{{Short description|Drugs that lower blood glucose levels to treat diabetes}} {{About|the treatment of diabetes mellitus|the treatment of diabetes insipidus|Diabetes insipidus}} {{Use mdy dates|date=September 2011}} {{cs1 config|name-list-style=vanc|display-authors=6}} '''Drugs used in diabetes''' treat types of [[diabetes mellitus]] by decreasing [[blood sugar level|glucose levels in the blood]]. Most [[GLP-1 receptor agonist]]s ([[liraglutide]], [[exenatide]], [[tirzepatide]], [[pramlintide]] and others) are administered by injection. Other anti-diabetes medications (including [[semaglutide]] as Rybelsus) are administered orally and are thus called oral hypoglycemic agents or oral antihyperglycemic agents. (Semaglutide is available both as a pill and as an injection.) There are different classes of hypoglycemic drugs, and selection of the appropriate agent depends on the nature of the diabetes (Type I vs Type II), the age and situation of the person, as well as other patient factors.

[[Type 1 diabetes]] is an endocrine disorder characterized by [[hyperglycemia]] due to autoimmune destruction of insulin-secreting pancreatic [[beta cells]]. [[Insulin]] is a hormone needed by cells to take in [[glucose]] from the blood.<ref name=NIH2025WID>{{cite web |title=What Is Diabetes? |date=April 2023 |website=NIDDK |url=https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes |access-date=21 August 2025 }}</ref> Insufficient levels of insulin due to Type 1 diabetes can lead to chronic hyperglycemia and eventual multiorgan damage, resulting in renal, neurologic, cardiovascular, and other serious complications.<ref>Klandorf, Hillar, PhD, and Sharon W. Stark. "Diabetes Mellitus." Salem Press Encyclopedia of Health, 2024. EBSCOhost, search.ebscohost.com/login.aspx?direct=true&AuthType=cookie,ip,shib,uid&db=ers&AN=86194054&site=eds-live&scope=site.</ref> The treatment for Type 1 diabetes involves regular insulin injections.

[[Type 2 diabetes]], the most common type of diabetes, occurs when cells exhibit [[insulin resistance]] and become unable to properly utilize insulin.<ref name=NIH2025DT2>{{cite web |title=Type 2 Diabetes |date=May 2017 |website=NIDDK |url=https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes/type-2-diabetes |access-date=21 August 2025 }}</ref> Insulin resistance requires the pancreas to compensate by increasing insulin production.<ref name="p213">{{cite web | last1=Freeman | first1=Andrew M. | last2=Acevedo | first2=Luis A. | last3=Pennings | first3=Nicholas | title=Insulin Resistance | publisher=StatPearls Publishing | date=2023-08-17 | pmid=29939616 | url=https://www.ncbi.nlm.nih.gov/books/NBK507839/ | access-date=2025-08-21}}</ref> Once compensation fails, chronic hyperglycemia can manifest and type 2 diabetes develops.<ref>Type 2 Diabetes: What You Need to Know. GovInfo. (2012, July). https://www.govinfo.gov/app/details/GOVPUB-HE20-PURL-gpo50043 </ref> Treatments include dietary changes emphasizing low [[glycemic index]] food, physical activity to improve insulin sensitivity, and medications that (1) increase the amount of insulin secreted by the pancreas, (2) increase the sensitivity of target organs to insulin, (3) decrease the rate at which glucose is absorbed from the gastrointestinal tract, and (4) increase the loss of glucose through urination.<ref name="p213">{{cite web | last1=Freeman | first1=Andrew M. | last2=Acevedo | first2=Luis A. | last3=Pennings | first3=Nicholas | title=Insulin Resistance | publisher=StatPearls Publishing | date=2023-08-17 | pmid=29939616 | url=https://www.ncbi.nlm.nih.gov/books/NBK507839/ | access-date=2025-08-21}}</ref>

Several drug classes are indicated for use in type 2 diabetes and are often used in combination. Therapeutic combinations may include several [[Insulin (medication)|insulin]] isoforms or varying classes of oral antihyperglycemic agents. As of 2020, 23 unique antihyperglycemic drug combinations were approved by the [[Food and Drug Administration|FDA]].<ref name="pmid35126141">{{Cite journal |vauthors=Dahlén AD, Dashi G, Maslov I, Attwood MM, Jonsson J, Trukhan V, Schiöth HB |date=January 2022 |title=Trends in Antidiabetic Drug Discovery: FDA Approved Drugs, New Drugs in Clinical Trials and Global Sales |journal=Front Pharmacol |volume=12 |page=4119 |article-number=807548 |doi=10.3389/fphar.2021.807548 |pmc=8807560 |pmid=35126141 |doi-access=free}}</ref> [[Dapagliflozin/saxagliptin/metformin|The first triple combination]] of oral anti-diabetics was approved in 2019, consisting of [[metformin]], [[saxagliptin]], and [[dapagliflozin]]. [[Empagliflozin/linagliptin/metformin|Another triple combination]] approval for [[metformin]], [[linagliptin]], and [[empagliflozin]] followed in 2020.<ref name="pmid35126141" />

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==Mechanisms of action== Diabetes medications have four main mechanisms of action:{{citation needed|date=January 2024}} * [[#Sensitizers|Insulin sensitization]]: Increased sensitivity of insulin receptors on cells leading to decreased [[insulin resistance]], and higher effects of insulin on blood glucose levels. * [[#Secretagogues|Stimulation of beta cells]]: This stimulation increases insulin secretion from [[beta cell]]s of [[pancreas]]. * [[#Alpha-glucosidase inhibitors|Alpha-glucosidase inhibition]]: Inhibition of the [[alpha-glucosidase]] enzyme, decreases the rate at which glucose is absorbed from the gastrointestinal tract.<ref>{{Cite web |title=Overview of Diabetes Drugs |url=https://www.diabetesdaily.com/learn-about-diabetes/treatment/overview-of-diabetes-drugs/ |website=diabetes daily}}</ref> * [[Α-Amylase|Alpha-amylase]] inhibition: Inhibition of the [[Α-Amylase|alpha-amylase]] enzyme, decreasing the digestion of starch.<ref name="fdm">{{Cite journal |last1=Moreira |first1=Fernanda Duarte |last2=Reis |first2=Caio Eduardo Gonçalves |last3=Gallassi |first3=Andrea Donatti |last4=Moreira |first4=Daniel Carneiro |last5=Welker |first5=Alexis Fonseca |date=2024-10-09 |editor-last=Dardari |editor-first=Dured |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 |language=en |volume=19 |issue=10 |article-number=e0311501 |doi=10.1371/journal.pone.0311501 |issn=1932-6203 |pmc=11463819 |pmid=39383145 |bibcode=2024PLoSO..1911501M |doi-access=free}}</ref> * [[#SGLT2 inhibitors|SGLT2 inhibition]]: Inhibition of [[SGLT2 inhibitor|sodium-glucose transport protein 2]] (SGLT2) decreases glucose reabsorption in the renal tubules of nephrons, thus increasing the amount of glucose excreted in urine.

