|
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
25 – 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.
BREAKING NEWS
Diabetes an independent risk factor for vascular disease
New data suggest that although diabetes doubles the risk of vascular disease, elevated fasting glucose has little effect on the risk of coronary heart disease (CHD) or major ischemic events. The results of a meta-analysis of 1.2 million patients in 120 randomized, controlled trials were presented Saturday morning at a special symposium cosponsored by ADA and The Lancet, which published the study in their June 26 issue.
“We’ve known for decades that diabetes is a risk for vascular disease,” said lead author Nadeem Sarwar, PhD, University of Cambridge, United Kingdom. “But how the risk varies by age, sex, and levels of other risk factors remains unknown.”
Sarwar represented the Emerging Risk Factors Collaboration, which designed and conducted the study. The collaboration represents more than 12 million person-years of risk, he said, with a mean follow-up of 10 years.
Analysis of contributed studies showed that diabetes roughly doubles the risk of cardiovascular events regardless of other factors. Having diabetes increases the risk of coronary death by 2.31 times and increases the risk of a nonfatal myocardial infarction (MI) by 1.82 times.
The presence of diabetes also increases the risk for ischemic stroke by 2.27 times, for hemorrhagic stroke by 1.56 times, and for other vascular deaths by 1.73 times.
Overall, the hazard ratios (HRs) for CHD were higher for women than for men and higher in younger (40-59 years) patients than in those 70 years old and older. The HRs were also higher for fatal events compared with nonfatal MIs.
Why diabetes produces a greater risk in groups that would be expected to be at lower risk is not clear, Sarwar said. Diabetes may be associated with more severe vascular lesions, but further study is needed.
“We did not see a linear relationship between fasting glucose and cardiovascular disease,” Sarwar continued. “The risk is essentially flat for serum glucose between 3.9% and 5.6%, then increases sharply.”
The analysis suggests that diabetes is responsible for about 10% of all vascular deaths, roughly 325,000 people annually in the developed world.
“Diabetes doubles the risk for vascular diseases independent of other factors,” Sarwar concluded. “In people who do not have diabetes, fasting glucose is not a useful predictor of vascular disease.”
EMERGING THERAPIES
Near agreement on CV risk assessment for diabetes drugs
 |
| Steven Nissen, MD |
It was billed as a debate, but played as a mild disagreement.
Should new diabetes drugs submitted to the FDA have a higher bar for cardiovascular safety than other drugs?
Yes, said Steven Nissen, MD, chair of cardiovascular medicine, Cleveland Clinic, Cleveland, Ohio, during a current issues debate Saturday afternoon.
Yes for some drugs, but not as a blanket rule, said David Orloff, MD, executive director, regulatory affairs, Medpace, Cincinnati, Ohio.
Too many diabetes drugs have been approved on the basis of surrogate markers rather than clinical outcomes, Nissen explained. If a drug lowered serum glucose, it would improve diabetes and warranted approval.
“I invented a word to describe what was going on at FDA,” he continued. “Glucocentricity. It’s the irrational belief that lowering blood sugar by any pharmacologic means will improve clinical outcomes. That’s why we got drugs like rosiglitazone.”
The agent was known to increase LDL by 20%, but it was approved because it prevented progression to diabetes. Meta-analysis showed that it also conferred a hazard ratio of 1.43 for myocardial infarction. A similar analysis of pioglitazone showed no effect on MI or other cardiovascular events.
“Drugs to lower blood sugar can help cardiovascular outcomes or they can seriously harm cardiovascular outcomes,” Nissen pointed out. “How are we going to know the difference if we don’t require a cardiac analysis? We have a real challenge if we just look at glycemia.”
 |
| David Orloff, MD |
His proposal, eventually adopted by FDA, was to require cardiovascular data for all new diabetes drugs. A preapproval trial must show that any cardiac risk is no greater than 1.8. That equates to about 120 cardiac events, he noted, and adds 6 to 12 months to the typical drug submission.
A postapproval outcomes trial must show cardiovascular risk of less than 1.3.
“That is a very small price to pay for good outcomes data,” Nissen said. “With 13 classes of drugs that lower blood sugar, we don’t need more drugs, we need better drugs. It matters as much how you lower sugar as how much you lower it.”
Very true, Orloff agreed, but requiring cardiovascular data on every new diabetes drug is untested.
“Today’s debate is about the wisdom and practicality of imposing an experimental regime on drug approval,” Orloff said. “To put a diabetes drugs through cardiovascular testing regardless of class or mechanism of action is not a rational expenditure of resources.
“We should be wary of any adverse events,” Orloff continued. “An obligatory focus on any single aspect has the strong possibility of becoming an untenably expensive approach. It isn’t about cutting corners, it is about finite resource allocation. We should make that decision case by case.”
