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Effectiveness of A GLP-1 Receptor Agonist Plus A TZD for Type 2 Diabetes

Therapy said superior to a basal/bolus insulin regimen at lowering HbA1c with less hypoglycemia and weight gain.

The study was done to examine the efficacy and safety of combination therapy with the GLP-1 receptor agonist exenatide plus the TZD pioglitazone versus basal-bolus insulin in poorly controlled type 2 diabetic patients with very high HbA1c (HbA1c>10%) on metformin plus sulfonylurea and long duration of disease.

Ralph DeFronzo, MD, at the University of Texas Health Science Center at San Antonio stated that, “Because neither metformin nor sulfonylureas preserve beta-cell function or improve insulin sensitivity, they are associated with a progressive rise in HbA1c… Despite severe hyperglycemia (HbA1c > 10%) and a long duration of diabetes (>10 years), combination therapy with pioglitazone and exenatide improves insulin sensitivity and beta-cell function … while normalizing glycemic control after 18 months of therapy.”

DeFronzo and colleagues analyzed data from 101 adults with poorly controlled type 2 diabetes (HbA1c 10%) who manifested symptoms of hyperglycemia, including polydipsia and nocturia (mean baseline HbA1c, 11%). The patients were participating in the Qatar study, a randomized controlled trial examining the efficacy, durability and safety of combination exenatide (Bydureon, AstraZeneca) plus pioglitazone therapy vs. basal/bolus insulin therapy in patients on metformin therapy plus a sulfonylurea. Patients were treated to an HbA1c of 7% or less. Follow-up occurred monthly for 6 months; researchers compared change in HbA1c from baseline to 6 months between treatment groups.

At 6 months, patients in the exenatide/pioglitazone group saw HbA1c fall to a mean of 6.7% vs. 7.4% for the insulin-treated group; results were independent of sex, race or BMI. Patients in the insulin group experienced more weight gain vs. the combination therapy group (5.3 kg vs. 2.7 kg; P = .002) and a 2.5-fold higher rate of hypoglycemia vs. those on combination therapy (5.8 vs. 2.1 events/patient per year; P < .0001). There were no incidents of severe hypoglycemia in either treatment group.

“With the combination of pioglitazone plus exenatide, the decline in fasting plasma glucose concentration and HbA1c was slower than with insulin therapy,” the researchers wrote. “This is explained by the slower onset of action of pioglitazone and the time (4-6 weeks) required to reach steady state plasma exenatide levels with Bydureon. Nonetheless, subjects receiving combination therapy were asymptomatic after 1 month. At month 2, the reductions in FPG concentration and HbA1c were similar in the combination and insulin therapy groups and at month[s] 3, 4 and 6, the reduction in HbA1c was significantly greater in subjects receiving combination therapy.”

After a mean follow-up of 12 months, combination therapy caused a robust decrease in HbA1c from 10.0 ± 0.6% (86 ± 5.2 mmol/mol) at baseline to 6.1 ± 0.1% (43 ± 0.7 mmol/mol) compared with 7.1 ± 0.1% (54 ± 0.8 mmol/mol) in subjects receiving insulin therapy. Combination therapy was effective in lowering the HbA1c independent of sex, ethnicity, BMI, or baseline HbA1c. Subjects in the insulin therapy group experienced significantly greater weight gain and a threefold higher rate of hypoglycemia than patients in the combination therapy group.

Dr. DeFronzo added that, “Nonetheless, the present results are impressive and, contrary to standard dogma, demonstrate that, even in very poorly controlled (HbA1c > 10%), long-standing [type 2 diabetes] individuals, combination therapy with a GLP-1 [receptor agonist] plus pioglitazone can achieve near normal/normal HbA1c levels…. Therefore, this combination can provide an alternative therapeutic option in addition to insulin in very poorly controlled [type 2 diabetes] patients without the need of multiple daily injections and dose titration, and with lower risk of weight gain and hypoglycemia.”

From the results, it was concluded that the combination exenatide/pioglitazone therapy is a very effective and safe therapeutic option in poorly controlled T2DM patients on metformin plus sulfonylurea with very high HbA1c (>10%).

Practice Pearls:

  • It took 2 months to show the major differences in using the combination versus insulin.
  • After 12 months, combination therapy caused a robust decrease in HbA1c from 10.0 (86 mmol/mol) at baseline to 6.1 (43 mmol/mol) compared with 7.1(54 mmol/mol) in subjects receiving insulin therapy.
  • The combination exenatide/pioglitazone therapy is a very effective and safe therapeutic option in poorly controlled T2DM patients.

Diabetes Care 2017 Jan; dc161738. https://doi.org/10.2337/dc16-1738