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Metformin

Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. It is sometimes used as an off-label adjunct to lessen the risk of metabolic syndrome in people who take antipsychotics. Metformin is not associated with weight gain and is taken by mouth.

Metformin is generally well tolerated. Common adverse effects include diarrhea, nausea, and abdominal pain. It has a small risk of causing low blood sugar. High blood lactic acid level (acidosis) is a concern if the medication is used in overly large doses or prescribed in people with severe kidney problems. It also inhibits inflammation.

Metformin is a biguanide anti-hyperglycemic agent. It works by decreasing glucose production in the liver, increasing the insulin sensitivity of body tissues, and increasing GDF15 secretion, which reduces appetite and caloric intake.

Metformin was first described in scientific literature in 1922 by Emil Werner and James Bell. French physician Jean Sterne began the study in humans in the 1950s. It was introduced as a medication in France in 1957. Metformin is on the World Health Organization's List of Essential Medicines, and is the most widely used medication for diabetes taken by mouth. It is available as a generic medication. In 2021, it was the second most commonly prescribed medication in the United States, with more than 91million prescriptions.

Medical uses
Metformin is used to lower the blood glucose in those with type2 diabetes. It is also used as a second-line agent for infertility in those with polycystic ovary syndrome.

Type 2 diabetes
The American Diabetes Association and the American College of Physicians both recommend metformin as a first-line agent to treat type2 diabetes. It is as effective as repaglinide and more effective than all other oral drugs for type2 diabetes.

Efficacy
Treatment guidelines for major professional associations, including the European Association for the Study of Diabetes, the European Society for Cardiology, and the American Diabetes Association, describe evidence for the cardiovascular benefits of metformin as equivocal. A 2020 Cochrane systematic review did not find enough evidence of reduction of cardiovascular mortality, non-fatal myocardial infarction or non-fatal stroke when comparing metformin monotherapy to other glucose-lowering drugs, behavior change interventions, placebo or no intervention.

The use of metformin reduces body weight in people with type2 diabetes in contrast to sulfonylureas, which are associated with weight gain. Some evidence shows that metformin is associated with weight loss in obesity in the absence of diabetes. Metformin has a lower risk of hypoglycemia than the sulfonylureas, although hypoglycemia has uncommonly occurred during intense exercise, calorie deficit, or when used with other agents to lower blood glucose. Metformin modestly reduces low density lipoprotein and triglyceride levels.

In individuals with prediabetes, a 2019 systematic review comparing the effects of metformin with other interventions in the reduction of risk of developing type2 diabetes found moderate-quality evidence that metformin reduced the risk of developing type2 diabetes when compared to diet and exercise or a placebo. However, when comparing metformin to intensive diet or exercise, moderate-quality evidence was found that metformin did not reduce risk of developing type2 diabetes and very low-quality evidence was found that adding metformin to intensive diet or exercise did not show any advantage or disadvantage in reducing risk of type2 diabetes when compared to intensive exercise and diet alone. The same review also found one suitable trial comparing the effects of metformin and sulfonylurea in reducing risk of developing type2 diabetes in prediabetic individuals, however this trial did not report any patient relevant outcomes.

Polycystic ovarian syndrome
In those with polycystic ovarian syndrome (PCOS), tentative evidence shows that metformin use increases the rate of live births. This includes in those who have not been able to get pregnant with clomiphene. Metformin does not appear to change the risk of miscarriage. A number of other benefits have also been found both during pregnancy and in nonpregnant women with PCOS. In an updated Cochrane (2020) review on metformin versus placebo/no treatment before or during IVF/ICSI in women with PCOS no conclusive evidence of improved live birth rates was found. In long GnRH-agonist protocols there was uncertainty in the evidence of improved live birth rates but there could be increases in clinical pregnancy rate. In short GnRH-antagonist protocols metformin may reduce live birth rates with uncertainty on its effect on clinical pregnancy rate. Metformin may result in a reduction of OHSS but could come with a greater frequency of side effects. There was uncertainty as to metformin's impact on miscarriage. The evidence does not support general use during pregnancy for improving maternal and infant outcomes in obese women.

The United Kingdom's National Institute for Health and Clinical Excellence recommended in 2004 that women with PCOS and a body mass index above 25 be given metformin for anovulation and infertility when other therapies fail to produce results. UK and international clinical practice guidelines do not recommend metformin as a first-line treatment or do not recommend it at all, except for women with glucose intolerance. The guidelines suggest clomiphene as the first medication option and emphasize lifestyle modification independently from medical treatment. Metformin treatment decreases the risk of developing type2 diabetes in women with PCOS who exhibited impaired glucose tolerance at baseline.

Diabetes and pregnancy
A total review of metformin use during pregnancy compared to insulin alone found good short-term safety for both the mother and baby, but unclear long-term safety. Several observational studies and randomized controlled trials found metformin to be as effective and safe as insulin for the management of gestational diabetes. Nonetheless, several concerns have been raised and evidence on the long-term safety of metformin for both mother and child is lacking. Compared with insulin, women with gestational diabetes treated with metformin gain less weight and are less likely to develop pre‐eclampsia during pregnancy. Babies born to women treated with metformin have less visceral fat, and this may make them less prone to insulin resistance in later life. The use of metformin for gestational diabetes resulted in smaller babies compared to treatment with insulin. However, despite initially lower birth weight, children exposed to metformin during pregnancy had accelerated growth after birth, and were heavier by mid-childhood than those exposed to insulin during pregnancy. This pattern of initial low birth weight followed by catch-up growth that surpasses comparative children has been associated with long-term cardiometabolic disease.

Weight change
Metformin use is typically associated with weight loss. It appears to be safe and effective in counteracting the weight gain caused by the antipsychotic medications olanzapine and clozapine. Although modest reversal of clozapine-associated weight gain is found with metformin, primary prevention of weight gain is more valuable.

Use with insulin
Metformin may reduce the insulin requirement in type1 diabetes, albeit with an increased risk of hypoglycemia.

