INTRODUCTION — Alpha-glucosidase inhibitors lower blood glucose by modifying the intestinal absorption of carbohydrates. The glycemic efficacy, adverse effects, and dosing of alpha-glucosidase inhibitors will be discussed here. Other oral hypoglycemic drugs are reviewed separately. (See "Metformin in the treatment of adults with type 2 diabetes mellitus" and "Thiazolidinediones in the treatment of type 2 diabetes mellitus" and "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus".)
GENERAL APPROACH — Although alpha-glucosidase inhibitors have been studied as monotherapy for initial treatment of diabetes and as part of a combination regimen, we do not consider them to be usual first-line therapy, because of relatively low efficacy and poor tolerance. They may play a role as part of a combination regimen in people who consume high-carbohydrate diets and have high postprandial glucose levels, as long as the gastrointestinal side effects are tolerated.
The alpha-glucosidase inhibitors (acarbose, miglitol, voglibose) have been studied extensively in Europe and Japan; two of them, acarbose and miglitol, are available in the United States. Taken orally, they inhibit the upper gastrointestinal enzymes (alpha-glucosidases) that convert complex polysaccharide carbohydrates into monosaccharides in a dose-dependent fashion. These drugs therefore slow the absorption of dietary carbohydrate; the slower rise in postprandial blood glucose concentrations is potentially beneficial in both type 1 and type 2 diabetes. In older patients with type 2 diabetes, acarbose may also increase insulin sensitivity [1], although this may have been a nonspecific effect associated with improved glycemia. Alpha-glucosidase inhibitors do not cause hypoglycemia when used as monotherapy or with other agents that do not cause hypoglycemia.
Acarbose and voglibose have also been evaluated for the prevention of type 2 diabetes. (See "Prevention of type 2 diabetes mellitus", section on 'Drugs not recommended for prevention'.)
CLINICAL OUTCOMES
Glycemic efficacy — Several trials have demonstrated the glycemic efficacy of alpha-glucosidase inhibitors in patients with type 2 diabetes [2-7].
●In a meta-analysis of 41 trials of alpha-glucosidase inhibitor therapy (acarbose 30 trials, miglitol 7, voglibose 1), alpha-glucosidase inhibitors reduced glycated hemoglobin (A1C) more than placebo (mean difference -0.77 and -0.68 percentage points for acarbose and miglitol, respectively) [8].
●In a separate meta-analysis involving nine major classes of glucose-lowering therapies (301 trials), monotherapy with alpha-glucosidase inhibitors was associated with a lower A1C than placebo (standardized mean difference [SMD] -0.66) but higher A1C compared with metformin (SMD 0.35) [9].
In general, alpha-glucosidase inhibitors have resulted in a relatively greater improvement in A1C values than in fasting blood glucose concentrations, consistent with its predominant effect on postprandial hyperglycemia [4]. In a meta-analysis of studies evaluating acarbose and miglitol, there was a reduction in mean postprandial glucose concentration by approximately 27 mg/dL (1.5 mmol/L) [10]. Some studies suggest that alpha-glucosidase inhibitors are more effective in reducing A1C in people consuming an East Asian diet compared with Western-type diet [11,12].
Alpha-glucosidase inhibitors are effective when combined with metformin [13,14], sulfonylureas [15,16], dipeptidyl peptidase 4 (DPP-4) inhibitors [17,18], or insulin [19]. However, in the meta-analysis involving major classes of glucose-lowering therapies [9], when added to metformin, alpha-glucosidase inhibitors were associated with a higher odds of treatment failure compared with sulfonylureas. When added as part of triple therapy to metformin and sulfonylurea, alpha-glucosidase inhibitors were associated with higher A1C levels compared with addition of thiazolidinediones, glucagon-like peptide 1 (GLP-1) receptor agonists, or basal insulin [9]. In a head-to-head comparison of acarbose versus saxagliptin added to metformin, there was no significant difference in A1C change between the two arms [20].
Cardiovascular effects
●Cardiovascular events – Alpha-glucosidase inhibitors do not appear to increase the risk of adverse cardiovascular events, and there are some data to suggest a possible reduction in risk of myocardial infarction [21]. In a propensity score-matched cohort study from Taiwan evaluating the addition of acarbose or a sulfonylurea to metformin in people with type 2 diabetes, use of acarbose was associated with a lower risk of major atherosclerotic events (5.9 versus 7.1 events per 1000 person-years, hazard ratio [HR] 0.69, 95% CI 0.52-0.91) compared with sulfonylurea [22]. In the meta-analysis above, alpha-glucosidase inhibitors were not significantly associated with the risk of myocardial infarction or cardiovascular mortality, but there were few events in the available studies [9].
