Metformin/ja

Metformin/ja

Clinical data
Pronunciation	/mɛtˈfɔːrmɪn/, met-FOR-min
Trade names	フォルタメット, グルコファージ, グルメッツァ, その他
Other names	N,N-dimethylbiguanide
AHFS/Drugs.com	Monograph
MedlinePlus	a696005
License data	US DailyMed: Metformin
Pregnancy category	AU: C
Routes of administration	経口
ATC code	A10BA02 (WHO) A10BD23 (WHO) A10BD02 (WHO) A10BD18 (WHO) A10BD11 (WHO) A10BD25 (WHO) A10BD22 (WHO) A10BD14 (WHO) A10BD16 (WHO) A10BD17 (WHO) A10BD05 (WHO) A10BD15 (WHO) A10BD07 (WHO) A10BD10 (WHO) A10BD13 (WHO) A10BD20 (WHO) A10BD08 (WHO) A10BD03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only EU: Rx-only
Pharmacokinetic data
Bioavailability	50–60%
Protein binding	Minimal
Metabolism	肝臓ではない
Elimination half-life	4–8.7 時間
Excretion	尿中 (90%)
Identifiers
IUPAC name N,N-Dimethylimidodicarbonimidic diamide
CAS Number	657-24-9 as HCl: 1115-70-4
PubChem CID	4091
IUPHAR/BPS	4779
DrugBank	DB00331
ChemSpider	3949
UNII	9100L32L2N as HCl: 786Z46389E
KEGG	D04966 as HCl: C07151
ChEBI	CHEBI:6801 as HCl: CHEBI:6802
ChEMBL	ChEMBL1431
Chemical and physical data
Formula	C4H11N5
Molar mass	129.167 g·mol−1
3D model (JSmol)	Interactive image
Density	1.3±0.1 g/cm3
SMILES CN(C)C(=N)N=C(N)N
InChI InChI=1S/C4H11N5/c1-9(2)4(7)8-3(5)6/h1-2H3,(H5,5,6,7,8) Key:XZWYZXLIPXDOLR-UHFFFAOYSA-N Y

メトホルミン（Metformin）は、グルコファージ（Glucophage）などの商品名で販売されており、特に太りすぎの2型糖尿病の治療のための主要な第一選択医薬品である。また、多嚢胞性卵巣症候群の治療にも用いられる。抗精神病薬を服用している人のメタボリックシンドロームのリスクを軽減するために、適応外の補助薬として使用されることもある。

メトホルミンは一般的に忍容性が高い。一般的な副作用には、下痢、吐き気、腹痛などがある。メトホルミンは低血糖を引き起こすリスクが小さい。高血中乳酸値（アシドーシス）は、医薬品を過度に大量に使用したり、重度の腎障害のある人に処方した場合に懸念される。

メトホルミンはビグアナイド系抗高血糖薬である。肝臓におけるグルコース産生を減少させ、体組織のインスリン感受性を高めることによって作用する。

メトホルミンは、1922年にEmil WernerとJames Bellによって初めて科学文献に記載された。フランスの医師ジャン・スターン（Jean Sterne）は1950年代にヒトでの研究を開始した。フランスでは1957年に、米国では1995年に医薬品として導入された。メトホルミンは世界保健機関の必須医薬品リストに掲載されており、口から服用する糖尿病治療薬として最も広く使用されている。ジェネリック医薬品としても販売されている。2021年には、米国で2番目に多く処方された医薬品であり、91 万以上の処方があった。

医療用途

メトホルミンは、2型糖尿病患者の血糖を低下させるために使用される。また、多嚢胞性卵巣症候群の不妊症の第二選択薬としても用いられる。

2型糖尿病

米国糖尿病学会と米国内科学会はともに、メトホルミンを2型糖尿病治療の第一選択薬として推奨している。メトホルミンはレパグリニドと同程度に有効であり、2型糖尿病に対する他のすべての経口薬物よりも有効である。