Contraindications
Metformin is contraindicated in people with:
 * Severe renal impairment (estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2)
 * Known hypersensitivity to metformin
 * Acute or chronic metabolic acidosis, including diabetic ketoacidosis (from uncontrolled diabetes), with or without coma

Adverse effects
The most common adverse effect of metformin is gastrointestinal irritation, including diarrhea, cramps, nausea, vomiting, and increased flatulence. Metformin is more commonly associated with gastrointestinal adverse effects than most other antidiabetic medications. The most serious potential adverse effect of metformin is lactic acidosis; this complication is rare, and seems to be related to impaired liver or kidney function. Metformin is not approved for use in those with severe kidney disease, but may still be used at lower doses in those with kidney problems.

Gastrointestinal
Gastrointestinal upset can cause severe discomfort; it is most common when metformin is first administered, or when the dose is increased. The discomfort can often be avoided by beginning at a low dose (1.0 to 1.7 g/day) and increasing the dose gradually, but even with low doses, 5% of people may be unable to tolerate metformin. Use of slow or extended-release preparations may improve tolerability.

Long-term use of metformin has been associated with increased homocysteine levels and malabsorption of vitamin B12. Higher doses and prolonged use are associated with increased incidence of vitamin B12 deficiency, and some researchers recommend screening or prevention strategies.

Lactic acidosis
Lactic acidosis almost never occurs with metformin exposure during routine medical care. Rates of metformin-associated lactic acidosis are about nine per 100,000 persons/year, which is similar to the background rate of lactic acidosis in the general population. A systematic review concluded no data exists to definitively link metformin to lactic acidosis.

Metformin is generally safe in people with mild to moderate chronic kidney disease, with proportional reduction of metformin dose according to severity of estimated glomerular filtration rate (eGFR) and with periodic assessment of kidney function, (e.g., periodic plasma creatinine measurement). The US Food and Drug Administration (FDA) recommends avoiding the use of metformin in more severe chronic kidney disease, below the eGFR cutoff of 30 mL/minute/1.73 m2. Lactate uptake by the liver is diminished with metformin use because lactate is a substrate for hepatic gluconeogenesis, a process that metformin inhibits. In healthy individuals, this slight excess is cleared by other mechanisms (including uptake by unimpaired kidneys), and no significant elevation in blood levels of lactate occurs. Given severely impaired kidney function, clearance of metformin and lactate is reduced, increasing levels of both, and possibly causing lactic acid buildup. Because metformin decreases liver uptake of lactate, any condition that may precipitate lactic acidosis is a contraindication. Common causes include alcoholism (due to depletion of NAD+ stores), heart failure, and respiratory disease (due to inadequate tissue oxygenation); the most common cause is kidney disease.

Metformin-associated lactate production may also take place in the large intestine, which could potentially contribute to lactic acidosis in those with risk factors. The clinical significance of this is unknown, though, and the risk of metformin-associated lactic acidosis is most commonly attributed to decreased hepatic uptake rather than increased intestinal production.

Overdose
The most common symptoms following an overdose include vomiting, diarrhea, abdominal pain, tachycardia, drowsiness, and rarely, hypoglycemia or hyperglycemia. Treatment of metformin overdose is generally supportive, as no specific antidote is known. Extracorporeal treatments are recommended in severe overdoses. Due to metformin's low molecular weight and lack of plasma protein binding, these techniques have the benefit of removing metformin from the blood plasma, preventing further lactate overproduction.

Metformin may be quantified in blood, plasma, or serum to monitor therapy, confirm a diagnosis of poisoning, or to assist in a forensic death investigation. Blood or plasma metformin concentrations are usually in a range of 1–4 mg/L in persons receiving therapeutic doses, 40–120 mg/L in victims of acute overdosage, and 80–200 mg/L in fatalities. Chromatographic techniques are commonly employed.

The risk of metformin-associated lactic acidosis is also increased by a massive overdose of metformin, although even quite large doses are often not fatal.

Interactions
The H2-receptor antagonist cimetidine causes an increase in the plasma concentration of metformin by reducing clearance of metformin by the kidneys; both metformin and cimetidine are cleared from the body by tubular secretion, and both, particularly the cationic (positively charged) form of cimetidine, may compete for the same transport mechanism. A small double-blind, randomized study found the antibiotic cephalexin to also increase metformin concentrations by a similar mechanism; theoretically, other cationic medications may produce the same effect.

Metformin also interacts with anticholinergic medications, due to their effect on gastric motility. Anticholinergic drugs reduce gastric motility, prolonging the time drugs spend in the gastrointestinal tract. This impairment may lead to more metformin being absorbed than without the presence of an anticholinergic drug, thereby increasing the concentration of metformin in the plasma and increasing the risk for adverse effects.

Mechanism of action
The molecular mechanism of metformin is not completely understood. Multiple potential mechanisms of action have been proposed: inhibition of the mitochondrial respiratory chain (complex I), activation of AMP-activated protein kinase (AMPK), inhibition of glucagon-induced elevation of cyclic adenosine monophosphate (cAMP) with reduced activation of protein kinase A (PKA), complex IV–mediated inhibition of the GPD2 variant of mitochondrial glycerol-3-phosphate dehydrogenase (thereby reducing glycerol-derived hepatic gluconeogenesis), and an effect on gut microbiota.

Metformin exerts an anorexiant effect in most people, decreasing caloric intake. Metformin decreases gluconeogenesis (glucose production) in the liver. Metformin inhibits basal secretion from the pituitary gland of growth hormone, adrenocorticotropic hormone, follicle stimulating hormone, and expression of proopiomelanocortin, which in part accounts for its insulin-sensitizing effect with multiple actions on tissues including the liver, skeletal muscle, endothelium, adipose tissue, and the ovaries. The average patient with type2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one-third.

Activation of AMPK was required for metformin's inhibitory effect on liver glucose production. AMPK is an enzyme that plays an important role in insulin signaling, whole-body energy balance, and the metabolism of glucose and fats. AMPK activation is required for an increase in the expression of small heterodimer partner, which in turn inhibited the expression of the hepatic gluconeogenic genes phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. Metformin is frequently used in research along with AICA ribonucleotide as an AMPK agonist. The mechanism by which biguanides increase the activity of AMPK remains uncertain: metformin increases the concentration of cytosolic adenosine monophosphate (AMP) (as opposed to a change in total AMP or total AMP/adenosine triphosphate) which could activate AMPK allosterically at high levels; a newer theory involves binding to PEN-2. Metformin inhibits cyclic AMP production, blocking the action of glucagon, and thereby reducing fasting glucose levels. Metformin also induces a profound shift in the faecal microbial community profile in diabetic mice, and this may contribute to its mode of action possibly through an effect on glucagon-like peptide-1 secretion.

