- GLP-1RA and SGLT2i (two new diabetes medicines) are likely to reduce the risk of death from cardiovascular disease and death from any cause in people with both diabetes and established cardiovascular disease (diseases of the heart and blood vessels).
- SGLT2i medicines are likely to reduce the risk of hospitalisation for heart failure and GLP-1RA medicines may reduce fatal and non-fatal stroke.
- We need further studies to find out if these medicines also have a positive effect on cardiovascular health in people without diabetes or if the effects seen in people with diabetes are due only to these medicines’ ability to control blood sugar.
What is cardiovascular disease?
Cardiovascular disease is a general term for conditions that affect the heart and blood vessels. It is one of the leading causes of death worldwide. Fatty substances in the blood can build up and block blood vessels, leading to problems such as heart failure – when the heart cannot pump blood around the body properly – stroke and heart attacks. People who are inactive or overweight, or have high blood pressure, high cholesterol or diabetes are at risk of cardiovascular disease.
Some new types of diabetes medicines, DPP4i, GLP-1RA and SGLT2i, have been designed to control blood sugar. They may also prevent cardiovascular complications in people with diabetes who also have cardiovascular disease.
What did we want to find out?
We wanted to know if DPP4i, GLP-1RA and SGLT2i medicines are effective treatments for cardiovascular disease in people with established cardiovascular disease, both with and without diabetes. We also wanted to know whether these medicines cause unwanted effects.
We were interested in whether people taking these medicines were at higher or lower risk of: dying from cardiovascular disease; having a fatal or non-fatal heart attack; having a fatal or non-fatal stroke; dying from any cause; being hospitalised due to heart failure; and experiencing unwanted effects, such as worsening kidney function, low blood sugar, bone fracture, and inflammation of the pancreas (pancreatitis).
What did we do?
We searched for studies that investigated DPP4i, GLP-1RA and SGLT2i medicines compared with each other or with placebo (a medicine that looks like the real medicine but that has no active ingredient).
We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found 31 studies. We were able to combine and analyse the evidence from 20 studies, with 129,465 participants. Six of the 20 studies investigated DPP4i, 7 studied GLP-1RA and 7 investigated SGLT2i medicines, all compared with placebo. People in the studies were aged between 60 and 71 years and most people had diabetes.
DPP4i medicines compared to placebo:
- do not reduce the risk of death from cardiovascular disease or from any cause, or risk of heart attack or stroke;
- probably do not reduce the risk of hospitalisation due to heart failure;
- may not increase the risk of worsening kidney function or bone fracture and probably do not increase the risk of low blood sugar;
- are likely to increase the risk of pancreatitis.
GLP-1RA medicines compared to placebo:
- reduce the risk of death due to cardiovascular disease and from any cause slightly, and reduce the risk of stroke slightly;
- probably do not reduce the risk of heart attack;
- do not reduce the risk of hospitalisation due to heart failure;
- may reduce the risk of worsening kidney function but may have no impact on pancreatitis;
- uncertainty about effects on low blood sugar and bone fracture.
SGLT2i medicines compared to placebo:
- probably reduce the risk of death from cardiovascular disease and from any cause slightly;
- reduce the risk of hospitalisation due to heart failure;
- do not reduce the risk of heart attack and probably do not reduce the risk of stroke;
- probably reduce the risk of worsening kidney function;
- may have no impact on pancreatitis and they have no effect on bone fracture.
Although none of the studies compared one medicine directly with another, we used a statistical technique called network meta-analysis that allowed us to compare one against another. The results were similar to those above.
What are the limitations of the evidence?
We are confident or moderately confident in the evidence for deaths from cardiovascular disease or any cause, heart attack, stroke and hospitalisation due to heart failure. We are less confident in the evidence for unwanted effects because few studies provided information on unwanted effects and they did not report many. Most studies included people with diabetes only so these results could be due to better control of their diabetes, rather than the medicines’ effect on cardiovascular disease.
How up-to-date is this evidence?
The evidence is current to 16 July 2020.
Findings from both standard and network meta-analyses of moderate- to high-certainty evidence suggest that GLP-1RA and SGLT2i are likely to reduce the risk of CVD mortality and all-cause mortality in people with established CVD; high-certainty evidence demonstrates that treatment with SGLT2i reduce the risk of hospitalisation for HF, while moderate-certainty evidence likely supports the use of GLP-1RA to reduce fatal and non-fatal stroke. Future studies conducted in the non-diabetic CVD population will reveal the mechanisms behind how these agents improve clinical outcomes irrespective of their glucose-lowering effects.
Cardiovascular disease (CVD) is a leading cause of death globally. Recently, dipeptidyl peptidase-4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) were approved for treating people with type 2 diabetes mellitus. Although metformin remains the first-line pharmacotherapy for people with type 2 diabetes mellitus, a body of evidence has recently emerged indicating that DPP4i, GLP-1RA and SGLT2i may exert positive effects on patients with known CVD.
To systematically review the available evidence on the benefits and harms of DPP4i, GLP-1RA, and SGLT2i in people with established CVD, using network meta-analysis.
We searched CENTRAL, MEDLINE, Embase, and the Conference Proceedings Citation Index on 16 July 2020. We also searched clinical trials registers on 22 August 2020. We did not restrict by language or publication status.
