#180 GLP-1 Analogues in Diabetes: As sweet as can be?
CLINICAL QUESTION
Do glucagon-like peptide 1 analogues (GLP-1) improve patient-oriented outcomes in type 2 diabetes?
BOTTOM LINE
Compared to placebo, semaglutide and liraglutide, but not lixisenatide, reduce cardiovascular disease (CVD) for ~1 in 50 diabetics with existing CVD over 2-4 years, irrespective of specific A1c targets (attaining ~7.5%). These drugs reduce weight
0.7-4.3 kg, but around one in 25 more than placebo will stop due to gastrointestinal effects. Some uncertainty around neoplasm risk remains.
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EVIDENCE
Three randomized controlled trials (RCTs), mean age 60-65, diabetic 9-14 years, >80% past CVD. All GLP-1 subcutaneous versus placebo. Statistically significant results:
- Liraglutide (1.8 mg daily): 9,340 patients x 3.8 years:1
- A1c from 8.7% to: ~7.7% liraglutude versus 8.1% placebo.
- CVD: 13% versus 14.9%, Number Needed to Treat (NNT)=53.
- Mortality: NNT=72.
- Harms: Gallbladder disease, Number Needed to Harm (NNH)=83.
- Semaglutide (0.5 or 1 mg weekly; pooled): 3,297 patients x 2.1 years:2
- A1c from 8.7% to: 7.3-7.6% semaglutide versus 8.3% placebo.
- CVD: 6.6% versus 8.9%, NNT=44.
- Mortality: No difference.
- Harms: Retinopathy, NNH=83.
- Lixisenatide (20 mcg daily): 6,068 patients x 2.1 years:3
- A1c from 7.6% to: ~7.3% lixisenatide versus ~7.6% placebo.
- CVD or mortality: No difference.
- Other findings: Weight loss (0.7-4.3 kg), reduced nephropathy (NNT=67-98; not lixisenatide), hypoglycemia no different or lower.
- More discontinued due to gastrointestinal irritation (NNH=16-33).
- Neoplasm (benign/malignant) numerically higher with GLP-1 agonist in each study.1-3
- Meta-analyses (missing above liraglutide and semaglutide RCTs): No cancer risk.4,5
- Except high-quality liraglutide RCTs, odds ratio=2.60 (1.08-6.27).5
- BMJ investigation questioned whether safety adequately evaluated.6
- 2014 FDA/EMA review “had not reached a final conclusion” on causality between incretins and (specifically) pancreatic cancer, despite indicating concerns were not consistent with evidence.7
- Meta-analyses (missing above liraglutide and semaglutide RCTs): No cancer risk.4,5
- Clinicians should prioritize patient-oriented outcomes (like CVD) rather than sugars or microalbuminuria.
- Large RCTs of DPP-4 medications demonstrate no effect on CVD and minimal to no effect on microvascular outcomes.8
- Liraglutide is the only GLP-1 agonist available in Canada with a large CVD trial (others: dulaglutide and exenatide), costs ~$185/month and while often covered by private insurance, it is not covered by public insurance plans outside of Quebec.
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