of elderly patients, aged ≥65 years, 350 received alogliptin; among the subset of younger patients (<65 years), 1,482 received alogliptin. Comparisons were made on placebo-corrected data.
Baseline values for A1C, fasting plasma glucose (FPG), and weight showed were similar between age cohorts, and there were no statistically significant age-group differences between age cohorts. Alogliptin was well tolerated in elderly patients, and overall, the rate of any serious adverse events and adverse events leading to discontinuation were somewhat higher in the elderly patients. Elderly patients, however, had the same beneficial effects of alogliptin on glycemic endpoints as younger patients.
A1C rates were lowered in elderly patients by -0.69% (12.5 mg) and -0.77% (25 mg) and in younger patients by -0.53% (12.5 mg) and -0.61% (25 mg).
Albiglutide Improved Glucose Control, Reduced Weight
Phase 2 data show that the investigational type 2 diabetes treatment albiglutide (Syncria, GlaxoSmithKline) significantly reduced blood glucose levels and provided weight loss across weekly, biweekly, and monthly dosing.
According to a company news release, the trial was a randomized, multicenter, double-blind, parallel-group study in 356 subjects with type 2 diabetes previously treated with diet and exercise or metformin (mean baseline A1C 8%). Patients received subcutaneous placebo, albiglutide weekly, (4, 15, or 30 mg), biweekly (15, 30, or 50 mg) or monthly (50 or 100 mg), or exenatide (Byetta, Eli Lilly and Company/Amylin) (open-label reference arm, in metformin-treated patients) during 16 weeks.
Dose-dependent reductions in A1C with albiglutide
30 mg weekly, 50 mg biweekly, and 100 mg monthly were 0.9%, 0.8%, and 0.9%, respectively (P<.05). The A1C reduction by placebo was 0.2% and by open-label exenatide was 0.5%. Weight loss (0.9 to 1.8 kg) was observed across all doses, and the most frequently reported adverse events included nausea, vomiting, and headache. Additionally, albiglutide was not shown to increase the risk of hypoglycemia.
"Despite a range of available diabetes therapies, over half of patients with type 2 diabetes are unable to achieve the ADA target blood sugar goal," said the study's lead investigator, Julio Rosenstock, MD, of the Dallas Diabetes and Endocrine Center at Medical City and Clinical Professor of Medicine, University of Texas Southwestern Medical School. "While these results need to be confirmed in ongoing studies, the findings with albiglutide are important since weight gain and fear of increased blood sugar levels can be major barriers to diabetes management."
New Ultrarapid-Acting Insulin Controls Postmeal Glucose With Less Weight Gain, Risk of Hypoglycemia
The findings of two 52-week studies show that the investigational ultrarapid-acting insulin Afresa Inhalation Powder (insulin human [rDNA origin], MannKind) combined with basal insulin is comparable to standard-of-care therapies in controlling postmeal blood sugar levels and also results in significantly less weight gain and risk of hypoglycemia for adult patients with diabetes.
"The unique pharmacokinetic profile of Afresa allows this product to rapidly achieve peak insulin levels," said John Gerich, MD, Program Director, Clinical Research Center, Department of Medicine, University of Rochester School of Medicine and Dentistry. "These results indicate that Afresa may be a promising new therapy for patients with type 1 and type 2 diabetes, as it controls postmeal-time glucose levels with the added benefits of less weight gain and lower risk of hypoglycemia."
According to the company, Afresa is a novel, ultrarapid acting mealtime insulin therapy with an action profile that mimics meal-related early insulin release. Based on an extensive phase 3 clinical program, an NDA has been accepted by the FDA requesting approval to market Afresa Inhalation Powder and the Afresa Inhaler for use in adult patients with type 1 and type 2 diabetes for the treatment of hyperglycemia.
Lantus Plus One, Two, or Three Shots of Apidra Lowered Patients' Blood Sugar
A study presented here evaluated patients adding prandial insulin Apidra (insulin glulisine [rDNA origin] injection, Sanofi-Aventis) administered before one meal, two meals, or three meals daily, already taking basal insulin, Lantus (insulin glargine [rDNA origin] injection, Sanofi-Aventis), with or without oral antidiabetic drugs (OADs).
The multicenter, randomized, open-label, parallel group study was conducted among insulin-na•ve patients. Patients received Lantus for a 14-week run-in period. Patients not at goal at that time (A1C <7%) were then randomized to a 24-week intensified regimen of Lantus plus Apidra. The dose was adjusted to achieve an A1C<7%, FPG, and preprandial blood glucose <110 mg/dL, and bedtime blood glucose <130 mg/dL, according to a news release from Sanofi-Aventis. FPG, Lantus dose, and weight were similar among the three arms. Overall incidence and severity of adverse events were comparable among the treatment arms. A greater but nonsignificant proportion of patients experienced serious and severe hypoglycemia.
