Clinical data | |
---|---|
Trade names | Glucobay, Precose, Prandase |
Other names | (2R,3R,4R,5S,6R)-5-{[(2R,3R,4R,5S,6R)-5- {[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl- 5-{[(1S,4R,5S,6S)-4,5,6-trihydroxy-3- (hydroxymethyl)cyclohex-2-en-1-yl]amino} tetrahydro-2H-pyran-2-yl]oxy}-3,4-dihydroxy- 6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}- 6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4-triol |
AHFS/Drugs.com | Monograph |
MedlinePlus | a696015 |
License data | |
Pregnancy category |
|
Routes of administration | By mouth |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | Extremely low |
Metabolism | Gastrointestinal tract |
Elimination half-life | 2 hours |
Excretion | Kidney (less than 2%) |
Identifiers | |
| |
CAS Number | |
PubChem CID | |
IUPHAR/BPS | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEMBL | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.054.555 |
Chemical and physical data | |
Formula | C25H43NO18 |
Molar mass | 645.608 g·mol−1 |
3D model (JSmol) | |
| |
| |
(verify) |
Acarbose (INN) [1] [2] is an anti-diabetic drug used to treat diabetes mellitus type 2 and, in some countries, prediabetes. It is a generic sold in Europe and China as Glucobay (Bayer AG), in North America as Precose (Bayer Pharmaceuticals), and in Canada as Prandase (Bayer AG).
Acarbose is a starch blocker. It works by inhibiting alpha glucosidase, an intestinal enzyme that releases glucose from larger carbohydrates such as starch and sucrose. It is composed of an acarviosin moiety with a maltose at the reducing terminus. It can be degraded by a number of gut bacteria. [3]
Acarbose is cheap and popular in China, but not in the U.S. One physician explains that use in the U.S. is limited because it is not potent enough to justify the side effects of diarrhea and flatulence. [4] However, a large study concluded in 2013 that "acarbose is effective, safe and well tolerated in a large cohort of Asian patients with type 2 diabetes." [5] A possible explanation for the differing opinions is an observation that acarbose is significantly more effective in patients eating a relatively high carbohydrate Eastern diet. [6]
Since acarbose prevents the digestion of complex carbohydrates, the drug should be taken at the start of main meals (taken with first bite of meal). [7]
In type II diabetic patients, acarbose averages an absolute decrease of 0.8 percentage points in HbA1c, which is a decrease of about 10% in typical HbA1c values in diabetes studies. [8] Individuals with higher baseline levels show higher reductions, about an 0.12% additional decrease for each point of baseline HbA1c. [8] Its effect on postprandial glucose, but not on HbA1c, scales with dose. [8] Among diabetic patients, acarbose may help reduce the damage done to blood vessels and kidneys by reducing glucose levels. [8]
A Cochrane systematic review assessed the effect of alpha-glucosidase inhibitors in people with prediabetes, defined as impaired glucose tolerance, impaired fasting blood glucose, elevated glycated hemoglobin A1c (HbA1c). [9] It was found that acarbose reduced the incidence of diabetes mellitus type 2 when compared to placebo, however there was no conclusive evidence that acarbose, when compared to diet and exercise, metformin, placebo, or no intervention, improved all-cause mortality, reduced or increased risk of cardiovascular mortality, serious or non-serious adverse events, non-fatal stroke, congestive heart failure, or non-fatal myocardial infarction. [9]
The combination of acarbose with metformin results in greater reductions of HbA1c, fasting blood glucose and post-prandial glucose than either agent alone. [10]
Since acarbose prevents the degradation of complex carbohydrates into glucose, some carbohydrate will remain in the intestine and be delivered to the colon. In the colon, bacteria digest (ferment) the complex carbohydrates, causing gastrointestinal side-effects such as flatulence (78% of patients) and diarrhea (14% of patients). Since these effects are dose-related, in general it is advised to start with a low dose and gradually increase the dose to the desired amount. One study found that gastrointestinal side effects decreased significantly (from 50% to 15%) over 24 weeks, even on constant dosing. [11] Sucrose is more likely to trigger GI side effects compared to starch. [8]