==Insulin== {{Main|Insulin (medication)}}

Insulin is usually given [[Subcutaneous tissue|subcutaneously]], either by injections or by an [[insulin pump]]. In acute care settings, insulin may also be given intravenously. Insulins are typically characterized by the rate at which they are metabolized by the body, yielding different peak times and durations of action.<ref>{{Cite book |title=[[Harrison's Principles of Internal Medicine]] |vauthors=Powers AC |date=2011 |publisher=McGraw-Hill |isbn=978-0-07-174889-6 |veditors=Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J |edition=18th |chapter=Diabetes Mellitus |editor-link2=Anthony Fauci}}</ref> Faster-acting insulins peak quickly and are subsequently metabolized, while longer-acting insulins tend to have extended peak times and remain active in the body for more significant periods.<ref name=":0">{{Cite book |title=Endotext |vauthors=Donner T, Sarkar S |date=2000 |publisher=MDText.com, Inc. |veditors=Feingold KR, Anawalt B, Boyce A, Chrousos G |chapter=Insulin – Pharmacology, Therapeutic Regimens, and Principles of Intensive Insulin Therapy |pmid=25905175 |access-date=2019-11-16 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK278938/}}</ref>

Examples of rapid-acting insulins (peak at ~1 hour) are:{{cn|date=July 2024}} * [[Insulin lispro]] (Humalog) * [[Insulin aspart]] (Novolog) * [[Insulin glulisine]] (Apidra)

Examples of short-acting insulins (peak 2–4 hours) are:{{cn|date=March 2025}} * Regular insulin (Humulin R, Novolin R) * Prompt insulin zinc (Semilente)

Examples of intermediate-acting insulins (peak 4–10 hours) are:{{cn|date=March 2025}} * Isophane insulin, neutral protamine Hagedorn (NPH) (Humulin N, Novolin N) * Insulin zinc (Lente)

Examples of long-acting insulins (duration 24 hours, often without peak) are: * Extended insulin zinc insulin (Ultralente) * Insulin glargine (Lantus) * Insulin detemir (Levemir) * Insulin degludec (Tresiba)

Insulin degludec is sometimes classed separately as an "ultra-long" acting insulin due to its duration of action of about 42 hours, compared with 24 hours for most other long-acting insulin preparations.<ref name=":0" />

As a systematic review of studies comparing insulin detemir, insulin glargine, insulin degludec and NPH insulin did not show any clear benefits or serious [[Side effect|adverse effects]] for any particular form of insulin for nocturnal [[hypoglycemia]], severe hypoglycemia, [[glycated hemoglobin]] A1c, non-fatal [[myocardial infarction]]/[[stroke]], [[Quality of life (healthcare)|health-related quality of life]] or [[all-cause mortality]].<ref name=":2">{{Cite journal |vauthors=Hemmingsen B, Metzendorf MI, Richter B |date=March 2021 |title=(Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus |journal=The Cochrane Database of Systematic Reviews |volume=3 |issue=4 |article-number=CD013498 |doi=10.1002/14651858.cd013498.pub2 |pmc=8094220 |pmid=33662147}}</ref> The same review did not find any differences in effects of using these insulin analogues between adults and children.<ref name=":2" />

Most oral anti-diabetic agents are contraindicated in pregnancy, in which case insulin is preferred.<ref name="agabegi2nd-185" />

Insulin is not administered by other routes, although this has been studied. An inhaled form was briefly licensed but was subsequently withdrawn.<ref>{{Cite journal |vauthors=Mastrandrea LD |date=March 2010 |title=Inhaled insulin: overview of a novel route of insulin administration |journal=Vascular Health and Risk Management |volume=6 |pages=47–58 |doi=10.2147/VHRM.S6098 |pmid=20234779 |pmc=2835554 |doi-access=free}}</ref>

==Sensitizers== Insulin sensitizers address the core problem in type 2 diabetes – [[insulin resistance]].

===Biguanides=== {{Main|Biguanide}}

[[Biguanide]]s reduce [[liver|hepatic]] glucose output and increase uptake of glucose by the periphery, including skeletal muscle. Although it must be used with caution in patients with impaired liver or [[kidney]] function, [[Metformin]], a biguanide, has become the most commonly used agent for type 2 diabetes in children and teenagers. Among common diabetic drugs, Metformin is the only widely used oral drug that does not cause weight gain.<ref>{{Cite journal |date=2024-01-04 |title=Erratum: Metformin: Current knowledge |journal=Journal of Research in Medical Sciences |language=en |volume=29 |issue=1 |page=6 |doi=10.4103/JRMS.JRMS_62_24 |issn=1735-1995 |pmc=10956562 |pmid=38524744 |doi-access=free}}</ref>

Typical reduction in [[glycated hemoglobin]]&nbsp;(A1C) values for Metformin is 1.5–2.0% * [[Metformin]] (Glucophage) may be the best choice for patients who also have heart failure,<ref name="pmid17761999">{{Cite journal |vauthors=Eurich DT, McAlister FA, Blackburn DF, Majumdar SR, Tsuyuki RT, Varney J, Johnson JA |date=September 2007 |title=Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review |journal=BMJ |volume=335 |issue=7618 |page=497 |doi=10.1136/bmj.39314.620174.80 |pmc=1971204 |pmid=17761999}}</ref> but it should be temporarily discontinued before any radiographic procedure involving intravenous [[iodine|iodinated]] [[radiocontrast|contrast]], as patients are at an increased risk of [[lactic acidosis]]. * [[Phenformin]] (DBI) was used from 1960s through 1980s, but was withdrawn due to lactic acidosis risk.<ref name="pmid16567854">{{Cite journal |vauthors=Fimognari FL, Pastorelli R, Incalzi RA |date=April 2006 |title=Phenformin-induced lactic acidosis in an older diabetic patient: a recurrent drama (phenformin and lactic acidosis) |url= |journal=Diabetes Care |volume=29 |issue=4 |pages=950–951 |doi=10.2337/diacare.29.04.06.dc06-0012 |pmid=16567854 |doi-access=free }}</ref> * [[Buformin]] also was withdrawn due to lactic acidosis risk.<ref name="Verdonck">{{Cite journal |vauthors=Verdonck LF, Sangster B, van Heijst AN, de Groot G, Maes RA |year=1981 |title=Buformin concentrations in a case of fatal lactic acidosis |journal=Diabetologia |volume=20 |issue=1 |pages=45–46 |doi=10.1007/BF01789112 |pmid=7202882 |doi-access=free}}</ref>

Metformin is a first-line medication used for treatment of type 2 diabetes. It is generally prescribed at initial diagnosis in conjunction with exercise and weight loss, as opposed to the past, where it was prescribed after diet and exercise had failed. There is an immediate-release as well as an extended-release formulation, typically reserved for patients experiencing [[gastrointestinal]] side-effects. It is also available in combination with other oral diabetic medications.{{cn|date=December 2024}}

