SUSTAIN-6: Another Medication for Diabetes with Cardiovascular Benefits?

Semaglutide (Ozempic) recently received its Notice of Compliance from Health Canada and is therefore now available for Canadians with Type 2 diabetes. So it only makes sense to take a closer look at its evidence, particularly the evidence for its cardiovascular benefits which was studied in SUSTAIN-6 and published in New England Journal of Medicine in 2016..

In SUSTAIN-6, the objective was to assess the non-inferiority of semaglutide as compared with placebo in cardiovascular safety with type 2 diabetes.  Below are some key highlights from the study:

Methods:  3297 Patients with Type 2 diabetes were randomized to

  • Placebo [n = 1649] or,
  • Once weekly semaglutide (0.5mg or 1.0,g)  [n=1648]

for 104 weeks.

Primary composite outcome: 1st occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.  The non-inferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio.

The study enrolled patients with type 2 diabetes and a HgA1c 7% or more who have not been treated with antihyperglycemic agent or had been treated with no more than two oral agents, with or without basal or premixed insulin. The specific inclusion and exclusion criteria are as follow:

Inclusion Criteria:

  • Age of 50 years or more with established disease (previous cardiovascular, cerebrovascular or peripheral vascular disease), chronic heart failure (NYHA Class II or III), or chronic kidney disease (stage 3 or higher) or
  • Age of 60 years or more with at least one cardiovascular risk factor

Exclusion Criteria: Treatment with DPP4 inhibitor within 30 days before screening or a GLP-1 receptor agonist or insulin other than basal or premixed within 90 days before screening; history of an acute coronary or cerebrovascular event within 90 days before randomization; planned revascularization of a coronary carotid or peripheral artery, or long-term dialysis.

Results:

 

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Results of SUSTAIN6 Part 2

Key Findings:

  • The primary composite outcome occurred in:
    • 108 of 1648 patients (6.6%) in the semaglutide group
    • 146 of 1649 patients (8.9%) in the placebo group
      • Hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; p<0.001 for non inferiority
  • Nonfatal Myocardial infarction occurred in:
    • 2.9% of patients in the Semaglutide group
    • 3.9% of patients in the placebo group
      • Hazard ratio, 0.74; 95% CI, 0.51-1.08; p=0.12
  • Nonfatal stroke occurred in:
    • 1.6% of patients in the semaglutide group
    • 2.7% of patients in the placebo group
      • Hazard ratio, 0.61; 95% CI, 0.38 to 0.99; p=0.04
  • Death from cardiovascular causes occurred in:
    • 2.7% of patients in semaglutide group
    • 2.8% of patients in placebo group
      • Hazard ratio, 0.98; 95% CI, 0.65-1.48; p=0.92

One outcome that was unexpectedly worse in the semaglutide group was diabetic retinopathy. It occurred in 50 patients (3.0%) in the semaglutide group and 29 patients (1.8%) in the placebo group. This translates into a hazard ratio of 1.76 (95% CI, 1.11-2.78; p=0.02).  Overall, more patients from the semaglutide group required retinal photocoagulation (2.3% vs 1.2%), the use of intravitreal agent (1.0% vs 0.8%), experienced a vitreous hemorrhage (1.0% vs 0.4%) and developed an onset of diabetes related blindness (0.3% vs. 0.1%).  While the overall incidence of retinopathy is low, it is still of clinical concern that the treatment arm with semaglutide appears to have a higher rate of diabetic retinopathy and its related complications.

My overall impression:

  • While the overall study demonstrates cardiovascular safety with the primary composite endpoint results, its significance is likely driven by the difference in nonfatal stroke as the authors have highlighted. In fact, the individual outcomes in myocardial infarction and death from cardiovascular causes were not statistically significant.

 

  • This is the second glycogon-like peptide 1 analogue to demonstrate cardiovascular benefits, after liraglutide of which the cardiovascular benefits were illustrated in LEADER.  It is interested to note that both liraglutide and semaglutide are products of NovoNordisk while other glucagon-like peptide 1 analogues such as exenatide or lixisenatide have yet to demonstrate any cardiovascular benefits. Is it a class effect or not? Some experts have argued that the earlier trials with exenatide or lixisenatide were not designed to measure any potential cardiovascular benefits but only to establish cardiovascular safety. But I am not certain if this factor alone explains the disparity of the results.

 

  • The higher incidence with diabetic retinopathy resonates with canagliflozin and its higher incidence of foot amputation from the CANVAS trial. It further emphasizes an important point that long term safety data is still very much lacking with semaglutide.

 

  • In terms of other advantages, semaglutide is given as a subcutaneous injection once weekly, thereby it is deemed more favourable for patients in terms of compliance. However, its high cost and reimbursement challenges will likely prohibit many patients from accessing this medication.

 

  • Other Practical Points: Semaglutide needs to be refrigerated. However after 1st use, it can remain at room temperature or refrigerated temperature for a total of 8 weeks. Other common side effects include nausea and other abdominal discomfort. Dosing titration:
    • Semaglutide can be started at 0.25mg subcutaneous once weekly for 4 weeks, then increase to 0.5mg once weekly for 4 weeks. Can continue to titrate to 1.0mg once weekly based on blood glucose results.  Refer to its product monograph for other details.

Thank you for reading my post. What are your thoughts with semaglutide in the management of Type 2 diabetes?

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drugopinions

My name is Cynthia Leung and I am a practicing pharmacist in Kingston Ontario, Canada. This blog is for me to share my ideas, opinions and perspectives on how medications are used in our health care system. Note that these posts are my own opinions and do not represent the opinions of my current or former employers and / or organizations that I may belong to. Any possible case scenarios described in my posts would be modified to maintain patient confidentiality. This blog is not a platform for professional advise for patients or health care providers and the content is not meant to support any clinical decisions or replace professional opinions. Also the images are either taken or created by the author, or adapted with permission. I hope you will enjoy reading my posts!

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