If a patient using acarbose has a bout of hypoglycemia, the patient must eat something containing monosaccharides, such as glucose tablets or gel (GlucoBurst, Insta-Glucose, Glutose, Level One) and a doctor should be called. Because acarbose blocks the breakdown of table sugar and other complex sugars, fruit juice or starchy foods will not effectively reverse a hypoglycemic episode in a patient taking acarbose. [12] Acarbose by itself carries minimal risk of hypoglycemia. [8]
Acarbose is associated with very rare elevated transaminases (19 out of 500,000). [8] Even rarer cases of hepatitis has been reported with acarbose use. It usually goes away when the medicine is stopped. Liver enzymes should be checked before and during use of this medicine as a precaution. [13] A 2016 meta-analysis confirms that alpha-glucosidase inhibitors, including acarbose, have a statistically significant link to elevated transaminase levels. [14]
Acarbose inhibits enzymes (glycoside hydrolases) needed to digest carbohydrates, specifically, alpha-glucosidase enzymes in the brush border of the small intestines, and pancreatic alpha-amylase. It locks up the enzymes by mimicking the transition state of the substrate with its amine linkage. [15] However, bacterial alpha-amylases from gut microbiome are able to degrade acarbose. [16] [17] [18]
Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine, whereas the membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the small intestine. Inhibition of these enzyme systems reduces the rate of digestion of complex carbohydrates. Less glucose is absorbed because the carbohydrates are not broken down into glucose molecules. In diabetic patients, the short-term effect of these drug therapies is to decrease current blood glucose levels; the long-term effect is a reduction in HbA1c level. [19]
Acarbose degradation is the unique feature of glycoside hydrolases in gut microbiota, acarbose degrading glucosidase, which hydrolyze acarbose into an acarviosine-glucose and glucose. [18] Human enzymes do transform acarbose: the pancreatic alpha-amylase is able to perform a rearrangement reaction, moving the glucose unit in the "tail" maltose to the "head" of the molecule. Analog drugs with the "tail" glucose removed or flipped to an α(1-6) linkage resist this transformation. [15]
It has been reported that the maltogenic alpha-amylase from Thermus sp. IM6501 (ThMA) and a cyclodextrinase (CDase) from Streptococcus pyogenes could hydrolyse acarbose to glucose and acarviosine-glucose, ThMA can further hydrolyze acarviosine-glucose into acarviosin and glucose. [20] [21] A cyclomaltodextrinase (CDase) from gut bacteria Lactobacillus plantarum degraded acarbose via two different modes of action to produce maltose and acarviosin, as well as glucose and acarviosine-glucose, suggest that acarbose resistance is caused by the human microbiome. [3] The microbiome-derived acarbose kinases are also specific to phosphorylate and inactivate acarbose. [22] The molecular modeling showed the interaction between gut bacterial acarbose degrading glucosidase and human α-amylase. [23]
In nature, acarbose is synthesized by soil bacteria Actinoplanes sp through its precursor valienamine. [24] And acarbose is also degraded by gut bacteria Lactobacillus plantarum and soil bacteria Thermus sp by acarbose degrading glucosidases.
Acarbose is described chemically as a pseudotetrasaccharide, [25] specifically a maltotetraose mimic inhibitor. As an inhibitor that mimics some natural substrates, it is useful for elucidating the structure of sugar-digesting enzymes, by binding into the same pocket. [26]
In human T2DM patients, acarbose reduces total triglyceride levels. [27] Acarbose has a similar effect in non-T2DM patients with isolated familial hypertriglyceridemia. [8]
In smaller samples of healthy human volunteers, acarbose increases postprandial GLP-1 levels. [8]
In studies conducted by three independent laboratories by the US National Institute on Aging's intervention testing programme, acarbose was shown to extend the lifespan of female mice by 5% and of male mice by 22%. [28] [29]
Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, fatigue and unexplained weight loss. Symptoms may also include increased hunger, having a sensation of pins and needles, and sores (wounds) that do not heal. Often symptoms come on slowly. Long-term complications from high blood sugar include heart disease, stroke, diabetic retinopathy which can result in blindness, kidney failure, and poor blood flow in the limbs which may lead to amputations. The sudden onset of hyperosmolar hyperglycemic state may occur; however, ketoacidosis is uncommon.
