acarbose

In type II diabetic patients, acarbose averages an absolute decrease of 0.8 percentage points in HbA_1c, which is a decrease of about 10% in typical HbA_1c values in diabetes studies. Individuals with higher baseline levels show higher reductions, about an 0.12% additional decrease for each point of baseline HbA_1c. Its effect on postprandial glucose, but not on HbA_1c, scales with dose. Among diabetic patients, acarbose may help reduce the damage done to blood vessels and kidneys by reducing glucose levels.

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 (HbA_1c).{{cite journal | vauthors = Moelands SV, Lucassen PL, Akkermans RP, De Grauw WJ, Van de Laar FA | title = 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 | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | issue = 12 | pages = CD005061 | date = December 2018 | pmid = 30592787 | pmc = 6517235 | doi = 10.1002/14651858.CD005061.pub3 | collaboration = Cochrane Metabolic and Endocrine Disorders Group }} 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.

Several studies showed that glucosidase inhibitors and alpha-amylase inhibitors promote loss of visceral fat and waist by acting as calorie restriction mimetics (linked to its acarbose-like action).{{cite journal | vauthors = Smith DL, Orlandella RM, Allison DB, Norian LA | title = Diabetes medications as potential calorie restriction mimetics-a focus on the alpha-glucosidase inhibitor acarbose | journal = GeroScience | volume = 43 | issue = 3 | pages = 1123–1133 | date = June 2021 | pmid = 33006707 | pmc = 8190416 | doi = 10.1007/s11357-020-00278-x }}

The combination of acarbose with metformin results in greater reductions of HbA1c, fasting blood glucose and post-prandial glucose than either agent alone.{{cite journal | vauthors = Hedrington MS, Davis SN | title = Considerations when using alpha-glucosidase inhibitors in the treatment of type 2 diabetes | journal = Expert Opinion on Pharmacotherapy | volume = 20 | issue = 18 | pages = 2229–2235 | date = December 2019 | pmid = 31593486 | doi = 10.1080/14656566.2019.1672660 | s2cid = 203985605 }}

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.{{cite journal | vauthors = Hoffmann J, Spengler M | title = Efficacy of 24-week monotherapy with acarbose, metformin, or placebo in dietary-treated NIDDM patients: the Essen-II Study | journal = The American Journal of Medicine | volume = 103 | issue = 6 | pages = 483–490 | date = December 1997 | pmid = 9428831 | doi = 10.1016/S0002-9343(97)00252-0 }} Sucrose is more likely to trigger GI side effects compared to starch.{{cite journal | vauthors = DiNicolantonio JJ, Bhutani J, O'Keefe JH | title = Acarbose: safe and effective for lowering postprandial hyperglycaemia and improving cardiovascular outcomes | journal = Open Heart | volume = 2 | issue = 1 | pages = e000327 | date = 2015 | pmid = 26512331 | pmc = 4620230 | doi = 10.1136/openhrt-2015-000327 }}

Acarbose is associated with very rare elevated transaminases (19 out of 500,000). 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.{{cite web | url = http://apps.who.int/medicinedocs/en/d/Js2268e/2.html#Js2268e.2.1 | archive-url = https://web.archive.org/web/20091015073058/http://apps.who.int/medicinedocs/en/d/Js2268e/2.html#Js2268e.2.1 | url-status = dead | archive-date = October 15, 2009 | title = Acarbose: hepatitis: France, Spain | work = WHO Pharmaceuticals Newsletter | date = 1999 | issue = 1&02 }} A 2016 meta-analysis confirms that alpha-glucosidase inhibitors, including acarbose, have a statistically significant link to elevated transaminase levels.{{cite journal | vauthors = Zhang L, Chen Q, Li L, Kwong JS, Jia P, Zhao P, Wang W, Zhou X, Zhang M, Sun X | title = Alpha-glucosidase inhibitors and hepatotoxicity in type 2 diabetes: a systematic review and meta-analysis | journal = Scientific Reports | volume = 6 | issue = 1 | pages = 32649 | date = September 2016 | pmid = 27596383 | pmc = 5011653 | doi = 10.1038/srep32649 | bibcode = 2016NatSR...632649Z | doi-access = free }}

