Alpha-glucosidase inhibitors for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk of developing type 2 diabetes mellitus

Abstract

Alpha‐glucosidase inhibitors (AGI) reduce blood glucose levels and may thus prevent or delay type 2 diabetes mellitus (T2DM) and its associated complications in people at risk of developing of T2DM. To assess the effects of AGI in people with impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these. We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, and the reference lists of systematic reviews, articles and health technology assessment reports. The date of the last search of all databases was December 2017. We included randomised controlled trials (RCTs), with a duration of one year or more, comparing AGI with any pharmacological glucose‐lowering intervention, behaviour‐changing intervention, placebo or no intervention in people with IFG, IGT, moderately elevated HbA1c or combinations of these. Two review authors read all abstracts and full‐text articles or records, assessed quality and extracted outcome data independently. One review author extracted data, which were checked by a second review author. We resolved discrepancies by consensus or involvement of a third review author. For meta‐analyses we used a random‐effects model with assessment of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall quality of the evidence by using the GRADE instrument. For this update of the Cochrane Review (first published 2006, Issue 4) we included 10 RCTs (11,814 participants), eight investigating acarbose and two investigating voglibose, that included people with IGT or people "at increased risk for diabetes". The trial duration ranged from one to six years. Most trials compared AGI with placebo (N = 4) or no intervention (N = 4). Acarbose reduced the incidence of T2DM compared to placebo: 670 out of 4014 people (16.7%) in the acarbose groups developed T2DM, compared to 812 out of 3994 people (20.3%) in the placebo groups (RR 0.82, 95% CI 0.75 to 0.89; P < 0.0001; 3 trials; 8008 participants; moderate‐certainty evidence). One trial including participants with coronary heart disease and IGT contributed 64% of cases for this outcome. Acarbose reduced the risk of T2DM compared to no intervention: 7 out 75 people (9.3%) in the acarbose groups developed T2DM, compared to 18 out of 65 people (27.7%) in the no‐intervention groups (RR 0.31, 95% CI 0.14 to 0.69; P = 0.004; 2 trials; 140 participants; very low‐certainty evidence). Acarbose compared to placebo did not reduce or increase the risk of all‐cause mortality (RR 0.98, 95% CI 0.82 to 1.18; P = 0.86; 3 trials; 8069 participants; very low‐certainty evidence), cardiovascular mortality (RR 0.88; 95% CI 0.71 to 1.10; P = 0.26; 3 trials; 8069 participants; very low‐certainty evidence), serious adverse events (RR 1.12, 95% CI 0.97 to 1.29; P = 0.13; 2 trials; 6625 participants; low‐certainty evidence), non‐fatal stroke (RR 0.50, 95% CI 0.09 to 2.74; P = 0.43; 1 trial; 1368 participants; very low‐certainty evidence) or congestive heart failure (RR of 0.87; 95% CI 0.63 to 1.12; P = 0.40; 2 trials; 7890 participants; low‐certainty evidence). Acarbose compared to placebo reduced non‐fatal myocardial infarction: one out of 742 participants (0.1%) in the acarbose groups had a non‐fatal myocardial infarction compared to 15 out of 744 participants (2%) in the placebo groups (RR 0.10, 95% CI 0.02 to 0.53; P = 0.007; 2 trials; 1486 participants; very low‐certainty evidence). Acarbose treatment showed an increased risk of non‐serious adverse events (mainly gastro‐intestinal events), compared to placebo: 751 of 775 people (96.9%) in the acarbose groups experienced an event, compared to 723 of 775 people (93.3%) in the placebo groups (RR 1.04; 95% CI 1.01 to 1.06; P = 0.0008; 2 trials; 1550 participants). Acarbose compared to no intervention showed no advantage or disadvantage for any of these outcome measures (very low‐certainty evidence). One trial each compared voglibose with placebo (1780 participants) or diet and exercise (870 participants). Voglibose compared to placebo reduced the incidence of T2DM: 50 out of 897 participants (5.6%) developed T2DM, compared to 106 out of 881 participants (12%) in the placebo group (RR 0.46, 95% CI 0.34 to 0.64; P < 0.0001; 1 trial; 1778 participants; low‐certainty evidence). For all other reported outcome measures there were no clear differences between voglibose and comparator groups. One trial with 90 participants compared