Diabetes update: Key research at 2014 ADA meeting

Focus on Diabetes

Cutting-edge diabetes research was featured at this year’s 74th Scientific Sessions of the American Diabetes Association (ADA). Research was presented on oral antidiabetic agents and fracture risk, long-term follow-up from the Diabetes Prevention Program Outcomes Study, dietary effects on diabetes risk, and much more. Highlights from the June 13–17 meeting in San Francisco are available at http://professional.diabetes.org. Following are a few key research studies with a pharmacotherapy focus.

Oral agents and fracture risk

Adequate glycemic control with hypoglycemic treatment plays an important role in preventing fractures; however, not all antidiabetic drugs help in preventing fractures. In fact, several studies have reported a strong association between thiazolidinediones and osteoporotic fractures. New data presented at ADA suggest that both sulfonylureas and thiazolidinediones may increase fracture risk.

Sandhya Mehta, MS, PhD, Health Services Researcher at Inovalon, and colleagues conducted a longitudinal retrospective cohort study to examine the comparative safety of oral antidiabetic drugs on risk of fracture in patients with diabetes. The investigators used data from the Medical Outcomes Research for Effectiveness and Economics (MORE) Registry to identify 99,892 adults (mean age 62 y) who were new users of antidiabetic drugs. Included patients had to have registry data for at least 12 months before, and at least 12 months after, the initiation of diabetes treatment—and could not have a diagnosis of fracture within 12 months before the start of the antidiabetic agent.

The majority of patients received metformin (77.8%), followed by sulfonylureas (15.3%), dipeptidyl peptidase-4 (DPP-4) inhibitors (2.7%), thiazolidinediones (2.7%), incretins (0.81%), and meglitinides (0.6%). The investigators found that the risk of fracture was 9%–40% higher in users of sulfonylureas (hazard ratio 1.09 [95% CI 1.03–1.16], P = 0.0054) and thiazolidinediones (HR 1.40 [95% CI 1.25–1.58], P < 0.0001) compared with metformin.

“There was a stronger association seen with thiazolidinediones than sulfonylureas for fracture risk, and patients should be educated about this risk,” Mehta told Pharmacy Today. “Clinicians should also keep these data in mind when selecting appropriate antidiabetic therapies for patients, especially for those already at higher risk for fracture.”

“Very few studies have been conducted regarding the direct effect of sulfonylureas on bone tissue, and previous epidemiological studies have found no positive association between sulfonylureas and fracture risk,” Antoine Kfuri, MD, MPH, CMQ Medical Director at Inovalon, told Today. “Our study is the first to find this association, and further investigation is needed to determine the association between sulfonylureas and fracture risk.”

DPPOS: Long-term follow-up

Fifteen-year follow-up from the landmark Diabetes Prevention Program (DPP) study was presented at ADA. It showed that use of metformin and lifestyle modification continue to be effective in decreasing the development of diabetes long-term in high-risk patients.

In the original DPP study, lifestyle modification and metformin reduced the development of diabetes by 58% and 31%, respectively, compared with placebo after 3 years of follow-up. Now, with a mean of 15 years of follow-up in the Diabetes Prevention Program Outcomes Study (DPPOS), patients assigned to lifestyle intervention and metformin during DPP continue to have lower rates of type 2 diabetes development compared with those originally assigned to placebo (27% and 17%, respectively).

Long-term effects on microvascular complications were also assessed, but no significant differences were observed among the three groups. Macrovascular complications, such as cardiovascular events, could not be assessed because of the relatively small number of these events among the participants. Longterm use of metformin was not associated with any serious safety signals, but metformin use was associated with more vitamin B12 deficiency.

“Use of metformin was associated with durable weight loss over the follow-up period,” said Jill Crandall, MD, Professor of Medicine at Albert Einstein College of Medicine, in discussing the clinical implications of the results with Today. “Patients in the metformin group lost weight and kept it off over time, whereas those in the lifestyle group had more weight loss at the beginning of the trial, but gradually have regained some of this weight back during the follow-up period.” Another finding was that long-term use of metformin appeared to be relatively safe. Even after an estimated 10,000 patient-years of follow-up with metformin use, there were no reported cases of lactic acidosis or serious hypoglycemic events requiring hospitalization.