CLINICAL TRIAL RESULTS
Liraglutide more successful than sitagliptin in achieving glycemic target
 |
| Melanie Davies, MD, MB ChB |
Liraglutide is more successful in reducing hemoglobin (Hb) A1c levels to 7% or less regardless of baseline HbA1c level compared with sitagliptin in adults with type 2 diabetes, said Melanie Davies, MD, MB ChB, professor of diabetes medicine, University of Leicester, United Kingdom.
Davies presented a post hoc analysis of a 26-week, randomized, open-label trial comparing the 2 agents in which she examined the effect of baseline HbA1c on the level of glycemic control achieved. In the study, 437 patients with type 2 diabetes treated with metformin for at least 3 months and baseline HbA1c levels of 7.5% to 10.0% were assigned to liraglutide 1.8 mg/day or sitagliptin 100 mg/day. As presented previously, mean A1c levels were reduced by a mean of 1.5% with liraglutide compared with 0.9% with sitagliptin (P<.0001), and more liraglutide recipients achieved an A1c less than 7% (55% vs 22%, respectively; P<.0001).
In the current analysis, patient groups were split into 5 categories according to their baseline HbA1c levels (≤7.5%, >7.5% to 8.0%, >8.0% to 8.5%, >8.5% to 9.0%, and >9.0%). The findings across these categories were
• In the ≤7.5% category, mean reductions in HbA1c levels were 0.9% with liraglutide and 0.2% with sitagliptin
• In the >7.5 to 8.0% category, mean reductions in HbA1c levels were 0.9% and 0.4% with liraglutide and sitagliptin, respectively
• In the >8.0% to 8.5% category, HbA1c levels were reduced by a mean of 1.2% and 0.7% with liraglutide and sitagliptin, respectively
• In the >8.5% to 9.0% category, HbA1c levels were reduced by a mean of 1.1% and 0.8% with liraglutide and sitagliptin, respectively
• In the >9.0% category, reductions in HbA1c were 2.3% versus 1.4% with liraglutide and sitagliptin, respectively
At each baseline category of HbA1c, significantly more liraglutide recipients than sitagliptin recipients achieved an HbA1c level less than 7%. In the liraglutide group, 85% of those with baseline HbA1c less than 7.5% achieved their target of 7% or less, and more than 30% in the highest 2 baseline groups achieved their target HbA1c. By comparison, only 36% of patients with baseline HbA1c levels less than 7.5% achieved their target with sitagliptin, and less than 20% of those with baseline HbA1c >8.5% achieved their glycemic target with sitagliptin.
Exenatide beats insulin glargine in HbA1C, weight control
Patients who are not well controlled on metformin may get better control of hemoglobin (Hb) A1c levels and weight using once-weekly exenatide than by titrating insulin glargine.
That is the clinical message from a trial reported Saturday morning during a special symposium cosponsored by ADA and The Lancet, which published the study on June 26.
“We clearly need to control glucose,” said lead author Michaela Diamant, MD, associate professor of endocrinology and scientific director, Diabetes Centre, VU University Medical Centre, Amsterdam, The Netherlands. “We also need to consider weight gain, avoid hypoglycemia, and most important, convenience to the patient so they actually use the treatment.”
Diamant and researchers in the United States, the European Union, Korea, Taiwan, Mexico, and Russia randomized 456 patients taking metformin with poorly controlled HbA1c to once-weekly exenatide (233 patients) or self-titrated insulin glargine (223 patients) for 26 weeks.
Diamant noted that it is impossible to blind the 2 drugs, a weekly abdominal injection of exenatide versus daily insulin injection. The trial was open label, but data analyzers were blinded. The sponsors, Amylin and Eli Lilly, were involved in study design; protocol development; collection, review, and analysis of data; and writing the published report. A 2.5-year, open-label, continuation study is underway.
Exenatide showed significantly better HbA1c lowering than insulin at 8 weeks, Diamant reported. The advantage continued through the end of the trial—a 1.5% reduction for exenatide versus 1.3% for insulin glargine (P=.017).
More exenatide patients reached an HbA1c goal of under 7% (60% vs 48%; P=.10). Exenatide was also superior at reducing HbA1c below 6.5% (35% vs 23%; P=.004).
Exenatide produced a mean weight loss of 2.6 kg at week 26 compared with a 1.4-kg weight gain for insulin glargine, a difference of 4 kg (P<.001). Within the exenatide group, 79% of patients showed reduced HbA1c and weight loss, whereas 63% of the insulin glargine group had an HbA1c reduction and weight gain. There was no difference in weight gain or loss or HbA1c reduction on the basis of baseline body mass index.