In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake (by inducing the phosphorylation of GLUT4 enhancer factor), decreases insulin-induced suppression of fatty acid oxidation, and decreases the absorption of glucose from the gastrointestinal tract. Increased peripheral use of glucose may be due to improved insulin binding to insulin receptors. The increase in insulin binding after metformin treatment has also been demonstrated in patients with type2 diabetes.

AMPK probably also plays a role in increased peripheral insulin sensitivity, as metformin administration increases AMPK activity in skeletal muscle. AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake. Some metabolic actions of metformin do appear to occur by AMPK-independent mechanisms, however AMPK likely has a modest overall effect and its activity is not likely to directly decrease gluconeogenesis in the liver.

Metformin has indirect antiandrogenic effects in women with insulin resistance, such as those with PCOS, due to its beneficial effects on insulin sensitivity. It may reduce testosterone levels in such women by as much as 50%. A Cochrane review, though, found that metformin was only slightly effective for decreasing androgen levels in women with PCOS.

Metformin also has significant effects on the gut microbiome, such as its effect on increasing agmatine production by gut bacteria, but the relative importance of this mechanism compared to other mechanisms is uncertain.

Due to its effect on GLUT4 and AMPK, metformin has been described as an exercise mimetic.

Pharmacokinetics
Metformin has an oral bioavailability of 50–60% under fasting conditions, and is absorbed slowly. Peak plasma concentrations (Cmax) are reached within 1–3 hours of taking immediate-release metformin and 4–8 hours with extended-release formulations. The plasma protein binding of metformin is negligible, as reflected by its very high apparent volume of distribution (300–1000 L after a single dose). Steady state is usually reached in 1–2 days.

Metformin has acid dissociation constant values (pKa) of 2.8 and 11.5, so it exists very largely as the hydrophilic cationic species at physiological pH values. The metformin pKa values make it a stronger base than most other basic medications with less than 0.01% nonionized in blood. Furthermore, the lipid solubility of the nonionized species is slight as shown by its low logP value (log(10) of the distribution coefficient of the nonionized form between octanol and water) of −1.43. These chemical parameters indicate low lipophilicity and, consequently, rapid passive diffusion of metformin through cell membranes is unlikely. As a result of its low lipid solubility it requires the transporter SLC22A1 in order for it to enter cells. The logP of metformin is less than that of phenformin (−0.84) because two methyl substituents on metformin impart lesser lipophilicity than the larger phenylethyl side chain in phenformin. More lipophilic derivatives of metformin are presently under investigation with the aim of producing prodrugs with superior oral absorption than metformin.

Metformin is not metabolized. It is cleared from the body by tubular secretion and excreted unchanged in the urine; it is undetectable in blood plasma within 24 hours of a single oral dose. The average elimination half-life in plasma is 6.2 hours. Metformin is distributed to (and appears to accumulate in) red blood cells, with a much longer elimination half-life: 17.6 hours (reported as ranging from 18.5 to 31.5 hours in a single-dose study of nondiabetics).

Some evidence indicates that liver concentrations of metformin in humans may be two to three times higher than plasma concentrations, due to portal vein absorption and first-pass uptake by the liver in oral administration.

Chemistry
Metformin hydrochloride (1,1-dimethylbiguanide hydrochloride) is freely soluble in water, slightly soluble in ethanol, but almost insoluble in acetone, ether, or chloroform. The pKa of metformin is 12.4. The usual synthesis of metformin, originally described in 1922, involves the one-pot reaction of dimethylamine hydrochloride and 2-cyanoguanidine over heat.

According to the procedure described in the 1975 Aron patent, and the Pharmaceutical Manufacturing Encyclopedia, equimolar amounts of dimethylamine and 2-cyanoguanidine are dissolved in toluene with cooling to make a concentrated solution, and an equimolar amount of hydrogen chloride is slowly added. The mixture begins to boil on its own, and after cooling, metformin hydrochloride precipitates with a 96% yield.

Impurities
In December 2019, the US FDA announced that it learned that some metformin medicines manufactured outside the United States might contain a nitrosamine impurity called N-nitrosodimethylamine (NDMA), classified as a probable human carcinogen, at low levels. Health Canada announced that it was assessing NDMA levels in metformin.

In February 2020, the FDA found NDMA levels in some tested metformin samples that did not exceed the acceptable daily intake.

In February 2020, Health Canada announced a recall of Apotex immediate-release metformin, followed in March by recalls of Ranbaxy metformin and in March by Jamp metformin.

In May 2020, the FDA asked five companies to voluntarily recall their sustained-release metformin products. The five companies were not named, but they were revealed to be Amneal Pharmaceuticals, Actavis Pharma, Apotex Corp, Lupin Pharma, and Marksans Pharma Limited in a letter sent to Valisure, the pharmacy that had first alerted the FDA to this contaminant in metformin via a Citizen Petition.

In June 2020, the FDA posted its laboratory results showing NDMA amounts in metformin products it tested. It found NDMA in certain lots of ER metformin, and is recommending companies recall lots with levels of NDMA above the acceptable intake limit of 96 nanograms per day. The FDA is also collaborating with international regulators to share testing results for metformin.

In July 2020, Lupin Pharmaceuticals pulled all lots (batches) of metformin after discovering unacceptably high levels of NDMA in tested samples.

In August 2020, Bayshore Pharmaceuticals recalled two lots of tablets.

History

The biguanide class of antidiabetic medications, which also includes the withdrawn agents phenformin and buformin, originates from the plant Goat's rue (Galega officinalis) also known as Galega, French lilac, Italian fitch, Spanish sainfoin, Pestilenzkraut, or Professor-weed. (The plant should not be confused with plants in the genus Tephrosia which are highly toxic and sometimes also called Goat's rue.) Galega officinalis has been used in folk medicine for several centuries. G. officinalis itself does not contain biguanide medications which are chemically synthesized compounds composed of two guanidine molecules and designed to be less toxic than the plant-derived parent compounds guanidine and galegine (isoamylene guanidine).