Crandall also discussed the higher incidence of vitamin B12 deficiency in the metformin group compared with the placebo group—approximately 7%–8% versus 3%–4% after 10–11 years of follow-up. “I think the take-home message here is that patients on long-term metformin need to be monitored periodically for potential vitamin B12 deficiency. At this point, the message is not to supplement these patients prophylactically with vitamin B12, as we do not have the data to support appropriate dosing, etc.”

Dietary modifications and diabetes risk

Improvements in overall diet quality were associated with a lower risk of type 2 diabetes independent of other healthy behaviors, according to new research assessing three cohorts of U.S. men and women.

Sylvia Ley, PhD, RD, of the Harvard School of Public Health, and colleagues investigated the association between diet quality changes during a 4-year period and subsequent 4-year type 2 diabetes risk and the effect of simultaneous changes in other lifestyle factors on diabetes risk. Approximately 150,000 participants from the Nurses’ Health Study I and II and Health Professionals Follow-Up Study were prospectively followed. The study found that those who improved their diet quality index by 10% over 4 years reduced their risk for type 2 diabetes by about 20% compared with those who made no changes to their diets. These changes included eating more whole grains, fruits, and vegetables and consuming fewer sweetened beverages and saturated fats. This alteration in diet and effect on diabetes risk occurred independently of the effects of weight loss and increased physical activity.

“If you improve other lifestyle factors, you also reduce your risk of type 2 diabetes even more; but improving diet quality alone has substantial benefits on reducing the risk for diabetes,” Ley told Today. “The results of this research are important because patients often have a difficult time maintaining a calorie restricted diet for a long time. These data support that if patients improve the overall quality of their diet by consuming less red meat and eating more whole grains, fruits, and vegetables, they are going to reduce their risk for diabetes.”

VIVIDD results

Recent data from clinical trials such as SAVOR-TIMI 53 (Does Saxagliptin Reduce the Risk of Cardiovascular Events When Used Alone or Added to Other Diabetes Medications) and EXAMINE (Cardiovascular Outcomes Study of Alogliptin in Patients with Type 2 Diabetes and Acute Coronary Syndrome) suggested that there may be a signal of possible heart failure associated with use of select DPP-4 inhibitors in patients with type 2 diabetes (saxagliptin [Onglyza—AstraZeneca] and alogliptin [Nesina—Takeda], respectively).

A new post-hoc analysis of data from the VIVIDD (Vildagliptin in Ventricular Dysfunction Diabetes) study presented at the meeting showed that use of vildagliptin, a DPP-4 inhibitor approved for use outside of the United States, in patients with type 2 diabetes and heart failure was not associated with an increase in hospitalizations for heart failure.

The investigators assessed data from 252 patients with type 2 diabetes who had systolic chronic heart failure with ejection fractions of less than 40%. Patients were treated with vildagliptin (n = 128) or placebo (n = 124) for 52 weeks. Results of the post-hoc analysis showed that 13 (10.2%) patients randomized to vildagliptin were hospitalized for heart failure compared with 10 (8%) of those in the trial who received placebo (P = 0.552). Adjusted worsening of heart failure was also not different between groups.

The investigators concluded that this post-hoc analysis suggests that the increased risk of heart failure hospitalizations observed with other DPP-4s was not seen with vildagliptin use in the VIVIDD population of patients with documented heart failure.

Hepatitis B vaccine for diabetes prevention

A new study found that patients who received the hepatitis B vaccination were much less likely to have diabetes, with hepatitis B vaccination being associated with a greater than 50% risk reduction of diabetes.

Researchers assessed a sample of participants from the NHANES (National Health and Nutrition Examination Survey) 2005–2010 and identified 7,142 subjects without a history of diabetes. Among them, 1,412 were noted to be successfully vaccinated with hepatitis B, as these participants had positive hepatitis B surface antibody and negative hepatitis B core antibody.

The investigators reported that diabetes was noted in 16 participants (1.13%) with hepatitis B vaccination compared with 325 participants (5.67%) who were not vaccinated. After adjustment for age, gender, and body mass index, the odds ratio (OR) for diabetes was 0.43 (95% CI 0.25–0.73), and after adjustment for additional covariates, the OR was still 0.48 (95% CI 0.28–0.82).

The investigators concluded that receipt of the hepatitis B vaccine was associated with a more than 50% risk reduction of diabetes. They advocated that a prospective study be conducted to examine the impact of hepatitis B vaccination in the prevention of diabetes.