===Thiazolidinediones=== {{Main|Thiazolidinedione}}

[[Thiazolidinedione]]s ([[TZD]]s), also known as "glitazones," bind to [[Peroxisome proliferator-activated receptor gamma|PPARγ]], peroxisome proliferator activated receptor [[Peroxisome proliferator-activated receptor gamma|γ]], a type of nuclear regulatory protein involved in the transcription of genes that regulate glucose and fat metabolism. These PPARs act on peroxisome proliferator responsive elements (PPRE).<ref>{{Cite web |title=diabetesinsulinPPAR |url=http://www.healthvalue.net/diabetesinsulinPPAR.html |url-status=live |archive-url=https://web.archive.org/web/20160303204348/http://www.healthvalue.net/diabetesinsulinPPAR.html |archive-date=March 3, 2016 |access-date=May 6, 2018 |website=www.healthvalue.net }}</ref> The PPREs influence insulin-sensitive genes, which enhance production of mRNAs of insulin-dependent enzymes. The final result is better use of glucose by the cells. These drugs also enhance PPAR-α activity and hence lead to a rise in HDL and some larger components of LDL.<ref>{{Cite journal |vauthors=Kersten S |date=2008-01-02 |title=Peroxisome proliferator activated receptors and lipoprotein metabolism |journal=PPAR Research |volume=2008 |issue=1 |article-number=132960 |doi=10.1155/2008/132960 |pmid=18288277 |doi-access=free |veditors=Chinetti G |pmc=2220040 }}</ref>

Typical reductions in [[glycated hemoglobin]]&nbsp;(A1C) values are 1.5–2.0%. Some examples are: * [[Rosiglitazone]] (Avandia): the [[European Medicines Agency]] recommended in September 2010 that it be suspended from the EU market due to elevated cardiovascular risks.<ref>European Medicines Agency, [http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2010/09/news_detail_001119.jsp&mid=WC0b01ac058004d5c1&jsenabled=true "European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim"] {{webarchive|url=https://web.archive.org/web/20140203052646/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fnews_and_events%2Fnews%2F2010%2F09%2Fnews_detail_001119.jsp&mid=WC0b01ac058004d5c1&jsenabled=true |date=February 3, 2014 }}, ''EMA'', 23 September 2009</ref> * [[Pioglitazone]] (Actos): remains on the market but has also been associated with increased cardiovascular risks.<ref name="pmid17848652">{{Cite journal |vauthors=Lincoff AM, Wolski K, Nicholls SJ, Nissen SE |date=September 2007 |title=Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials |journal=JAMA |volume=298 |issue=10 |pages=1180–1188 |doi=10.1001/jama.298.10.1180 |pmid=17848652}}</ref> * [[Troglitazone]] (Rezulin): used in 1990s, withdrawn due to [[hepatitis]] and liver damage risk.<ref>{{Cite news |date=October 1, 2008 |title=Retired Drugs: Failed Blockbusters, Homicidal Tampering, Fatal Oversights |url=https://www.wired.com/medtech/drugs/multimedia/2008/10/gallery_retired_drugs?slide=6&slideView=6 |url-status=live |archive-url=https://web.archive.org/web/20081204050525/http://www.wired.com/medtech/drugs/multimedia/2008/10/gallery_retired_drugs?slide=6&slideView=6 |archive-date=December 4, 2008 |access-date=2009-06-21 |publisher=[[Wired News]] |vauthors=Hinterthuer A}}</ref>

Multiple retrospective studies have resulted in a concern about rosiglitazone's safety, although it is established that the group, as a whole, has beneficial effects on diabetes. The greatest concern is an increase in the number of severe cardiac events in patients taking it. The ADOPT study showed that initial therapy with drugs of this type may prevent the progression of disease,<ref>{{Cite web |year=2007 |title=Expert Column – A Diabetes Outcome Progression Trial (ADOPT) |url=http://www.medscape.com/viewarticle/552484 |access-date=2007-09-21 |publisher=Medscape |vauthors=Haffner SM}}</ref> as did the DREAM trial.<ref>{{Cite web |date=24 October 2006 |title=DREAM: Rosiglitazone Effective in Preventing Diabetes |url=http://www.medscape.com/viewarticle/546503 |url-status=live |archive-url=https://web.archive.org/web/20081202225351/http://www.medscape.com/viewarticle/546503 |archive-date=December 2, 2008 |access-date=2007-09-21 |publisher=Medscape |vauthors=Gagnon L}}</ref> The [[American Association of Clinical Endocrinologists]] (AACE), which provides clinical practice guidelines for management of diabetes, retains thiazolidinediones as recommended first, second, or third line agents for type 2 diabetes mellitus, as of their 2019 executive summary, over sulfonylureas and α-glucosidase inhibitors. However, they are less preferred than GLP-1 agonists or SGLT2 inhibitors, especially in patients with cardiovascular disease (which [[liraglutide]], [[empagliflozin]], and [[canagliflozin]] are all FDA approved to treat).<ref name=":1">{{Cite journal |vauthors=Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Dagogo-Jack S, DeFronzo RA, Einhorn D, Fonseca VA, Garber JR, Garvey WT, Grunberger G, Handelsman Y, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Rosenblit PD, Umpierrez GE |date=January 2019 |title=Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2019 Executive Summary |journal=Endocrine Practice |volume=25 |issue=1 |pages=69–100 |doi=10.4158/cs-2018-0535 |pmid=30742570 |doi-access=free}}</ref>

Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in [[the New England Journal of Medicine]].<ref>{{Cite journal |vauthors=Nissen SE, Wolski K |date=June 2007 |title=Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes |journal=The New England Journal of Medicine |volume=356 |issue=24 |pages=2457–2471 |doi=10.1056/NEJMoa072761 |pmid=17517853 |doi-access=free}}</ref> There have been a significant number of publications since then, and a [[Food and Drug Administration]] panel<ref>{{Cite web |date=2007-07-31 |title=FDA Advisory Panels Acknowledge Signal of Risk With Rosiglitazone, but Stop Short of Recommending Its Withdrawal |url=http://www.medscape.com/viewarticle/560709 |url-status=live |archive-url=https://web.archive.org/web/20140318013618/http://www.medscape.com/viewarticle/560709 |archive-date=March 18, 2014 |access-date=2007-09-21 |publisher=Heartwire |vauthors=Wood S}}</ref> voted, with some controversy, 20:3 that available studies "supported a signal of harm", but voted 22:1 to keep the drug on the market. The meta-analysis was not supported by an interim analysis of the trial designed to evaluate the issue, and several other reports have failed to conclude the controversy. This weak evidence for adverse effects has reduced the use of rosiglitazone, despite its important and sustained effects on [[glycemic control]].<ref name="Ajjan">{{Cite journal |vauthors=Ajjan RA, Grant PJ |date=July 2008 |title=The cardiovascular safety of rosiglitazone |journal=Expert Opinion on Drug Safety |volume=7 |issue=4 |pages=367–376 |doi=10.1517/14740338.7.4.367 |pmid=18613801 |s2cid=73109231}}</ref> Safety studies are continuing.

