Meta-analysis of the impact of alpha-glucosidase inhibitors on incident diabetes and cardiovascular outcomes

Alpha-glucosidase inhibitors (AGIs) such as acarbose, miglitol and voglibose are oral drugs used in the management of diabetes, primarily to reduce post-prandial glucose concentrations. Their use in individuals with impaired glucose tolerance (IGT) has been shown to delay progression to diabetes, but their effects on cardiovascular (CV) outcomes remain uncertain [1]. A previous systematic review evaluated the effects of acarbose on various outcomes, including CV, but it did not include a meta-analysis of randomized controlled trials [2].

STOP-NIDDM was a placebo-controlled randomized trial conducted in centres across Canada, Germany, Austria, Norway, Denmark, Sweden, Finland, Israel, and Spain that randomly allocated participants with IGT to 100 mg acarbose or placebo three times daily [3]. The trial showed a 25% reduction in the incidence of type 2 diabetes with acarbose, compared with placebo (hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.63–0.90, p = 0.001) over a mean follow-up of 3.3 years. A pre-specified secondary analysis, also showed that there was a 49% reduction in cardiovascular outcomes over the same time period (HR 0.51 [0.28–0.95], p = 0.03) suggesting that acarbose might confer cardio protection, although this finding was based on only 47 CV events in total. Similarly, a meta-analysis of seven studies conducted between 1987 and 1999 reported a reduction in myocardial infarction (MI) in individuals assigned acarbose compared with placebo, but was based on only 28 events [4]. When a composite CV outcome (MI, stroke, CV death, angina or coronary revascularization) was examined, a 35% reduction in events was demonstrated based on 167 events in total [4].

The recently completed Acarbose Cardiovascular Evaluation (ACE) trial [5] was a randomized, double-blind, placebo-controlled, phase 4 study conducted in China that recruited patients with coronary heart disease and IGT. Participants were randomly allocated to acarbose (50 mg three times daily) or placebo, given in addition to fully-optimized CV secondary prevention therapy. The ACE trial showed that acarbose delayed progression to type 2 diabetes by 18% (odds ratio 0.82 (95% CI 0.71–0.94, p = 0.005) but was neutral with respect to major adverse cardiovascular events (HR 0.98, 0.86–1.11, p = 0.73).

The aim of this analysis was to identify the overall impact of AGIs with respect to incident type 2 diabetes specifically in individuals with IGT, and on combined CV outcomes in those with IGT or type 2 diabetes.

This meta-analysis shows an overall statistically significant 23% reduced risk of new-onset diabetes with AGIs in people with IGT (p < 0.0001). These results affirm the benefit of AGIs in reducing the risk of new-onset diabetes, and with acarbose licensed in China and 52 other countries for the treatment of IGT affords a pharmacological opportunity to help in the battle to contain the worldwide diabetes epidemic of type 2 diabetes [13].

AGIs, however, showed no overall impact of on CV outcomes, suggesting that the 49% risk reduction reported for the STOP-NIDDM [3] was most likely a chance finding, particularly with so few events for this secondary outcome, although this was a primary CVD prevention population mostly not taking cardioprotective medications such as statins and renin-angiotensin system inhibitors. An earlier meta-analysis of randomised controlled trials of alpha-glucosidase inhibitors suggested that they may prevent the progression if carotid intima thickness in patients with IGT or type 2 diabetes, [14] but our CV meta-analysis suggests this does not translate into fewer CV events. Our analysis was driven by the neutral outcome results reported by ACE [5] and UKPDS [11], with 949 and 200 events respectively, suggests that AGIs neither increase nor decrease the risk of major adverse cardiovascular events in people with IGT or diabetes, although given the mean follow-up for this analysis is 4.0 years the possibility that AGI use might reduce CV risk in the longer term cannot be excluded. Aggressive treatment of other cardiovascular risk factors, such as hypertension and dyslipidemia, as well as the use of antiplatelet therapy and inhibitors of the renin angiotensin system have resulted in significant reductions in CVD events in populations with [15] or without diabetes [16]. However, the impact of glycaemic reduction on CV disease is modest, [17] possibly making it difficult to detect the effect of some glucose-lowering agents, especially when added to optimized CV risk therapy. Recent studies have demonstrated cardio protection with sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists [18, 19] probably via non-glycaemic mechanisms. AGIs, however, might reduce CV risk indirectly in the longer term by delaying the onset of type 2 diabetes in people with IGT [20]. Such an effect was seen in the Chinese Da Qing study where a 6-year lifestyle intervention program which delayed the onset of type 2 diabetes was shown to be associated with an 11.9% reduction in CV death and a 28.1% reduction in all-cause mortality after 23 years follow-up [21].

Strengths of these analyses include the use of data from all randomized controlled trials reporting outcomes that could be compared, with a minimum 1-year follow-up to enable collection and adjudication of the required endpoints (>1600 incident diabetes events and > 1200 CV events). Our meta-analysis has several limitations. We used study-level rather than patient-level data, which is considered the gold standard for meta-analysis and which restricts our ability to investigate further any subgroups of interest.

Only a small number of eligible trials could be identified, although it is noteworthy that for CV outcomes no other trials with published CV outcomes would have been excluded by our selection criteria. For incident diabetes, a further two small-scale trials were identified but not included. These were the Early Diabetes Intervention programme (EDIP), which reported 62 events of progression to type 2 diabetes defined as FPG ≥ 7.8 mmol/l in 196 subjects followed for 5 years, [22] and the Dutch acarbose intervention study in persons with impaired glucose tolerance (DAISI) which reported 25 events of progression to diabetes in 118 individuals followed for 3 years based on a single glucose measurement [23]. Although these trials did not meet our inclusion criteria, we conducted a sensitivity analysis for incident diabetes which yielded a similar result (HR 0.74 [95% CI 0.67–0.82], p < 0.0001). In addition, the Cochrane collaboration recently published the results of trials reporting the incidence of type 2 diabetes, and separately CV mortality, non-fatal MI and non-fatal stroke in all populations without normal glucose levels (impaired fasting glucose, IGT or elevated HbA_1c) [24], which yielded similar results to our analysis showing a type 2 diabetes incidence risk ratio of 0.73 (95% CI 0.59–0.90), but the combined MACE-3 endpoint was not reported.

This meta-analysis demonstrates that the overall impact of AGIs on CV outcomes is neutral, it is clear that they cannot be indicated for CV secondary prevention. To date, although many countries have licensed AGIs for use in IGT, very few currently approve any medication for diabetes prevention. Given that this meta-analysis demonstrates that allocation of people with IGT to an AGI can significantly reduce their risk of incident diabetes, AGIs should be considered as one approach to delaying or preventing new-onset diabetes in people with or without pre-existing CV disease.