Safety and efficacy of acarbose in the treatment of Type 2 diabetes: data from a 5-year surveillance study

doi:10.1016/S0168-8227(01)00221-2

Diabetes Research and Clinical Practice

Volume 52, Issue 3, June 2001, Pages 193-204

https://doi.org/10.1016/S0168-8227(01)00221-2 Get rights and content

Abstract

This 5-year surveillance study assessed the tolerability and safety of acarbose in patients with diabetes. A total of 2035 patients were enrolled of whom 1954 were classified as having Type 2 diabetes. The study was open with no control group. Physicians had sole control of the acarbose doses prescribed. Fasting blood glucose levels, 2-h postprandial glucose levels, HbA₁ or HbA_1c and other clinical parameters, such as lipids and liver enzyme levels, were also assessed as measures of efficacy and safety. One-third of the patients received acarbose as monotherapy and two-thirds in combination with other glucose-lowering treatment. The concomitant diseases were also assessed. Doses of acarbose were low in the majority of the patients and well tolerated. The incidence of acarbose-associated side effects was 4.7%. No sustained adverse changes in laboratory measures occurred. Over the 5 years, HbA₁ and glycated haemoglobin (HbA_1c) decreased by 2.4 and 1.8% points, respectively, and the mean fasting glucose and 2-h postprandial glucose decreased by 2.7 and 3.4 mmol/l. Mean body weight was reduced by 0.9 kg. The results suggest that when used in long-term day-to-day management of diabetes, acarbose is well tolerated and can improve glycaemic control as monotherapy, as well as in combination therapy. In a high-risk patient group acarbose proved to be a safe drug.

Introduction

Acarbose is an α-glucosidase inhibitor that delays the enzymatic break down of carbohydrates in the small intestine. Thus, acarbose adapts glucose resorption to the response of the β-cells, delayed in Type 2 diabetes due to disturbed early-phase insulin secretion. As a result of the lower postprandial glucose resorption per unit time, the absorbed glucose can be metabolized more effectively and the area under the blood glucose curve is reduced. Accordingly, the disturbed early-phase insulin secretion is relieved and compensatory hyperinsulinaemia is avoided [1], [2], [3]. Acarbose has also been found to improve insulin sensitivity [4], [5] and increase daily levels of the intestinal hormone glucagon-like peptide 1 (GLP-1) [6] even when such patients have poor metabolic control and secondary failure following sulphonylurea treatment [7].

The net result is improved glycaemic control. In double-blind, long-term studies of upto 3 years, acarbose decreased glycated haemoglobin levels (HbA₁ or HbA_1c) by 0.9% points (mean of meta-analysis), as well as fasting and postprandial blood glucose [8], [9]. Adverse events included dose-dependent intestinal symptoms and rare cases of reversible elevation of hepatic enzymes [8]. The surveillance study described in the present paper assessed the tolerability and safety of acarbose over a 5-year period when prescribed to patients with diabetes who had not earlier received the drug. The study also recorded concomitant diseases, blood glucose control and other laboratory measures in over 2000 patients.

This study was conducted as an observational study to complement the randomized trials. Randomized studies can have limited applicability to clinical practice [10]: although necessary to show a causal link between treatment and response, they often cannot be replicated in routine practice because they are driven by protocol and involve intense interventions. The limited number of volunteer patients selected for randomized trials is unlikely to be representative, and may receive less complex treatment than in routine practice. Furthermore, the detection of rare side effects is unlikely in randomized trials with a limited number of patients. Observational studies provide more direct data establishing the effectiveness of therapy in a non-experimental setting, although they too are not without their limitations. Thus, treatment is selected for each patient, rather than randomly assigned, so there is a risk of selection bias influencing outcome. Data from both types of trials are, therefore, required to provide the complementary information needed to determine optimal health care strategies.

The objective of the present study was thus to determine the clinical characteristics of acarbose when prescribed over a long period in day-to-day clinical practice.

Section snippets

Subjects and methods

A total of 320 internists and general practitioners in Germany participated in the study. These physicians enrolled 2035 people of whom 1954 were classified as having Type 2 diabetes, 78 as having Type 1 diabetes, one with impaired glucose tolerance (IGT) and two with dumping syndrome. Only the data from people with Type 2 diabetes are included in the present evaluation.

The acarbose doses used were determined solely by physicians together with the patients. Patients were evaluated every 3

Dosage of acarbose

The mean starting daily dose of acarbose was 152 mg (range 50–300 mg, median 150 mg). In 85.3% of patients, the physicians prescribed a daily dose of 150 mg or less. Only 9.5% of patients started with an initial daily dose of 300 mg. At the end of the 5-year surveillance period the mean daily dose was 201 mg (range 50–300 mg, median 200 mg). Just over half of the patients (51.8%) received a daily dose of 150 mg or less, while 40% of patients were treated with 300 mg/day (Table 2). The initial

Discussion

A surveillance study provides a good opportunity to monitor the long-term safety and tolerability of a drug in normal day-to-day clinical practice [11]. Such studies are, therefore, more likely to reflect the real-world patient experience than studies performed under controlled conditions, where the artificiality of a rigid trial protocol may lead to incorrect inferences regarding a drug's safety and tolerability profile [10]. This may apply especially to drugs for which tolerability is largely