Metformin was first described in the scientific literature in 1922, by Emil Werner and James Bell, as a product in the synthesis of N,N-dimethylguanidine. In 1929, Slotta and Tschesche discovered its sugar-lowering action in rabbits, finding it the most potent biguanide analog they studied. This result was ignored, as other guanidine analogs such as the synthalins, took over and were themselves soon overshadowed by insulin.

Interest in metformin resumed at the end of the 1940s. In 1950, metformin, unlike some other similar compounds, was found not to decrease blood pressure and heart rate in animals. That year, Filipino physician Eusebio Y. Garcia used metformin (he named it Fluamine) to treat influenza; he noted the medication "lowered the blood sugar to minimum physiological limit" and was not toxic. Garcia believed metformin to have bacteriostatic, antiviral, antimalarial, antipyretic, and analgesic actions. In a series of articles in 1954, Polish pharmacologist Janusz Supniewski was unable to confirm most of these effects, including lowered blood sugar. Instead he observed antiviral effects in humans.

French diabetologist Jean Sterne studied the antihyperglycemic properties of galegine, an alkaloid isolated from G. officinalis, which is related in structure to metformin, and had seen brief use as an antidiabetic before the synthalins were developed. Later, working at Laboratoires Aron in Paris, he was prompted by Garcia's report to reinvestigate the blood sugar-lowering activity of metformin and several biguanide analogs. Sterne was the first to try metformin on humans for the treatment of diabetes; he coined the name "Glucophage" (glucose eater) for the medication and published his results in 1957.

Metformin became available in the British National Formulary in 1958. It was sold in the UK by a small Aron subsidiary called Rona.

Broad interest in metformin was not rekindled until the withdrawal of the other biguanides in the 1970s. Metformin was approved in Canada in 1972, but did not receive approval by the U.S. Food and Drug Administration (FDA) for type2 diabetes until 1994. Produced under license by Bristol-Myers Squibb, Glucophage was the first branded formulation of metformin to be marketed in the U.S., beginning on 3 March 1995. Generic formulations are available in several countries, and metformin is believed to have become the world's most widely prescribed antidiabetic medication.

Environmental impact
Metformin and its major transformation product guanylurea are present in wastewater treatment plant effluents and regularly detected in surface waters. Guanylurea concentrations above 200 μg/L have been measured in the German river Erpe, which are amongst the highest reported for pharmaceutical transformation products in aquatic environments.

Formulations

Metformin is the British Approved Name (BAN), the United States Adopted Name (USAN), and the International Nonproprietary Name (INN). It is sold under several brand names. Common brand names include Glucophage, Riomet, Fortamet, and Glumetza in the US. In other areas of the world, there is also Obimet, Gluformin, Dianben, Diabex, Diaformin, Metsol, Siofor, Metfogamma and Glifor. There are several formulations of metformin available on the market, and all but the liquid form have generic equivalents.

Combination with other medications
When used for type2 diabetes, metformin is often prescribed in combination with other medications. Several medications are available as fixed-dose combinations, with the potential to reduce pill burden, decrease cost, and simplify administration.

Rosiglitazone
A combination of metformin and rosiglitazone was released in 2002, and sold as Avandamet by GlaxoSmithKline, or as a generic medication. Formulations are 500/1, 500/2, 500/4, 1000/2, and 1000 mg/4 mg of metformin/rosiglitazone.

In 2009, it was the most popular metformin combination.

In 2005, the stock of Avandamet was removed from the market, after inspections showed the factory where it was produced was violating good manufacturing practices. The medication pair continued to be prescribed separately, and Avandamet was again available by the end of that year. A generic formulation of metformin/rosiglitazone from Teva received tentative approval from the FDA and reached the market in early 2012.

However, following a meta-analysis in 2007, that linked the medication's use to an increased risk of heart attack, concerns were raised over the safety of medicines containing rosiglitazone. In September 2010, the European Medicines Agency recommended that the medication be suspended from the European market because the benefits of rosiglitazone no longer outweighed the risks.

It was withdrawn from the market in the UK and India in 2010, and in New Zealand and South Africa in 2011. From November 2011 until November 2013 the FDA did not allow rosiglitazone or metformin/rosiglitazone to be sold without a prescription; moreover, makers were required to notify patients of the risks associated with its use, and the drug had to be purchased by mail order through specified pharmacies.

In November 2013, the FDA lifted its earlier restrictions on rosiglitazone after reviewing the results of the 2009 RECORD clinical trial (a six-year, open-label randomized control trial), which failed to show elevated risk of heart attack or death associated with the medication.

Pioglitazone
The combination of metformin and pioglitazone (Actoplus Met, Piomet, Politor, Glubrava) is available in the US and the European Union.

DPP-4 inhibitors
Dipeptidyl peptidase-4 inhibitors inhibit dipeptidyl peptidase-4 and thus reduce glucagon and blood glucose levels.

DPP-4 inhibitors combined with metformin include a sitagliptin/metformin combination (Janumet), a saxagliptin/metformin combination (Kombiglyze XR, Komboglyze),  and an alogliptin/metformin combination (Kazano, Vipdomet).

Linagliptin combined with metformin hydrochloride is sold under the brand name Jentadueto. As of August 2021, linagliptin/metformin is available as a generic medicine in the US.

SGLT-2 inhibitors
There are combinations of metformin with the SGLT-2 inhibitors dapagliflozin, empagliflozin, and canagliflozin.

Sulfonylureas
Sulfonylureas act by increasing insulin release from the beta cells in the pancreas.

A 2019 systematic review suggested that there is limited evidence if the combined used of metformin with sulfonylurea compared to the combination of metformin plus another glucose-lowering intervention, provides benefit or harm in mortality, severe adverse events, macrovascular and microvascular complications. Combined metformin and sulfonylurea therapy did appear to lead to higher risk of hypoglicaemia.

