Elsevier

The Lancet

Volume 384, Issue 9961, 20 December 2014–2 January 2015, Pages 2228-2234
The Lancet

Articles
Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis

https://doi.org/10.1016/S0140-6736(14)61335-0Get rights and content

Summary

Background

Combination treatment with a glucagon-like peptide-1 (GLP-1) agonist and basal insulin has been proposed as a treatment strategy for type 2 diabetes that could provide robust glucose-lowering capability with low risk of hypoglycaemia or weight gain. We thus did a systematic review and meta-analysis of randomised controlled trials to assess the effect of this combination treatment on glycaemic control, hypoglycaemia, and weight gain in patients with type 2 diabetes.

Methods

We systematically searched PubMed, Embase, Cochrane, Web of Knowledge, FDA.gov, and ClinicalTrials.gov for randomised controlled trials (published between Jan 1, 1950, and July 29, 2014; no language restrictions) comparing GLP-1 agonist and basal insulin combination treatment to other anti-diabetic treatments. Our main endpoints were glycaemic control, hypoglycaemia, and change in weight. We assessed pooled data by use of a random-effects model.

Findings

Of 2905 identified studies, 15 were eligible and were included in our analysis (N=4348 participants). Compared with other anti-diabetic treatments, GLP-1 agonist and basal insulin combination treatment yielded an improved mean reduction in glycated haemoglobin (HbA1c) of −0·44% (95% CI −0·60 to −0·29), an improved likelihood of achieving the target HbA1c of 7·0% or lower (relative risk [RR] 1·92; 95% CI 1·43 to 2·56), no increased relative risk of hypoglycaemia (0·99; 0·76 to 1·29), and a mean reduction in weight of −3·22 kg (−4·90 to −1·54). Furthermore, compared with basal-bolus insulin regimens, the combination treatment yielded a mean reduction in HbA1c of −0·1% (−0·17 to −0·02), with lower relative risk of hypoglycaemia (0·67, 0·56 to 0·80), and reduction in mean weight (−5·66 kg; −9·8 to −1·51).

Interpretation

GLP-1 agonist and basal insulin combination treatment can enable achievement of the ideal trifecta in diabetic treatment: robust glycaemic control with no increased hypoglycaemia or weight gain. This combination is thus a potential therapeutic strategy that could improve the management of patients with type 2 diabetes.

Funding

None.

Introduction

Type 2 diabetes mellitus is a chronic disorder characterised by progressive deterioration of the pancreatic β cells that synthesise and secrete insulin, resulting in worsening hyperglycaemia over time.1 Available anti-diabetic treatments have not been shown to reliably alter this natural history of deteriorating β-cell function.2, 3 As such, the typical clinical course of type 2 diabetes involves the sequential addition of anti-diabetic drugs over time, followed eventually by basal insulin treatment before more complex treatment regimens with the addition of prandial or bolus insulin.4 Basal-bolus regimens, in which patients take basal insulin once or twice a day and bolus insulin before each meal, are typically the last line in this therapeutic progression. Even with intensive basal-bolus insulin treatment, however, the achievement of glycaemic targets in practice is often limited by inadequate insulin dose titration, owing to concerns about the risks of hypoglycaemia and weight gain.4 Indeed, an ideal anti-diabetic treatment would be one that can couple the achievement of glycaemic control with a low propensity for causing hypoglycaemia and weight gain.

Glucagon-like peptide-1 (GLP-1) agonists are a novel class of injectable anti-diabetic drugs that can improve glycaemic control and induce weight loss.5 In clinical practice, approved GLP-1 agonists are widely used as second-line or third-line agents after the failure of one or more oral anti-diabetic drugs.6, 7 However, their optimal role in the clinical management of type 2 diabetes has not been established.

In this context, there is much interest in the potential benefits of combination treatment consisting of a GLP-1 agonist and basal insulin—strong physiological and clinical rationale lend support to such a strategy.8, 9 First, this combination offers the potential for robust glucose-lowering, owing to the complementary effects of its components. Specifically, while basal insulin can target fasting and post-absorptive glucose control, GLP-1 agonists can reduce postprandial glycaemic excursion through the inhibition of gastric emptying, stimulation of glucose-dependent insulin secretion, and suppression of hyperglucagonaemia.7 Second, their low hypoglycaemic potential suggests that GLP-1 agonists are less likely than bolus insulin to cause hypoglycaemia when combined with basal insulin. Third, the weight-lowering effect of a GLP-1 agonist might limit the weight gain associated with insulin. Finally, this combination might allow insulin dosage to be reduced, which could further lower the risks of hypoglycaemia and weight gain.

In view of this compelling rationale, a series of clinical trials have assessed GLP-1 agonist and basal insulin combination treatment versus a variety of anti-diabetic treatments, including basal-bolus insulin regimens. Recognising that individual studies might not be able to provide sufficient data on their own to affect practice, we sought to objectively assess the potential role of this treatment in the management of type 2 diabetes. We therefore did a systematic review and meta-analysis of randomised controlled trials to establish the effect of GLP-1 agonist and basal insulin combination treatment on the key outcomes of glycaemic control, hypoglycaemia, and weight regulation in patients with type 2 diabetes.

Section snippets

Search strategy and selection criteria

This systematic review and meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement and was registered at International Prospective Register of Systematic Reviews (number CRD42014010688).10

We selected relevant studies published between Jan 1, 1950, and July 29, 2014, by searching Embase, PubMed, Cochrane, Web of Knowledge, FDA.gov, and ClinicalTrials.gov. We applied no language restrictions. We used the following

Results

We identified 2905 studies, of which 15 (with data for 4348 participants) were included in our analysis (figure 1). The 15 trials were all published between 2011 and 2014 (nine were published in 2014) (table 1).11, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 Mean trial duration was 24·8 weeks (range 12 weeks to 36 weeks). Patients had mean baseline HbA1c of 8·13% (range 7·4–8·8), mean baseline body-mass index of 32·9 kg/m2 (25·2–39·6), and mean duration of diabetes of 12·2 years

Discussion

Our results show that, compared with other anti-diabetic treatments, combination treatment with a GLP-1 agonist and basal insulin can yield improved glycaemic control, with no increase in hypoglycaemia and a reduction in weight. Furthermore, compared with basal-bolus insulin regimens, this combination offers greater HbA1c reduction with lower risk of hypoglycaemia and a reduction in weight. These data thus lend support to GLP-1 agonist and basal insulin combination treatment as a therapeutic

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