acarbose with diet and exercise and another trial with 98 participants reported data on acarbose versus metformin. There were no clear differences for any outcome measure between these two acarbose interventions and the associated comparator groups. None of the trials reported amputation of lower extremity, blindness or severe vision loss, end‐stage renal disease, health‐related quality of life, time to progression to T2DM, or socioeconomic effects. AGI may prevent or delay the development of T2DM in people with IGT. There is no firm evidence that AGI have a beneficial effect on cardiovascular mortality or cardiovascular events. Alpha‐glucosidase inhibitors for prevention or delay of type 2 diabetes and associated complications in people at increased risk of type 2 diabetes Review question Can alpha‐glucosidase inhibitors prevent or delay type 2 diabetes mellitus and its associated complications in people at increased risk of developing type 2 diabetes mellitus? Background People with moderately elevated glucose levels are often said to be at an increased risk of developing type 2 diabetes. Therefore, these people are frequently recommended to increase exercise and lower calorie intake to prevent type 2 diabetes. Alpha‐glucosidase inhibitors (acarbose, miglitol, voglibose), are used to lower blood glucose in people with type 2 diabetes mellitus. It is currently not known whether alpha‐glucosidase inhibitors should be prescribed for people with moderately raised blood glucose levels. We wanted to find out whether alpha‐glucosidase inhibitors could prevent or delay type 2 diabetes mellitus in people with moderately elevated glucose levels. We searched medical literature for randomised controlled trials (clinical trials where people are randomly put into one of two or more treatment groups), of at least one year's duration, investigating alpha‐glucosidase inhibitors in participants with glucose levels higher than considered normal, but below the diagnostic criteria for type 2 diabetes mellitus. Trial characteristics We found 10 randomised controlled trials representing 11,814 participants, eight investigating acarbose and two investigating voglibose. The trial duration ranged from one to six years. This evidence is up to date as of December 2017. Key results When comparing acarbose with placebo (a substance thought to have no therapeutic effect), 670 out of 4014 participants (17%) receiving acarbose developed type 2 diabetes, compared to 812 out of 3994 participants (20%) receiving placebo. Most data for this comparison came from a trial including people with heart disease. When comparing acarbose with no intervention, seven out of 75 participants (9%) receiving acarbose developed type 2 diabetes, compared to 18 out 65 participants (28%) receiving no intervention. Acarbose treatment did not reduce or increase the risk of death from any cause, death from heart disease, serious side effects, strokes or heart failure. Compared to placebo, acarbose reduced the risk for heart attacks (one out of 742 participants (0.1%) receiving acarbose had a heart attack compared to 15 out of 744 participants (2%) receiving placebo). Acarbose treatment showed an increased risk of non‐serious side effects (mainly gastro‐intestinal events), compared to placebo: 751 of 775 people (97%) receiving acarbose had a non‐serious side effect, compared to 723 of 775 people (93%) receiving placebo. One trial compared voglibose with placebo and another trial compared voglibose with diet and exercise. When comparing voglibose with placebo, 50 out of 897 participants (5.6%) receiving voglibose developed type 2 diabetes, compared to 106 out of 881 participants (12%) receiving placebo. One trial with 90 participants compared acarbose with diet and exercise and another trial with 98 participants compared acarbose with metformin. There were no important differences for any outcome for these comparisons. None of the trials reported amputation of lower limbs, blindness or severe vision loss, kidney disease, health‐related quality of life, time to progression to type 2 diabetes mellitus, or socioeconomic effects (such as absence from work or costs). Quality of the evidence For most of our outcomes we are uncertain or very uncertain how valid the results of our comparisons are. Reasons for this uncertainty are systematic errors in some of the included trials, the overall low number of trials for a particular outcome, imprecise results and missing data of one included trial.