Metformin is available combined with the sulfonylureas glipizide (Metaglip) and glibenclamide (US: glyburide) (Glucovance). Generic formulations of metformin/glipizide and metformin/glibenclamide are available (the latter is more popular).

Meglitinide
Meglitinides are similar to sulfonylureas, as they bind to beta cells in the pancreas, but differ by the site of binding to the intended receptor and the drugs' affinities to the receptor. As a result, they have a shorter duration of action compared to sulfonylureas, and require higher blood glucose levels to begin to secrete insulin. Both meglitinides, known as nateglinide and repanglinide, is sold in formulations combined with metformin. A repaglinide/metformin combination is sold as Prandimet, or as its generic equivalent.

Triple combination
The combination of metformin with dapagliflozen and saxagliptin is available in the United States as Qternmet XR.

The combination of metformin with pioglitazone and glibenclamide is available in India as Accuglim-MP, Adglim MP, and Alnamet-GP; and in the Philippines as Tri-Senza.

The combination of metformin with pioglitazone and lipoic acid is available in Turkey as Pional.

Research
Metformin is a pleiotropic drug, with extensive off-target activity beyond its antidiabetic effect. Much of this has been attributed to its action on AMPK, although other mechanisms have been proposed. Metformin has been studied for its effects on multiple other conditions, including:
 * Non-alcoholic fatty liver disease
 * Premature puberty
 * Cancer
 * Cardiovascular disease in people with diabetes
 * Aging

Aging and life extension
Metformin has received substantial interest as an agent that delays aging, possibly through similar mechanisms as its treatment of diabetes (insulin and carbohydrate regulation). It has been studied in animal models (C. elegans and crickets) for effects on aging.

A 2017 review found that people with diabetes who were taking metformin had lower all-cause mortality. They also had reduced cancer and cardiovascular disease compared with those on other therapies. In people without diabetes, metformin does not appear to reduce the risk of cancer and cardiovascular disease. Whether metformin may be helpful in extending life, even in otherwise healthy people, remains controversial; a 2021 review of the literature found it is likely to improve healthspan, i.e., the number of years spent in good health, rather than lifespan overall.

Cancer
The potential anticancer effects of metformin are believed to be mediated through multiple pathways, particularly involving AMPK activation and IGF-1R modulation. Research has focused particularly on stomach cancer, with evidence of protective impact (reducing risk of cancer) and improving survival rates among patients in whom cancer has already developed. Despite promising findings, evidence is still preliminary and there is no consensus on its preventive and therapeutic role.

COVID-19
A study found a benefit using metformin to reduce the occurrence of long COVID.

It is unclear if there is a reduced risk of death using metformin to treat people with COVID-19.

Neurological and neurodegenerative disorders
There has been extensive research into the potential neuroprotective effects of metformin in developmental and neurodegenerative diseases, including Alzheimer's disease and other dementias, Parkinson's disease, Huntington's disease, certain types of epilepsy, and fragile X syndrome, with mixed results.

Preliminary studies have examined whether metformin can reduce the risk of Alzheimer's disease, and whether there is a correlation between type2 diabetes and risk of Alzheimer's disease.

While metformin may reduce body weight in persons with fragile X syndrome, whether it improves neurological or psychiatric symptoms is uncertain.

Derivatives
A derivative HL156A, also known as IM156, is a potential new drug for medical use.

title: Metformin


text:
Diabetes medication

Drugs used in diabetes treat diabetes mellitus by decreasing glucose levels in the blood. With the exception of insulin, most GLP-1 receptor agonists (liraglutide, exenatide, and others), 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.

Diabetes mellitus type 1 is a disease caused by the lack of insulin. Thus, Insulin is the main treatment agent for type 1 and is typically administered via subcutaneous injection.

Diabetes mellitus type 2 is a disease of insulin resistance by cells. Type 2 diabetes mellitus is the most common type of diabetes. Treatments include agents 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.

Several drug classes are indicated for use in type 2 diabetes and are often used in combination. Therapeutic combinations may include several insulin isoforms or varying classes of oral antihyperglycemic agents. As of 2020, 23 unique antihyperglycemic drug combinations were approved by the FDA. The first triple combination of oral anti-diabetics was approved in 2019, consisting of metformin, saxagliptin, and dapagliflozin. Another triple combination approval for metformin, linagliptin, and empagliflozin followed in 2020.

Mechanisms of action
Diabetes medications have four main mechanisms of action:
 * Insulin sensitization: Increased sensitivity of insulin receptors on cells leading to decreased insulin resistance, and higher effects of insulin on blood glucose levels.
 * Stimulation of beta cells: This stimulation increases insulin secretion from beta cells of pancreas.
 * Alpha-glucosidase inhibition: Inhibition of the alpha-glucosidase enzyme decreases the rate at which glucose is absorbed from the gastrointestinal tract.
 * SGLT2 inhibition: Inhibition of 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
Insulin is usually given 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. 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.

Examples of rapid-acting insulins (peak at ~1 hour) are:
 * Insulin lispro (Humalog)
 * Insulin aspart (Novolog)
 * Insulin glulisine (Apidra)

Examples of short-acting insulins (peak 2–4 hours) are:
 * Regular insulin (Humulin R, Novolin R)
 * Prompt insulin zinc (Semilente)

Examples of intermediate-acting insulins (peak 4–10 hours) are:
 * 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.

As a systematic review of studies comparing insulin detemir, insulin glargine, insulin degludec and NPH insulin did not show any clear benefits or serious adverse effects for any particular form of insulin for nocturnal hypoglycemia, severe hypoglycemia, glycated hemoglobin A1c, non-fatal myocardial infarction/stroke, health-related quality of life or all-cause mortality. The same review did not find any differences in effects of using these insulin analogues between adults and children.

Most oral anti-diabetic agents are contraindicated in pregnancy, in which case insulin is preferred.

Insulin is not administered by other routes, although this has been studied. An inhaled form was briefly licensed but was subsequently withdrawn.

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

Biguanides
Biguanides reduce 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.

