Elsevier

The Lancet

Volume 369, Issue 9557, 20–26 January 2007, Pages 201-207
The Lancet

Articles
Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis

https://doi.org/10.1016/S0140-6736(07)60108-1Get rights and content

Summary

Background

The effect of different classes of antihypertensive drugs on incident diabetes mellitus is controversial because traditional meta-analyses are hindered by heterogeneity across trials and the absence of trials comparing angiotensin-converting-enzyme (ACE) inhibitors with angiotensin-receptor blockers (ARB). We therefore undertook a network meta-analysis, which accounts for both direct and indirect comparisons to assess the effects of antihypertensive agents on incident diabetes.

Methods

We undertook a systematic review up to Sept 15, 2006, and identified 48 randomised groups of 22 clinical trials with 143 153 participants who did not have diabetes at randomisation and so were eligible for inclusion in our analysis. 17 trials enrolled patients with hypertension, three enrolled high-risk patients, and one enrolled those with heart failure. The main outcome was the proportion of patients who developed diabetes.

Findings

Intitial drug therapy used in the trials (and the number of patients with diabetes of the total number at risk) included: an ARB (1189 of 14 185, or 8·38%), ACE inhibitor (1618 of 22 941, or 7·05%), calcium-channel blocker (CCB, 2791 of 38 607, or 7·23%), placebo (1686 of 24 767, or 6·81%), β blocker (2705 of 35 745, or 7·57%), or diuretic (998 of 18 699, or 5·34%). With an initial diuretic as the standard of comparison (eight groups), the degree of incoherence (a measure of how closely the entire network fits together) was small (ω=0·000017, eight degrees of freedom). The odds ratios were: ARB (five groups) 0·57 (95% CI 0·46–0·72, p<0·0001); ACE inhibitor (eight groups) 0·67 (0·56–0·80, p<0·0001); CCB (nine groups): 0·75 (0·62–0·90, p=0·002); placebo (nine groups) 0·77 (0·63-0·94, p = 0·009); β blocker (nine groups) 0·90 (0·75-1·09, p=0·30). These estimates changed little in many sensitivity analyses.

Interpretation

The association of antihypertensive drugs with incident diabetes is therefore lowest for ARB and ACE inhibitors followed by CCB and placebo, β blockers and diuretics in rank order.

Introduction

The propensity for some antihypertensive drugs to lower glucose tolerance and precipitate diabetes has been known since at least 1958.1, 2, 3, 4, 5, 6 Because hypertension is often associated in large populations with impaired glucose tolerance, insulin resistance, and obesity, many patients with hypertension develop diabetes,7, 8, 9 even when treated with placebo.10, 11 Some long-term clinical trials of antihypertensive agents have shown significant differences in the rates of new cases of diabetes between treatment groups.6, 12, 13, 14 Four independent meta-analyses have shown that direct inhibitors of the renin-angiotensin system reduce the risk of incident diabetes, but no comparison was attempted in these studies between angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARB).15, 16, 17, 18 Traditional meta-analyses that attempt to summarise all the existing data from clinical trials comparing one drug class with any other treatment show significant heterogeneity for ACE inhibitors, calcium-channel blockers (CCB),19 diuretics, and β blockers. When the nine trials of an initial CCB versus any other therapy (including placebo in the Felodipine Events Reduction trial [FEVER]20) are separated by comparator, the significant p value for homogeneity (<0·0001) for the overall meta-analysis becomes less significant. In four trials comparing an initial CCB with an initial ACE inhibitor or ARB, the CCB was associated with a significantly increased risk (by 26%, 95% CI 15–39, homogeneity p=0·77). In six trials that compared an initial CCB with either a diuretic or a β blocker or both, the proportion of patients developing diabetes was significantly smaller in the CCB group than in the other groups (by 21%, 16–26, homogeneity p=0·04).

Network meta-analysis is a fairly new statistical technique that allows both direct and indirect comparisons to be undertaken, even when two of the strategies have not been directly compared (eg, ACE inhibitor vs ARB).21 This type of analysis can summarise randomised clinical trials of several different treatment strategies, and provide point estimates (and 95% CI) for their association with a given endpoint, as well as an estimate of incoherence (a measure of how well the entire network fits together, with smaller values suggesting better internal agreement of the model). We therefore used the network meta-analysis technique to estimate the relative odds of developing diabetes during long-term treatment with an initial class of antihypertensive drug, on the basis of the reported numbers of participants with, or at risk of, incident diabetes in randomised clinical trials.

Section snippets

Identification of trials

We undertook a systematic review to identify long-term randomised clinical trials of antihypertensive drugs that reported the number of new cases of diabetes from 1966 to Sept 15, 2006. This search was repeated four times by one reviewer independently of the other. Data abstraction was done by one reviewer and verified independently by the other. We searched MEDLINE, the Cochrane Collaboration's Database of Systematic Reviews, PubMed, and OvidWeb using the MeSH terms: “diabetes mellitus-Type 2,

Results

Table 1 shows a summary of the trials included in the base-case network meta-analysis. Figure 2 shows the network of clinical trials according to the comparison of specific classes of initial antihypertensive drugs, as well as point estimates for the results of traditional meta-analyses. In this figure the arrows point towards the class of drug with the higher risk of incident diabetes according to the summary odds ratio for a traditional meta-analysis of studies comparing the two drugs

Discussion

Our findings show that ARB and ACE inhibitors are the antihypertensive agents least associated with incident diabetes followed by CCB and placebo, β blockers, and diuretics.

These results summarise international experience of incident diabetes in long-term clinical trials of antihypertensive agents, incorporating both direct and indirect comparisons of agents, including those that have never been compared directly (ie, ACE inhibitor vs ARB). The network meta-analysis technique overcomes the

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