In contrast, at least one large prospective study, PROactive 05, has shown that [[pioglitazone]] may decrease the overall incidence of cardiac events in people with type 2 diabetes who have already had a heart attack.<ref>{{Cite journal |vauthors=Erdmann E, Dormandy JA, Charbonnel B, Massi-Benedetti M, Moules IK, Skene AM |date=May 2007 |title=The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study |journal=Journal of the American College of Cardiology |volume=49 |issue=17 |pages=1772–1780 |doi=10.1016/j.jacc.2006.12.048 |pmid=17466227 |doi-access=free}}</ref>

===LYN Kinase Activators=== The [[LYN]] kinase activator [[Tolimidone]] has been reported to potentiate insulin signaling in a manner that is distinct from the glitazones.<ref name="Müller2000a">{{Cite journal |vauthors=Müller G, Wied S, Frick W |date=July 2000 |title=Cross talk of pp125(FAK) and pp59(Lyn) non-receptor tyrosine kinases to insulin-mimetic signaling in adipocytes |journal=Molecular and Cellular Biology |volume=20 |issue=13 |pages=4708–4723 |doi=10.1128/mcb.20.13.4708-4723.2000 |pmc=85892 |pmid=10848597}}</ref> The compound has demonstrated positive results in a Phase 2a clinical study involving 130 diabetic subjects.<ref>{{Cite web |date=June 13, 2016 |title=Melior Pharmaceuticals Announces Positive Phase 2A Results in Type 2 Diabetes Study |url=http://www.businesswire.com/news/home/20160613005028/en/Melior-Pharmaceuticals-Announces-Positive-Phase-2A-Results |url-status=live |archive-url=https://web.archive.org/web/20170812162052/http://www.businesswire.com/news/home/20160613005028/en/Melior-Pharmaceuticals-Announces-Positive-Phase-2A-Results |archive-date=August 12, 2017 |access-date=May 6, 2018 |website=businesswire.com }}</ref>

==Secretagogues== [[Secretagogue]]s are drugs that increase output from a gland, in the case of insulin from the [[pancreas]].{{cn|date=December 2024}}

===Sulfonylureas=== {{Main|Sulfonylurea}}

[[Sulfonylurea]]s were the first widely used oral anti-hyperglycemic medications. They are ''insulin secretagogues'', triggering insulin release by inhibiting the [[ATP-sensitive potassium channel|K<sub>ATP</sub>]] channel of the pancreatic [[beta cell]]s. Eight types of these pills have been marketed in North America, but not all remain available. The "second-generation" sulfonylureas are now more commonly used. They are more effective than first-generation drugs and have fewer side-effects. All may cause weight gain.{{cn|date=December 2024}}

Current clinical practice guidelines from the [[American Association of Clinical Endocrinologists|AACE]] rate sulfonylureas (as well as glinides) below all other classes of antidiabetic drugs in terms of suggested use as first, second, or third line agents - this includes [[Bromocriptine]], the bile acid sequestrant [[Colesevelam]], [[Alpha-glucosidase inhibitor|α-glucosidase inhibitors]], [[Thiazolidinedione]]s (glitazones), and [[Dipeptidyl peptidase-4 inhibitor|DPP-4 inhibitors]] (gliptins).<ref name=":1" /> The low cost of most sulfonylureas, however, especially when considering their significant efficacy in blood glucose reduction, tends to keep them as a more feasible option in many patients - neither SGLT2 inhibitors nor GLP-1 agonists, the classes most favored by the AACE guidelines after metformin, are currently available as generics.{{cn|date=December 2024}}

Sulfonylureas bind strongly to [[plasma protein]]s. Sulfonylureas are useful only in type 2 diabetes, as they work by stimulating endogenous release of insulin. They work best with patients over 40 years old who have had diabetes mellitus for under ten years. They cannot be used with type 1 diabetes, or diabetes of pregnancy. They can be safely used with metformin or glitazones. The primary side-effect is [[hypoglycemia]], which appears to happen more commonly with sulfonylureas than with other treatments.<ref name=":3">{{Cite journal |vauthors=Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A |date=October 2011 |title=Glucagon-like peptide analogues for type 2 diabetes mellitus |journal=The Cochrane Database of Systematic Reviews |volume=2011 |issue=10 |article-number=CD006423 |doi=10.1002/14651858.cd006423.pub2 |pmc=6486297 |pmid=21975753}}</ref>

A [[Cochrane (organisation)|Cochrane]] [[systematic review]] from 2011 showed that treatment with [[Sulfonylurea]]s did not improve control of glucose levels more than insulin at 3 nor 12 months of treatment.<ref name=":4">{{Cite journal |vauthors=Brophy S, Davies H, Mannan S, Brunt H, Williams R |date=September 2011 |title=Interventions for latent autoimmune diabetes (LADA) in adults |journal=The Cochrane Database of Systematic Reviews |volume=2011 |issue=9 |article-number=CD006165 |doi=10.1002/14651858.cd006165.pub3 |pmc=6486159 |pmid=21901702}}</ref> This same review actually found evidence that treatment with Sulfonylureas could lead to earlier insulin dependence, with 30% of cases requiring insulin at 2 years.<ref name=":4" /> When studies measured fasting [[C-peptide]], no intervention influenced its concentration, but insulin maintained concentration better compared to Sulphonylurea.<ref name=":4" /> Still, it is important to highlight that the studies available to be included in this review presented considerable flaws in quality and design.<ref name=":4" />

Typical reductions in [[glycated hemoglobin]]&nbsp;(A1C) values for second-generation sulfonylureas are 1.0–2.0%. * First-generation agents ** [[tolbutamide]] ** [[acetohexamide]] ** [[tolazamide]] ** [[chlorpropamide]] * Second-generation agents ** [[glipizide]] ** glyburide or [[glibenclamide]] ** [[glimepiride]] ** [[gliclazide]] ** [[glyclopyramide]] ** [[gliquidone]]

===Meglitinides=== {{Main|Meglitinide}}

[[Meglitinide]]s help the pancreas produce insulin and are often called "short-acting secretagogues." They act on the same potassium channels as sulfonylureas, but at a different binding site.<ref>{{Cite journal |vauthors=Rendell M |date=September 2004 |title=Advances in diabetes for the millennium: drug therapy of type 2 diabetes |journal=MedGenMed |volume=6 |issue=3 Suppl |page=9 |pmc=1474831 |pmid=15647714}}</ref> By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, thereby enhancing insulin secretion.<ref name="diabetespancreasbeta">{{Cite web |title=Helping the pancreas produce insulin |url=http://www.healthvalue.net/diabetespancreasbeta.html |url-status=live |archive-url=https://web.archive.org/web/20070927043729/http://www.healthvalue.net/diabetespancreasbeta.html |archive-date=September 27, 2007 |access-date=2007-09-21 |publisher=HealthValue}}</ref>

They are taken with or shortly before meals to boost the insulin response to each meal. If a meal is skipped, the medication is also skipped. {{cn|date=January 2025}}

Typical reductions in [[glycated hemoglobin]]&nbsp;(A1C) values are 0.5–1.0%. {{cn|date=January 2025}} * [[repaglinide]] * [[nateglinide]]

Adverse reactions include weight gain and hypoglycemia.

