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Greater HbA1c Reduction with DPP4 Inhibitor, AGI Combination

Additive glucose-lowering effect of a dipeptidyl peptidase-4 (DPP4) inhibitor and an alpha-glucosidase inhibitors (AGI) might be beneficial in patients with T2DM.

According to a literature review published online on September 26, 2017 in the Journal of Diabetes Investigation by researchers from Republic of Korea, the addition of a dipeptidyl peptidase-4 (DPP4) inhibitor to diabetic treatment in patients with T2DM who are inadequately controlled with an alpha-glucosidase inhibitors (AGI) may provide an additive or synergistic glucose-lowering effect as the drugs have a complementary mechanism of action, without further increasing the risk of weight gain and hypoglycemia. The dipeptidyl peptidase-4 (DPP4) inhibitor increases plasma concentration of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which leads to an increase in insulin secretion and decreases glucagon secretion. The alpha-glucosidase inhibitors (AGI) such as acarbose, miglitol, and voglibose inhibit the hydrolysis of carbohydrate, which delay its absorption from the small intestine.

Researchers conducted a systematic review and meta-analysis search of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and through October 2016. Any randomized controlled trials written in English that compared DPP4i plus AGI (DPP4i/AGI) and placebo plus AGI (PCB/AGI) in patients with T2DM were eligible for inclusion. Studies that are duplicates or extensions of another study were excluded. Researchers retrieved 756 relevant studies of which data from 5 studies with a total of 1,799 study participants (845 patients randomized to DPP4i/AGI and 832 patients randomized to PCB/AGI) were included for the meta-analysis. A mean study duration is 14 weeks.

The result from all 5 studies reported the changes in HbA1c level and fasting plasma glucose level from baseline. DPP4i/AGI correlated with a greater reduction in HbA1c level than PCB/AGI (Weight Mean Difference -1.2%; 95% CI -1.6% to -0.8%) and a greater reduction in fasting plasma glucose levels than PCB/AGI (Weight Mean Difference -26.8 mg/dL; 95% CI -39.9 to -13.8 mg/dL). Four out of 5 studies reported reduction in two-hour postprandial plasma glucose levels was greater in the DPP4i/AGI group than in the PCB/AGI group (Weight Mean Difference -34.5 mg/dL; 95% CI -52.9 to -16.1mg/dL).

Weight gain and hypoglycemia are two unwanted side effects when increasing the dose or adding another antidiabetic drug in patients with consistently high blood glucose levels. Four out of five studies reported that the DPP4i/AGI group did not show any significant changes in body weight and risk of hypoglycemia compared with the PCB/AGI group; (Weight Mean Difference 0.1 kg; 95% CI -0.3 to -0.4 kg) and (RR 1.4, 95% CI 0.4 to 4.6), respectively. Some AGIs can reduce appetite and APP4 inhibitors have neutral effects on body weight. Given that the combination of the two agents might be a favorable option for patients with type 2 who are overweight or have obesity. In addition, AGI monotherapy does not cause hypoglycemia, unless it is used in combination with sulfonylureas or insulin. DPP4 inhibitors monotherapy or in combination with insulin are unlikely to cause hypoglycemia. Therefore, the addition of DPP4 inhibitors to AGI therapy does not increase the risk of hypoglycemia.

One of the limitations of the study is that it includes a small number of the included studies. Another limitation is that researchers were unable to compare the outcomes among DPP4 inhibitor plus AGI, placebo plus AGI, placebo plus DPP4 inhibitor, and placebo alone in patients with T2DM who were naïve to DPP4 inhibitors or AGIs. Lastly, most of study participants were Asians whose glucose-lowering responses to incretin-based therapy are known to be greater than in other ethnic groups.

Practice Pearls:

  • The addition of a DPP4 inhibitor with an AGI therapy in patients with type 2 who have consistently high blood glucose levels achieved a clinically significant improvement in glycemic control.
  • The addition of a DPP4 inhibitor to an AGI therapy does not increase the risk of weight gain and hypoglycemia.
  • The combination of a DPP4 inhibitor and an AGI agent is a viable option for patients with T2DM who are overweight or have obesity.


Se Hee Min, Jeong Hwa Yoon, Seokyung Hahn, Young Min Cho. Efficacy and safety of combination therapy with an alpha-glucosidase inhibitor and a dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes mellitus: A systematic review with meta-analysis. Journal of Diabetes Investigation. 2017 Sep 26.

Kay Lynn Tran, Doctor of Pharmacy Candidate: Class of 2018; LECOM College of Pharmacy