Triple Drug Regimen Tops Conventional Treatment In New-onset Diabetes

Triple-drug regimen of metformin, exenatide, and pioglitazone at the onset of type 2 diabetes decreased 2-year treatment failure rates by 84%…. 

In an open-label study, researchers compared the conventional stepwise treatment strategy to starting a triple-drug regimen of metformin, exenatide, and pioglitazone at the onset of type 2 diabetes. The conventional therapy consisted of an escalating dose of metformin (1000→2000 mg/d) followed by sequential addition of sulfonylurea (glipizide, 20 mg/d) and basal insulin to maintain HbA_1c < 6.5. Patients were removed from the study and censored if their blood sugar remained elevated despite being on all three drugs, including the maximum insulin dose. The triple-drug therapy used three drugs from the very beginning: metformin 1 g/day; pioglitazone 30 mg/day; and exenatide 10 mcg/day. All medications could be adjusted as necessary to avoid hypoglycemia. The triple-drug combination was chosen to combat diabetes on three pathophysiologic fronts. As stated by Dr. Ralph DeFronzo, "Metformin is a good insulin sensitizer in the liver, but has no effect on muscle and does nothing for beta cells. Pioglitazone is a powerful insulin sensitizer that works in both muscle and liver. And exenatide exerts beneficial effects on both alpha- and beta-cells, and promotes weight loss."

The study randomized 169 participants with newly diagnosed type 2 diabetes who were also drug-naive to either the conventional therapy (90 patients) or triple therapy (79 patients). The patients had mean disease duration of 5 months, and all had been diagnosed less than 2 years earlier. The patients were seen every 12 weeks, at which time they had measures of fasting plasma glucose, postprandial glucose, HbA_1c, and weight. Their daily home blood glucose monitoring data were also reviewed. The primary endpoint was treatment failure, defined as an HbA_1c of more than 6.5% on two consecutive visits 3 months apart, despite being on maximum therapy. Secondary endpoints were changes in fasting and postprandial glucose, rates of hypoglycemia, and other adverse events.

In the first 6 months of treatment, HbA_1c in both groups fell rapidly and significantly, to a mean of 6.6%. However after 6 months the patientsin the conventional group began to experience a slow increase in their blood sugar levels. By the end of 24 months the mean HbA_1c was 6.6% and 5.9% in the conventional group and the triple-therapy group, respectively. This difference was significant. Significantly more of the triple-therapy group achieved a median HbA_1c of less than 6% (60% vs. 27%), and of less than 7% (92% vs. 72%). By 24 months, treatment failure occurred in 17% of the triple-therapy group and 42% of the conventional therapy group – also a significant difference. Patients randomized to the triple therapy were 84% more likely to achieve sustained treatment response (hazard ratio, 0.16), a difference that was significant. They also lost a mean of 1.2 kg during the study, compared with a mean 4 kg weight gain in the conventional treatment group. There were no episodes of severe hypoglycemia in either group. Patients taking the triple therapy had significantly more edema (5% vs. 1%), which Dr. DeFronzo said was related to pioglitazone.

If those interim results hold for the length of the 3-year study, they have the potential to dramatically alter the long-term consequences of poorly controlled type 2 diabetes, said Dr. DeFronzo.

• Significantly more of the triple-therapy group achieved a median HbA_1c of less than 6%.
• Patients taking the triple therapy had significantly more edema (5% vs. 1%).
• Patients randomized to the triple therapy were 84% more likely to achieve sustained treatment response.

Presentation 244 at The EASD Annual Meeting, September 2013