"By combining basal insulin Lantus plus Apidra mealtime insulin at one, two, or three meals throughout the day, we observed A1C reductions with many patients achieving the target A1C of <7%," said Mayer Davidson, MD, Professor of Medicine, UCLA School of Medicine.
Colesevelam Improved Metabolic Control, Bile Acid Metabolism
Treatment with colesevelam (Welchol, Daiichi-Sankyo) resulted in improved metabolic control and positive changes in bile acid metabolism, according to data presented here.
Type 2 diabetes has been associated with abnormalities in bile acid metabolism, which may contribute to the metabolic phenotype, according to a poster presentation by Elizabeth Murphy, MD, of the University of California, and colleagues. Colesevelam—a bile acid sequestrant—has been shown to improve glycemic control and low-density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes.
Dr. Murphy and colleagues examined whether the metabolic effects of colesevelam are related to changes in bile acid reduction in a study of 12 men with type 2 diabetes who were matched for age and BMI with men who had normal glucose tolerance. Investigators determined bile acid pool sizes and synthesis/input rates before and after 8-week treatment with colesevelam (3.75 g/d).
As previously reported, at baseline, patients with type 2 diabetes had a higher cholic acid synthesis rate, deoxycholic acid input rate, deoxycholic acid pool size and percent contribution of deoxycholic acid to total bile acid pool and lower chenodeoxycholic acid percent contribution to total bile acid pool. Treatment with colesevelam reduced A1C by 0.65% (P=.02) and increased fasting triglycerides by 40 mg/dL (P=.03) in the men with type 2 diabetes. LDL-C was also reduced (10.7 mg/dL, P=.04) across both groups, according to the poster.
Colesevelam treatment resulted in an expected, significant increase in bile acid synthesis in both groups and an unexpected increase in cholic acid pool size, Dr. Murphy reported. Chenodeoxycholic acid and deoxycholic acid pool sizes as well as deoxycholic acid input rates were decreased significantly only for the control group. Consequently, percent deoxycholic acid in the total pool decreased in both groups.
The investigators concluded that colesevelam treatment led to improved glycemic control in type 2 diabetes. Also, it was associated with increased bile acid synthesis, unchanged total bile acid pool size, and differential effects on individual bile acid pool sizes in both groups resulting in increased hydrophilicity of the bile acid pool and, thus reduced susceptibility to gallstone formation in type 2 diabetes. Triglyceride changes with colesevelam treatment were correlated to bile acid kinetic changes, suggesting a potential metabolic link, they wrote in the abstract.
NEWS FROM THE ENDOCRINE SOCIETY'S 9th ANNUAL MEETING (ENDO 09) - WASHINGTON, DC
JUNE 10–13, 2009
Testosterone Replacement Improves Liver Function, Metabolic Syndrome
In middle-aged and older men with low testosterone levels, long-term testosterone replacement therapy greatly improves fatty liver disease and risk factors for cardiovascular disease (CVD) and diabetes, a new study found.
Testosterone deficiency is linked to the metabolic syndrome. Nonalcoholic fatty liver disease, also called a fatty liver, commonly co-occurs with the metabolic syndrome and may aggravate the metabolic problems.
"Physicians often are reluctant to prescribe testosterone for conditions not related to sexual function," said the study's coauthor, Farid Saad, PhD, of Berlin-headquartered Bayer Schering Pharma. "However, our study shows that testosterone has a much wider therapeutic role than just for improving sexual desire and erectile function."
According to an Endocrine Society news summary, the study included 122 testosterone-deficient men, aged 36 to 69 years (mean age, 59.5 years). Results showed that restoring testosterone to normal levels led to major and progressive improvements in many features of the metabolic syndrome over the 2 years of treatment. Specifically, the men's weight, waist circumference, and BMI continued to decline over the full study period. The other metabolic risk factors also significantly improved during the first year of testosterone treatment. Of the 47 men who met the criteria for a diagnosis of the metabolic syndrome at the beginning of the study, 36 (77%) no longer had the diagnosis after 2 years of treatment, the authors reported.
"We conclude that testosterone therapy in men with testosterone deficiency can largely improve or even remedy the metabolic syndrome, which will most likely decrease their risk of diabetes and CVD," Dr. Saad said.
German study participants were treated with slow-release, injectable testosterone undecanoate that is not yet available in the United States.