We searched for randomised controlled trials (RCTs) investigating DPP4i, GLP-1RA, or SGLT2i that included participants with established CVD. Outcome measures of interest were CVD mortality, fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, all-cause mortality, hospitalisation for heart failure (HF), and safety outcomes.
Three review authors independently screened the results of searches to identify eligible studies and extracted study data. We used the GRADE approach to assess the certainty of the evidence. We conducted standard pairwise meta-analyses and network meta-analyses by pooling studies that we assessed to be of substantial homogeneity; subgroup and sensitivity analyses were also pursued to explore how study characteristics and potential effect modifiers could affect the robustness of our review findings. We analysed study data using the odds ratios (ORs) and log odds ratios (LORs) with their respective 95% confidence intervals (CIs) and credible intervals (Crls), where appropriate. We also performed narrative synthesis for included studies that were of substantial heterogeneity and that did not report quantitative data in a usable format, in order to discuss their individual findings and relevance to our review scope.
We included 31 studies (287 records), of which we pooled data from 20 studies (129,465 participants) for our meta-analysis. The majority of the included studies were at low risk of bias, using Cochrane's tool for assessing risk of bias. Among the 20 pooled studies, six investigated DPP4i, seven studied GLP-1RA, and the remaining seven trials evaluated SGLT2i. All outcome data described below were reported at the longest follow-up duration.
1. DPP4i versus placebo
Our review suggests that DPP4i do not reduce any risk of efficacy outcomes: CVD mortality (OR 1.00, 95% CI 0.91 to 1.09; high-certainty evidence), myocardial infarction (OR 0.97, 95% CI 0.88 to 1.08; high-certainty evidence), stroke (OR 1.00, 95% CI 0.87 to 1.14; high-certainty evidence), and all-cause mortality (OR 1.03, 95% CI 0.96 to 1.11; high-certainty evidence). DPP4i probably do not reduce hospitalisation for HF (OR 0.99, 95% CI 0.80 to 1.23; moderate-certainty evidence). DPP4i may not increase the likelihood of worsening renal function (OR 1.08, 95% CI 0.88 to 1.33; low-certainty evidence) and probably do not increase the risk of bone fracture (OR 1.00, 95% CI 0.83 to 1.19; moderate-certainty evidence) or hypoglycaemia (OR 1.11, 95% CI 0.95 to 1.29; moderate-certainty evidence). They are likely to increase the risk of pancreatitis (OR 1.63, 95% CI 1.12 to 2.37; moderate-certainty evidence).
2. GLP-1RA versus placebo
Our findings indicate that GLP-1RA reduce the risk of CV mortality (OR 0.87, 95% CI 0.79 to 0.95; high-certainty evidence), all-cause mortality (OR 0.88, 95% CI 0.82 to 0.95; high-certainty evidence), and stroke (OR 0.87, 95% CI 0.77 to 0.98; high-certainty evidence). GLP-1RA probably do not reduce the risk of myocardial infarction (OR 0.89, 95% CI 0.78 to 1.01; moderate-certainty evidence), and hospitalisation for HF (OR 0.95, 95% CI 0.85 to 1.06; high-certainty evidence). GLP-1RA may reduce the risk of worsening renal function (OR 0.61, 95% CI 0.44 to 0.84; low-certainty evidence), but may have no impact on pancreatitis (OR 0.96, 95% CI 0.68 to 1.35; low-certainty evidence). We are uncertain about the effect of GLP-1RA on hypoglycaemia and bone fractures.
3. SGLT2i versus placebo
This review shows that SGLT2i probably reduce the risk of CV mortality (OR 0.82, 95% CI 0.70 to 0.95; moderate-certainty evidence), all-cause mortality (OR 0.84, 95% CI 0.74 to 0.96; moderate-certainty evidence), and reduce the risk of HF hospitalisation (OR 0.65, 95% CI 0.59 to 0.71; high-certainty evidence); they do not reduce the risk of myocardial infarction (OR 0.97, 95% CI 0.84 to 1.12; high-certainty evidence) and probably do not reduce the risk of stroke (OR 1.12, 95% CI 0.92 to 1.36; moderate-certainty evidence). In terms of treatment safety, SGLT2i probably reduce the incidence of worsening renal function (OR 0.59, 95% CI 0.43 to 0.82; moderate-certainty evidence), and probably have no effect on hypoglycaemia (OR 0.90, 95% CI 0.75 to 1.07; moderate-certainty evidence) or bone fracture (OR 1.02, 95% CI 0.88 to 1.18; high-certainty evidence), and may have no impact on pancreatitis (OR 0.85, 95% CI 0.39 to 1.86; low-certainty evidence).
4. Network meta-analysis
Because we failed to identify direct comparisons between each class of the agents, findings from our network meta-analysis provided limited novel insights. Almost all findings from our network meta-analysis agree with those from the standard meta-analysis. GLP-1RA may not reduce the risk of stroke compared with placebo (OR 0.87, 95% CrI 0.75 to 1.0; moderate-certainty evidence), which showed similar odds estimates and wider 95% Crl compared with standard pairwise meta-analysis. Indirect estimates also supported comparison across all three classes. SGLT2i was ranked the best for CVD and all-cause mortality.