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Overview

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-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.

View this summary online at guidelines.co.uk/456200.article

Key messages

  • 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.

DPP-IV inhibitors

ABCD position

  • 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 DPP-IV inhibitors

MedicationRecommendations

Saxagliptin

  • Neutral effect on CV risk
  • Increases risk of HF, precluding its use in those at increased risk of HF

Alogliptin

  • SPC advises caution in patients with NYHA III and IV stages of HF and therefore best avoided in such situations
  • The only DPP-IV inhibitor to have demonstrated safety in patients after an acute coronary syndrome

Sitagliptin

  • No restriction in patients with HF
  • Appears to be a safe and reliable DPP-IV inhibitor given extensive clinical trial information including a prolongation of the time to insulin dependence

Linagliptin

  • May be used to improve glycaemic control without concerns for CV safety or HF
  • Licensed regardless of the state of renal function

Additional information

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

CKD=chronic kidney disease; CV=cardiovascular; CVD=cardiovascular disease; DPP-IV= dipeptidyl peptidase 4; ESRD=end-stage renal disease; HF=heart failure; HHF=hospitalisation due to heart failure; NYHA=New York Heart Association; SGLT=sodium-glucose cotransporter-2; SPC=summary of product characteristics

GLP-1 RA

ABCD position

  • 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

MedicationRecommendations

Lixisenatide

  • Safe to use in patients following acute coronary syndrome but is unlikely to provide additional CV benefit in this situation

Liraglutide

  • Evidence supports CVD benefit in patients with pre-existing CVD and also those at high risk for CVD
  • A dose of 1.8 mg once daily should be used to get the full benefit of such an effect

Semaglutide

  • Offers benefit by reducing the risk of CVD in patients with pre-existing CVD and those at high risk for CVD, but given uncertainty regarding the yet unknown risk of worsening retinopathy in association with rapid improvement in glucose control, caution must be exercised in patients with significant diabetic retinopathy
  • Offers reduction in non-fatal stroke

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

Dulaglutide

  • Reduces CV outcomes to a similar degree in patients with established CVD and those at high risk
  • Offers reduction in non-fatal stroke

Additional information

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; GLP1-RA=glucagon-like peptide-1 receptor agonists

SGLT2 inhibitors

ABCD position

  • 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 SGLT2 inhibitors

MedicationRecommendations

Canagliflozin

  • Offers CV benefit
  • 100 mg daily has been shown to provide reno-protection by reducing the composite endpoints of decline in glomerular filtration rate, progression to ESRD, or death from renal or CV causes in patients with established CKD. Reduced the incidence of HHF in such patients
  • A reduction in CV death and all-cause mortality has not been demonstrated

Empagliflozin

  • Offers CV benefit
  • Offers reduction in CV death and all-cause mortality
  • Has shown benefit in patients with established HF even in the absence of diabetes

Dapagliflozin

  • 10 mg daily has been shown to provide reno-protection by reducing the composite endpoints of decline in glomerular filtration rate, progression to ESRD, or death from renal or CV causes in patients with established CKD. Reduced the incidence of HHF in such patients
  • A reduction in CV death and all-cause mortality has not been demonstrated
  • Has shown benefit in patients with established HF even in the absence of diabetes

Ertugliflozin

  • Ertugliflozin, alongside the other SGLT2 inhibitors canagliflozin, dapagliflozin, and empagliflozin, will reduce the risk of incipient HF

ABCD=Association of British Clinical Diabetologists; 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

Metformin

  • Does not appear to have an adverse CV profile and appears to decrease CVD events in certain populations.

Sulfonylureas

  • 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.

Meglitinides

  • There are no long-term studies of the meglitinides, repaglinide or nateglinide, to assess CV outcomes or mortality in patients with type 2 diabetes.

Acarbose

  • 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.

Thiazolidinediones

  • 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.

 

Full guideline:

Basu A, Patel D, Winocour P, Ryder REJ. Cardiovascular impact of new drugs (GLP-1 and gliflozins): the ABCD position statement. Br J Diabetes 2021; 21 (1): 132–148.
Available at: bjd-abcd.com/index.php/bjd/article/view/711/909

Published date: June 2021.