A combination of pioglitazone and the glucagonlike peptide 1 (GLP-1) agonist exenatide (Bydureon, AstraZeneca) 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 findings, from the open-label, randomized 12-month Qatar study were published online January 17 in Diabetes Care by Muhammad Abdul-Ghani, MD, PhD, of Hamad General Hospital, Doha, Qatar, and the University of Texas Health Science Center at San Antonio, and colleagues. The results were first presented at the ADA meeting in New Orleans last year.
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]," Dr Abdul-Ghani and colleagues write.
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.
"Contrary to standard dogma," the authors write, the results "demonstrate that even in individuals with very poorly controlled, long-standing [type 2 diabetes], combination therapy with a GLP-1 receptor agonist plus pioglitazone can achieve nearly normal/normal HbA1c levels."
M Sue Kirkman, MD, clinical professor of medicine and medical director of the Diabetes Care Center Clinical Trials Unit at the University of North Carolina School of Medicine, Chapel Hill, was one of the chairpersons when the Qatar study was presented at the ADA meeting.
Asked to comment now it is published, Dr Kirkman told Medscape Medical News: "The study results are impressive and certainly counter the common wisdom that insulin therapy is the only option for patients with long-standing type 2 diabetes who have poor glycemic control on several oral agents."
However, she added that 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.
"Carrying out such trials in more typical 'advanced type 2' [diabetes] patients with renal or cardiovascular comorbidities would allow a better assessment of the generalizability of these findings as well as the longer-terms risks and benefits," Dr Kirkman said, adding, "Larger studies might also help us decide whether the current fears of and limited use of TZDs were justified or not."
Greater Glycemic Benefits With Combo
The study subjects all had baseline HbA1c levels above 7.5% (mean 10.0%) despite maximal or near-maximal metformin and sulfonylurea doses.
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.
Dr Kirkman commented, "The combination of a GLP-1 receptor agonist with a [peroxisome proliferator-activated receptor] alpha agonist [or TZD] has a strong pathophysiologic rationale, but it is surprising that it seemed to work equally well in those with more advanced [or] uncontrolled disease compared with those with better control at baseline."
Less Weight Gain and Hypoglycemia but More Edema With Combination
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 say, although two patients in the combination group discontinued therapy because of it.
Five cardiovascular events occurred, all in the insulin-therapy group.
"Continued follow-up will be required to ascertain how long the beneficial effects of combination therapy are maintained," Dr Abdul-Ghani and colleagues acknowledge.
Also needed now, Dr Kirkman said, is "a larger, preferably multinational study of this intervention."
This study was supported by a Qatar Foundation grant. Dr Abdul-Ghani has no relevant financial relationships. Disclosures for the coauthors are listed in the paper. Dr Kirkman receives research support from Novo Nordisk, Bayer, and Theracos.
Diabetes Care. Published January 17, 2017.
Exenatide-Pioglitazone Combo Tops Insulin in Type 2 Diabetes. Medscape. Jan. 17, 2017.