“Exenatide gave superior A1c reduction and weight loss,” Diamant concluded. “If we consider convenience and weight, it is important to consider once-weekly exenatide for our patients.”
Investigational GLP-1 analog produces glycemic control similar to available agents but with equal or better weight loss
 |
| Michael Nauck, MD |
Data from phase 3 trials of an investigational once-weekly injectable human GLP-1 analog—taspoglutide—show that it compares favorably with currently available agents in terms of glycemic control while offering favorable gastrointestinal (GI) tolerability and equal or superior weight loss. Findings at 24 weeks’ follow-up were reported here; the trials are ongoing.
• Taspoglutide (10 mg titrated to 20 mg weekly) was compared with placebo and sitagliptin (100 mg/day orally) in 666 adults with type 2 diabetes inadequately controlled on metformin (patients had to be on a stable dose of metformin of at least 1,500 mg for at least 12 weeks to be eligible). The reductions in hemoglobin (Hb) A1c, the primary endpoint, were 0.10% with placebo, 1.23% with 10 mg of taspoglutide, 1.30% with 20 mg of taspoglutide, and 0.89% with sitagliptin, reported Richard Bergenstal, MD, from the International Diabetes Center, Minneapolis, Minnesota. A dose-dependent reduction in body weight was observed with taspoglutide: patients assigned to 10 mg lost a mean of 1.8 kg, and those assigned to 20 mg lost a mean of 2.6 kg compared with a 0.9-kg weight reduction in the sitagliptin group.
• Taspoglutide 10 mg or 20 mg twice weekly was compared with insulin glargine once daily in 1,049 adult insulin-naive patients with type 2 diabetes inadequately controlled with metformin plus a sulfonylurea. Taspoglutide demonstrated noninferiority versus insulin glargine in reducing HbA1c levels (reduction of 0.96% in the combined taspoglutide groups vs 0.84% with insulin glargine), and more patients assigned to taspoglutide achieved an HbA1c level of 6.5% or less (24% vs 14%, respectively), said Michael Nauck, MD, from Diabeteszentrum Bad Lauterberg im Harz, Germany. Taspoglutide recipients had a mean weight loss of 4.1 kg versus 0.4 kg for insulin glargine recipients.
• The safety and efficacy of taspoglutide was compared with exenatide twice daily in an open-label study of 1,189 patients with type 2 diabetes inadequately controlled with metformin +/– a thiazolidinedione. The primary outcome—the change in HbA1c—was –1.2% with taspoglutide 10 mg, –1.3% with taspoglutide 20 mg, and –1.0% with exenatide, meeting the criterion for noninferiority, said Julio Rosenstock, MD, clinical professor of medicine, University of Texas Southwestern Medical School, Dallas. More patients in the taspoglutide groups achieved target A1c levels of 7% or less compared with exenatide. Weight loss was similar between the 2 agents.
• In all 3 trials, GI complaints (ie, nausea, vomiting, diarrhea) were the most frequent adverse events and occurred significantly more often with taspoglutide than with the comparator agents.
TZDs associated with increased hip fractures
 |
| Helen Colhoun, PhD |
New data from Scotland suggest that drug regulators should change labeling on thiazolidinediones to warn of elevated risk for hip fractures in both men and women.
“It is a class effect,” said Helen Colhoun, PhD, professor of public health, University of Dundee, Dundee, Scotland, United Kingdom. “There is no significant difference in the increased risk for hip fractures between rosiglitazone and pioglitazone. The FDA should strongly consider changing thiazolidinedione labeling to reflect this risk.”
Colhoun detailed findings based on a retrospective analysis conducted by the Scottish Diabetes Research Network of more than 90% of all patients with diabetes in Scotland. About 144,000 patients met the study criteria, taking at least 1 oral antidiabetic agent but not insulin, during the 2000 to 2008 study period. Researchers linked detailed patient health data with hospital data to track admissions that involved fractures in patients with diabetes. The mean follow-up period was 3.8 years.
Thiazolidinediones are widely recognized as being associated with distal fractures in women, Calhoun noted. There is a growing body of evidence indicating that the risk includes hip fractures in both men and women.
This study confirms that TZDs elevate the risk of distal fracture in women by 1.57 times (P<.0001). Thiazolidinediones also elevate the risk of hip fracture in women by 1.9 times (P<.001) and in men by 2.23 times (P=.016) for a combined hazard ratio of 1.98 (P<.0001). The class does not significantly elevate the risk of distal fractures in men.
“The risk of hip fracture is doubled in both men and women,” Calhoun noted. “In men, the effect is strongest in younger men between the ages of 50 and 60. We calculate that up to 17% of all hip fractures in the diabetic population can be attributed to TZDs.”
