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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 HbA1c (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, HbA1c 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

Outcomes

Number of trials (and people)

Effect of treatment*

HbA1c levels

38 trials (21,163 people)

All SGLT2 inhibitor drugs reduced HbA1c levels more than placebo by about 0.6% to 0.9%.

Canagliflozin, 300 mg/day, reduced HbA1c levels more than other SGLT2 inhibitor drugs by about 0.1% to 0.3%.

Fasting plasma glucose (FPG) levels

37 trials (19,491 people)

All SGLT2 inhibitor drugs reduced FPG levels more than placebo by about 1.1 to 1.9 mmol/L.

Canagliflozin, 300 mg/day, reduced FPG levels more than other SGLT2 inhibitor drugs by about 0.3 to 0.8 mmol/L.

Body weight

37 trials (20,214 people)

All SGLT2 inhibitor drugs reduced weight more than placebo by about 4 to 6 pounds.

There wasn’t enough information to determine if some SGLT2 inhibitors were better than others.

Systolic blood pressure (SBP)

33 trials (17,600 people)

All SGLT2 inhibitor drugs reduced SBP more than placebo by about 2.8 to 4.9 mm Hg.

Canagliflozin, 300 mg/day, reduced SBP more than canagliflozin, 100 mg/day, empagliflozin, 10 mg/day, and any dose of dapagliflozin by about 1.0 to 2.0 mm Hg.

Diastolic blood pressure (DBP)

27 trials (15,551 people)

All SGLT2 inhibitor drugs reduced DBP more than placebo by about 1.5 to 2.0 mm Hg.

All SGLT2 inhibitor drugs had similar effects.

Low-density lipoprotein cholesterol (LDL-C) levels

26 trials (13,222 people)

Canagliflozin, 100 or 300 mg/day, increased LDL-C levels more than placebo by about 0.1 to 0.2 mmol/L.

Canagliflozin, 300 mg/day, increased LDL-C levels more than other SGLT2 inhibitor drugs by about 0.1 to 0.2 mmol/L.

High-density lipoprotein cholesterol (HDL-C) levels

24 trials (12,467 people)

All SGLT2 inhibitor drugs increased HDL-C levels more than placebo by about 0.04 to 0.07 mmol/L.

All SGLT2 inhibitor drugs had similar effects.

Triglyceride levels

25 trials (13,141 people)

Canagliflozin, 100 or 300 mg/day, reduced triglyceride levels more than placebo or empagliflozin by about 0.2 mmol/L.

Hypoglycemia

37 trials (22,753 people)

Canagliflozin, 100 or 300 mg/day, increased hypoglycemic events more than placebo, dapagliflozin 10 mg/day, or empagliflozin 10 mg/day (relative increase of about 40% to 50%, from as little as 3% to as much as 91%).

Urinary tract infections

38 trials (24,037 people)

Dapagliflozin, 10 mg/day, increased urinary tract infections more than placebo and empagliflozin, 25 mg/day (relative increase of about 40%, from as little as 7% to as much as 81%).

Genital infections

37 trials (22,753 people)

All SGLT2 inhibitor drugs increased genital infections more than placebo; people were about 4 to 6 times more likely to get an infection with the drugs than with placebo.

All SGLT2 inhibitor drugs had similar effects.

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




Glossary

Diastolic
The lower number in a blood pressure reading. It is the pressure when the heart rests between beats.
Placebo
A harmless, inactive, and simulated treatment.
Randomized controlled trials
Studies where people are assigned to one of the treatments purely by chance.
Systolic
The higher number in a blood pressure reading. It is the pressure in the arteries when the heart beats.

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