Zelniker TA, Wiviott SD, Raz I, et al. Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus. Circulation. 2019 Apr 23;139(17):2022-2031. doi: 10.1161/CIRCULATIONAHA.118.038868. (Systematic review)

BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as 2 new classes of antihyperglycemic agents that also reduce cardiovascular risk. The relative benefits in patients with and without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs remain undefined.

METHODS: We performed a systematic review and trial-level meta-analysis of GLP1-RA and SGLT2i cardiovascular outcomes trials using the PubMed and EMBASE databases (Excerpta Medica Database). The primary outcomes were the composite of myocardial infarction, stroke, and cardiovascular death (MACE); hospitalization for heart failure; and progression of kidney disease.

RESULTS: In total, data from 8 trials and 77 242 patients, 42 920 (55.6%) in GLP1-RA trials, and 34 322 (44.4%) in SGLT2i trials, were included. Both drug classes reduced MACE in a similar magnitude with GLP1-RA reducing the risk by 12% (hazard ratio [HR], 0.88; 95% CI, 0.84-0.94; P<0.001) and SGLT2i by 11% (HR, 0.89; 95% CI, 0.83-0.96; P=0.001). For both drug classes, this treatment effect was restricted to a 14% reduction in those with established atherosclerotic cardiovascular disease (HR, 0.86; 95% CI, 0.80-0.93; P=0.002), whereas no effect was seen in patients without established atherosclerotic cardiovascular disease (HR, 1.01; 95% CI, 0.87-1.19; P=0.81; P interaction, 0.028). SGLT2i reduced hospitalization for heart failure by 31% (HR, 0.69; 95% CI, 0.61-0.79; P<0.001), whereas GLP1-RA did not have a significant effect (HR, 0.93; 95% CI, 0.83-1.04; P=0.20). Both GLP1-RA (HR, 0.82; 95% CI, 0.75-0.89; P<0.001) and SGLT2i (HR, 0.62; 95% CI, 0.58-0.67; P<0.001) reduced the risk of progression of kidney disease including macroalbuminuria, but only SGLT2i reduced the risk of worsening estimated glomerular filtration rate, end-stage kidney disease, or renal death (HR, 0.55; 95% CI, 0.48-0.64; P<0.001).

CONCLUSIONS: In trials reported to date, GLP1-RA and SGLT2i reduce atherosclerotic MACE to a similar degree in patients with established atherosclerotic cardiovascular disease, whereas SGLT2i have a more marked effect on preventing hospitalization for heart failure and progression of kidney disease. Their distinct clinical benefit profiles should be considered in the decision-making process when treating patients with type 2 diabetes mellitus.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 7 / 7
General Internal Medicine-Primary Care(US) 7 / 7
Internal Medicine 6 / 7
Cardiology 6 / 7
Endocrine 6 / 7
Comments from MORE raters

Endocrine rater

These results confirm known findings from large trials that are well known by physicians in my field. While this review suggests that SGLT2 inhibitors have superior overall benefits to GLP1RAs, there lacks mention of the greater side effects with the former class of agents that need to be balanced against the benefits.

Endocrine rater

Given the limitations identified in the study, this meta analysis is a good resource to compare these relatively new class of drugs: GLP1 analogues and SGLT2 inhibitors. This may provide guidance to practitioners on the drug of choice after metformin in patients with known CV disease or CKD.

Family Medicine (FM)/General Practice (GP) rater

This is a systematic review and meta-analysis of the CV effects of GLP-1 agonists and SGLT2 inhibitors for treating type 2 diabetes. The results show that both types of medication reduce equally the number of CV events, but only in patients with already established atherosclerotic CV disease.

Internal Medicine rater

A couple of issues: Comparing SGLT2 with GLP1 is not necessarily a relevant comparison since the latter is used infrequently (because it is parenteral). Also, I find the results surprising (suspicious validity) in that the RRR is not a constant (it is different depending on the baseline risk). The ARR should change with prevalence, but the RRR is supposed to be a property of the drug and not influenced by the population risk. Further, the difference in RRR is not a sample size (event rate) issue as the point estimates are very different between groups with different baseline risk (and the failed significance is not just the result of a wide 95% CI).

Internal Medicine rater

This is a good summary of the existing trials on these two drug classes.

Internal Medicine rater

Apparently, in previous papers the effects of iSGLT2 are not related to prevention of atherosclerotic diseases; however, due to a reduction of MACE attributed to empaglifozin, the overall result seems to have a protector outcome, but the pathways involved are not yet well defined.
Comments from EvidenceAlerts subscribers

Dr. Dan Ewald (5/5/2019 7:49 PM)

These are not head-to-head trials, so the comparison is limited to the extent that the participant selection and control group management were the same in all trials.