CHICAGO – Starting patients with newly diagnosed type 2 diabetes on the combination of metformin, pioglitazone, and exenatide from the get-go proved superior to standard guideline-recommended sequential add-on therapy with metformin, a sulfonylurea, and basal insulin in a 2-year randomized trial.
The triple-therapy group achieved significantly greater and more durable reductions in hemoglobin A1c with less risk of hypoglycemia than patients on the conventional treatment strategy. They also experienced weight loss rather than the weight gain seen with conventional management, Dr. Muhammad A. Abdul-Ghani reported at the annual scientific sessions of the American Diabetes Association.
Dr. Muhammad A. Abdul-Ghani
The observed differences in therapeutic effectiveness and safety validate the strategy behind initial triple therapy, namely that it’s better to target the insulin resistance and progressive beta cell failure that constitute the core metabolic defects responsible for hyperglycemia and type 2 diabetes instead of simply focusing on lowering plasma glucose, added Dr. Abdul-Ghani of the University of Texas Health Science Center, San Antonio.
"My take home message for you is when you treat people with type 2 diabetes, treat the disease – diabetes – not the symptom of hyperglycemia," he declared.
The open-label study comprised 155 patients who had been recently diagnosed with type 2 diabetes. Average age was 47 years, average body mass index was 30.5 kg/m2, and average baseline HbA1c was 8.6%. Those randomized to triple therapy started on metformin at 1,000 mg/day, pioglitazone at 15 mg/day, and exenatide at 5 mcg twice daily. After 1 month, the doses of all three drugs were doubled. If 3 months into the study a patient hadn’t achieved the goal of an HbA1c below 6.5%, pioglitazone was boosted to 45 mg/day.
The conventional treatment group started on metformin followed by sequential addition of glipizide and then basal insulin as needed in an effort to reach an HbA1c below 6.5%.
The primary outcome was the HbA1c difference between the two groups at 2 years. The mean HbA1c decreased from 8.6% at baseline to 6% in the triple-therapy group, significantly better than the 6.6% with conventional therapy. The median HbA1c was 5.8% with triple therapy compared to 6.4% with add-on therapy. In the triple therapy group, 60% had an HbA1c below 6% compared to 27% of controls. In the triple therapy, 92% met the ADA target of an HbA1c below 7% compared to 72% on conventional therapy.
Participants were seen in the clinic every 3 months. Treatment failure, defined as an HbA1c above 6.5% on two consecutive visits 3 months apart, occurred in 17% of the triple-therapy group and 42% on conventional therapy.
Even though the mean HbA1c was 0.5% lower in the triple-therapy group, their incidence of hypoglycemia over the course of 2 years was also significantly lower: 15% versus 46% in the conventional therapy group, the diabetologist continued.
Patients receiving triple therapy had a mean 1.2-kg weight loss over 24 months versus a 4.1-kg weight gain with conventional therapy.
In a multivariate regression analysis, triple-therapy was associated with an 84% reduction in the risk of treatment failure. The other protective factor was age: for each decade beyond age 40 years, a patient’s risk of treatment failure was reduced by 64%.
"We don’t know yet whether this is an issue of patient compliance with therapy or there is something in the pathophysiology of the disease that makes age protective against treatment failure," Dr. Abdul-Ghani said.
Metformin was selected for inclusion in the triple-drug regimen because it corrects insulin resistance in the liver, pioglitazone because it corrects insulin resistance in adipocytes and muscle along with preserving beta cell function, and exenatide because it enhances beta cell function, the physician explained.
Several audience members called the study controversial, noting that it was a single-center study with fewer than 200 patients, yet it aims to overturn current guideline-based clinical practice.
In an interview, Dr. Abdul-Ghani said he and his coinvestigators are trying to drum up support for a larger, multicenter follow-up study featuring microvascular complications as a primary endpoint.
"Every novel approach is controversial at first. But if the difference we’ve seen in A1c can be maintained for longer than 24 months it could result in a substantially reduced risk of microvascular complications. That would really be a game changer in terms of attitudes toward patient treatment," he observed.
He added that even in the absence of data showing a reduction in retinopathy and other microvascular complications, he would "absolutely" recommend that physicians start applying initial triple therapy in their patients with newly diagnosed type 2 diabetes.