NPC Archive Item: Limited observational evidence for CV risk reduction with exenatide▼

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2 December 2010

A retrospective, US-based cohort study identified that patients with type 2 diabetes who were prescribed exenatide twice daily were less likely to have a cardiovascular (CV) event than patients treated with other glucose-lowering drugs. In view of the limitations of this study, a prospective randomised controlled trial is required to confirm the findings.

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

Health professionals should continue to follow NICE guidelines for the care of people with type 2 diabetes, with regard to the management of CV risk factors and control of blood glucose. NPH insulin is the preferred third-line option for a patient who remains hyperglycaemic on dual therapy with metformin (usually first-line) and a sulphonylurea (usually second line). However, exenatide can be considered as an alternative third-line option when control of blood glucose remains or becomes inadequate (HbA1c ≥7.5%, or other higher level agreed with the individual), and the person has:

  • a body mass index (BMI) ≥35.0 kg/m2 in those of European descent (with appropriate adjustment for other ethnic groups) and specific psychological or medical problems associated with high body weight, or
  • a BMI <35.0 kg/m2, and therapy with insulin would have significant occupational implications or weight loss would benefit other significant obesity-related comorbidities.

Exenatide should only be continued if the person has had a beneficial metabolic response (a reduction of at least 1.0% HbA1c and a weight loss of at least 3% of initial body weight at 6 months).

Exenatide prescribing should be on the basis of an informed patient decision. Although there have been no randomised controlled trials (RCT) of exenatide demonstrating improvements in CV events compared with other glucose lowering agents, prescribers may wish to consider the findings of this study in their discussions with patients about benefits and risks of side effects.

What is the background to this?
The role of newer hypoglycaemic agents in the management of type 2 diabetes, particularly in the pursuit of ever tighter blood glucose control, is controversial, as we have previously blogged (MeReC Rapid Review No. 1017, MeReC Rapid Review No. 435, MeReC Rapid Review No. 336). Prescribers should be concerned about the risk of adverse events with newer glucose lowering agents, especially in the light of the recent withdrawal of rosiglitazone from clinical use because of increased CV risk, and the potential harms associated with over-intensive glucose-lowering therapies (see MeReC Rapid Review 1017). As yet, there is no robust evidence that glucagon-like peptide-1 analogues (exenatideand liraglutide) reduce the likelihood of patient-oriented outcomes such as cardiovascular disease or other diabetic complications. In addition, these drugs are injectable preparations and their long-term safety data are limited.

The present study utilised data from a US healthcare database to compare the incidence of CV events in people with type 2 diabetes who were treated with exenatide or other glucose-lowering drugs during a four-year period.

What does this study claim?
In this large retrospective cohort study, use of exenatide twice daily was associated with a statistically significant lower risk of CV events (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.68 to 0.95, P=0.01) compared with use of other glucose-lowering therapies. Statistically significant benefits were also found for exenatide with regard to CV disease-related hospitalisation or hospitalisation for any reason.

So what?
NICE guidance for type 2 diabetes gives exenatide a limited third-line role in the treatment of patients with type 2 diabetes (see Actions above). Although exenatide is effective in reducing HbA1c and increasing weight loss, there is no evidence from long-term randomised controlled studies that it reduces CV events or other patient-oriented outcomes. Long-term safety of exenatide has yet to be established, and its use has been associated with reports of severe pancreatitis and renal failure.

Broadly speaking, the present study is encouraging with regard to the CV safety of exenatide as it suggests a CV benefit over other glucose lowering therapies. However, there are limitations to consider when interpreting the results of this study. Observational studies of this type are prone to confounding. Unlike in the setting of a RCT, in ‘real life’, treatment plans are chosen, changed, or actively not chosen in the light of individual patients’ risk factors, preferences and tolerability or response to other drugs. Thus observed differences in outcomes may well be due to differences among the patients, not only the different treatments. Although attempts were made to adjust for some confounding factors in this study, it was not possible to reliably adjust for baseline CV risk factors. Patients in the exenatide group were at higher CV risk and received more medications to reduce their CV risk; we do not know the effect that these or other interventions had in reducing their risk. We cannot rule out the possibility that the benefits seen are not, at least in part, due to the failure to address CV risk appropriately in the non-exenatide group or due to increased risks associated with other drugs received. Importantly, the study provides no information of the relative risk of exenatide compared with insulin, liraglutide, or any other glucose-lowering drug that might be considered for third-line use. These questions can only be properly answered by prospective randomised controlled trials.

Study details
Best JH, Hoogwerf BJ, Herman WH, et al. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the GLP-1 receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the LifeLinkTM database. Diabetes Care 2010. Published online before print October 7, doi: 10.2337/dc10-1393

Retrospective cohort study. Analysis of patient information and prescriptions received between June 2005 and March 2009 using the US LifelinkTM database.

Patients with type 2 diabetes with no history in the preceding nine months of myocardial infarction (MI), ischaemic stroke, or coronary revascularization procedure. Mean age 53 years.

Intervention and comparison
21,754 patients initiated on treatment with exenatide twice daily compared with 361,771 patients initiated on treatment with other glucose lowering therapies.

Outcomes and results
Patients who were treated with exenatide twice daily were less likely to have a CV event (first occurrence of MI, stroke, coronary vascularisation procedure) compared with patients who were treated with other glucose-lowering therapies (HR 0.81, 95%CI 0.68 to 0.95, P=0.01). They were also less likely to be hospitalised for a CV event (HR 0.88, 95%CI 0.79 to 0.98, P=0.02) or hospitalised for any cause (HR 0.94, 95%CI 0.91 to 0.97, P<0.001). Patients in the exenatide group were significantly more likely to be female, to have a higher comorbidity index, and to have diabetic retinopathy, peripheral neuropathy, hyperlipidaemia, hypertension, ischaemic heart disease, hypertriglyceridaemia, arthritis, or obesity. They were also more likely to be receiving more glucose-lowering drugs on average in the pre-exposure period (1.9 vs.  0.6) and other medications (e.g. antihypertensives 78% vs. 58%, antihyperlipidaemic drugs 64% vs. 39%).

Not stated. Lead authors are employees, stockholders and/or consultants of Amylin Pharmaceuticals and/or Eli Lilly and Co.

More information on can be found on the type 2 diabetes section of NPC

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