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NIHR Signal GLP-1 drug for diabetes gives modest cardiovascular benefits compared with placebo

Published on 29 January 2020

doi: 10.3310/signal-000866

Taking a glucagon-like peptide-1 receptor (GLP-1) agonist drug lowers the likelihood of having a stroke, heart attack or dying due to cardiovascular causes by 12%. The drugs give a similar 12% reduction in overall mortality. They do not increase the risk of heart failure, very low blood sugar levels or pancreatic disease.

Diabetes causes one in five strokes along with other cardiovascular complications. Clinicians aim to reduce these risks and lower blood sugar levels. This meta-analysis is the first to combine data on cardiovascular outcomes from seven large trials of the GLP-1 agonists, including over 56,000 participants. Most trial participants had established heart disease.

These findings suggest that GLP-1 agonists are an effective and safe treatment option for people with diabetes and co-existing heart disease. However, these drugs are expensive, and cost-effectiveness evidence is needed for the NHS.

Share your views on the research.

Why was this study needed?

About 4.7 million people (about 7% of the population) in the UK have diabetes, of which 90% is type 2 diabetes. High blood sugar levels can damage the heart and blood vessels. Every week, this condition results in around 700 strokes, 500 heart attacks and 2,000 cases of heart failure. The NHS spends about £10 billion a year (10% of its budget) budget on treating diabetes and its complications.

GLP-1 agonists are one of two types of sugar-lowering drugs that reduce sugar levels and have positive cardiovascular effects. Trials of individual GLP-1 drugs have involved different patient populations and had mixed findings.

This systematic review aimed to combine the results of several trials and to update the evidence base for the cardiovascular impact of GLP-1 drugs. This is the first review to incorporate new trials of dulaglutide and oral semaglutide, published in summer 2019.

What did this study do?

In this meta-analysis, the researchers combined results from seven trials in which patients with type 2 diabetes were randomised to receive either a GLP-1 agonist or a placebo, in addition to any other medications prescribed. In six of these trials, the GLP-1 drug was administered by daily or weekly injection.

The review included published trials with cardiovascular outcomes and more than 500 participants. In all but one of these trials, over 70% of participants had established cardiovascular disease. The remaining participants had cardiovascular risk factors. Patients were followed-up for between one and five years.

All the trials were assessed as high quality and so we can have confidence in these results.

What did it find?

  • Around 75 people would need to take a GLP-1 receptor agonist to prevent one serious cardiovascular event (heart attack, stroke, or death due to cardiovascular causes) over an average (median) follow-up period of 3.2 years (number needed to treat [NNT] 75, 95% confidence interval [CI] 50 to 151; hazard ratio [HR] 0.88, 95% CI 0.82 to 0.94; 7 trials, 56,004 participants).
  • Subgroup analyses show no clear difference in the rate of these cardiovascular events according to established cardiovascular disease, baseline blood sugar level, kidney function, duration of follow-up, daily or weekly drugs, BMI or age.
  • Around 108 people would need to take the drug to prevent one death from any cause over 3.2 years (NNT 108, 95% CI 77 to 260; HR 0.88, 95% CI 0.83 to 0.95; 7 trials, 56,004 participants).
  • Compared with placebo, taking a GLP-1 receptor agonist has a very small effect on the risk of hospital admission for heart failure. This is a marginally statistically significant result, with 312 patients needing to take the drug for each admission prevented over 3.2 years (NNT 312, 95% CI 165 to 2,810; HR 0.91, 95% CI 0.83 to 0.99; 7 trials, 56,004 participants).
  • The drug does not cause any increased risk of severe low blood sugar, inflammation of the pancreas or pancreatic cancer, compared with placebo.

What does current guidance say on this issue?

NICE’s 2015 guideline on type 2 diabetes recommends that GLP-1 agonists are used as a second-order drug for weight reduction. It does not include recommendations for these drugs in relation to cardiovascular outcomes and predates the GLP-1 cardiovascular trials.

Guidance published jointly by the European Association for the Study of Diabetes and the American Diabetes Association (2018) recommends an individualised approach to treatment incorporating patient risk factors and co-existing conditions. For patients with established cardiovascular disease and poor control of blood sugar, a proven GLP-1 receptor agonist or an SGLT2 inhibitor can be added to metformin.

What are the implications?

A 2019 NICE surveillance report proposes that a new NICE diabetes guideline will include a cost-effectiveness analysis of GLP-1 receptor agonists and other anti-diabetic drugs. The average annual cost of GLP-1 drugs varies between £700 and £1,500 annually.

This meta-analysis did not include sufficient patients without cardiovascular disease to establish whether GLP-1 drugs are effective for primary prevention in lower-risk patients.

Longer-term trials are needed as people with diabetes are likely to require treatment for longer than five years.

Citation and Funding

Kristensen S, Rorth R, Jhund P et al. 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. 2019;7(10):776-85.

