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A New Combination Diabetes Treatment Could Become the Standard Instead of Insulin

Study shows significant improvement in diabetes control with a 1 point drop in A1c with less hypoglycemia.

With thousands of possible combinations of diabetes drugs, it can be difficult to find the right combination for an individual patient, as no two patients are the same.

A study in Diabetes Care showed that patients with poorly controlled type 2 diabetes who received a combination of exenatide and pioglitazone had a threefold lower rate of hypoglycemia, a one-percentage-point greater reduction in A1C and less weight gain than those in the basal-bolus insulin therapy group. Researchers used a cohort of 251 diabetes patients and found that the difference in A1C between the two groups increased from 0.7% at six months to 0.9% at 12 months and 1% at 18 months.

The Qatar Study was designed to examine the efficacy of combination therapy with exenatide plus pioglitazone versus basal-bolus insulin in patients with long-standing poorly controlled type 2 diabetes mellitus (T2DM) on metformin plus a sulfonylurea.

The study randomized 231 patients with poorly controlled (HbA1c >7.5%, 58 mmol/mol) T2DM on a sulfonylurea plus metformin to receive 1) pioglitazone plus weekly exenatide (combination therapy), or 2) basal plus prandial insulin (insulin therapy) to maintain HbA1c <7.0% (53 mmol/mol).

They were randomized to weekly 2-mg/week extended-release exenatide injection plus 15 mg/day of oral pioglitazone titrated up to 30 mg/day or to insulin glargine given at breakfast plus 4 to 6 units of insulin aspart before each meal.

The primary end point, difference in HbA1c at 6 months, was a statistically significant 0.7% (down to 6.7% with the combination vs 7.4% with insulin, P < .0001). By 12 months, the difference had widened to 0.9% and by 18 months to 1% (P < .0001).  More subjects receiving combination therapy achieved the ADA treatment goal of HbA1c  <7.0% vs those receiving insulin therapy (83% vs 53%, P = .003). More patients also achieved HbA1c <6.5% with the combination (50% vs 13%, P < .0001).

Reductions in HbA1c were equivalent among those in the upper and lower halves of baseline HbA1c level (above 9.5% vs 7.5%–9.5%) and were independent of age, sex, body mass index, or diabetes duration.

Mean body weight increased in both groups, but only half as much with the combination vs insulin therapy (2.1 vs 4.2 kg, P < .0001).

Hypoglycemia was the most common treatment-related adverse event, reported by 91% of those on insulin vs 66% with the combination treatment. Overall, hypoglycemia was three times more common with insulin (6.6 vs. 2.3 events per patient-year, P < .0001). Only one severe hypoglycemic event occurred, in the insulin group.

Peripheral edema was reported in 3.4% of the insulin group vs 9.3% with the combination and was “mild and easily controlled with the addition of a distally acting diuretic,” the authors said, although two patients in the combination group discontinued therapy because of it.

Exenatide improves beta-cell function, while pioglitazone, a thiazolidinedione (TZD), improves both beta-cell function and insulin sensitivity. Together, they correct the major metabolic defects responsible for the development of progressive hyperglycemia in type 2 diabetes.

The 129 patients randomized to the combination experienced a one-percentage point greater drop in HbA1c, a threefold lower hypoglycemia rate, and less weight gain compared with 122 patients randomized to basal-bolus insulin therapy. All were kept on both metformin and a sulfonylurea, although the study protocol allowed the latter to be titrated down.

Limitations of the study include that it was from a single site (in Doha) and was performed primarily in an ethnically homogenous population that was also free of significant comorbidities.

From the results it was concluded that the combination exenatide/pioglitazone therapy is a very effective and safe therapeutic option in patients with long-standing poorly controlled T2DM on metformin plus a sulfonylurea.

Practice Pearls:

  • The combination of pioglitazone and exenatide may represent an effective and safe alternative to insulin for the treatment of type 2 diabetes in patients who are poorly controlled despite use of both metformin and a sulfonylurea.
  • The study demonstrates that even in individuals with very poorly controlled, long-standing type 2 diabetes, this combination therapy can achieve nearly normal/normal HbA1c levels.
  • Study results show that insulin therapy is NOT the only option for patients with long-standing type 2 diabetes who have poor glycemic control on several oral agents.

Published online January 17 in Diabetes The results were first presented at the ADA meeting in New Orleans last year.