==Alpha-glucosidase inhibitors== {{Main|Alpha-glucosidase inhibitor}}

[[Alpha-glucosidase inhibitor]]s are a class of diabetes drugs found in plants/herbs like cinnamon;<ref name=fdm/> however, they are technically not hypoglycemic agents because they do not have a direct effect on insulin secretion or sensitivity. These agents slow the digestion of starch in the small intestine, such that glucose from the starch enters the bloodstream at a slower rate, and can be matched more effectively by an impaired insulin response or sensitivity. The intake of a single dose before a meal containing complex carbohydrates clearly suppresses the glucose spike and may decrease the [[postprandial hyperglycemia]] (higher than 140 mg/dL; >7.8 mmol/L) in patients with type II diabetes.<ref name=fdm/> These agents are effective by themselves only in the earliest stages of [[impaired glucose tolerance]], but can be helpful in combination with other agents in [[type 2 diabetes]].{{cn|date=March 2025}}

Typical reductions in [[glycated hemoglobin]]&nbsp;(A1C) values are 0.5–1.0%.{{cn|date=March 2025}} * [[miglitol]] * [[acarbose]] * [[voglibose]] These medications are rarely used in the United States because of the severity of their side-effects (flatulence and bloating). They are more commonly prescribed in Europe. They do have the potential to cause weight loss by lowering the amount of sugar metabolized.{{cn|date=March 2025}}

==Peptide analogs== {{more citations needed section|date=January 2016}} [[Image:Incretins and DPP 4 inhibitors.svg|thumb|300px|right|Overview of insulin secretion]]

===Injectable incretin mimetics=== [[Incretin]]s are also insulin [[secretagogue]]s. The two main candidate molecules that fulfill criteria for being an incretin are [[glucagon-like peptide-1]] (GLP-1) and [[gastric inhibitory peptide]] (glucose-dependent insulinotropic peptide, GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme [[dipeptidyl peptidase-4]] (DPP-4).

====Injectable glucagon-like peptide analogs and agonists==== Glucagon-like peptide (GLP) agonists bind to a membrane GLP receptor.<ref name=diabetespancreasbeta/> As a consequence, insulin release from the pancreatic beta cells is increased. Endogenous GLP has a half-life of only a few minutes, thus an analogue of GLP would not be practical. As of 2019, the [[American Association of Clinical Endocrinologists|AACE]] lists GLP-1 agonists, along with SGLT2 inhibitors, as the most preferred anti-diabetic agents after metformin. [[Liraglutide]] in particular may be considered first-line in diabetic patients with cardiovascular disease, as it has received FDA approval for reduction of risk of major adverse cardiovascular events in patients with type 2 diabetes.<ref name=":1" /><ref>{{Cite web |title=Victoza (liraglutide) is Approved to Reduce the Risk of Three Major Adverse Cardiovascular Events in Type 2 Diabetes Patients |url=https://www.drugs.com/newdrugs/victoza-liraglutide-approved-reduce-risk-three-major-adverse-cardiovascular-events-type-2-diabetes-4582.html |access-date=2019-11-16 |website=Drugs.com |language=en}}</ref> In a 2011 [[Cochrane (organisation)|Cochrane]] [[Systematic review|review]], GLP-1 agonists showed approximately a 1% reduction in HbA1c when compared to placebo.<ref name=":3" /> GLP-1 agonists also show improvement of [[Beta cell|beta-cell]] function, but this effect does not last after treatment is stopped.<ref name=":3" /> Due to shorter duration of studies, this review did not allow for long-term positive or negative effects to be assessed.<ref name=":3" /> * [[Exenatide]] (also Exendin-4, marketed as Byetta) is the first [[glucagon-like peptide-1|GLP-1]] agonist approved for the treatment of [[type 2 diabetes]]. Exenatide is not an analogue of GLP but rather a GLP agonist.<ref>{{Cite journal |vauthors=Briones M, Bajaj M |date=June 2006 |title=Exenatide: a GLP-1 receptor agonist as novel therapy for Type 2 diabetes mellitus |journal=Expert Opinion on Pharmacotherapy |volume=7 |issue=8 |pages=1055–1064 |doi=10.1517/14656566.7.8.1055 |pmid=16722815 |s2cid=43740629}}</ref><ref>{{Cite journal |vauthors=Gallwitz B |date=December 2006 |title=Exenatide in type 2 diabetes: treatment effects in clinical studies and animal study data |journal=International Journal of Clinical Practice |volume=60 |issue=12 |pages=1654–1661 |doi=10.1111/j.1742-1241.2006.01196.x |pmid=17109672 |s2cid=8800490 |doi-access=free}}</ref> Exenatide has only 53% homology with GLP, which increases its resistance to degradation by DPP-4 and extends its half-life.<ref name="pmid17428109">{{Cite journal |vauthors=Cvetković RS, Plosker GL |year=2007 |title=Exenatide: a review of its use in patients with type 2 diabetes mellitus (as an adjunct to metformin and/or a sulfonylurea) |journal=Drugs |volume=67 |issue=6 |pages=935–954 |doi=10.2165/00003495-200767060-00008 |pmid=17428109 |s2cid=195691202}}</ref> A 2011 Cochrane review showed a HbA1c reduction of 0.20% more with Exenatide 2&nbsp;mg compared to insulin glargine, exenatide 10&nbsp;μg twice daily, sitagliptin and pioglitazone.<ref name=":3" /> Exenatide, together with liraglutide, led to greater weight loss than glucagon-like peptide analogues.<ref name=":3" /> * [[Liraglutide]], a once-daily human analogue (97% homology), has been developed by [[Novo Nordisk]] under the brand name [[Victoza]]. The product was approved by the [[European Medicines Agency]] (EMEA) on July 3, 2009, and by the [[U.S. Food and Drug Administration]] (FDA) on January 25, 2010.<ref>{{Cite web |title=Novo Nordisk Files for Regulatory Approval of Liraglutide in Both the US and Europe |url=https://www.drugs.com/nda/liraglutide_080530.html |url-status=live |archive-url=https://web.archive.org/web/20171215054200/https://www.drugs.com/nda/liraglutide_080530.html |archive-date=December 15, 2017 |access-date=2018-01-23 }} May 2008</ref><ref>{{Cite web |title=Liraglutide Provides Significantly Better Glucose Control Than Insulin Glargine in Phase 3 Study |url=http://www.medicalnewstoday.com/articles/74913.php |url-status=live |archive-url=https://web.archive.org/web/20100723042509/http://www.medicalnewstoday.com/articles/74913.php |archive-date=July 23, 2010 |access-date=2010-02-09 }} "Liraglutide Provides Significantly Better Glucose Control Than Insulin Glargine In Phase 3 Study" June 2007</ref><ref>{{Cite web |title=Clinical Study Shows Liraglutide Reduced Blood Sugar, Weight, and Blood Pressure in Patients with Type 2 Diabetes |url=http://www.medicalnewstoday.com/articles/110349.php |url-status=live |archive-url=https://web.archive.org/web/20090205233559/http://www.medicalnewstoday.com/articles/110349.php |archive-date=February 5, 2009 |access-date=2010-02-09 }} "Clinical Study Shows Liraglutide Reduced Blood Sugar, Weight, And Blood Pressure In Patients With Type 2 Diabetes" June 2008</ref><ref>{{Cite web |title=Liraglutide – Next-Generation Antidiabetic Medication |work=Drug Development Technology |url=http://www.drugdevelopment-technology.com/projects/liraglutide/ |url-status=live |archive-url=https://web.archive.org/web/20100618110150/http://www.drugdevelopment-technology.com/projects/liraglutide/ |archive-date=June 18, 2010 |access-date=2010-02-09 }}</ref><ref>{{Cite web |title=Quarterly R&D; Update - Novo Nordisk A/S |url=http://www.novonordisk.com/science/about_rd/quarterly_rd_update.asp |archive-url=https://web.archive.org/web/20100109101501/http://www.novonordisk.com/science/about_rd/quarterly_rd_update.asp |archive-date=January 9, 2010 |access-date=2010-02-09}} Oct 2008 Inc results of LEAD 6 extension</ref><ref>{{Cite web |title=Novo Nordisk Receives US Approval for Victoza(R) (Liraglutide) for the Treatment of Type 2 Diabetes |url=https://money.cnn.com/news/newsfeeds/articles/marketwire/0580389.htm |url-status=dead |archive-url=https://web.archive.org/web/20100129215943/https://money.cnn.com/news/newsfeeds/articles/marketwire/0580389.htm |archive-date=January 29, 2010 |access-date=2010-02-09 }} January 2009</ref> A 2011 Cochrane review showed a HbA1c reduction of 0.24% more with liraglutide 1.8&nbsp;mg compared to insulin glargine, 0.33% more than exenatide 10&nbsp;μg twice daily, sitagliptin and rosiglitazone.<ref name=":3" /> Liraglutide, together with exenatide, led to greater weight loss than glucagon-like peptide analogues.<ref name=":3" /> * [[Taspoglutide]] is presently in Phase III clinical trials with [[Hoffman-La Roche]]. * [[Lixisenatide]] (Lyxumia) Sanofi Aventis * [[Semaglutide]] (Ozempic) (oral version is Rybelsus) * [[Dulaglutide]] ([[Trulicity]]) - once weekly * [[Albiglutide]] (Tanzeum) - once weekly * [[Tirzepatide]] - once weekly (dual GLP-1 and [[Gastric inhibitory polypeptide receptor|GIP]] agonist; manufactured by [[Eli Lilly]], and approved in 2022. It is marketed under the brand name Mounjaro for type II diabetes, and Zepbound for obesity.)<ref>{{Cite journal |vauthors=Frías JP, [[Melanie Davies|Davies MJ]], Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, Liu B, Cui X, Brown K |date=August 2021 |title=Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes |journal=[[The New England Journal of Medicine]] |volume=385 |issue=6 |pages=503–515 |doi=10.1056/NEJMoa2107519 |pmid=34170647 |s2cid=235635529 |doi-access=free}}</ref> These agents may also cause a decrease in gastric motility, responsible for the common side-effect of nausea, which tends to subside with time.<ref name=":3" />