Drugs used in diabetes treat diabetes mellitus by decreasing glucose levels in the blood. With the exception of insulin, most GLP-1 receptor agonists, and pramlintide, all diabetes medications are administered orally and are thus called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of hypoglycemic drugs, and selection of the appropriate agent depends on the nature of diabetes, age, and situation of the person, as well as other patient factors.
Maltase is an informal name for a family of enzymes that catalyze the hydrolysis of disaccharide maltose into two simple sugars of glucose. Maltases are found in plants, bacteria, yeast, humans, and other vertebrates.
Glycated hemoglobin, glycohemoglobin, glycosylated hemoglobin is a form of hemoglobin (Hb) that is chemically linked to a sugar. Several types of glycated hemoglobin measures exist, of which HbA1c, or simply A1c, is a standard single test. Most monosaccharides, including glucose, galactose, and fructose, spontaneously bond with hemoglobin when present in the bloodstream. However, glucose is only 21% as likely to do so as galactose and 13% as likely to do so as fructose, which may explain why glucose is used as the primary metabolic fuel in humans.
The term diabetes includes several different metabolic disorders that all, if left untreated, result in abnormally high concentrations of a sugar called glucose in the blood. Diabetes mellitus type 1 results when the pancreas no longer produces significant amounts of the hormone insulin, usually owing to the autoimmune destruction of the insulin-producing beta cells of the pancreas. Diabetes mellitus type 2, in contrast, is now thought to result from autoimmune attacks on the pancreas and/or insulin resistance. The pancreas of a person with type 2 diabetes may be producing normal or even abnormally large amounts of insulin. Other forms of diabetes mellitus, such as the various forms of maturity-onset diabetes of the young, may represent some combination of insufficient insulin production and insulin resistance. Some degree of insulin resistance may also be present in a person with type 1 diabetes.
Alpha-glucosidase inhibitors (AGIs) are oral anti-diabetic drugs used for diabetes mellitus type 2 that work by preventing the digestion of carbohydrates. Carbohydrates are normally converted into simple sugars (monosaccharides) by alpha-glucosidase enzymes present on cells lining the intestine, enabling monosaccharides to be absorbed through the intestine. Hence, alpha-glucosidase inhibitors reduce the impact of dietary carbohydrates on blood sugar.
α-Glucosidase (EC 3.2.1.20, is a glucosidase located in the brush border of the small intestine that acts upon α bonds:
A diabetic diet is a diet that is used by people with diabetes mellitus or high blood sugar to minimize symptoms and dangerous complications of long-term elevations in blood sugar.
In biochemistry, glycoside hydrolases are a class of enzymes which catalyze the hydrolysis of glycosidic bonds in complex sugars. They are extremely common enzymes, with roles in nature including degradation of biomass such as cellulose (cellulase), hemicellulose, and starch (amylase), in anti-bacterial defense strategies, in pathogenesis mechanisms and in normal cellular function. Together with glycosyltransferases, glycosidases form the major catalytic machinery for the synthesis and breakage of glycosidic bonds.
Miglitol is an oral anti-diabetic drug that acts by inhibiting the ability of the patient to break down complex carbohydrates into glucose. It is primarily used in diabetes mellitus type 2 for establishing greater glycemic control by preventing the digestion of carbohydrates into monosaccharides which can be absorbed by the body.