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.{{cite journal | vauthors = Li C, Begum A, Numao S, Park KH, Withers SG, Brayer GD | title = Acarbose rearrangement mechanism implied by the kinetic and structural analysis of human pancreatic alpha-amylase in complex with analogues and their elongated counterparts | journal = Biochemistry | volume = 44 | issue = 9 | pages = 3347–3357 | date = March 2005 | pmid = 15736945 | doi = 10.1021/bi048334e }} However, bacterial alpha-amylases from gut microbiome are able to degrade acarbose.{{cite journal | vauthors = Park KH, Kim MJ, Lee HS, Han NS, Kim D, Robyt JF | title = Transglycosylation reactions of Bacillus stearothermophilus maltogenic amylase with acarbose and various acceptors | journal = Carbohydrate Research | volume = 313 | issue = 3–4 | pages = 235–246 | date = December 1998 | pmid = 10209866 | doi = 10.1016/S0008-6215(98)00276-6 }}{{cite journal | vauthors = Oh SW, Jang MU, Jeong CK, Kang HJ, Park JM, Kim TJ | title = Modulation of hydrolysis and transglycosylation activity of Thermus maltogenic amylase by combinatorial saturation mutagenesis | journal = Journal of Microbiology and Biotechnology | volume = 18 | issue = 8 | pages = 1401–1407 | date = August 2008 | pmid = 18756100 | url = https://www.koreascience.or.kr/article/JAKO200835054207140.page }}

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 HbA_1c level.Drug Therapy in Nursing, 2nd Edition.

Acarbose degradation is the unique feature of glycoside hydrolases in gut microbiota, acarbose degrading glucosidase, which hydrolyze acarbose into an acarviosine-glucose and glucose.{{cite journal | vauthors = Kim TJ, Kim MJ, Kim BC, Kim JC, Cheong TK, Kim JW, Park KH | title = Modes of action of acarbose hydrolysis and transglycosylation catalyzed by a thermostable maltogenic amylase, the gene for which was cloned from a Thermus strain | journal = Applied and Environmental Microbiology | volume = 65 | issue = 4 | pages = 1644–1651 | date = April 1999 | pmid = 10103262 | doi = 10.1128/AEM.65.4.1644-1651.1999 | pmc = 91232 | bibcode = 1999ApEnM..65.1644K }} 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.

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.{{Cite journal| vauthors = Jang MU, Kang HJ, Jeong CK, Oh GW, Lee EH, Son BS, Kim TJ |date=2017|title=Functional expression and enzymatic characterization of cyclomaltodextrinase from Streptococcus pyogenes |journal=Korean Journal of Microbiology|volume=53|issue=3|pages=208–215|doi=10.7845/kjm.2017.7062|issn=0440-2413}}{{cite journal | vauthors = Baek JS, Kim HY, Abbott TP, Moon TW, Lee SB, Park CS, Park KH | title = Acarviosine-simmondsin, a novel compound obtained from acarviosine-glucose and simmondsin by Thermus maltogenic amylase and its in vivo effect on food intake and hyperglycemia | journal = Bioscience, Biotechnology, and Biochemistry | volume = 67 | issue = 3 | pages = 532–539 | date = March 2003 | pmid = 12723600 | doi = 10.1271/bbb.67.532 | s2cid = 2813481 | doi-access = free }} 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.{{cite journal | vauthors = Jang MU, Kang HJ, Jeong CK, Kang Y, Park JE, Kim TJ | title = Functional expression and enzymatic characterization of Lactobacillus plantarum cyclomaltodextrinase catalyzing novel acarbose hydrolysis | journal = Journal of Microbiology | volume = 56 | issue = 2 | pages = 113–118 | date = February 2018 | pmid = 29392561 | doi = 10.1007/s12275-018-7551-3 | s2cid = 2660911 }} The microbiome-derived acarbose kinases are also specific to phosphorylate and inactivate acarbose.{{cite journal | vauthors = Balaich J, Estrella M, Wu G, Jeffrey PD, Biswas A, Zhao L, Korennykh A, Donia MS | title = The human microbiome encodes resistance to the antidiabetic drug acarbose | journal = Nature | volume = 600 | issue = 7887 | pages = 110–115 | date = December 2021 | pmid = 34819672 | doi = 10.1038/s41586-021-04091-0 | pmc = 10258454 | bibcode = 2021Natur.600..110B | s2cid = 244644880 }} The molecular modeling showed the interaction between gut bacterial acarbose degrading glucosidase and human α-amylase.{{Cite journal | vauthors = Park KH |date=2006 |title=Function and Tertiary- and Quaternary-structure of Cyclodextrin-hydrolyzing Enzymes (CDase), a Group of Multisubstrate Specific Enzymes Belonging to the α-Amylase Family |url=https://www.jstage.jst.go.jp/article/jag/53/1/53_1_35/_article |journal=Journal of Applied Glycoscience |language=en |volume=53 |issue=1 |pages=35–44 |doi=10.5458/jag.53.35 |s2cid=86894203 |issn=1344-7882|doi-access=free }}

File:Acarbose degradation in gut microbiome.jpgFile:Acarbose degradation by gut bacterial maltogenic amylase.png