====Gastric inhibitory peptide analogs====

====Dipeptidyl peptidase-4 inhibitors==== {{Main|Dipeptidyl peptidase-4 inhibitor}}

GLP-1 analogs resulted in weight loss and had more gastrointestinal side-effects, while in general [[dipeptidyl peptidase-4]] (DPP-4) inhibitors were weight-neutral and are associated with increased risk for infection and headache. Both classes appear to present an alternative to other antidiabetic drugs. However, weight gain and/or hypoglycemia have been observed when [[dipeptidyl peptidase-4 inhibitor]]s were used with sulfonylureas; effects on long-term health and morbidity rates are still unknown.<ref name="nps01">{{Cite journal |last=National Prescribing Service |date=1 August 2010 |title=Dipeptidyl peptidase-4 inhibitors ('gliptins') for type 2 diabetes mellitus |url=https://www.nps.org.au/radar/articles/dipeptidyl-peptidase-4-inhibitors-gliptins-for-type-2-diabetes-mellitus |journal=RADAR |access-date=7 March 2021}}</ref>

DPP-4 inhibitors increase blood concentration of the [[incretin]] GLP-1 by inhibiting its degradation by DPP-4.

Examples are: * [[vildagliptin]] (Galvus) EU Approved 2008 * [[sitagliptin]] (Januvia) FDA approved Oct 2006 * [[saxagliptin]] (Onglyza) FDA Approved July 2009 * [[linagliptin]] (Tradjenta) FDA Approved May 2, 2011 * [[alogliptin]] * septagliptin * [[teneligliptin]] * [[gemigliptin]] (Zemiglo)

DPP-4 inhibitors lowered hemoglobin [[Glycated hemoglobin|A1C]] values by 0.74%, comparable to other antidiabetic drugs.<ref>{{Cite journal |vauthors=Amori RE, Lau J, Pittas AG |date=July 2007 |title=Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis |journal=JAMA |volume=298 |issue=2 |pages=194–206 |doi=10.1001/jama.298.2.194 |pmid=17622601}}</ref>

A result in one RCT comprising 206 patients aged 65 or older (mean baseline HgbA1c of 7.8%) receiving either 50 or 100&nbsp;mg/d of [[sitagliptin]] was shown to reduce HbA1c by 0.7% (combined result of both doses).<ref>{{Cite journal |vauthors=Barzilei N, Mahoney EM, Guo H |year=2009 |title=Sitagliptin is well tolerated and leads to rapid improvement in blood glucose in the first days of monotherapy in patients aged 65 years and older with T2DM |journal=Diabetes |volume=58 |page=587}}</ref> A combined result of 5 RCTs enlisting a total of 279 patients aged 65 or older (mean baseline HbA1c of 8%) receiving 5&nbsp;mg/d of [[saxagliptin]] was shown to reduce HbA1c by 0.73%.<ref>{{Cite journal |vauthors=Doucet J, Chacra A, Maheux P, Lu J, Harris S, Rosenstock J |date=April 2011 |title=Efficacy and safety of saxagliptin in older patients with type 2 diabetes mellitus |journal=Current Medical Research and Opinion |volume=27 |issue=4 |pages=863–869 |doi=10.1185/03007995.2011.554532 |pmid=21323504 |s2cid=206965817}}</ref> A combined result of 5 RCTs enlisting a total of 238 patients aged 65 or older (mean baseline HbA1c of 8.6%) receiving 100&nbsp;mg/d of [[vildagliptin]] was shown to reduce HbA1c by 1.2%.<ref>{{Cite journal |vauthors=Pratley RE, Rosenstock J, Pi-Sunyer FX, Banerji MA, Schweizer A, Couturier A, Dejager S |date=December 2007 |title=Management of type 2 diabetes in treatment-naive elderly patients: benefits and risks of vildagliptin monotherapy |journal=Diabetes Care |volume=30 |issue=12 |pages=3017–3022 |doi=10.2337/dc07-1188 |pmid=17878242 |doi-access=free}}</ref> Another set of 6 combined RCTs involving [[alogliptin]] (approved by FDA in 2013) was shown to reduce HbA1c by 0.73% in 455 patients aged 65 or older who received 12.5 or 25&nbsp;mg/d of the medication.<ref>{{Cite journal |vauthors=Pratley RE, McCall T, Fleck PR, Wilson CA, Mekki Q |date=November 2009 |title=Alogliptin use in elderly people: a pooled analysis from phase 2 and 3 studies |journal=Journal of the American Geriatrics Society |volume=57 |issue=11 |pages=2011–2019 |doi=10.1111/j.1532-5415.2009.02484.x |pmid=19793357 |s2cid=28683917}}</ref>

