Do SGLT2 inhibitors lower blood sugar by increasing insulin sensitivity in diabetes patients?

SGLT2 inhibitors are FDA-approved to be used with exercise and diet to lower blood sugar in type 2 diabetes patients. Medications in the SGLT2 inhibitor class include dapagliflozin, canagliflozin, and empagliflozin. They are available as single-ingredient products and also in combination with other diabetes medicines such as metformin. SGLT2 inhibitors lower blood sugar by causing the kidneys to remove sugar from the body through the urine.

Recent evidence has shown that SGLT2 inhibitors may increase insulin sensitivity; these results, however, are heterogeneous and require systematic assessment.

Considering the above, Davood Shafie, Isfahan University of Medical Sciences, Isfahan, Iran, and colleagues searched online databases using a predefined search query. Randomized clinical trials on SGLT2 inhibitors with a passive control group or metformin-controlled group were included. Cochrane risk of bias assessment tool was utilized to perform the risk of bias assessment. Separate meta-analysis was performed in studies with type 2 diabetes (T2D) population and studies with non-T2D and also for passive- and active-controlled studies through standardized mean difference (SMD) as the measure for the effect size. Subgroup analysis was conducted per different SGLT2is types. Meta-regression analysis was done according to the duration and dose of intervention.

The study led to the following findings:

• The study included twenty-two studies (6 on non-T2D population) with 1421 (243 non-T2D) patients.
• Six studies (3 on T2D and three on non-T2D) were controlled by metformin, and others were passively managed.
• SGLT2Is could remarkably increase insulin sensitivity in T2DM patients (SMD = 0.72).
• SGLT2Is could reduce insulin resistance in the non-T2DM population, but this was insignificant.
• SGLT2 inhibitors were not inferior to metformin for decreasing insulin resistance.
• Subgroup analysis showed that dapagliflozin could notably increase Insulin Sensitivity, but empagliflozin was not linked with significant improvement in Insulin Sensitivity.
• Meta-regression analysis showed no effect for dose but duration of SGLT2 inhibitor administration on Insulin Sensitivity.

"SGLT2Is, dapagliflozin in specific, could increase insulin sensitivity," the researchers wrote in their study. Dapagliflozin demonstrated a greater Insulin resistance reducing effect compared to empagliflozin, and when compared to metformin, SGLT2Is were not inferior to metformin in reducing Insulin resistance.

"These findings need to be consolidated by further studies."However, in diabetic patients using insulin and insulin secretagogues, the dose of administered insulin or secrtagugues should be adjusted if using SGLT2Is to prevent hypoglycemia.

The biggest limitation accounts to this study is that a considerable number of included studies were identified with a high risk of bias.

Reference:

Fakhrolmobasheri, M., Abhari, A.P., Manshaee, B. et al. Effect of sodium–glucose cotransporter 2 inhibitors on insulin resistance; a systematic review and meta-analysis. Acta Diabetol (2022). https://doi.org/10.1007/s00592-022-01981-1