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Acarbose

An Update of its Pharmacology and Therapeutic Use in Diabetes Mellitus

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Abstract

Synopsis

Acarbose delays digestion of complex carbohydrates and disaccharides to absorbable monosaccharides, by reversibly inhibiting α-glucosidases within the intestinal brush border, thereby attenuating postprandial blood glucose peaks.

Clinical trials have demonstrated that acarbose generally improves glycaemic control in patients with non-insulin-dependent diabetes mellitus (NIDDM) managed with diet alone, or with other antidiabetic therapy, as evidenced by decreased postprandial plasma glucose and glycosylated haemoglobin levels. It does not appear to directly alter insulin resistance, but may lower postprandial plasma insulin levels. Fasting plasma glucose, triglyceride and/or cholesterol levels may also be decreased. Acarbose also improved metabolic control in patients with insulin-dependent diabetes mellitus (IDDM), frequently decreasing insulin requirements, although further studies are required in this indication.

Improved metabolic control appears to delay or prevent long term vascular complications of diabetes, and indeed, acarbose appeared to inhibit development of such complications in preliminary animal studies, but this finding requires confirmation in clinical studies.

While acarbose seldom causes systemic adverse effects, it is associated with a high incidence of gastrointestinal disturbances such as flatulence, abdominal distension, borborygmus and diarrhoea, caused by fermentation of unabsorbed carbohydrates. However, these symptoms tend to subside with continued treatment and adherence to an appropriate diet.

Thus, acarbose appears to be a worthwhile adjunctive therapeutic option for patients with NIDDM inadequately managed by diet alone, or with pharmacological therapy, and possibly also for patients with IDDM. However, further long term efficacy and tolerability data are required, particularly in the latter indication.

Pharmacological Properties

Acarbose is an oligosaccharide which reversibly inhibits intestinal α-glucosidase enzymes responsible for digestion of complex carbohydrates and disaccharides to absorbable monosaccharides. Thus, acarbose delays postprandial absorption of glucose, resulting in attenuation of postprandial plasma glucose, insulin and triglyceride peaks in healthy volunteers. The beneficial effects of acarbose on postprandial glucose levels have been confirmed in patients with insulin-dependent or non-insulin-dependent diabetes mellitus (IDDM or NIDDM), whereas postprandial insulin and triglyceride levels were only occasionally lowered. Pooled data from several clinical trials indicate that acarbose lowers postprandial and fasting blood glucose levels in patients with NIDDM by approximately 20 and 10%, respectively, the latter presumably by an indirect mechanism. Acarbose does not appear to exert any direct effect on insulin resistance in humans.

By decreasing the hyperglycaemic stimulus to insulin secretion, acarbose attenuates the blood glucose nadir and associated clinical symptoms which occur after carbohydrate ingestion in patients with reactive hypoglycaemia.

Delayed carbohydrate digestion increases the amount of fermentable carbohydrate in the bowel, which does not appear to cause calorie loss, because of metabolism to other absorbable nutrients by colonic microflora, but can induce gastrointestinal adverse effects such as flatulence and borborygmi. Acarbose decreases the postprandial gastric inhibitory polypeptide response, while increasing the enteroglucagon response, and also decreases intestinal absorption of iron. It does not generally appear to lower bodyweight in humans, although this effect has consistently been demonstrated in animal models.

Acarbose decreases serum triglycerides, cholesterol and free fatty acid levels in animal models of diabetes and/or hyperlipidaemia, but in human studies in diabetic and nondiabetic individuals, does not consistently lower fasting plasma triglycerides and produces only occasional decreases in fasting plasma cholesterol.

The Diabetes Control and Complications Trial (DCCT) has demonstrated that optimal control of blood glucose levels can retard long term complications of diabetes. Indeed, acarbose decreases levels of glycosylated haemoglobin in patients with diabetes, and glycosylation of other body proteins in preliminary animal studies. Moreover, acarbose appeared to inhibit development of renal, cardiovascular, retinal, and neurological complications in various animal models of diabetes and/or hyperlipidaemia. The latter findings await confirmation in clinical studies.

Consistent with its intestinal site of action, acarbose is minimally (<2%) absorbed in unchanged form following oral administration to healthy volunteers. However, it is rapidly and extensively metabolised by intestinal digestive enzymes, and absorption of metabolites formed in the gut yields a biphasic pattern of absorption in studies with radiolabelled acarbose, with separate peaks at 1 to 2 and 6 to 24 hours. Administration of acarbose 300mg 3 times daily for 90 days to healthy volunteers did not result in accumulation.

Acarbose has a small volume of distribution (0.32 L/kg) and was minimally bound to animal plasma proteins at concentrations ≥ 1 μg/L, and 98% bound at 0.008 μg/L. Acarbose and/or its metabolites were secreted into breast milk and penetrated across the placental barrier in rats.

Approximately 35% of an orally administered dose of acarbose is excreted in the urine, virtually all in metabolised form, and approximately 50% in the faeces. The total body clearance of acarbose was around 600 L/h and values of up to 39.5 hours have been reported for the terminal elimination half-life.

