Tools for Practice


#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
Context:
  • 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.
February 6, 2017

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Author(s):

  • Adrienne J Lindblad BSP ACPR PharmD
  • G. Michael Allan MD CCFP

1. Marso SP, Daniels GH, Brown-Frandsen K, et al. N Engl J Med. 2016; 375:311-22.

2. Marso SP, Bain SC, Consoli A, et al. N Engl J Med. 2016; 375(10):1834-44.

3. Pfeffer MA, Claggett B, Diaz R, et al. N Engl J Med. 2015; 373:2247-57.

4. Chen H, Zhou X, Chen T, et al. Diabetes Ther. 2016; 7(4):725-42.

5. Alves C, Batel-Marques F, Macedo AF. Diabetes Res Clin Pract. 2012 Nov; 98(2):271-84.

6. Cohen D. BMJ. 2013; 346:f3680.

7. Egan AG, Blind E, Dunder K, et al. New Engl J Med. 2014; 370:794-7.

8. Barry A, Allan GM. Tools for Practice. Available at: https://www.acfp.ca/wp-content/uploads/tools-for-practice/1447085079_tfp150dpp-4inhibitorfv2.pdf. Last accessed: January 18, 2017.

Authors have no conflicts of interest to declare.