The study group is still analyzing dosing data to determine whether there is a dose-related association, Calhoun said in response to a question. She added that early analysis suggests that the elevated risk persists for at least for several years after a TZD is stopped.
Obesity, poor glycemic control predict which insulin-treated patients will be started on exenatide
In clinical practice, exenatide is often started in patients with type 2 diabetes who are on insulin therapy, even though the prescribing information states that the concurrent use of exenatide with insulin has not been studied and cannot be recommended, according to analysis of a large nationwide database.
Combination of exenatide with insulin was more likely to be started in obese patients with comorbid conditions, found Irl B Hirsch, MD, professor of medicine, division of metabolism, endocrinology and nutrition, University of Washington, Seattle.
“Glycemic control in obese patients with comorbid conditions is difficult to obtain with either drug alone; therefore, despite the absence of clinical evidence to support the combination, it is conceivable that a GLP-1 receptor agonist plus insulin was prescribed due to inability to reach treatment targets while controlling weight gain,” according to Hirsch.
Hirsch examined data obtained from the General Electric Centricity research database, which contains approximately 30 million patient records from about 8 million patients in 49 states, including 540,000 persons with type 2 diabetes. The analysis included 7,383 patients who received exenatide and 183,061 who did not.
In a multivariate analysis, a high body mass index (BMI) was the strongest predictor of exenatide initiation, including patients who were on insulin, oral antidiabetic medications, or both. The 9,810 patients who initiated exenatide as their first incretin-based therapy were generally white, younger than 65 years old, heavier than 200 lb, had a hemoglobin (Hb) A1c level of 7% to 9%, had a blood pressure of at least 130/90 mmHg, lived in the southern or Midwestern regions of the United States, had commercial insurance, and had a creatinine clearance less than 2.
Patients in whom exenatide was initiated while also on insulin therapy were more likely to be heavier than 250 lb, have a BMI greater than 40 kg/m2, have a creatinine clearance less than 2, have a baseline HbA1c greater than 9%, and have Medicare as a payer.
Is HDL too much of a good thing in type 1 diabetes?
Too much high-density lipoprotein (HDL) cholesterol could be harmful for women with type 1 diabetes. Men with type 1 diabetes, however, continue to experience cardioprotection with increasing HDL, said Tina Costacou, PhD.
Cardiovascular disease is increased markedly in patients with type 1 diabetes despite generally higher HDL concentrations compared with the general population. One hypothesis is that HDL particle structure and function might be altered in type 1 diabetes. To explore the relationship further, Costacou and colleagues assessed the relationship between HDL cholesterol and HDL subfractions with coronary artery disease (CAD) in 599 patients with childhood-onset type 1 diabetes (diagnosed before age 17) who were free of CAD and participated in the Epidemiology of Diabetes Complications Study. For this analysis, CAD was defined as angina, ischemic electrocardiographic changes, confirmed myocardial infarction, an angiographic stenosis of 50% or greater, revascularization, or CAD death.
Study participants were followed for 18 years, during which 29.6% of men and 25.5% of women had a CAD event. At baseline HDL levels of less than 47 mg/dL, CAD incidence was elevated in both genders compared with baseline HDL levels of 47 mg/dL or greater. The risk of a CAD event kept decreasing in men as HDL concentration increased, but in women, there was a U-shaped association such that the incidence of CAD increased with HDL cholesterol levels of 80 mg/dL or greater. In this group of women with HDL cholesterol of at least 80 mg/dL, the incidence of CAD was 36%, which was similar to the incidence of CAD in women with HDL cholesterol levels less than 47 mg/dL, said Costacou, assistant professor of epidemiology, University of Pittsburgh Graduate School of Public Health. This U-shaped association between HDL cholesterol and CAD events remained significant after adjusting for levels of apolipoprotein (apo) A1 and apo B.
The investigators also measured HDL subfractions, and “the loss of cardioprotection with high HDL cholesterol largely reflected the relationship between the smaller, denser HDL3 particles and incident events,” Costacou said.
“Very high (>80 mg/dL) HDL cholesterol does not appear to protect against CAD in type 1 diabetes,” Costacou continued. “While this relationship was observed only among women, gender specificity could not be determined as only 2 men had HDL greater than or equal to 80 mg/dL.”
DISCLAIMER:
This information has been independently developed and provided by the editors of Medical Economics and its sister publications. The sponsor does not endorse and is not responsiblefor the accuracy of the content or for practices or standards of non-sponsor sources. These articles may discuss regimens that have not been approved by the FDA. For full prescribing information including indications, contraindications, warnings, precautions, and adverse experiences please see the appropriate manufacturer's product circular.
|
