#202 Sulfonylureas in Diabetes: Sweet on the Heart or Surrogate Charlatan?
CLINICAL QUESTION
Does treating type 2 diabetes with sulfonylureas affect mortality or cardiovascular events?
BOTTOM LINE
There is a lack of convincing evidence that sulfonylureas reduce cardiovascular events or mortality in type 2 diabetic patients. If anything, sulfonylureas potentially increase cardiovascular harm.
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EVIDENCE
Sulfonylurea versus placebo:
- Most Randomized Controlled Trials (RCTs) investigate HbA1c, not patient-oriented outcomes.1-5
- Largest RCT for patient outcomes (n=409), ~5 years, tolbutamide versus placebo:6,7
- Non-significant: All-cause mortality (14.7% versus 10.2%), myocardial infarction (13.7% versus 10.7%).
- Significant increase: Cardiovascular (CV) mortality (12.7% versus 4.9%), Number Needed to Harm (NNH)=13.
- Limitations: Possible randomization imbalance, smoking not included in baseline demographics, first generation sulfonylurea.
- RCT (n=304) five years, patients with coronary artery disease, mean HbA1c 7.6%, glipizide versus metformin:8
- Sulfonylureas increased composite CV events: 35% versus 25%, NNH=10.
- RCT (n=2,895), four years, mean HbA1c 7.4%, glyburide versus metformin:9
- Non-significant: All-cause mortality (2.2% versus 2.1%), total CV events (2.9% versus 4.0%).
- Limitations: ~40% withdrew after randomization.
- Systematic review: No other RCTs with more than one death.10
- RCT (n=3028), ~5 years, sulfonylurea versus pioglitazone:
- No difference in CV events.11
- Other studies reported CV events or mortality as adverse events:
- Sulfonylurea versus DPP-4 inhibitors:
- No difference in death:12 0.5% versus 0.4%.
- Major CV events:13 3.4% versus 1.5%, NNH=53.
- Versus other drugs:
- Studies underpowered to find a difference in patient outcomes compared to GLP-1 agonists, SGLT2 inhibitors, or insulin.14,15,16
- Sulfonylurea versus DPP-4 inhibitors:
- Two systematic reviews of observational studies report increased CV risk with sulfonylureas, however multiple confounders limit conclusions.17,18
- UKPDS is frequently cited to support sulfonylureas, but confounded by use of insulin.19
- CV disease causes ~50% of diabetes type 2 deaths.20
- Sulfonylureas increase risk of severe hypoglycemia (<1% overall) and weight gain (~2.1kg).21
- We need to think critically about the use of sulfonylureas beyond HbA1C reduction (~0.8%) and low cost.21
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neutral cv effect?
good article
I wish our New Brunswick drug plan formulary coverage for diabetes medications took into consideration the potential negative side effects and covered SGLT2 inhibitors or GLP-1 agonists without trying sulfonylureas first.