For type 2 diabetes, canagliflozin lowers blood sugar levels more than other drugs in its class but increases risk of hypoglycemia and genital infections

Zaccardi F, Webb DR, Htike ZZ, et al. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus: Systematic review and network meta-analysis. Diabetes Obes Metab. 2016;18:783-94.

Review questions

In people with type 2 diabetes, which of a new class of drugs, sodium-glucose co-transporter-2 (SGLT2) inhibitors, work best for lowering blood sugar levels? What are the side effects of these drugs?

Background

Type 2 diabetes is a disease that increases blood sugar levels. Over time, high blood sugar levels can lead to complications such as kidney failure, vision loss, heart disease, and stroke. Some people with type 2 diabetes can control their blood sugar levels through exercise and diet. Many people will also need to use drugs to help manage their diabetes. SGLT2 inhibitors are a newer class of drugs used to treat diabetes. They work well to control blood sugar levels compared with placebo. We need to know how well they work compared with one another and if they have side effects.

How the review was done

The reviewers found 38 studies (randomized controlled trials) that were published up to November 2015.

The studies included 23,997 people with type 2 diabetes. People were, on average, 58 years old, and most were men.

Studies assessed SGLT2 inhibitors at their approved doses: 100 or 300 mg/day for canagliflozin; 5 or 10 mg/day for dapagliflozin; and 10 or 25 mg/day for empagliflozin. SGLT2 inhibitors were compared with placebo or other antidiabetes drugs. Studies were combined using a type of analysis that lets you compare treatments even if they were not compared directly in the individual studies.

People were followed for 24 weeks to 4 years.

Studies that included only in people with chronic kidney disease were excluded.

What the researchers found

Compared with placebo:

• all SGLT2 inhibitors reduced HbA_1c (a longer-term measure of blood sugar control) and fasting plasma glucose levels, body weight, and blood pressure;
• all SGLT2 inhibitors increased high-density lipoprotein (HDL or “good”) cholesterol levels;
• all SGLT2 inhibitors increased genital infections;
• canagliflozin, 100 or 300 mg/day, had more adverse effects: It increased low-density lipoprotein (LDL or “bad”) cholesterol levels and hypoglycemic events (sugars that are too low), particularly in people also taking insulin or a sulfonylurea (e.g., glyburide or gliclazide); and
• dapagliflozin, 10 mg/day, increased upper urinary tract infections.

Compared with other SGLT2 inhibitors, canagliflozin, 300 mg/day:

• reduced, by a small amount, HbA_1c and fasting glucose levels, and systolic blood pressure; and
• increased, by a small amount, LDL cholesterol levels and hypoglycemic events.

All SGTL2 inhibitors had similar effects on HDL cholesterol levels and genital infections.

Conclusions

In people with type 2 diabetes, all SGLT2 inhibitor drugs lower blood sugar levels but increase genital infections more than placebo. Canagliflozin, 300 mg/day, lowers blood sugar levels a little more than other SGLT2 inhibitor drugs but also increases the risk of hypoglycemia. The studies were not analyzed for serious complications of diabetes, so these differences may or may not be important in the long run.

SGLT2 inhibitor drugs for the treatment of type 2 diabetes

*Trials were combined using a type of analysis that lets you compare treatments even if they were not compared directly in the individual trials.