Combination Therapy with Metformin and an SGLT2 Inhibitor

Black patients may have lower odds of achieving target HbA1C levels on metformin and SGLT2 alone. 

The pathogenesis and progression of type 2 diabetes mellitus (T2DM) is a complicated mechanism involving multiple pathways. This presents challenges when creating therapeutic regimens for patients in advanced stages. Mainly, monotherapy may be of little to no benefit in patients with higher HbA1c levels. With the many prescription products available today, combination drug therapy has become standard in these patients. The use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for the treatment of T2DM has become more prevalent in recent years, due in part to their low risk for causing hypoglycemia. SGLT2 inhibitors work by blocking glucose reabsorption in the proximal renal tubule, thus increasing glucose excretion. The low hypoglycemia risk is attributed to the mechanism of action, which is independent of beta-cell function and insulin sensitivity. There are four SGLT2 inhibitors currently on the market: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin, although several combination formulations also exist.  

Several recent studies have been published illustrating the benefits and limitations of SGLT2 inhibitors. For example, a systematic review, including data from fifteen randomized controlled trials, showed a statistically significant reduction in HbA1c in patients who initiated SGLT2 inhibitors with metformin versus metformin alone. While an independent systematic review of 64 studies showed similar results, this research compared the effects of different dual therapies on HbA1c. Results showed that the most considerable reductions in HbA1c occurred in patients taking metformin and glucagon-like peptide 1 receptor agonist (GLP-1RA) dual therapy, followed by those on metformin with an SGLT2 inhibitor. In addition, a retrospective study published in the Indian Journal of Endocrinology and Metabolism evaluated the weight loss and glycemic control outcomes of multidrug therapy, reporting more significant reductions in weight and HbA1c in patients taking metformin and SGLT2 inhibitors compared to other metformin-containing combinations. Of note, younger patients showed these benefits to a greater extent than older patients. Finally, a single-center, open-label single-armed prospective study of only 20 patients, published in Endocrine Connections, sought to investigate the effect of SGLT2 inhibitors on insulin sensitivity in the early phase of treatment initiation. The study concluded that people with a short duration of T2DM and insulin resistance might be good candidates for short-term SGLT2 inhibitor administration due to improved insulin sensitivity in skeletal muscle. 

A new study published in the June 2020 issue of Diabetes, a journal by the ADA, aims to determine the benefits of SGLT2 in combination with metformin and the socioeconomic factors that may influence the achievement of HbA1c <8%. Three thousand four hundred ninety-one adult patients with T2DM were selected from the IQVIA EMR database. To be included in the observational, retrospective cohort study, patients must have been on a metformin and SGLT2 inhibitor regimen for the duration of the study, which was conducted from June 2015 to June 2018. Researchers tested the role of sociodemographic factors in achieving HbA1c <8% using a multivariable logistic regression with backward stepwise selection via SAS 9.4. In the study, the mean age was 56.5 years. 54.6% of patients were male, and 47.4% were female. Most patients were white (74.5%), followed by Black (13.7%). Asians represented 13.7% of patients; all others were unknown. Statistically significant demographic factors affecting treatment outcomes were age <65 years (OR: 1.01, 95% CI: 1.01-1.02) and being of Black race (OR: 0.69, 95% CI: 0.57-0.85). There was no predictive value for gender, smoking status, or cardiovascular or chronic kidney disease history. In the US study, 62% of patients treated with metformin and an SGLT2 achieved HbA1c levels of <8%. While patients under 65 years of age had no clinically relevant differences, Black patients had lower odds of reaching HbA1c levels <8%. Further research may be needed due to this study’s observational, retrospective design.  

In recent years, SGLT2 inhibitors have been of significant interest in treating T2DM. Due to their HbA1c lowering capacity, weight-loss benefits, and low risk of hypoglycemia, this class of medications is becoming more commonly prescribed. In addition, studies have shown marked improvements in diabetes control for patients on both metformin and an SGLT2 inhibitor versus those on metformin alone. However, it is essential to understand the limitations of SGLT2 inhibitors as these medications may not always be sufficient in specific populations, such as Black Americans.   

Practice Pearls: 

• Many patients with type 2 diabetes uncontrolled on metformin alone may benefit from add-on therapy with a sodium-glucose cotransporter-2 inhibitor (SGLT2). 
• Age <65 may not accurately predict the odds of achieving target A1C with metformin and SGLT2. 
• Black Americans may benefit from this combination at lower rates than other racial or ethnic groups.  

Diabetes Obes Metab. 2014;16(5):410-417. doi:10.1111/dom.12233 

Acta Diabetol. 2020;10.1007/s00592-020-01542-4. doi:10.1007/s00592-020-01542-4 

Endocrinol Metab. 2019;23(4):460-467. doi:10.4103/ijem.IJEM_185_19 

Jia S, Wang Z, [published online ahead of print, 2020 Jun 8]. Acta Diabetol. 2020;10.1007/s00592-020-01542-4. doi:10.1007/s00592-020-01542-4 

Melinda Rodriguez, PharmD Candidate 2021, Lake Erie College of Osteopathic Medicine – L|E|C|O|M School of Pharmacy