有効性

欧州糖尿病学会、欧州心臓病学会、米国糖尿病学会などの主要な専門学会の治療ガイドラインでは、メトホルミンの心血管ベネフィットに関するエビデンスは曖昧であると記述されている。2020年のコクランでは システマティックレビューでは、メトホルミン単剤療法を他の糖低下薬物、行動変容介入、プラセボ、介入なしと比較した場合、心血管死亡率、非致死的心筋梗塞、非致死的脳卒中の減少を示す十分なエビデンスは認められなかった。

メトホルミンの使用は、体重増加と関連するスルホニル尿素とは対照的に、2型糖尿病患者の体重を減少させる。メトホルミンが糖尿病がない肥満の体重減少に関連することを示す証拠もある。メトホルミンはスルホニル尿素系薬剤よりも低血糖のリスクが低いが、低血糖は激しい運動、カロリー不足、または血糖を低下させる他の薬剤との併用時に起こることがまれである。メトホルミンは、低密度リポ蛋白およびトリグリセリド値を緩やかに低下させる。

糖尿病予備軍の個人において、2019年に行われた2型糖尿病の発症リスク低下におけるメトホルミンと他の介入との効果を比較したシステマティックレビューでは、メトホルミンが食事療法や運動療法、またはプラセボと比較した場合に2型糖尿病の発症リスクを低下させるという中程度の質のエビデンスが認められた。しかし、メトホルミンと集中的な食事療法または運動療法を比較した場合、メトホルミンは2型糖尿病の発症リスクを減少させないという中等度の質のエビデンスが得られ、集中的な食事療法または運動療法にメトホルミンを追加しても、集中的な運動療法と食事療法のみと比較した場合、2型糖尿病のリスクを減少させるという利点も欠点も示さないという非常に質の低いエビデンスが得られた。同レビューでは、糖尿病予備軍における2型糖尿病発症リスクの低下におけるメトホルミンとスルホニル尿素の効果を比較した適切な試験も1件見つかったが、この試験では患者に関連するアウトカムは報告されていない。

多嚢胞性卵巣症候群

多嚢胞性卵巣症候群（PCOS）では、メトホルミンの使用により生児出生率が増加するという暫定的なエビデンスがある。これには、クロミフェンで妊娠できなかった人も含まれる。メトホルミンは流産のリスクを変化させないようである。その他にも、妊娠中および非妊娠中のPCOS女性において、多くの有益性が認められている。PCOS女性におけるIVF/ICSI前または治療中のメトホルミン対プラセボ/無治療に関するコクラン（2020年）の最新レビューでは、生児出生率の改善に関する決定的な証拠は見つかっていない。長時間のGnRHアゴニストプロトコールでは、生児出生率改善のエビデンスには不確実性があったが、臨床的妊娠率の増加はあり得た。要するに、GnRHアンタゴニストプロトコールのメトホルミンは、臨床的妊娠率への影響については不確実であるが、生児出生率を低下させる可能性がある。メトホルミンはOHSSの減少をもたらすかもしれないが、副作用の頻度が高くなる可能性がある。流産に対するメトホルミンの影響については不明確であった。エビデンスは、肥満女性の母体および乳児の転帰を改善するための妊娠中の一般的な使用を支持していない。

イギリスの米国国立医療技術評価機構は2004年に、PCOSで肥満度が25を超える女性に対して、他の治療法で効果が得られない場合に無排卵と不妊のためにメトホルミンを投与することを推奨した。英国および国際的な臨床実践ガイドラインでは、耐糖能異常のある女性を除き、メトホルミンを第一選択治療として推奨していないか、まったく推奨していない。ガイドラインでは、クロミフェンを第一選択医薬品として推奨し、内科的治療とは別に生活習慣の改善を強調している。メトホルミン治療は、ベースライン時に耐糖能障害を示したPCOS女性における2型糖尿病の発症リスクを低下させる。

胃癌

胃癌（GC）は、その高い有病率と死亡率から、世界的な健康上の大きな問題となっている。様々な治療法がある中で、2型糖尿病（T2DM）の一般的な医薬品であるメトホルミンは、その潜在的な抗がん作用が注目されている。GCに対するメトホルミンの有効性については議論の的となってきたが、最近の臨床研究では、GC患者のリスクを低減し生存率を向上させるというメトホルミンの保護作用が優勢に支持されている。メトホルミンの抗癌作用は、複数の経路、特にAMPKの活性化とIGF-1Rの調節を介すると考えられている。有望な知見にもかかわらず、GCの予防と治療におけるメトホルミンの応用に関するコンセンサスは得られていないため、その治療的役割を確認するためには、さらなる臨床的およびメカニズム的研究が必要である。