Typical reduction in glycated hemoglobin (A1C) values for Metformin is 1.5–2.0%
 * Metformin (Glucophage) may be the best choice for patients who also have heart failure, but it should be temporarily discontinued before any radiographic procedure involving intravenous iodinated 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.
 * Buformin also was withdrawn due to lactic acidosis risk.

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.

Thiazolidinediones
Thiazolidinediones (TZDs), also known as "glitazones," bind to PPARγ, peroxisome proliferator activated receptor 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). 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.

Typical reductions in glycated hemoglobin (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.
 * Pioglitazone (Actos): remains on the market but has also been associated with increased cardiovascular risks.
 * Troglitazone (Rezulin): used in 1990s, withdrawn due to hepatitis and liver damage risk.

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, as did the DREAM trial. 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).

Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the New England Journal of Medicine. There have been a significant number of publications since then, and a Food and Drug Administration panel 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. 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.

LYN Kinase Activators
The LYN kinase activator Tolimidone has been reported to potentiate insulin signaling in a manner that is distinct from the glitazones. The compound has demonstrated positive results in a Phase 2a clinical study involving 130 diabetic subjects.

Secretagogues
Secretagogues are drugs that increase output from a gland, in the case of insulin from the pancreas.

Sulfonylureas
Sulfonylureas were the first widely used oral anti-hyperglycemic medications. They are insulin secretagogues, triggering insulin release by inhibiting the KATP channel of the pancreatic beta cells. 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.

Current clinical practice guidelines from the 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, α-glucosidase inhibitors, Thiazolidinediones (glitazones), and DPP-4 inhibitors (gliptins). 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.

Sulfonylureas bind strongly to plasma proteins. 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.

A Cochrane systematic review from 2011 showed that treatment with Sulfonylureas did not improve control of glucose levels more than insulin at 3 nor 12 months of treatment. 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. When studies measured fasting C-peptide, no intervention influenced its concentration, but insulin maintained concentration better compared to Sulphonylurea. Still, it is important to highlight that the studies available to be included in this review presented considerable flaws in quality and design.

Typical reductions in glycated hemoglobin (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
Meglitinides 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. By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, thereby enhancing insulin secretion.

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.

Typical reductions in glycated hemoglobin (A1C) values are 0.5–1.0%.
 * repaglinide
 * nateglinide

Adverse reactions include weight gain and hypoglycemia.

Alpha-glucosidase inhibitors
Alpha-glucosidase inhibitors are a class of diabetes drugs, 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 of enters the bloodstream at a slower rate, and can be matched more effectively by an impaired insulin response or sensitivity. 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.

Typical reductions in glycated hemoglobin (A1C) values are 0.5–1.0%. 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.
 * miglitol
 * acarbose
 * voglibose

Injectable incretin mimetics
Incretins are also insulin secretagogues. 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. 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 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. In a 2011 Cochrane review, GLP-1 agonists showed approximately a 1% reduction in HbA1c when compared to placebo. GLP-1 agonists also show improvement of beta-cell function, but this effect does not last after treatment is stopped. Due to shorter duration of studies, this review did not allow for long-term positiver or negative effects to be assessed.
 * Exenatide (also Exendin-4, marketed as Byetta) is the first GLP-1 agonist approved for the treatment of type 2 diabetes. Exenatide is not an analogue of GLP but rather a GLP agonist. Exenatide has only 53% homology with GLP, which increases its resistance to degradation by DPP-4 and extends its half-life. A 2011 Cochrane review showed a HbA1c reduction of 0.20% more with Exenatide 2 mg compared to insulin glargine, exenatide 10 μg twice daily, sitagliptin and pioglitazone. Exenatide, together with liraglutide, led to greater weight loss than glucagon-like peptide analogues.
 * 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.     A 2011 Cochrane review showed a HbA1c reduction of 0.24% more with liraglutide 1.8 mg compared to insulin glargine, 0.33% more than exenatide 10 μg twice daily, sitagliptin and rosiglitazone. Liraglutide, together with exenatide, led to greater weight loss than glucagon-like peptide analogues.
 * 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

These agents may also cause a decrease in gastric motility, responsible for the common side-effect of nausea, which tends to subside with time.

Dipeptidyl peptidase-4 inhibitors
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 inhibitors were used with sulfonylureas; effects on long-term health and morbidity rates are still unknown.

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 A1C values by 0.74%, comparable to other antidiabetic drugs.

A result in one RCT comprising 206 patients aged 65 or older (mean baseline HgbA1c of 7.8%) receiving either 50 or 100 mg/d of sitagliptin was shown to reduce HbA1c by 0.7% (combined result of both doses). A combined result of 5 RCTs enlisting a total of 279 patients aged 65 or older (mean baseline HbA1c of 8%) receiving 5 mg/d of saxagliptin was shown to reduce HbA1c by 0.73%. A combined result of 5 RCTs enlisting a total of 238 patients aged 65 or older (mean baseline HbA1c of 8.6%) receiving 100 mg/d of vildagliptin was shown to reduce HbA1c by 1.2%. 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 mg/d of the medication.

Injectable amylin analogues
Amylin agonist analogues slow gastric emptying and suppress glucagon. They have all the incretins actions except stimulation of insulin secretion. , 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%.

SGLT2 inhibitors
SGLT2 inhibitors block the sodium-glucose linked transporter 2 proteins in renal tubules of nephrons 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. Oral preparations may be available alone or in combination with other agents. 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. Because they are taken by mouth, rather than injected (like GLP-1 agonists), patients who are 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. 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.

Examples include:
 * 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 infections, candidal vulvovaginitis, and hypoglycemia.

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.

Generics
Many anti-diabetes drugs are available as generics. These include: No generics are available for dipeptidyl peptidase-4 inhibitors (Onglyza), the glifozins, the incretins and various combinations. Sitagliptin patent expired in July 2022, leading to launch of generic sitagliptin brands. This lowered the cost of therapy for type 2 diabetes using sitagliptin.
 * Sulfonylureas – glimepiride, glipizide, glyburide
 * Biguanides – metformin
 * Thiazolidinediones (Tzd) – pioglitazone, Actos generic
 * Alpha-glucosidase inhibitors – Acarbose
 * Meglitinides – nateglinide
 * Combination of sulfonylureas plus metformin – known by generic names of the two drugs

Alternative Medicine
The effect of 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.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Diabetes medication


text:
Uncle Luke

Luther Roderick Campbell (born December 22, 1960), also known as Luke Skyywalker, Uncle Luke and simply Luke, is an American rapper, promoter, record executive, actor, and former leader of the rap group 2 Live Crew. He is known for having helped create the Miami bass genre, for establishing one of the first rap groups and rap labels in Southern hip hop, and his sexually crude call and response lyrics which were unique for the time period. He also starred in a short-lived show on VH1, Luke's Parental Advisory.

