The contribution of glucose-lowering strategies to reduce cardiovascular (CV) events in patients with diabetes are modest compared to lipid lowering with statins and the control of blood pressure. Despite this, improvement in glycaemic control is necessary to improve CV outcomes.
The Association of British Clinical Diabetologists (ABCD) publication, Cardiovascular impact of new drugs (GLP-1 and gliflozins): the ABCD position statement, examined cardiovascular outcomes trials to assess the possible CV impact of newer oral hypoglycaemic drugs on people with diabetes, and makes recommendations on the outcomes.
This Guidelines summary covers the ABCD’s position for the use of dipeptidyl peptidase 4 (DPP-IV) inhibitors: saxagliptin, alogliptin, sitagliptin, and linagliptin; glucagon-like peptide-1 receptor agonists (GLP-1 RA): lixisenatide, liraglutide, semaglutide, prolonged-release exenatide, and dulaglutide; and sodium-glucose cotransporter-2 (SGLT2) inhibitors: canagliflozin, empagliflozin, dapagliflozin, and ertugliflozin. The GLP-1 RA albiglutide is not included, as it is not currently available in the UK. It also summarises the ABCD’s review of the CV impact of older antidiabetes drugs: metformin, sulfonylureas, meglitinides, acarbose, and thiazolidinediones.
For further information, refer to the full position statement.
- The newer oral hypoglycaemic drugs used in diabetes have demonstrated CV safety in all cases, with evidence of benefit in a few
- There is significant heterogeneity in study design which makes meaningful comparison somewhat difficult; results of systematic reviews have indicated a common trend within drug classes. These effects are around atherosclerotic cardiovascular disease (CVD) using time to the first major cardiac event as a primary endpoint and hospitalisation due to heart failure (HF) as a co-primary, secondary, or exploratory outcome measure
- Only two drugs—alogliptin and lixisenatide—have been trialled in patients after acute coronary syndrome demonstrating safety
- DPP-IV inhibitors are safe to use in those with CVD, although caution must be exercised in the presence of HF
- GLP-1 inhibitors are similarly safe and, in some cases, offer benefit
- Dapagliflozin is the only SGLT2 inhibitor that is currently licensed for use in patients with HF independent of the presence of diabetes. There is no evidence for their use either for HF or reno-protection in patients with type 1 diabetes
- Clinical judgement should always be used to make specific therapeutic choices, as results from clinical trials can sometimes be difficult to generalise to individual patients.
- Exercise caution in patients with HF as other therapeutic agents such as SGLT2 inhibitors have clearly demonstrated benefit
- Sitagliptin, alogliptin, and linagliptin are all safe in patients with pre-existing CVD—alogliptin particularly so in patients after acute coronary syndrome, and linagliptin in patients with renal impairment.
Table 1: Recommendations on the Cardiovascular Impact of DPP-IV Inhibitors
A systematic review of clinical trials and observational studies suggest that there is an overall excess risk of HF with DPP-IV inhibitors in individuals with pre-existing CVD, although this meta-analysis was largely driven by the increased incidence of HF seen in the SAVOR-TIMI 53 trial.
CV=cardiovascular; CVD=cardiovascular disease; DPP-IV= dipeptidyl peptidase 4; HF=heart failure; NYHA=New York Heart Association; SPC=summary of product characteristics
- Consider the use of a long-acting GLP-1 RA—in particular, semaglutide 1 mg once weekly, dulaglutide 1.5 mg once weekly, or liraglutide 1.8 mg daily—in patients with pre-existing CVD or CVD risk if tolerated by the patient
- Lixisenatide and prolonged-release exenatide are both safe in patients with pre-existing CVD and lixisenatide in patients following acute coronary syndrome. These two drugs will help lower HbA1c and promote weight loss but may not confer additional CVD benefits.
Table 2: Recommendations on the Cardiovascular Impact of GLP-1 RA
|Lixisenatide||Safe to use in patients following acute coronary syndrome but is unlikely to provide additional CV benefit in this situation|
|Prolonged-release exenatide||Safe to prescribe in patients with pre-existing CVD but lacks definitive clinical trial evidence that it can offer cardio-protection from future CVD events|
All GLP-1 RAs can be used safely to improve glycaemic control without having any adverse effect on CVD or HF
The increase in heart rate associated with trials with GLP-1 RA is still not clearly understood
CV=cardiovascular; CVD=cardiovascular disease; HF=heart failure; GLP-1 RA=glucagon-like peptide-1 receptor agonists
- Use canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin in patients with pre-existing CVD and type 2 diabetes
- in patients with established CVD either canagliflozin, dapagliflozin, or empagliflozin should be considered after metformin
- in the presence of chronic kidney disease (CKD), the first choice should be dapagliflozin 10 mg once daily, which has shown benefit in patients with CKD and macroalbuminuria with or without diabetes; canagliflozin 100 mg has proven benefit in patients with type 2 diabetes. SGLT2 inhibitors should not be used in patients with CKD and type 1 diabetes
- dapagliflozin and empagliflozin have shown significant benefits in patients with established HF (HF with reduced ejection fraction [40% or less], New York Heart Association class II–IV), independent of the presence of diabetes
- Whether a reduction in bone density is a class effect among SGLT2 inhibitors remains to be seen; a putative mechanism for bone loss and fracture risk needs to be ascertained. ABCD suggests exercising caution in the elderly.
Table 3: Recommendations on the Cardiovascular Impact of SGLT2 Inhibitors
|Ertugliflozin||Ertugliflozin, alongside the other SGLT2 inhibitors canagliflozin, dapagliflozin, and empagliflozin, will reduce the risk of incipient HF|
|CKD=chronic kidney disease; CV=cardiovascular; ESRD=end-stage renal disease; HF=heart failure HHF=hospitalisation due to heart failure; SGLT2=sodium-glucose cotransporter-2|
Older Antidiabetes Drugs
- Does not appear to have an adverse CV profile and appears to decrease CVD events in certain populations.
- The CV effects of sulfonylureas have previously been questioned in the absence of properly designed cardiovascular outcome trials
- The CVD concerns with sulfonylureas are likely to be due to glibenclamide
- Gliclazide and glimepiride have been shown to carry a low risk of all-cause and CV mortality.
- There are no long-term studies of the meglitinides, repaglinide or nateglinide, to assess CV outcomes or mortality in patients with type 2 diabetes.
- Analysis of the CVD events in the STOP-NIDDM trial of patients with impaired glucose tolerance showed 49% relative risk reduction in the incidence of the composite of any CV event with acarbose
- The Acarbose Cardiovascular Evaluation (ACE) trial conducted in China did not show any reduction in the five-point major adverse cardiovascular events with acarbose in patients with impaired glucose tolerance.
- Recent evidence has dismissed concerns about rosiglitazone and the excess risks of myocardial infarction
- The accumulated evidence from clinical trials favours the use of pioglitazone as a drug with CV benefit.