Voglibose is an alpha-glucosidase inhibitor used for lowering postprandial blood glucose levels in people with diabetes mellitus. Voglibose is a research product of Takeda Pharmaceutical Company, Japan's largest pharmaceutical company. Vogilbose was discovered in 1981, and was first launched in Japan in 1994, under the trade name BASEN, to improve postprandial hyperglycemia in diabetes mellitus.
The dawn phenomenon, sometimes called the dawn effect, is an observed increase in blood sugar (glucose) levels that takes place in the early-morning, often between 2 a.m. and 8 a.m. First described by Schmidt in 1981 as an increase of blood glucose or insulin demand occurring at dawn, this naturally occurring phenomenon is frequently seen among the general population and is clinically relevant for patients with diabetes as it can affect their medical management. In contrast to Chronic Somogyi rebound, the dawn phenomenon is not associated with nocturnal hypoglycemia.
Glucosidases are the glycoside hydrolase enzymes categorized under the EC number 3.2.1.
Remogliflozin etabonate (INN/USAN) is a drug of the gliflozin class for the treatment of non-alcoholic steatohepatitis ("NASH") and type 2 diabetes. Remogliflozin was discovered by the Japanese company Kissei Pharmaceutical and is currently being developed by BHV Pharma, a wholly owned subsidiary of North Carolina, US-based Avolynt, and Glenmark Pharmaceuticals through a collaboration with BHV. In 2002, GlaxoSmithKline (GSK) received a license to use it. From 2002 to 2009, GSK carried out a significant clinical development program for the treatment of type-2 diabetes mellitus in various nations across the world and obesity in the UK. Remogliflozin etabonate's pharmacokinetics, pharmacodynamics, and clinical dose regimens were characterized in 18 Phase I and 2 Phase II investigations. Due to financial concerns, GSK stopped working on remogliflozin and sergliflozin, two further SGLT2 inhibitors that were licensed to the company, in 2009. Remogliflozin was commercially launched first in India by Glenmark in May 2019.
Canagliflozin, sold under the brand name Invokana among others, is a medication used to treat type 2 diabetes. It is used together with exercise and diet. It is not recommended in type 1 diabetes. It is taken by mouth.
1,5-Anhydroglucitol, also known as 1,5-AG, is a naturally occurring monosaccharide found in nearly all foods. Blood concentrations of 1,5-anhydroglucitol decrease during times of hyperglycemia above 180 mg/dL, and return to normal levels after approximately 2 weeks in the absence of hyperglycemia. As a result, it can be used for people with either type-1 or type-2 diabetes mellitus to identify glycemic variability or a history of high blood glucose even if current glycemic measurements such as hemoglobin A1c (HbA1c) and blood glucose monitoring have near normal values. Despite this possible use and its approval by the FDA, 1,5-AG tests are rarely ordered. There is some data suggesting that 1,5-AG values are useful to fill the gap and offer complementary information to HbA1c and fructosamine tests.
Prevention of type 2 diabetes can be achieved with both lifestyle changes and use of medication. The American Diabetes Association categorizes people with prediabetes, who have glycemic levels higher than normal but do not meet criteria for diabetes, as a high-risk group. Without intervention, people with prediabetes progress to type 2 diabetes with a 5% to 10% rate. Diabetes prevention is achieved through weight loss and increased physical activity, which can reduce the risk of diabetes by 50% to 60%.
Gemigliptin (rINN), sold under the brand name Zemiglo, is an oral anti-hyperglycemic agent of the dipeptidyl peptidase-4 inhibitor class of drugs. Glucose lowering effects of DPP-4 inhibitors are mainly mediated by GLP-1 and gastric inhibitory polypeptide (GIP) incretin hormones which are inactivated by DPP-4.
Empagliflozin, sold under the brand name Jardiance, among others, is an antidiabetic medication used to improve glucose control in people with type 2 diabetes. It is taken by mouth.
Glucan 1,4-alpha-maltohydrolase is an enzyme with systematic name 4-alpha-D-glucan alpha-maltohydrolase. This enzyme catalyses the following chemical reaction