Stopping Progression to Diabetes

Nancy A. Melville
September 21, 2018

In patients with prediabetes determined to be at high risk of progression to diabetes through oral glucose testing, treatment with a triple regimen of medications significantly reduced the likelihood of progression to type 2 diabetes compared with lifestyle modifications alone, according to new research.

"The results of our analysis show that pharmacological treatment with antidiabetic agents that target insulin resistance (pioglitazone) and beta-cell dysfunction (pioglitazone and glucagonlike peptide 1 [GLP-1] receptor agonist) markedly reduces development of type 2 diabetes in a real-world setting," John P. Armato, MD, of Providence Little Company of Mary Cardiometabolic Center, Torrance, California, and colleagues report in a study published online September 14 in Lancet Diabetes & Endocrinology.

"Our study suggests that clinicians might want to reconsider their approach to prediabetes on the basis of the pathophysiology of the disease in individual patients and should not simply rely on fasting plasma glucose and HbA1c concentrations," they add.

Senior author Ron J. Ruby, MD, of the same center, told Medscape Medical News: "Our biggest take-home message is: 'Don't be afraid to use pathophysiology to guide your therapy.'"

"We believe that this is light years ahead of present guidelines. Your patients will be happy when you tell them diabetes can be prevented using available tests and targeted anti-hyperglycemic medications."

In an accompanying editorial, Robert E.J. Ryder, MD, of the Department of Diabetes and Endocrinology, Sandwell and West Birmingham Hospitals NHS Trust, City Hospital, UK, agrees that — in light of the risks of diabetes — the strategy of medication in the prediabetes stage, guided by known pathophysiological risk factors, is worthwhile.

"Many would consider intervention with three pharmaceutical agents, one of which is an injectable, to be excessive in this population," Ryder writes.

"However, the complications of type 2 diabetes can be devastating and anything that can be done to avoid diabetes and therefore its complications is worthy of consideration."

None of Those at Highest Risk on Triple Therapy Progressed to Diabetes

In the STOP DIABETES study, 422 patients identified as having prediabetes at an internal medicine and endocrinology community practice between 2009 and 2016 were assessed.

By measuring the glycemic response during oral glucose tolerance testing (1-h glucose concentration > 8.6 mmol/L), insulin sensitivity, and β-cell function, the investigators were able to categorize the patients according to risk.

"With this information, a personalized restorative pharmacological plan can be implemented in a real-world setting," they emphasize.

In total, 81 patients determined to be at high-risk were treated with a triple therapy regimen of low-dose metformin, pioglitazone, and a GLP-1 receptor agonist. Those assessed as having an intermediate risk (n = 141) were treated only with metformin and pioglitazone. Both groups also received lifestyle therapy.

The lowest doses considered to have a physiological effect were used, 850 mg/day for metformin and 15 mg/day for pioglitazone. For the GLP-1 receptor agonist, medications were used based on insurance coverage: exenatide 10 µg twice daily (n = 26), liraglutide 1.2 mg daily (n = 49), exenatide extended-release 2 mg weekly (n = 3), or dulaglutide 1.5 mg weekly (n = 3). Doses of the GLP-1 receptor agonist were not modified during the study.

A third group of 200 patients (76 high risk and 124 intermediate risk) who refused pharmacological therapy were assigned to lifestyle therapy only.

At a mean follow-up of 32 months, 28 of the 422 (7%) patients developed type 2 diabetes.

Whereas seven (5%) of the 141 intermediate-risk participants receiving metformin and pioglitazone progressed, none (0%) of the 81 participants who received triple therapy developed type 2 diabetes and 21 (11%) of the 200 participants who received lifestyle therapy progressed.

The adjusted hazard ratios for progression to type 2 diabetes, compared with those who received lifestyle therapy alone, were 0.29 (P = .0009) for those who received metformin and pioglitazone and 0.12 (P = .04) for the high-risk patients who received triple therapy.

"Our data show that prediabetes patients treated with lifestyle progress to diabetes at a rate of 4.1% per year where moderate treatment with pioglitazone and metformin reduces the rate to 1.7% per year and triple therapy with a GLP-1 receptor agonist reduces the rate to 0% per year," Ruby told Medscape Medical News.

Importance of Stratifying Patients According to Physiology

The strongest predictor associated with the prevention of type 2 diabetes was improvement in beta-cell function, the authors note.

The findings underscore the benefits of taking the time to stratify patients with prediabetes according to their underlying pathophysiological defects — an approach that is not commonly practiced, Ruby explained.

"Although some physicians treat prediabetic patients with lifestyle modification and pharmacologic agents, we are unaware of other real-world practices that utilize physiologic assessments of glucose response, insulin sensitivity, and beta-cell response to prospectively determine personalized prevention strategies."

Barriers to the adoption of the approach range from insurance coverage challenges to resistance to the work required to calculate and interpret physiologic results, Ruby said.

Cost of the drugs — a key concern — could soon be offset by more generic options. "Regimens using inexpensive agents (metformin and pioglitazone) provide substantial benefit and expensive agents are nearing generic availability," he and his coauthors point out.

Meanwhile, considering the extensive health risks caused by diabetes and evidence that disturbances in normal physiology precede development of type 2 diabetes by years, if not decades, the stakes are high, Ruby stressed.

Ryder concurs. In his editorial, he concludes that by the time people are diagnosed with type 2 diabetes they have typically lost more than 80% of their beta-cell function, hence, "intervening with therapies designed to interrupt the pathophysiological mechanisms that lead to type 2 diabetes is logical."

The study did not receive outside funding. The authors and editorialists have reported no relevant financial relationships.

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SOURCE: Medscape, September 21, 2018. Lancet Diabetes Endocrinol. Published online September 3, 2018.

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