Lanreotide Well Tolerated, Associated With IGF-1 and GH Control in Acromegaly
Researchers here said that self- or partner-administered lanreotide (Somatuline Depot, Ipsen) is generally well-tolerated and associated with insulin-like growth factor-1 (IGF-1) and growth hormone (GH) control in many patients with acromegaly.
According to a poster presentation by Roberto Salvatori, MD, Associate Professor of Medicine, Division of Endocrinology and Metabolism at Johns Hopkins University School of Medicine, treatment with long-acting somatostatin analogs is indicated in acromegaly patients with GH excess that persists following surgery.
Dr. Salvatori and colleagues undertook a 6-month, single-arm, open-label trial to evaluate the convenience, safety, and efficacy of lanreotide in acromegaly patients switched from long-acting octreotide (LAO) and in treatment-na•ve patients.
A total of 59 patients were enrolled in the study, 33 switched from LAO, and 26 did not. Final data available for 47 study completers and seven who withdrew early showed that 60% of the switch patients and 32% of the others had normal IGF-1 levels and glucose-suppressed GH levels ≤2.5 ng/mL at week 24. The injection was deemed not painful, somewhat painful, or moderately painful by 50%, 42%, and 8% of switch patients, respectively.
"Most switch patients preferred lanreotide over LAO for future use (77% vs 15%)," Dr. Salvatori said.
Depression Symptoms in Obese Children Linked to Elevated Cortisol Levels
A new study connects abnormalities of the stress hormone cortisol with symptoms of depression in obese children, and confirms that obesity and depression often occur together, even in children.
"There is evidence in adults that abnormal regulation of cortisol plays a role in both obesity and depression," said the study's lead author, Panagiota Pervanidou, MD, of Athens University Medical School in Athens, Greece. "Our study indicates that cortisol abnormalities may underlie obesity and depression starting in childhood."
Cortisol is a steroid hormone that helps the body respond to stress, however it also has other functions including converting fat, protein, and carbohydrates into energy, according to the news release. Normally, levels of this hormone peak in the early morning, start to drop in late morning, and reach their low point at night. Depressed adults have slightly elevated cortisol levels at night—"the endocrine equivalent of chronic stress," Dr. Pervanidou said. This chronic elevation of cortisol contributes to development of the metabolic syndrome.
In this new study, Dr. Pervanidou and colleagues measured cortisol five times a day in the saliva of 50 obese children and teenagers as well as in their blood in the morning. The 20 boys and 30 girls, ages 8 to 15 years, were patients in the Athens University pediatric obesity clinic and did not have a prior diagnosis of depression. All patients completed the Children's Depression Inventory.
Cortisol levels in the saliva in the afternoon and evening correlated positively with symptoms of depression, the authors reported. The more depressive symptoms that subjects reported, the higher the cortisol levels at those times. This finding indicates that obesity and depression may not only be related to behavior but may also have a hormonal link, according to Dr. Pervanidou. Obesity and depression often co-occur, therefore, prevention and screening should focus on both disorders and should start in childhood.
Laparoscopic Banding Weight-Loss Surgery Reduces Teens' Risk Factors for Heart Disease, Diabetes
In teenagers, laparoscopic gastric banding surgery for treatment of extreme obesity can significantly improve and even reverse the metabolic syndrome, a new study found.
An increasing number of obese adolescents have the metabolic syndrome, said study coauthor, Ilene Fennoy, MD, MPH, a pediatric endocrinologist at New York City's Columbia University Medical Center. "Few treatments, however, have succeeded in achieving major weight loss or greatly improving adolescents' medical complications of obesity—until now," Dr. Fennoy said.
In the new study, 24 morbidly obese teens between the ages of 14 and 17 years underwent laparoscopic gastric banding, a minimally invasive weight-loss surgery that uses a band that can repeatedly be adjusted to make the stomach smaller. Six months after the operation, patients had a statistically significant decrease in BMI as well as waist circumference and blood levels of C-reactive protein. These improvements continued to 1 year in the 12 patients whose follow-up was that long.
Other features of the metabolic syndrome improved rapidly in the first 6 months and continued to 1 year but with less dramatic changes, the authors reported in their abstract. Five patients with 12-month follow-up met the criteria for a diagnosis of the metabolic syndrome before surgery. Only two still had this diagnosis 1 year later, a decrease in prevalence from 41.7% to 16.7%.
"Laparoscopic gastric banding surgery may be a useful intervention for morbidly obese teenagers to decrease the risk of early development of cardiovascular disease and other illnesses related to obesity," Dr. Fennoy said.
Currently approved for use only in adults, laparoscopic gastric banding is being studied in teenagers. Long-term studies are needed to confirm that this procedure effectively improves the metabolic syndrome in adolescents, Dr. Fennoy said.
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