This project received no specific funding.

Bibliography

Davies M, D’Alessio M, Fradkin J et al. 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). Diabetologia. 2018;61(12):2461-98.

Diabetes UK. Us, diabetes and a lot of facts and stats. London: Diabetes UK; updated 2019.

Masters I. Diabetes and your heart. Birmingham: British Heart Foundation; 2018.

NHS website. Type 2 diabetes. London: Department of Health and Social Care; updated 2017.

NICE. Type 2 diabetes in adults: management. NG28. London: National Institute for Health and Care Excellence; 2015 (updated 2019).

NICE. 2019 surveillance of diabetes (NICE guidelines NG17, NG18, NG19 and NG28). London: National Institute for Health and Care Excellence; 2019.

Standl E. GLP-1 receptor agonists and cardiovascular outcomes: an updated synthesis. Lancet Diabetes Endocrinol. 2019;7(10):741-43.

Trent Medicines Information Service. Cardiovascular outcomes with GLP-1 receptor agonists. NHS Specialist Pharmacy Service; 2019. 

Why was this study needed?

About 4.7 million people (about 7% of the population) in the UK have diabetes, of which 90% is type 2 diabetes. High blood sugar levels can damage the heart and blood vessels. Every week, this condition results in around 700 strokes, 500 heart attacks and 2,000 cases of heart failure. The NHS spends about £10 billion a year (10% of its budget) budget on treating diabetes and its complications.

GLP-1 agonists are one of two types of sugar-lowering drugs that reduce sugar levels and have positive cardiovascular effects. Trials of individual GLP-1 drugs have involved different patient populations and had mixed findings.

This systematic review aimed to combine the results of several trials and to update the evidence base for the cardiovascular impact of GLP-1 drugs. This is the first review to incorporate new trials of dulaglutide and oral semaglutide, published in summer 2019.

What did this study do?

In this meta-analysis, the researchers combined results from seven trials in which patients with type 2 diabetes were randomised to receive either a GLP-1 agonist or a placebo, in addition to any other medications prescribed. In six of these trials, the GLP-1 drug was administered by daily or weekly injection.

The review included published trials with cardiovascular outcomes and more than 500 participants. In all but one of these trials, over 70% of participants had established cardiovascular disease. The remaining participants had cardiovascular risk factors. Patients were followed-up for between one and five years.

All the trials were assessed as high quality and so we can have confidence in these results.

What did it find?

  • Around 75 people would need to take a GLP-1 receptor agonist to prevent one serious cardiovascular event (heart attack, stroke, or death due to cardiovascular causes) over an average (median) follow-up period of 3.2 years (number needed to treat [NNT] 75, 95% confidence interval [CI] 50 to 151; hazard ratio [HR] 0.88, 95% CI 0.82 to 0.94; 7 trials, 56,004 participants).
  • Subgroup analyses show no clear difference in the rate of these cardiovascular events according to established cardiovascular disease, baseline blood sugar level, kidney function, duration of follow-up, daily or weekly drugs, BMI or age.
  • Around 108 people would need to take the drug to prevent one death from any cause over 3.2 years (NNT 108, 95% CI 77 to 260; HR 0.88, 95% CI 0.83 to 0.95; 7 trials, 56,004 participants).
  • Compared with placebo, taking a GLP-1 receptor agonist has a very small effect on the risk of hospital admission for heart failure. This is a marginally statistically significant result, with 312 patients needing to take the drug for each admission prevented over 3.2 years (NNT 312, 95% CI 165 to 2,810; HR 0.91, 95% CI 0.83 to 0.99; 7 trials, 56,004 participants).
  • The drug does not cause any increased risk of severe low blood sugar, inflammation of the pancreas or pancreatic cancer, compared with placebo.

What does current guidance say on this issue?

NICE’s 2015 guideline on type 2 diabetes recommends that GLP-1 agonists are used as a second-order drug for weight reduction. It does not include recommendations for these drugs in relation to cardiovascular outcomes and predates the GLP-1 cardiovascular trials.

Guidance published jointly by the European Association for the Study of Diabetes and the American Diabetes Association (2018) recommends an individualised approach to treatment incorporating patient risk factors and co-existing conditions. For patients with established cardiovascular disease and poor control of blood sugar, a proven GLP-1 receptor agonist or an SGLT2 inhibitor can be added to metformin.

What are the implications?

A 2019 NICE surveillance report proposes that a new NICE diabetes guideline will include a cost-effectiveness analysis of GLP-1 receptor agonists and other anti-diabetic drugs. The average annual cost of GLP-1 drugs varies between £700 and £1,500 annually.

This meta-analysis did not include sufficient patients without cardiovascular disease to establish whether GLP-1 drugs are effective for primary prevention in lower-risk patients.

Longer-term trials are needed as people with diabetes are likely to require treatment for longer than five years.