Early life and education
Luther Campbell was born on December 22, 1960, in Miami. His mother was a beautician of Bahamian ancestry and his father was a custodian of Jamaican ancestry. He was the youngest of five sons and was named after Martin Luther King Jr. He was raised Catholic.

After graduating from Miami Beach Senior High School in 1979, Campbell was asked by his mother to leave the house every weekday from 8:30am to 4:30pm regardless of his employment status.

1980s
In the early 1980s, Campbell worked as a cook at Mount Sinai Hospital in Miami Beach and as a concert promoter in Miami, bringing rap groups of that era to Miami. In 1983, he also enrolled in an eight-week study course at Miami public radio station WDNA, where he learned basic audio editing and production techniques.

In 1984, Campbell took notice of a single from California named "Revelation" by 2 Live Crew, which consisted of two rappers (Fresh Kid Ice and Amazing V) and a DJ (Mr. Mixx). The single was a hit on the South Florida club circuit, and Campbell decided to bring them from California to Miami for a performance. He took a special interest in the group and began managing them.

2 Live Crew eventually fully relocated to Florida without Amazing Vee and in 1986, 2 Live Crew recorded "Throw the D" with "Ghetto Bass" on the B-side, they went into a joint venture with Campbell to start Luke Skyywalker Records, which was also his first MC name.

In April of that year, Brother Marquis joined the group in Miami. Campbell gave The 2 Live Crew a record deal and officially joined the group. They exploded on the local scene with their gold-selling debut album, The 2 Live Crew Is What We Are (1986). This made Luke Skyyywalker and his bandmates rap superstars in south Florida.

In 1988, the group released their second album, Move Somethin'. It was certified Gold and featured the singles "Move Somethin'" and "Do Wah Diddy Diddy". The album improved on the charts from the previous album, making it to #68 on the Billboard 200 and #20 on the Top R&B/Hip Hop Albums chart.

Campbell decided to sell a separate clean version in addition to the explicit version of the album. A record store clerk in Alexander City, Alabama, was cited for selling a copy to an undercover police officer in 1988. It was the first time in the United States that a store owner was held liable for obscenity over music. The charges were dropped after a jury found the owner not guilty.

Their third album As Nasty As They Wanna Be (1989) became the group's largest seller, being certified platinum by the Recording Industry Association of America. In 1990, the United States District Court for the Southern District of Florida ruled that the album was legally obscene; this ruling was later overturned by the Eleventh Circuit. It is the first album in history to be deemed legally obscene. An obscenity trial followed, in which Henry Louis Gates, Jr., addressed the court on behalf of the defendants, all of whom were eventually acquitted.

University of Miami "pay-for-play" allegations
Campbell was also infamous in the late 1980s and early 1990s for his association with the University of Miami football team. Campbell was alleged to have been behind what was referred to as a "pay-for-play" system, which involved cash rewards for acts such as scoring touchdowns and big hits, although Campbell has never actually donated to the University of Miami or its athletics department.

In 1993, Campbell threatened to go public with various alleged violations by the university's athletic department and its football program if Ryan Collins, a black player on the team, wasn't named starting quarterback that season.

1990s
1990 saw the release of Banned in the U.S.A., originally credited as Campbell's solo album featuring 2 Live Crew and in later editions credited as a 2 Live Crew album. The album included the hits "Do the Bart" and the title track. It was also the very first release to bear the RIAA-standard Parental Advisory warning sticker. It peaked at number 20 on the Hot 100.

The eponymous title single is a reference to the decision in a court case that the group's album As Nasty As They Wanna Be was obscene. Bruce Springsteen granted the group permission to interpolate his song "Born in the U.S.A." for it.

Displeased over the decision of Florida Governor Bob Martinez who, on being asked to examine the album, decided it was obscene and recommended local law enforcement take action against it and over the subsequent action of Broward County, Florida, sheriff Nick Navarro, who arrested local record-store owners on obscenity charges for selling the group's albums and the subsequent arrest of members of the group on obscenity charges, the group included the song "Fuck Martinez", which also includes multiple repetitions of the phrase "fuck Navarro". The group found two other men with the same names, and had them sign releases, as they thought that this action would make it impossible for Martinez or Navarro to sue them.

That same year they released Live in Concert, the group's first and only live album, and their fifth record overall. It was released under the Effect subsidiary label of Luke Records, a move that was deemed necessary for the company to be able to release additional 2 Live Crew material outside of their distribution deal with Atlantic Records. The album peaked at number 46 on the Top R&B/Hip-Hop Albums.

Sports Weekend: As Nasty as They Wanna Be, Pt. 2 (1991) is the sixth album overall and fifth studio album by the 2 Live Crew. A clean version was released later that same year titled Sports Weekend: As Clean As They Wanna Be Part II and was the sequel of As Clean As They Wanna Be. This would be the last studio album by all original members of the 2 Live Crew.

In 1992, I Got Shit on My Mind was released. It was his first official solo album without The 2 Live Crew. It peaked at #52 on the Billboard 200 chart and #20 on the Top R&B/Hip-Hop Albums chart. It was the album that spawned the hit single "I Wanna Rock" (better known more prominently as "Doo-Doo Brown"), which became Campbell's signature song. Upon its initial release in 1992, the song did not garner much attention until the following year, when it became a runaway hit, and charted at 73 on the Hot 100.

June 8, 1993 saw the release of his third solo album In the Nude. It was another success, reaching #54 on the Billboard 200 and #8 on the Top R&B/Hip-Hop Albums.