===Injectable amylin analogues===

[[Amylin]] agonist analogues slow gastric emptying and suppress [[glucagon]]. They have all the incretins actions except stimulation of insulin secretion. {{As of|2007}}, [[pramlintide]] is the only clinically available amylin analogue. Like insulin, it is administered by [[subcutaneous injection]]. The most frequent and severe adverse effect of pramlintide is [[nausea]], which occurs mostly at the beginning of treatment and gradually reduces. Typical reductions in A1C values are 0.5–1.0%.<ref>{{Cite journal |vauthors=Ryan G, Briscoe TA, Jobe L |date=February 2009 |title=Review of pramlintide as adjunctive therapy in treatment of type 1 and type 2 diabetes |journal=Drug Design, Development and Therapy |volume=2 |pages=203–214 |doi=10.2147/DDDT.S3225 |pmid=19920907 |pmc=2761191 |doi-access=free}}</ref>

==SGLT2 inhibitors== {{Main|Gliflozin}}

[[SGLT2 inhibitor]]s block the sodium-glucose linked transporter 2 proteins in [[renal tubule]]s of [[nephron]]s in kidneys, reabsorption of glucose in into the renal tubules, promoting excretion of glucose in the urine. This causes both mild weight loss, and a mild reduction in blood sugar levels with little risk of hypoglycemia.<ref>{{Cite journal |vauthors=Dietrich E, Powell J, Taylor JR |date=November 2013 |title=Canagliflozin: a novel treatment option for type 2 diabetes |journal=Drug Design, Development and Therapy |volume=7 |pages=1399–1408 |doi=10.2147/DDDT.S48937 |pmc=3840773 |pmid=24285921 |doi-access=free}}</ref> Oral preparations may be available alone or in combination with other agents.<ref>{{Cite web |last=Center for Drug Evaluation and Research |title=Drug Safety and Availability - Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors |url=https://www.fda.gov/Drugs/DrugSafety/ucm446852.htm |archive-url=https://web.archive.org/web/20161129094121/http://www.fda.gov/Drugs/DrugSafety/ucm446852.htm |archive-date=November 29, 2016 |access-date=2017-08-26 |website=www.fda.gov |language=en }}</ref> Along with GLP-1 agonists, they are considered preferred second or third agents for type 2 diabetics sub-optimally controlled with metformin alone, according to most recent clinical practice guidelines.<ref name=":1" /> Because they are taken by mouth, rather than injected (like GLP-1 agonists), patients who are [[Fear of needles|injection-averse]] may prefer these agents over the former. They may be considered first line in diabetic patients with cardiovascular disease, especially [[heart failure]], as these medications have been shown to reduce the risk of hospitalization in patients with such comorbidities.<ref>{{Cite web |title=UpToDate |url=https://www.uptodate.com/contents/sodium-glucose-co-transporter-2-inhibitors-for-the-treatment-of-hyperglycemia-in-type-2-diabetes-mellitus?search=sglt2%20inhibitors&source=search_result&selectedTitle=2~69&usage_type=default&display_rank=1#H3506386806 |access-date=2019-11-16 |website=www.uptodate.com}}</ref> Because they are not available as generic medications, however, cost may limit their feasibility for many patients. Furthermore, there has been growing evidence that the effectiveness and safety of this drug class could depend on genetic variability of the patients.<ref>[https://www.bjbms.org/ojs/index.php/bjbms/article/view/5646 Imamovic Kadric S, Kulo Cesic A, Dujic T. Pharmacogenetics of new classes of antidiabetic drugs. Bosn J of Basic Med Sci. 2021.] DOI: https://doi.org/10.17305/bjbms.2021.5646</ref>

Examples include:{{cn|date=March 2025}} * [[Dapagliflozin]] * [[Canagliflozin]] * [[Empagliflozin]] * [[Remogliflozin]]

The side effects of SGLT2 inhibitors are derived directly from their mechanism of action; these include an increased risk of: [[ketoacidosis]], [[urinary tract infection]]s, [[Vaginal yeast infection|candidal vulvovaginitis]], and [[hypoglycemia]].<ref>{{Cite news |title=SGLT2 Inhibitors (Gliflozins) – Drugs, Suitability, Benefits & Side Effects |url=http://www.diabetes.co.uk/diabetes-medication/sglt2-inhibitors.html |url-status=live |archive-url=https://web.archive.org/web/20170827050028/http://www.diabetes.co.uk/diabetes-medication/sglt2-inhibitors.html |archive-date=August 27, 2017 |access-date=2017-08-26 }}</ref>

==Comparison== The following table compares some common anti-diabetic agents, generalizing classes, although there may be substantial variation in individual drugs of each class. When the table makes a comparison such as "lower risk" or "more convenient" the comparison is with the other drugs on the table.

{| class="wikitable sortable" |- ! colspan="5" style="background-color: #CCEEEE;" | Comparison of anti-diabetic medication<ref>{{Cite journal |vauthors=Cambon-Thomsen A, Rial-Sebbag E, Knoppers BM |date=August 2007 |title=Trends in ethical and legal frameworks for the use of human biobanks |journal=The European Respiratory Journal |volume=30 |issue=2 |pages=373–382 |doi=10.1183/09031936.00165006 |pmid=17666560 |doi-access=free}} adapted from table 2, which includes a list of issues</ref><ref name="BBDdiabetesM2">{{Cite journal |last=Consumer Reports Health Best Buy Drugs |author-link=Consumer Reports |title=The Oral Diabetes Drugs: Treating Type 2 Diabetes |url=http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/DiabetesUpdate-FINAL-Feb09.pdf |url-status=live |journal=Best Buy Drugs |publisher=[[Consumer Reports]] |page=20 |archive-url=https://web.archive.org/web/20130227145458/http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/DiabetesUpdate-FINAL-Feb09.pdf |archive-date=February 27, 2013 |access-date=September 18, 2012 }}, which is citing * {{cite journal|title=Oral Diabetes Medications for Adults With Type 2 Diabetes. An Update|journal=Comparative Effectiveness Review|date=March 2011|number=27|url=http://effectivehealthcare.ahrq.gov/ehc/products/155/645/Oral%20Diabetes_ExSumm%20%282%29.pdf|access-date=28 November 2012|author=Agency for Healthcare Research and Quality|author-link=Agency for Healthcare Research and Quality|archive-url=https://web.archive.org/web/20130927121129/http://effectivehealthcare.ahrq.gov/ehc/products/155/645/Oral%20Diabetes_ExSumm%20%282%29.pdf|archive-date=September 27, 2013}} * {{cite journal | vauthors = Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R, Marinopoulos SS, Puhan MA, Ranasinghe P, Block L, Nicholson WK, Hutfless S, Bass EB, Bolen S | title = Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations | journal = Annals of Internal Medicine | volume = 154 | issue = 9 | pages = 602–613 | date = May 2011 | pmid = 21403054 | pmc = 3733115 | doi = 10.7326/0003-4819-154-9-201105030-00336 }}</ref> |- ! Drug class<ref name="BBDdiabetesM2" /> ! Mechanism of action<ref name="agabegi2nd-185">Table entries taken from page 185 in: {{Cite book |last1=Elizabeth D Agabegi |url=https://archive.org/details/stepuptomedicine0000agab |title=Step-Up to Medicine (Step-Up Series) |last2=Agabegi, Steven S. |publisher=Lippincott Williams & Wilkins |year=2008 |isbn=978-0-7817-7153-5 |location=Hagerstwon, MD |url-access=registration}}</ref> ! Advantages<ref name="BBDdiabetesM2" /> ! Disadvantages<ref name="BBDdiabetesM2" /> |- | [[Sulfonylurea]]s ([[glyburide]], [[glimepiride]], [[glipizide]]) | Stimulating insulin release by pancreatic [[beta cell]]s by inhibiting the [[ATP-sensitive potassium channel|K<sub>ATP</sub> channel]] | * Inexpensive * Fast onset of action * No effect on [[blood pressure]] * No detrimental effect on [[low-density lipoprotein]] * Lower risk of [[Human gastrointestinal tract|gastrointestinal]] side effects than metformin * Convenient dosing | * Cause an average of 2–5&nbsp;kg [[weight gain]] * Increase the risk of hypoglycemia * Glyburide increases risk of [[hypoglycemia]] slightly more compared to glimepiride and glipizide