Citation and Funding

Kristensen S, Rorth R, Jhund P et al. 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. 2019;7(10):776-85.

This project received no specific funding.

Bibliography

Davies M, D’Alessio M, Fradkin J et al. 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). Diabetologia. 2018;61(12):2461-98.

Diabetes UK. Us, diabetes and a lot of facts and stats. London: Diabetes UK; updated 2019.

Masters I. Diabetes and your heart. Birmingham: British Heart Foundation; 2018.

NHS website. Type 2 diabetes. London: Department of Health and Social Care; updated 2017.

NICE. Type 2 diabetes in adults: management. NG28. London: National Institute for Health and Care Excellence; 2015 (updated 2019).

NICE. 2019 surveillance of diabetes (NICE guidelines NG17, NG18, NG19 and NG28). London: National Institute for Health and Care Excellence; 2019.

Standl E. GLP-1 receptor agonists and cardiovascular outcomes: an updated synthesis. Lancet Diabetes Endocrinol. 2019;7(10):741-43.

Trent Medicines Information Service. Cardiovascular outcomes with GLP-1 receptor agonists. NHS Specialist Pharmacy Service; 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

Published on 20 August 2019

Kristensen, S. L.,Rorth, R.,Jhund, P. S.,Docherty, K. F.,Sattar, N.,Preiss, D.,Kober, L.,Petrie, M. C.,McMurray, J. J. V.

Lancet Diabetes Endocrinol , 2019

BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists differ in their structure and duration of action and have been studied in trials of varying sizes and with different patient populations, with inconsistent effects on cardiovascular outcomes reported. We aimed to synthesise the available evidence by doing a systematic review and meta-analysis of cardiovascular outcome trials of these drugs. METHODS: We searched MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials for eligible placebo-controlled trials reporting major adverse cardiovascular events (MACE; ie, cardiovascular death, stroke, or myocardial infarction) up to June 15, 2019. We did a meta-analysis using a random-effects model to estimate overall hazard ratios (HRs) for MACE, its components, death from any cause, hospital admission for heart failure, kidney outcomes, and key safety outcomes (severe hypoglycaemia, pancreatitis, and pancreatic cancer). We also examined MACE in several subgroups based on patient characteristics (history of cardiovascular disease, BMI, age, baseline HbA1c, and baseline estimated glomerular filtration rate), trial duration, treatment dosing interval, and structural homology. FINDINGS: Of 27 publications screened, seven trials, with a combined total of 56 004 participants, were included: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide). Overall, GLP-1 receptor agonist treatment reduced MACE by 12% (HR 0.88, 95% CI 0.82-0.94; p<0.0001). There was no statistically significant heterogeneity across the subgroups examined. HRs were 0.88 (95% CI 0.81-0.96; p=0.003) for death from cardiovascular causes, 0.84 (0.76-0.93; p<0.0001) for fatal or non-fatal stroke, and 0.91 (0.84-1.00; p=0.043) for fatal or non-fatal myocardial infarction. GLP-1 receptor agonist treatment reduced all-cause mortality by 12% (0.88, 0.83-0.95; p=0.001), hospital admission for heart failure by 9% (0.91, 0.83-0.99; p=0.028), and a broad composite kidney outcome (development of new-onset macroalbuminuria, decline in estimated glomerular filtration rate [or increase in creatinine], progression to end-stage kidney disease, or death attributable to kidney causes) by 17% (0.83, 0.78-0.89; p<0.0001), mainly due to a reduction in urinary albumin excretion. There was no increase in risk of severe hypoglycaemia, pancreatitis, or pancreatic cancer. INTERPRETATION: Treatment with GLP-1 receptor agonists has beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes. FUNDING: None.

Glucagon-like peptide-1 (GLP-1) receptor agonists are sometimes known as incretin mimetics. They mimic a hormone produced by the stomach and help the body produce insulin. Their effect on cardiovascular outcomes is thought to be longer-term.

The review included dulaglutide, liraglutide, semaglutide (oral and injected), exenatide, lixisenatide and albiglutide, with the first five of these authorised in the UK.

Expert commentary

The meta-analysis performed by Kristensen and colleagues examined the cardiovascular, mortality and kidney outcomes in people with type 2 diabetes treated with GLP-1 agonists. Seven cardiovascular outcome trials were included in the analysis, amounting to over 56,000 subjects, half of whom received placebo.

Overall, there was no statistical heterogeneity between the trials, which showed a 12% reduction in the hazard ratio for major adverse cardiovascular events (cardiovascular death, non-fatal stroke or non-fatal myocardial infarction) and a reduction of all-cause mortality of 12%.

Renal outcomes also improved, driven by a reduction of new cases of micro- and macroalbuminuria.

Steven Bain, Professor in Medicine (Diabetes), Swansea University

The commentator declares no conflicting interests