SGLT-2 vs. Sulfonylureas

The most common treatment for T2D has been the metformin-sulfonylureas combo, but how do SGLT-2 inhibitors compare in all-cause mortality risk?

The addition of SGLT-2 inhibitors has been accepted in type 2 diabetes treatment as a class of antihyperglycemics that lowers the possibilities of unfavorable cardiovascular and kidney events.

Exercise, dietary changes, smoking cessation, and weight loss are the first non-pharmacologic interventions to treating a patient newly diagnosed with type 2 diabetes. However, most patients with type 2 diabetes will also need glucose-lowering drugs to attain and maintain specific glycemic levels. In patients with type 2 diabetes, metformin is currently first-line therapy due to its various benefits, such as cardioprotective effects, weight loss, and some comorbid disease prevention. However, if the glycemic target is not reached within a three-month follow-up despite non-pharmacologic intervention and the highest tolerated dose of metformin, combination therapy will be necessary.

Metformin-sulfonylurea is the most utilized combination as 2nd line treatment of type 2 diabetes. When prescribed alone as first-line treatment, sulfonylureas are associated with greater rates of ischemic stroke, cardiovascular mortality, and hypoglycemia. Current therapies for type 2 diabetes have been designed to increase insulin availability, improve the body’s sensitivity to insulin, slow down the delivery and absorption of carbohydrates from the GI tract, or increase urinary excretion. SGLT-2 inhibitors lower blood glucose by increasing the excretion of urinary glucose from the body. However, the SGLT-2 inhibitor’s ability to reduce blood glucose levels and hemoglobin (A1C) levels are restricted by the filtered amount of glucose and osmotic diuresis due to this therapy.

Sulfonylureas and SGLT-2 inhibitors are commonly utilized after metformin as 2nd line antihyperglycemic agents. Given the knowledge acquired from randomized clinical trials as real-world evidence, it is hypothesized that SGLT-2 inhibitors are also correlated with a lower risk of all-cause mortality among patients using metformin, compared with sulfonylureas. Utilizing the US Department of Veterans Affairs electronic health care databases, this study aims to determine the comparative effectiveness of SGLT-2 inhibitors, vs. sulfonylureas’ association with all-cause mortality in patients receiving metformin therapy.

23,870 patients newly utilizing SGLT-2 inhibitors and 104,423 patients newly utilizing sulfonylureas were enrolled in the study. All participants used metformin therapy between October 1, 2016, and February 29, 2020, with a follow-up through January 31, 2021. The study examined the results of all-cause mortality. The result of SGLT-2 inhibitors, when put next to sulfonylureas, was a lower risk of all-cause mortality despite CVD status in several categories of estimated GFR and patients with no albuminuria, microalbuminuria, and macroalbuminuria. The addition of SGLT-2 inhibitor treatment with metformin resulted in an exceedingly reduced risk of death compared to the employment of SGLT-2 inhibitors treatment without metformin in patients with type 2 diabetes

A significant strength is that the study had one clear and concise objective: to compare the effectiveness of metformin and sulfonylureas as a combination therapy vs. metformin and SGLT-2 inhibitors. However, due to this topic not being addressed in randomized clinical trials, the study relied on observational data from the US department of veteran affairs to put together a cohort that mainly consisted of older, white and male participants, which caused generalization in the study’s findings. In addition, participants utilizing SGLT-2 inhibitors were also older and suffered from more comorbidities, including cardiovascular and kidney disease, compared to the participants using sulfonylureas, which could have caused some limitations and bias throughout the study.

Although the use of sulfonylureas has various benefits in the short term, sodium-glucose co-transporter 2 inhibitors are more effective in the long term as an add-on to metformin therapy. In addition to being a better combination therapy with metformin in the longer term, sodium-glucose co-transporter 2 inhibitors produce fewer hypoglycemic incidents and lead to a more significant amount of weight reduction and lowered blood pressure compared to sulfonylureas.

Practice Pearls:

• Metformin is used as first-line therapy antihyperglycemic agent in a patient with type 2 diabetes.
• Sulfonylureas and SGLT-2 inhibitors are second-line therapy.
• When added to metformin therapy, SGLT-2 is the best option for reducing all-cause mortality despite CVD status in patients with type 2 diabetes.

Xie, Yan et al. “Comparative Effectiveness of Sodium-Glucose Cotransporter 2 Inhibitors vs. Sulfonylureas in Patients with Type 2 Diabetes.” JAMA internal medicine June 2021

Davidson, Jaime A, and Louis Kuritzky. “Sodium-glucose co-transporter 2 inhibitors and their mechanism for improving glycemia in patients with type 2 diabetes.” Postgraduate medicine

Chen, Ze, and Gerui Li. “Sodium-Glucose Co-Transporter 2 Inhibitors Compared with Sulfonylureas in Patients with Type 2 Diabetes Inadequately Controlled on Metformin: A Meta-Analysis of Randomized Controlled Trials.” Clinical drug investigation

Emmanuella Louissaint, PharmD candidate, LECOM College of Pharmacy