|- | [[Metformin]] | Acts on the liver to reduce gluconeogenesis and causes a decrease in [[insulin resistance]] via increasing [[AMPK]] signalling. | * Associated with weight loss * Lower risk of hypoglycemia compared to other antidiabetics * Decreases [[low-density lipoprotein]] * Decreases [[triglycerides]] * No effect on blood pressure * Lowered all-cause mortality in diabetics * Inexpensive | * Higher risk of [[Human gastrointestinal tract|gastrointestinal]] side effects * Due to the risk of potentially fatal [[lactic acidosis]], contraindicated in people with [[shock (circulatory)|shock]]; with acute or chronic, moderate or severe [[kidney disease]] or at risk for impaired kidney function from [[Radiocontrast agent|intravenous dye]]; and with acute or chronic [[metabolic acidosis]] * Risk of lactic acidosis also is increased for people with unstable or acute [[heart failure]], [[liver disease]], or [[alcoholism]], or who are recovering from major [[surgery]] * Increased risk of [[vitamin B12 deficiency]]<ref name=agabegi2nd-185/> * [[Metallic taste]]<ref name=agabegi2nd-185/> |- | [[Alpha-glucosidase inhibitor]]s ([[acarbose]], [[miglitol]], [[voglibose]]) | Inhibit carbohydrate digestion in the small intestine by inhibiting enzymes that break down polysaccharides | * Slightly lower risk of hypoglycemia compared to sulfonylureas * Associated with modest weight loss * Decreases triglycerides * No detrimental effect on cholesterol | * Less effective than most other diabetes pills in lowering [[glycated hemoglobin]] * Increased risk of GI side effects than other diabetes pills except metformin * Inconvenient dosing |- | [[Thiazolidinediones]] ([[Pioglitazone]], [[Rosiglitazone]]) | Reduce insulin resistance by activating [[Peroxisome proliferator-activated receptor gamma|PPAR-γ]] in fat and muscle | * Lower the risk of hypoglycemia * May slightly increase [[high-density lipoprotein]] * Rosiglitazone linked to decreased triglycerides * Convenient dosing | * Increase the risk of [[heart failure]] * Cause an average of 2–5&nbsp;kg [[weight gain]] * Are associated with a higher risk of edema, anemia and bone fractures * Can increase low-density lipoprotein * Rosiglitazone has been linked to increased triglycerides and an increased risk of a heart attack * Pioglitazone has been linked to an increased risk of bladder cancer * Have a slower onset of action * Require monitoring for [[hepatotoxicity]] * Expensive |- |[[SGLT2 inhibitors]] |}

==Generics== Many anti-diabetes drugs are available as generics. These include:<ref>{{Cite web |title=The Oral Diabetes Drugs Treating Type 2 Diabetes Comparing Effectiveness, Safety, and Price |url=http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/DiabetesUpdate-FINAL-Feb09.pdf |url-status=live |archive-url=https://web.archive.org/web/20130615083100/http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/DiabetesUpdate-FINAL-Feb09.pdf |archive-date=June 15, 2013 |access-date=July 17, 2013 }}</ref> * [[Sulfonylureas]] – glimepiride, glipizide, glyburide * [[Biguanides]] – metformin * [[Thiazolidinediones]] (Tzd) – pioglitazone, Actos generic * [[Alpha-glucosidase inhibitor]]s – Acarbose * [[Meglitinide]]s – nateglinide * Combination of sulfonylureas plus metformin – known by generic names of the two drugs No generics are available for [[dipeptidyl peptidase-4 inhibitor]]s (Onglyza), the glifozins, the incretins and various combinations. Sitagliptin patent expired in July 2022, leading to launch of generic sitagliptin<ref>{{Cite web |date=31 January 2024 |title=Sitagliptin Generic Alternatives |url=https://sastimedic.com/219-price-of-Januvia-100-mg-Tablet-Strip-of-7-Tablets-price-in-india |access-date=31 January 2024 |website=www.sastimedic.com}}</ref> brands . This lowered the cost of therapy for type 2 diabetes using sitagliptin .{{cn|date=March 2025}}

== Alternative Medicine == The effect of [[Ayurveda|Ayurvedic]] treatments has been researched, however due to methodological flaws of relevant studies and research, it has not been possible to draw conclusions regarding efficacy of these treatments and there is insufficient evidence to recommend them.<ref>{{Cite journal |vauthors=Sridharan K, Mohan R, Ramaratnam S, Panneerselvam D |date=December 2011 |title=Ayurvedic treatments for diabetes mellitus |journal=The Cochrane Database of Systematic Reviews |issue=12 |article-number=CD008288 |doi=10.1002/14651858.CD008288.pub2 |pmc=3718571 |pmid=22161426 |collaboration=Cochrane Metabolic and Endocrine Disorders Group}}</ref>

== References == {{Reflist|30em}}

== Further reading == * {{Cite book |last=Lebovitz, Harold E. |url=https://archive.org/details/therapyfordiabet0000unse_w1x1 |title=Therapy For Diabetes Mellitus and Related Disorders |publisher=[[American Diabetes Association]] |year=2004 |isbn=978-1-58040-187-6 |edition=4th |location=Alexandria, VA |url-access=registration}} * {{Cite book |last1=Adams, Michael Ian |url=https://archive.org/details/coreconceptsinph0000holl |title=Core Concepts in Pharmacology |last2=Holland, Norman Norwood |publisher=Prentice Hall |year=2003 |isbn=978-0-13-089329-1 |location=Englewood Cliffs, NJ |url-access=registration}}

{{Oral hypoglycemics}} {{Major Drug Groups}} {{Diabetes}} {{Authority control}}

{{DEFAULTSORT:Anti-Diabetic Drug}} [[Category:Anti-diabetic drugs| ]]