In nature, acarbose is synthesized by soil bacteria Actinoplanes sp through its precursor valienamine.{{cite journal | vauthors = Tsunoda T, Samadi A, Burade S, Mahmud T | title = Complete biosynthetic pathway to the antidiabetic drug acarbose | journal = Nature Communications | volume = 13 | issue = 1 | pages = 3455 | date = June 2022 | pmid = 35705566 | doi = 10.1038/s41467-022-31232-4 | pmc = 9200736 | bibcode = 2022NatCo..13.3455T }} 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,{{cite journal | vauthors = Bozonnet S, Jensen MT, Nielsen MM, Aghajari N, Jensen MH, Kramhøft B, Willemoës M, Tranier S, Haser R, Svensson B | title = The 'pair of sugar tongs' site on the non-catalytic domain C of barley alpha-amylase participates in substrate binding and activity | journal = The FEBS Journal | volume = 274 | issue = 19 | pages = 5055–5067 | date = October 2007 | pmid = 17803687 | doi = 10.1111/j.1742-4658.2007.06024.x | s2cid = 25592455 }} 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.{{cite journal | vauthors = Miyazaki T, Park EY | title = Structure-function analysis of silkworm sucrose hydrolase uncovers the mechanism of substrate specificity in GH13 subfamily 17 exo-α-glucosidases | journal = The Journal of Biological Chemistry | volume = 295 | issue = 26 | pages = 8784–8797 | date = June 2020 | pmid = 32381508 | pmc = 7324511 | doi = 10.1074/jbc.RA120.013595 | doi-access = free }}

Most studies investigating alpha-glucosidase and alpha-amylase inhibitory activity use acarbose as reference.{{cite journal | vauthors = Moreira FD, Reis CE, Gallassi AD, Moreira DC, Welker AF | title = Suppression of the postprandial hyperglycemia in patients with type 2 diabetes by a raw medicinal herb powder is weakened when consumed in ordinary hard gelatin capsules: A randomized crossover clinical trial | journal = PLOS ONE | volume = 19 | issue = 10 | pages = e0311501 | date = 2024-10-09 | pmid = 39383145 | pmc = 11463819 | doi = 10.1371/journal.pone.0311501 | title-link = doi | doi-access = free | bibcode = 2024PLoSO..1911501M | veditors = Dardari D }}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}{{cite journal | vauthors = Hayward NJ, McDougall GJ, Farag S, Allwood JW, Austin C, Campbell F, Horgan G, Ranawana V | title = Cinnamon Shows Antidiabetic Properties that Are Species-Specific: Effects on Enzyme Activity Inhibition and Starch Digestion | journal = Plant Foods for Human Nutrition | volume = 74 | issue = 4 | pages = 544–552 | date = December 2019 | pmid = 31372918 | pmc = 6900266 | doi = 10.1007/s11130-019-00760-8 }}

In human T2DM patients, acarbose reduces total triglyceride levels.{{cite journal | vauthors = Yousefi M, Fateh ST, Nikbaf-Shandiz M, Gholami F, Rastgoo S, Bagher R, Khadem A, Shiraseb F, Asbaghi O | title = The effect of acarbose on lipid profiles in adults: a systematic review and meta-analysis of randomized clinical trials | journal = BMC Pharmacology & Toxicology | volume = 24 | issue = 1 | pages = 65 | date = November 2023 | pmid = 37990256 | pmc = 10664642 | doi = 10.1186/s40360-023-00706-6 | doi-access = free }} Acarbose has a similar effect in non-T2DM patients with isolated familial hypertriglyceridemia.

In smaller samples of healthy human volunteers, acarbose increases postprandial GLP-1 levels.

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%.{{cite journal | vauthors = Harrison DE, Strong R, Allison DB, Ames BN, Astle CM, Atamna H, Fernandez E, Flurkey K, Javors MA, Nadon NL, Nelson JF, Pletcher S, Simpkins JW, Smith D, Wilkinson JE, Miller RA | title = Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males | journal = Aging Cell | volume = 13 | issue = 2 | pages = 273–282 | date = April 2014 | pmid = 24245565 | pmc = 3954939 | doi = 10.1111/acel.12170 }}{{cite journal | vauthors = Ladiges W, Liggitt D | title = Testing drug combinations to slow aging | journal = Pathobiology of Aging & Age Related Diseases | volume = 8 | issue = 1 | pages = 1407203 | year = 2017 | pmid = 29291036 | pmc = 5706479 | doi = 10.1080/20010001.2017.1407203 }}

{{Reflist}}

{{Oral_hypoglycemics}}

{{Carbohydrates}}

{{Portal bar | Medicine}}

{{Authority control}}

Category:Alpha-glucosidase inhibitors

Category:Amino sugars

Category:Drugs developed by Bayer

Category:Oligosaccharides

Category:Cyclohexenes