Glucagon-like peptide-1 (GLP-1) receptor agonists are now advocated for early use in patients with type 2 diabetes in several guidelines, including the influential joint ADA and EASD consensus (Davies et al, 2018). The meta-analysis undertaken by Kristensen et al (2019), see our Digest here, used a random-effects model to estimate overall hazard ratios for all of the important clinical outcomes studied, including cardiovascular outcomes, all-cause mortality and kidney outcomes. The meta-analysis included data from seven large randomised controlled trials of GLP-1 receptor agonists:
- Lixisenatide – Evaluation of Cardiovascular Outcomes in Patients with Type 2 Diabetes after Acute Coronary Syndrome During Treatment with AVE0010 (ELIXA)
- Liraglutide – Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER)
- Exenatide – Exenatide Study of Cardiovascular Event Lowering (EXSCEL)
- Albiglutide – Albiglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease (HARMONY)
- Semaglutide – Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) and Peptide Innovation for Early Diabetes Treatment 6 (PIONEER 6)
- Dulaglutide – Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes (REWIND).
These agents were administered subcutaneously in all trials except PIONEER 6, in which was semaglutide was administered orally.
It is truly astonishing that 56,004 participants were studied globally across the trials, each of which included more than 3,000 participants. The participants, many of whom were in their late middle age – the median age range across the trials was 60–66 years – were followed up for a median duration of 3.2 years (range 1.3–5.4 years). All local investigators were encouraged to use current standards of care. The statistically significant results from these studies are summarised in Table 1.
In the subgroup analyses there was no heterogeneity for interaction in relation to whether or not the patient group had established cardiovascular disease, high or lower HbA1c, high or low body mass index or were aged 60 years or more. This meta-analysis uses numbers needed to treat (NNT) as a measure of absolute risk for each main outcome, estimated by a weighted average of the follow-up period in each trial (Altman and Andersen, 1999).
In addition to these results, I calculated a ‘YoDa’ value for each of the main outcomes for GLP-1 receptor agonists and SGLT-2 inhibitors. The YoDa, or the Years of Drug Administration, is an idea I use in teaching. This is calculated by simply multiplying the NNT by the trial length in years. This allows us to ascertain the number of years of treatment a particular drug needs to be given in order to accrue a beneficial (or, indeed, a harmful) outcome. This then leads to an estimation of cost to achieve a given outcome. For some of the main outcomes, it is useful to compare the NNT and YoDa for GLP-1 receptor agonists with comparable data for SGLT-2 inhibitors (Zelniker et al, 2019), see Table 2. With respect to the major adverse cardiovascular event endpoint, the NNT and YoDa calculations for both classes of agents were similar, with both showing an approximate 14% reduction.
To conclude, both GLP-1 receptor agonists and SGLT-2 inhibitors offer significant benefits to our patients with type 2 diabetes, in terms of reducing hard clinically-important outcomes for the patient and reducing costly complications. This has not been the case with previous classes of glucose-lowering agents across such a broad range of diabetes complications. However, there is the consideration that SGLT-2 inhibitors are more cost-efficient, as fewer years of treatment are needed. This point is further impacted by the fact that SGLT-2 inhibitors are cheaper than GLP-1 receptor agonists at present. Clearly – with the robust evidence-based benefits offered by GLP-1 receptor agonists – these agents will need to be used, especially when the more cost-efficient SGLT-2 inhibitors may not be suitable.
Click the links below to access the latest Diabetes Digests related to cardiovascular disease:
- GLP-1 receptor agonists have a wide range of benefits
- Early blood pressure control reduces atherosclerotic event risk
- Early intensive multifactorial therapy reduces stroke risk
- Canagliflozin effective in primary and secondary prevention of CV outcomes
Altman DG, Andersen PK (1999) Calculating the number needed to treat for trials where the outcome is time to an event. BMJ 319: 1492–95
Davies MJ, D’Alessio DA, Fradkin J et al (2018) Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 41: 2669–701
Kristensen SL, Rørth R, Jhund PS et al (2019) Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 7: 776–85
Zelniker TA, Wiviott SD, Raz I et al (2019) SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 393: 31–9
Amid accumulating evidence of benefits with new diabetes drugs, Vinod Patel asks whether the costs can be justified.
9 Nov 2023