Therapeutic Use

In noncomparative and placebo-controlled studies of 2 to 12 months’ duration, acarbose generally improved metabolic control in patients with NIDDM, whether used with diet alone, or with other antidiabetic agents, including sulphonylureas, biguanides or insulin. Postprandial plasma glucose levels were lowered by approximately 2 to 3 mmol/L and glycosylated haemoglobin levels were also decreased. Fasting plasma glucose and triglyceride levels, and insulin requirements, were also occasionally decreased. Acarbose was not effective in some patients, possibly reflecting low dosages used and/or severe carbohydrate restrictions in some instances, or lack of sensitivity of intestinal α-amylases to acarbose.

Acarbose tended to be slightly less effective than sulphonylureas and biguanides, particularly with regard to effects on fasting plasma glucose, but was at least as effective as guar gum in 1 study.

Acarbose has been less well studied in patients with IDDM, but improved glycaemic control, as evidenced by improved daily blood glucose profiles and decreased glycosylated haemoglobin levels, and frequently, decreased insulin requirements. It may also lower the risk of late hypoglycaemic episodes (those occurring several hours after a meal) in patients with IDDM.

Data from preliminary studies indicated that acarbose might be useful in patients with reactive hypoglycaemia, dumping syndrome and types IIb or IV hyperlipidaemia, but to date no large-scale studies appear to have been performed in these indications.

Tolerability

Gastrointestinal disturbances such as flatulence, abdominal distension, diarrhoea and borborygmus, caused by fermentation of unabsorbed carbohydrate in the bowel, are the most common adverse effects associated with acarbose therapy and may occur in up to two-thirds of patients. These symptoms generally improve with continued treatment, and may be minimised by initiating therapy at a low dosage and adherence to diet. The tolerability of acarbose in children aged 5 to 16 years is similar to that in adults.

Systemic adverse effects are rare during acarbose therapy. However, analysis of data from phase III US studies indicated that anaemia and elevated transaminase levels were significantly more common in acarbose, than in placebo recipients, occurring in 3.8 and 1.1% of patients, respectively.

Acarbose was reported to decrease both peak concentrations and area under the concentration-time curve of metformin by 35% when the 2 drugs were given concurrently to healthy volunteers.

Dosage and Administration

The recommended starting dose of acarbose for patients with NIDDM is 50mg 3 times daily, taken before meals, which may be increased to 100mg 3 times daily after 6 to 8 weeks if necessary, and subsequently to a maximum of 200mg 3 times daily if required. Dosages used in patients with IDDM in clinical trials were similar to those used in NIDDM. Patients receiving the maximum dose should be monitored closely for elevation of serum transaminase levels, preferably at monthly intervals, for the first 6 months of treatment. Contraindications to acarbose use include inflammatory bowel disease, partial intestinal obstruction or predisposition to intestinal obstruction, chronic intestinal disease associated with marked disorders of absorption or digestion, conditions which might be exacerbated by increased intestinal gas formation (such as hernias), and impaired hepatic function. Additionally, acarbose has not been studied in patients with severe renal impairment.

As acarbose may potentiate the hypoglycaemic effects of insulin and sulphonylureas, dosages of these agents may require adjustment when acarbose is administered concurrently. If hypoglycaemia occurs, patients should take glucose rather than carbohydrate foods. The effects of acarbose may be reduced by concomitant administration of intestinal adsorbents such as charcoal, and digestive enzyme preparations such as amylase or pancreatin, and enhanced by concomitant administration of neomycin or cholestyramine.

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    Julia A. Balfour & Donna McTavish

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Various sections of the manuscript reveiewed by: C. Couet, Laboratoire de Nutrition, Hôpital Bretonneau, Tours, France; J.D. Dean, Department of Medicine, Manchester Royal Infirmary, Manchester, England; U.R. Fölsch, Medizinische Klinik, Klinikum der Christian-Albrechts-Universität zu Kiel, Kiel, Federal Republic of Germany; M. Hanefeld, Klinik für Innere Medizin, Medizische Akademie ‘Carl Gustav Carus’ Dresden, Dresden, Federal Republic of Germany; P. Hollander, International Diabetes Center, Park Nicollet Medical Center, Minneapolis, Minnesota, USA; N. Hotta, Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, Japan; H.E. Lebovitz, Department of Medicine, Division of Endocrinology, State University of New York, Health Science Center at Brooklyn, New York, New York, USA; P.J. Lefèbvre, Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, University of Liège, Liège, Belgium; S. Marena, Istituto di Medicine Interna, Cattedra di Patologia Speciale Medica e Metodologia Clinica, University of Turin, Turin, Italy; J. Rybka, Internal Clinic, Postgraduate Medical School, Zlin, Czech Republic; A. Sima, Diabetes Research and Training Center, University of Michigan Medical Center, Ann Arbor, Michigan, USA; L. Van Goal, Department of Endocrinology, Metabolism and General Nutrition, University of Antwerp. Wilrijk, Belgium; G.C. Weir, Joslin Diabetes Center, Boston, Massachusetts, USA.

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Balfour, J.A., McTavish, D. Acarbose. Drugs 46, 1025–1054 (1993). https://doi.org/10.2165/00003495-199346060-00007

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