ACE Inhibitors and ARBs Seen Least Likely to Lead to Diabetes

CHICAGO, Jan. 19 -- Inhibitors of the renin-angiotensin system trumped calcium-channel-blockers, beta-blockers, and diuretics in preventing new-onset diabetes, according to a network meta-analysis of hypertension trials.

The association of anti-hypertensive drugs with incident diabetes was lowest for angiotensin-receptor blockers (ARBs) and angiotensin-converting-enzyme (ACE) inhibitors, followed by calcium-channel blockers and placebo, beta-blockers and diuretics in that order, reported William Elliott, M.D., and Peter Meyer, Ph.D., of Rush University here in the Jan. 20 issue of The Lancet.

The network meta-analysis is but the latest chapter in the ongoing hypertension-drug controversy with its many studies and varying and conflicting renditions.

Some long-term clinical trials comparing antihypertensive agents have shown significant differences in the rates of new cases of diabetes between treatment groups, but the results have been inconsistent. Traditional meta-analyses are hindered by heterogeneity across trials and the absence of trials comparing ACE inhibitors and ARBs, Drs. Elliott and Meyer said.

The researchers therefore undertook a network meta-analysis, a fairly new statistical technique that accounts for both direct and indirect comparisons during long-term treatment with each individual class of drug or placebo.

In a systematic review up to Sept. 15, 2006, the investigators identified 48 randomized groups of 22 clinical trials with 143,153 participants who did not have diabetes at the outset.

Initial drug therapy used in the trials (and the number of patients with diabetes of the total number at risk) included: an ARB (1,189 of 14,185, or 8.38%), ACE inhibitor (1,618 of 22, 941, or 7.05%), calcium-channel blocker (2,791 of 38,607, or 7.23%), placebo (1,686 of 24,767, or 6.81%), beta-blocker (2,705 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 (?=0.000017, eight degrees of freedom). A low degree of incoherence suggests that the results could provide "useful estimates of the effects of individual agents."

According to these data, the initial use of ARB, ACE inhibitor, calcium channel blocker, or placebo is associated with significantly lower rate of new onset diabetes than use of a diuretic as initial therapy. When the referent agent was changed to placebo, they said, the rank ordering of the agents according to their association with onset of diabetes remained the same.

The odds ratios versus diuretic, which changed little in many sensitivity analyses, were as follows:

• 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);
• Beta-blocker (nine groups) 0.90 (0.75-1.09, P=0.30).

These results summarize international experience of incident diabetes in long-term clinical trials, incorporating both direct and indirect comparisons of agents, including those that have never been compared directly, namely ACE inhibitors versus ARBs, the investigators said.

The findings, they added, are consistent with those of previous meta-analyses, but go beyond them, because the network technique allowed dissection of the individual drug classes' association with incident diabetes.

There are several reasons why antihypertensive drugs might have differing effects on the risk of diabetes, Drs. Elliott and Meyer said.

Most reasons proposed so far implicate the different actions of these drugs on circulating kinins, pancreatic insulin release, and insulin's peripheral effects, particularly since antihypertensive drugs interact with the sympathetic nervous system and adipocytes.

Animal studies have also implicated the ?-subtype peroxisome proliferator-activated receptor. Which of these is most important in human beings remains a topic for further research, they said.

These findings had several inherent limitations, the authors wrote. First, incident diabetes has only rarely been a pre-specified endpoint in long-term clinical trials of antihypertensive drugs.

Second, the diagnostic criteria for diabetes changed in 1999 so that studies done or reported before that date used the older criteria (?7.8 mmol/L); since then, most studies have used the current threshold of ?7.0 mmol/L.

Also, in meta-analyses of clinical trials, observations were grouped by the initial randomized drug class, but differences might exist between drugs in the same class, they said.

In summing up, Drs. Elliott and Meyer wrote that the implications of these data for clinical practice are uncertain. For example, the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-VII) recommends the use of a diuretic for most patients with uncomplicated stage 1 hypertension. However, the United Kingdom's National Institute for Health and Clinical Excellence (NICE) recommends diuretics or beta-blockers only as third-line or fourth-line agents for controlling high blood pressure.

Future research, the researchers said, is likely to provide better quality data to help establish the importance of the glycemic effects of commonly used antihypertensive drugs. For example, they said, these trials might be helpful in establishing whether ACE inhibitors and ARBs have significantly different effects on incident diabetes.

Until these trials are reported, they wrote, "our network meta-analysis provides a useful and complete picture of the propensity of antihypertensive drugs to be associated with incident diabetes."

Furthermore, they said, "this technique not only includes the results of all clinical trials that directly compare two initial antihypertensive drugs, but also incorporates indirect comparisons (particularly important for ACE inhibitors versus ARBs, which have not yet been directly compared), and results in estimates that are highly coherent and robust to many sensitivity analyses."