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A series of new phenyl acetylene and isoxazole analogues of arjunolic acid were designed, synthesized and evaluated (3–8) for their tyrosinase and alpha glucosidase inhibitory potential. All the tested analogues exhibited stronger inhibitory activity than the standard drug or parent compound. Of these, compound (7) displayed the most potent tyrosinase inhibitory action with IC₅₀ (14.3 ± 7.6) of about three folds more than the standard drug, kojic acid (41.5 ± 1.0). Further, compound (8) (14.5 ± 0.15) possessed the potent alpha glucosidase inhibitory action with IC₅₀ value comparable to that of standard, acarbose (10.4 ± 0.06). Henceforth, compounds (7) and (8) are promising candidates for further studies.
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The inhibition of α-amylase by some hypoglycaemic drugs, such as acarbose and miglitol, may lead to fermented undigested carbohydrates in the large intestine. This is regarded as the main cause of gastrointestinal side effects, including flatulence, diarrhoea, abdominal pain, and constipation (Gao et al., 2018; Mertes, 2001; van de Laar et al., 2005). These symptoms were not significantly observed in this study, except for one subject in the test group who reported mild flatulence, suggesting the good safety and tolerability of MWEM.
Mulberry leaves and white kidney beans may improve postprandial glycaemic control. However, data are lacking on the combined anti-diabetic effect of these two plant extracts among pre-diabetic individuals. This randomized controlled study aimed to evaluate the acute and chronic effects of mulberry leaf and white kidney bean extract mix (MWEM) on postprandial glycaemic control in 66 pre-diabetic subjects. In the acute effect test, ingestion of MWEM led to a significant decrease in the postprandial glucose, insulin, and C-peptide, as well as the incremental area under the curves from 0 to 120 min (iAUCs_0–120min) for glucose, insulin, and C-peptide. In the chronic effect test, no significant treatment × time interactions were observed in the iAUCs_0–120min, as well as the homeostatic model assessment-insulin resistance (HOMA-IR), haemoglobin A1c (HbA1c), and glycated serum protein (GSP) levels. The consumption of MWEM with a meal could potentially help to improve postprandial glycaemic control in pre-diabetic individuals.
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Control of postprandial hyperglycemia is an essential component of diabetes treatment. Alpha glucosidase inhibitors are a class of oral antidiabetic drugs that primarily act on postprandial hyperglycemia. They regulate the availability of glucose for intestinal absorption by modification of carbohydrate digestion. Three alpha glucosidase inhibitors are in therapeutic use: acarbose, miglitol, and voglibose. Control of HbA1c is equipotent to other oral antidiabetics. Alpha glucosidase inhibitors exert beneficial effects on major components of the metabolic syndrome, microbiota, and cardiovascular risk factors. Acarbose has evidence-based effects of prevention of type 2 diabetes and cardiovascular risk in patients with impaired glucose tolerance.
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Weight loss was not seen when other agents, such as sulfonylureas, meglitinides, thiazolidinediones, dipeptidyl-peptidase-4 (DPP-4) inhibitors, basal insulin, and biphasic insulin, were added to metformin (Gross et al., 2011; McIntosh et al., 2011). Other studies, including a 5-year observational trial in Germany (Mertes, 2001), have also confirmed the ability of acarbose to reduce body weight when given as monotherapy or combination therapy. In addition, Pan & Landen (2007) and Yang (2013) showed that acarbose provides comparable reductions in glycated hemoglobin (HbA1c) to vildagliptin and metformin, respectively, but greater reductions in body weight compared with each active comparator (Pan & Landen, 2007; Yang, 2013).
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The mean relative reduction in body weight was 1.45 ± 3.24% at the 3-month visit (n = 43,510; mean baseline 73.4 kg) and 1.40 ± 3.28% at the last visit (n = 54,760; mean baseline 73.6 kg) (both p < 0.0001). These reductions were dependent on baseline body weight (overweight: –1.33 ± 2.98% [n = 13,498; mean baseline 71.6 kg]; obese: –1.98 ± 3.40% [n = 20,216; mean baseline 81.3 kg]). When analysed by baseline glycemic parameter quartiles, the reduction was independent of fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated hemoglobin (HbA_1c) and postprandial glucose excursion (PPGE). A bivariate analysis of covariance identified female sex, South East Asian and East Asian ethnicity, younger age, higher body mass index, short duration of diabetes, and no previous treatment as factors likely to impact positively on body weight reduction with acarbose.
This post-hoc analysis showed that acarbose treatment reduces body weight independent of glycemic control status but dependent on baseline body weight.

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Safety and efficacy of acarbose in the treatment of Type 2 diabetes: data from a 5-year surveillance study

Abstract

Introduction

Section snippets

Subjects and methods

Dosage of acarbose

Discussion

Diab. Res. Clin. Pract.

Clin. Ther.

Microbial alpha-glucosidase inhibitors: chemistry, biochemistry and therapeutic potential

Prog. Clin. Biochem. Med.

The effects of alpha-glucosidase inhibitor BAY G 5421 (acarbose) on meal-stimulated elevations of circulating glucose, insulin and triglyceride levels in man

Res. Exp. Med.

The effect of acarbose on insulin sensitivity in subjects with impaired glucose tolerance

Diab. Care

The effect of acarbose on insulin sensitivity and proinsulin in overweight subjects with impaired glucose tolerance

Exp. Clin. Endocrinol. Diab.

Glucagon-like peptide 1 (7–36 amide) secretion in response to luminal sucrose from the upper and lower gut. A study using α-glucosidase inhibition (acarbose)

Scand. J. Gastroenterol.

Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in Type 2 (non-insulin-dependent) diabetic patients

Diabetologia

Alpha-glucosidase inhibitors as agents in the treatment of diabetes

Diab. Rev.

A randomized double-blind trial of acarbose in Type 2 diabetes shows improved glycemic control over 3 years (UKPDS 44)

Diab. Care

Are randomized controlled trials sufficient evidence to guide clinical practice in Type II (non-insulin-dependent) diabetes mellitus?

Diabetologia