One of The 2 Live Crew’s songs, which used a parody of Roy Orbison's "Oh, Pretty Woman", was the subject of a 1993-1994 lawsuit, Campbell v. Acuff-Rose Music, Inc., which was argued in front of the U.S. Supreme Court. The Miami New Times described Campbell as "the man whose booty-shaking madness once made the U.S. Supreme Court stand up for free speech".

In 1994, he reunited with Fresh Kid Ice, and a local rapper named Verb made an album under the banner The New 2 Live Crew. It is the last 2 Live Crew related project to feature him. The album became a moderate hit, peaking at #52 on the Billboard 200 and #9 on the Top R&B/Hip-Hop Albums, as well as producing two charting singles, "Hell, Yeah" and "You Go Girl" who were both made into music videos.

Freak for Life is Campbell's fourth album. It was released on July 12, 1994, through Luke Records. Freak for Life peaked at #174 on the Billboard 200 and #24 on the Top R&B/Hip-Hop Albums, making it his lowest charting album at the time. One single found mild success, "It's Your Birthday" peaked at #33 on the Hot Rap Singles and #91 on the Hot R&B/Hip-Hop Singles & Tracks.

Also in 1994, Campbell co-founded Liberty City Optimists, an inner city youth sports program. One of his notable apprentices is Devonta Freeman, who went on to play college football for Florida State Seminoles, rival of the Hurricanes.

Campbell and his label, Luke Records, Inc. went bankrupt in 1995 and sold their catalogs to Joseph Weinberger and Lil' Joe Records, Inc. in 1996.

Uncle Luke was released on May 14, 1996, on Luther Campbell Music and was mainly produced by Darren "DJ Spin" Rudnick, and Rod XL, with additional production by Frankie Cutlass, Ice Cube and Doug E. Fresh. Uncle Luke was a success, peaking at #51 on the Billboard 200 and #8 on the Top R&B/Hip-Hop Albums and spawned a single, "Scarred", which made it to #64 on the Billboard Hot 100 and #7 on the Hot Rap Singles, the song was also turned into a Video.

Changin' the Game is the sixth album released by Campbell. It was released on November 11, 1997, on the Island Black Music label in collaboration with Luke Records and featured production from Campbell, Rod XL, Lil' Jon and Louis "Ugly" Howard. Though the album was met with some positive reviews, the album was a flop and remains Campbell's lowest charting album, only making it to #49 on the Top R&B/Hip-Hop Albums. However, the single "Raise the Roof" found great success peaking at #26 on the Billboard Hot 100 and #1 on the Hot Rap Singles. The song helped to popularize the arm gesture by the same name which involved repeatedly extending ones arms upwards with the palms of the hands also facing upwards. The song is also featured in the compilation album Jock Jams Volume 4.

In 1998 he played a supporting role in the movie Ride a comedy film written and directed by Millicent Shelton. It stars Malik Yoba, Fredro Starr, and Melissa De Sousa. Also that year he made a special cameo appearance in Ice Cube's The Players Club. The comedy/drama film stars Bernie Mac, Monica Calhoun, Jamie Foxx, John Amos, A. J. Johnson, Alex Thomas, Charlie Murphy, Terrence Howard, Faizon Love and LisaRaye.

2000s
Somethin' Nasty is the seventh album released by Campbell. It was released on March 13, 2001, on Luke Records through Koch Records' short-lived independent label distribution unit, KELA (Koch Entertainment Label Alliance) and featured production by Campbell's former 2 Live Crew bandmate, Mr. Mixx, Daz Dillinger, Gorilla Tek, and Campbell himself. The album found minor success, peaking at #149 on the Billboard 200, #36 on the Top R&B/Hip-Hop Albums and #6 on the Top Independent Albums.

Campbell's last release, My Life & Freaky Times, was released in March 2006, and peaked at 32 at the Top R&B/Hip-Hop Albums. The first singles serviced to radio were "Holla at Cha Homeboy", featuring Pitbull & Petey Pablo, and the reggaeton-leaning "Pop That" by Plan B and Rey Chester Secretweapon.

That same year, Campbell appeared in Grand Theft Auto: Vice City Stories as DJ Luke for the hip-hop station Fresh 105 FM. Campbell hosts a sports talk show on Miami's 790 The Ticket with former football player Terry Kirby on Saturdays.

Campbell has previously entered the adult film industry and cites on his MySpace page the need to clean up the "sometimes amateurish new courtship of Hip-Hop and Adult Entertainment". He produced the adult entertainment movie Luke's Bachelor Party in 2007.

In December 2007, Campbell launched The Luke Entertainment Group and took the company public trading under the symbol LKEN on Pink Sheets.

In 2008, he starred in his own short-lived show on VH1, Luke's Parental Advisory.

Campbell was interviewed about his involvement with the University of Miami football program for the documentary The U, which premiered December 12, 2009, as part of ESPN's 30 for 30 series.

In 2010, he briefly reunited with Fresh Kid Ice, Brother Marquis, and Mr. Mixx as the 2 Live Crew were honorees winners at the 2010 VH1 Hip-Hop Honors: The Dirty South Edition.

On February 2, 2011, Campbell announced his intention to run for mayor of Miami-Dade County on a platform that includes making housing projects safer, transparency in local government, and taxing strippers. He came in fourth in a field of 11 candidates, winning 11% of the vote.

By Thanksgiving 2014, Campbell reunited with 2 Live Crew (Fresh Kid Ice and Brother Marquis) for a series of shows until 2015.

Personal life
On February 18, 2009, Campbell was arrested for falling behind on child support payments. He allegedly has 6 or 7 kids, all of which are from a different mother.

In February 2010, Campbell became a columnist for Miami New Times, an alternative weekly newspaper distributed in the Miami metropolitan area. Campbell's column, called "Luke's Gospel", provides "a forum for his crazy-ass views on current events," which include politics, sports and entertainment. He is quoted on the Miami New Times website as saying, "It's the perfect place for me. I am a free-speech guy. It's just a match made in Heaven. Can you believe it? Me turned loose on the world in New Times. Wow."

Compilation albums

 * 1996: Greatest Hits
 * 2000: Luke's Freak Fest 2000
 * 2002: Scandalous: The All Star Compilation

title: Uncle Luke