SGLT2 Inhibitors or DPP-4 Inhibitors with Insulin

June 7, 2016

As adjunctive therapy with insulin in poorly controlled type 2 diabetes, which drugs proved more effective – SGLT2 inhibitors or DPP-4 inhibitors?

With adjunctive therapy, SGLT2 inhibitors may result in better glucose control and more weight loss than DPP-4 inhibitors, without increasing the risk of hypoglycemia, according to a meta-analysis published online in Diabetes Metabolism Research Review.1

“As adjunctive agents to insulin therapy, SGLT2 inhibitors with an insulin-independent mode of action might confer greater efficacy compared to DPP4 inhibitors with a partially insulin-dependent mode of action,” wrote lead author Young Min Cho, MD, PhD, of Seoul National University College of Medicine (South Korea), and colleagues.

The progressive nature of diabetes means that patients often need to intensify their regimens, sometimes requiring insulin. But insulin can cause weight gain and hypoglycemia. GLP-1 agonists and several oral antihyperglycemics, including DPP-4 inhibitors and SGLT2 inhibitors, have been shown to reduce body weight when added to insulin, without increasing the risk of hypoglycemia, according to background information in the article. 

As oral agents DPP-4 inhibitors and SGLT2 inhibitors may be preferable to GLP-1 agonists, which require injections. However, no randomized controlled trials have directly compared SGLT2 inhibitors to DPP-4 inhibitors as adjuncts to insulin.

In the study, researchers searched MEDLINE, EMBASE, LILACS, the Cochrane Central Register of Controlled trials, and Clinicaltrials.gov for randomized controlled trials published in English only from inception to June 2015. To be included, trials had to last at least 12 weeks, and compare SGLT2 inhibitors plus insulin with placebo plus insulin and DPP4 inhibitors plus insulin with placebo plus insulin.

The analysis included 14 double-blinded RCTs covering 6980 patients with T2DM: five SGLT2 inhibitor studies with a mean duration of 19 weeks and nine DPP-4 inhibitor studies with a mean duration of 23 weeks. All 14 studies were industry-funded.

Key results from:

• SGLT2 inhibitors plus insulin performed better than DPP-4 inhibitors plus insulin on:

♦ Change in HbA1c from baseline: Weighted mean difference (WMD) -0.24% (95% CI -0.43 to -0.05%, P=0.020), (adjusted for age, sex, BMI, and baseline insulin dose)

♦ Change in fasting plasma glucose from baseline: WMD -18.0 mg/dL (95% CI -28.5 to -7.6 mg/dL, P=0.003) (adjusted for BMI at baseline HbA1c)

♦ Change in body weight from baseline: WMD -2.38 kg, 95% CI -3.18 to -1.58 kg, P<0.001), (adjusted for sex, BMI, baseline HbA1c, and insulin dose)

► SGLT2 inhibitors plus insulin: Significant decrease in body weight compared to placebo (WMD -2.12 kg, 95% CI -2.38 to -1.86 kg, P<0.001)

► DPP-4 inhibitors plus insulin: No significant change in body weight compared to placebo (WMD -0.04 kg, 95% CI -0.25 to 0.16 kg, P=0.682).

• Reduction in insulin dose: No significant difference between SGLT2 inhibitors and DPP-4 inhibitors (P=0.432) (adjusted for BMI and baseline insulin)

• Risk of hypoglycemia: No significant increase in risk for SGLT2 inhibitors vs DPP-4 inhibitors (P=0.395)

• Urinary tract Infections: Increased with SGLT2 inhibitors

♦ No significant difference between SGLT2 inhibitors and DPP-4 inhibitors (RR 1.38 [95% CI 0.87 to 2.19, P=0.149])

• Genital infections: Increased with SGLT2 inhibitors

♦ Comparison with DPP-4 inhibitors not calculable due to lack of information from DPP-4 inhibitor studies

The authors noted several limitations. DPP-4 inhibitors enhance the action of incretin hormones, which are predominantly secreted postprandially. As such, DPP-4 inhibitors may help decrease postprandial hyperglycemia, but the study could not look at this variable because of lack of data. Also, the analysis could not evaluate some safety outcomes like genital infections and volume depletion due to lack of data. Finally, the small number of studies had a large amount of heterogeneity between them, and the possibility of publication bias exists. 

Nevertheless, the authors concluded: “[A]s an adjunctive oral agent to preexisting insulin therapy in patients with inadequately controlled type 2 diabetes, SGLT2 inhibitors resulted in a greater reduction in HbA1c, FPG levels, and body weight than DPP4 inhibitors, with a similar risk of hypoglycemia. In the absence of a head-to-head comparison, the results of our current study could serve as the best available evidence in selecting oral agents to improve glycemic control in insulin-treated type 2 diabetes patients.”

Take-home Points

• A meta-analysis of 14 RCTs comparing SGLT2 inhibitors to DPP-4 inhibitors added to insulin found SGLT2 inhibitors were better at reducing HbA1c, fasting plasma glucose, and body weight.

• There was no significant reduction in insulin dose for SGLT2 inhibitors vs DPP-4 inhibitors added to insulin.

• There was no significantly increased risk in hypoglycemia for SGLT2 inhibitors vs DPP-4 inhibitors.

• The study could not compare certain safety variables due to lack of information from DPP-4 inhibitor trials.

The study was supported by the Seoul National University Hospital Research Fund.

Dr. Cho reports lecture and consultation fees from Astra-Zeneca, Boeringer-Ingelheim, MSD, LG Life Sciences, and Hanmi. Dr. Hahn reports consultation fees from Novartis and Actelion.

Reference: Min SH, et al. Comparison between SGLT2 inhibitors and DPP4 inhibitors added to insulin therapy in type 2 diabetes: a systematic review with indirect comparison meta-analysis. Diabetes Metab Res Rev. 2016 May 7.