Two trials in patients with impaired glucose tolerance report conflicting results:
•In the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) trial, acarbose appeared to reduce the risk of a composite cardiovascular disease outcome in patients with impaired glucose tolerance. In this trial, 1429 patients with impaired glucose tolerance were randomly assigned to acarbose (100 mg three times daily or placebo for a mean of 3.3 years) [23]. An a priori secondary objective of the study (primarily designed to evaluate the incidence of diabetes) was to evaluate the development of major cardiovascular events or hypertension. Acarbose therapy significantly reduced the risk of cardiovascular events compared with placebo (absolute risk reduction 2.5 percent; HR 0.51, 95% CI 0.28-0.95). This was an unanticipated finding. The major reduction was in myocardial infarction (one event in the acarbose group versus 12 in the placebo group, HR 0.09, 95% CI 0.01-0.72). In addition, there was a reduction in risk of developing hypertension (11 versus 17 percent, absolute risk reduction 5.3 percent, HR 0.66, 95% CI 0.49-0.89). Methodologic flaws (including selection bias, inadequate blinding, and bias in analysis and reporting) have been suggested and reduce our confidence in these findings [24].
•In a subsequent Acarbose Cardiovascular Evaluation (ACE) trial, designed to compare acarbose with placebo in 6522 Chinese patients with established coronary heart disease and impaired glucose tolerance, the primary composite endpoint (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospital admission for unstable angina, hospital admission for heart failure) occurred in a similar proportion of patients in each group (14 and 15 percent, HR 0.98, 95% CI 0.86-1.11) [25].
●Cardiovascular risk factors – Data on the effects of alpha-glucosidase inhibitors on serum lipids are conflicting. As an example, in a study of 96 patients with type 2 diabetes, those treated with acarbose (100 mg three times daily) for 24 weeks had a 27 percent decrease in the ratio of serum low-density lipoprotein (LDL) cholesterol to high-density lipoprotein (HDL) cholesterol, due to both a decrease in serum LDL cholesterol concentrations (158 to 123 mg/dL [4.1 to 3.2 mmol/L]) and an increase in serum HDL cholesterol concentrations (55 to 64 mg/dL [1.4 to 1.6 mmol/L]) [26]. By comparison, patients treated with metformin had no change, while those receiving placebo had a 14 percent increase in the serum LDL/HDL ratio.
In the meta-analysis noted above [8], however, no beneficial effects on lipids were seen.
Weight loss — In short-term trials evaluating alpha-glucosidase inhibitors, there was either no change in weight [4] or mild weight loss (acarbose -0.4 kg, miglitol -0.7 kg) [27]. In a network meta-analysis, acarbose was associated with greater weight loss compared with DPP-4 inhibitors (mean difference -1.2 kg) [28].
ADVERSE EFFECTS — The main side effects of these drugs are flatulence (which affected 73 percent of patients versus 39 percent in the placebo group in one of the above studies [3]) and diarrhea. These symptoms are usually mild, but they may reduce compliance [4]. In one prospective study of 893 patients in Canada treated with acarbose, only 16 to 20 percent were still taking the drug after one year [29]. Slow increases in dose minimize these adverse effects.
High serum aminotransferase concentrations have been reported with acarbose [30-32]. In a meta-analysis of 14 trials, alpha-glucosidase inhibitors were associated with a higher odds of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations of more than threefold above the upper limit of normal (odds ratio [OR] 6.9, 95% CI 2.5-18.8 and OR 6.5, 95% CI 2.4-17.5, respectively) [33]. However, no clinically important adverse events were reported. It is unclear if this is a toxic or hypersensitivity-related reaction.
In one of the meta-analyses described above, acarbose doses greater than 50 mg three times daily provided no additional glycemic benefit but were associated with more side effects [8].
DOSING — Acarbose is available as 50 and 100 mg tablets, which should be taken with the first bite of each meal. We begin with 50 mg three times daily. Flatulence, diarrhea, and abdominal discomfort are dose related and almost always resolve if the dose is decreased. Few people tolerate more than 300 mg daily.
Miglitol is available as tablets. The initial dose is 25 mg three times daily, taken at the start of each meal. After one to two months, if tolerated, the dose may be increased to 50 mg three times daily.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in adults".)
SUMMARY AND RECOMMENDATIONS
●General approach – Although alpha-glucosidase inhibitors have been studied as monotherapy for initial treatment of diabetes and as part of a combination regimen, we do not consider them to be usual first-line therapy, because of modest efficacy and poor tolerance. They may play a role as part of a combination regimen in people who consume high-carbohydrate diets and have high postprandial glucose levels, as long as the gastrointestinal side effects are tolerated. (See 'General approach' above and "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Medications not usually recommended'.)
●Mechanism of action – Alpha-glucosidase inhibitors (acarbose, miglitol, voglibose) inhibit the upper gastrointestinal enzymes (alpha-glucosidases) that convert complex polysaccharide carbohydrates into monosaccharides and thereby slow absorption of glucose and reduce postprandial blood glucose concentration. (See 'General approach' above.)
●Glycemic efficacy – Alpha-glucosidase inhibitors are less potent than the sulfonylureas or metformin, lowering glycated hemoglobin (A1C) by only 0.4 to 0.9 percentage points. (See 'Clinical outcomes' above.)
●Cardiovascular effects – Alpha-glucosidase inhibitors do not appear to increase risk of adverse cardiovascular events, and there are some data to suggest a possible reduction in risk of myocardial infarction. (See 'Clinical outcomes' above.)
●Gastrointestinal adverse effects – The main side effects of alpha-glucosidase inhibitors, which may limit their acceptance, are flatulence and diarrhea. (See 'Adverse effects' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David K McCulloch, MD, who contributed to an earlier version of this topic review.
