Comparison between sodium–glucose cotransporter 2 inhibitors and pioglitazone as additions to insulin therapy in type 2 diabetes patients: A systematic review with an indirect comparison meta‐analysis

Abstract

Aims/IntroductionWe aimed to evaluate the efficacy and safety of pioglitazone (PIO) and sodium–glucose cotransporter 2 inhibitors (SGLT2i) as additions to insulin therapy for the management of type 2 diabetes mellitus.Materials and MethodsWe searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov through December 2016. Randomized controlled trials published in English that compared SGLT2i plus insulin (SGLT2i/INS) or PIO plus insulin (PIO/INS) with placebo plus insulin (PCB/INS) in type 2 diabetes mellitus patients were included. We compared the efficacy and safety between SGLT2i/INS and PIO/INS indirectly.ResultsA total of 14 randomized controlled trials comparing 7,226 participants were included (8 SGLT2i and 6 PIO studies). SGLT2i/INS achieved similar reductions in hemoglobin A1c (weighted mean difference [WMD] −0.01% [−0.1 mmol/mol], 95% confidence interval [CI] −0.25 to 0.22% [−2.7 to −2.4 mmol/mol]; P = 0.896) and fasting plasma glucose (WMD −0.90 mg/dL, 95% CI: −15.50 to 13.71 mg/dL; P = 0.904), and a similar proportion of participants achieved hemoglobin A1c <7.0% (<53.0 mmol/mol; relative risk 0.98, 95% CI: 0.73 to 1.33; P = 0.917) as compared with the PIO/INS group, with greater weight reduction (WMD −4.54 kg, 95% CI: −5.67 to −3.41 kg; P < 0.001). PIO/INS showed non‐significant trends toward a higher risk of hypoglycemia (relative risk 1.15, 95% CI: 0.97 to 1.35; P = 0.102) and higher reduction of total daily insulin doses (WMD −2.45 IU/day, 95% CI: −7.30 to 2.40 IU/day; P = 0.438).ConclusionsBoth PIO and SGLT2i are feasible adjunctive oral agents to pre‐existing insulin therapy in individuals with inadequately controlled type 2 diabetes mellitus.

Prospect of Sodium–Glucose Co-transporter 2 Inhibitors Combined With Insulin for the Treatment of Type 2 Diabetes

“…In a comparative review by Singh and Singh, DPP-4 inhibitors plus insulin resulted in a 10-20% reduction in total daily insulin dose, whereas SGLT2 inhibitors plus insulin only resulted in a 0-10% reduction (21). A study comparing SGLT2 inhibitors with pioglitazone reported that combining both drugs with insulin therapy significantly decreased the insulin demand relative to the placebo; however, the difference in total daily insulin dose reduction between the two groups was not significant (19).…”

“…By comparing SGLT2 inhibitors to DPP-4 inhibitors combined with insulin therapy for patients with T2D, a meta-analysis revealed that the former resulted in better glycemic control and lower levels of HbA1c [weighted mean difference (WMD) 0.24%, 95% CI 0.05-0.43] and FBG (WMD 18.0 mg/dl, 95% CI 7.6-28.5 mg/dl) than the latter (18). However, no significant difference was observed between SGLT2 inhibitors and pioglitazone plus insulin as treatment regimens for patients with T2D (19).…”

“…Several clinical trials (8-13) and a meta-analysis 7have reported that combining SGLT2 inhibitors with insulin as a treatment regimen for T2D would impede this weight gain and would result in a significant decrease in body weight ( Table 1). Compared with other antidiabetic drugs, such as pioglitazone and DPP-4 inhibitors, SGLT2 inhibitors can significantly accelerate weight reduction (18,19,21). However, compared with GLP-1 agonists, the results are controversial.…”

New perspectives on insulin therapy

“…These effects of SGLT2i might provide beneficial effects to suppress cardiovascular events, but the increased risk of hypoglycemia, and urinary tract and genital infection related to SGLT2i should be of note. Another study compared the impacts of SGLT2i with pioglitazone when added to insulin therapy in patients with type 2 diabetes with an indirect comparison meta‐analysis 11 . As the results, SGLT2i and pioglitazone achieved comparable reductions in HbA1c and fasting blood glucose, SGLT2i showed greater weight reduction, and pioglitazone achieved a higher reduction of daily insulin doses.…”

A practical approach and algorithm for intensifying beyond basal insulin in type 2 diabetes

“…Results from studies comparing SGLT2is to active comparators added to insulin therapy provide compelling reasons for intensifying beyond basal insulin with SGLT2is. A network meta‐analysis of 14 12‐week or longer studies comparing SGLT2is and pioglitazone as add‐ons to insulin therapy revealed a similar HbA1c reduction in both groups, with the bonus of an additional 4.5 kg weight loss in the SGLT2i arm, despite lower end‐of‐study insulin doses with pioglitazone . When SGLT2is were evaluated in a network meta‐analysis against DPP‐4i as add‐on to insulin therapy in studies longer than 12 weeks, the SGLT2is were found to exert a 0.24% greater reduction in HbA1c than the DPP‐4i, and this was coupled with 2.4 kg more weight loss and similar incidences of hypoglycaemia …”