糖尿病と妊娠

妊娠中のメトホルミン使用について、インスリン単独と比較した総説では、母児ともに短期的な安全性は良好であったが、長期的な安全性は不明であった。いくつかの観察研究およびランダム化比較試験では、メトホルミンは妊娠糖尿病の管理においてインスリンと同様に有効かつ安全であることが明らかにされた。それにもかかわらず、いくつかの懸念が提起されており、母子双方に対するメトホルミンの長期安全性に関するエビデンスは不足している。インスリンと比較して、メトホルミンを投与された妊娠糖尿病の女性は体重増加が少なく、妊娠中に子癇前症を発症する可能性が低い。メトホルミンを投与された女性から生まれた赤ちゃんは内臓脂肪が少なく、そのため、その後の人生でインスリン抵抗性になりにくい可能性がある。妊娠糖尿病にメトホルミンを使用すると、インスリンによる治療と比較して赤ちゃんが小さくなる。しかし、妊娠中にメトホルミンを投与された子どもは、当初は出生体重が低かったにもかかわらず、出生後の成長が促進され、妊娠中にインスリンを投与された子どもよりも小児期半ばまでに体重が増加した。このように、出生時低体重の後、比較対照児を上回るキャッチアップ成長というパターンは、長期的な心代謝疾患と関連している。

体重の変化

メトホルミンの使用は一般的に体重減少を伴う。メトホルミンは、抗精神病薬であるオランザピンおよびクロザピンによって引き起こされる体重増加を打ち消すのに安全かつ有効であるようである。メトホルミンによりクロザピンによる体重増加の緩やかな逆転が認められるが、体重増加の一次予防の方がより価値がある。

インスリンとの併用

メトホルミンは、低血糖のリスクは増加するものの、1型糖尿病におけるインスリン必要量を減少させる可能性がある。

寿命延長

メトホルミンは、健康な人でも寿命延長に役立つ可能性があることを示す証拠がいくつかある。メトホルミンは、おそらく糖尿病治療（インスリンと糖質調節）と同様のメカニズムで老化を遅らせる薬剤として大きな関心を集めている。

アルツハイマー病

予備研究では、メトホルミンがアルツハイマー病のリスクを低下させるかどうか、2型糖尿病とアルツハイマー病のリスクに相関があるかどうかが検討されている。

禁忌事項

メトホルミンは以下の併用禁忌である：

• 重度の腎機能障害（推定糸球体濾過量（eGFR）が30 mL/分/1.73 m²未満）。
• メトホルミンに対する既知の過敏症
• 糖尿病性ケトアシドーシス（コントロールされていない糖尿病による）を含む急性または慢性の代謝性アシドーシスで、昏睡を伴うか伴わない。

副作用

メトホルミンの最も一般的な副作用は、下痢、けいれん、吐き気、嘔吐、および鼓腸の増加などの消化管刺激である。メトホルミンは、他のほとんどの抗糖尿病医薬品よりも一般的に消化器系の副作用と関連している。メトホルミンの最も重篤な潜在的副作用は乳酸アシドーシスである；この合併症はまれであり、肝機能または腎機能の低下に関連しているようである。メトホルミンは重度の腎臓病患者への使用は承認されていないが、腎臓に問題のある患者には低用量で使用することができる。

胃腸

胃腸の不調は激しい不快感を引き起こすことがある；メトホルミンの初回投与時または増量時に最もよくみられる。低用量（1.0～1.7g/日）から開始し、徐々に増量することで不快感を回避できることが多いが、低用量でも5％の人はメトホルミンに耐えられないことがある。徐放性製剤または徐放性製剤を用いると、忍容性が改善することがある。

メトホルミンの長期使用は、ホモシステイン値の上昇およびビタミンB₁₂の吸収不良と関連している。高用量や長期間の使用はビタミンB₁₂欠乏症の発生率の増加と関連しており、スクリーニングや予防戦略を推奨する研究者もいる。

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.

Pharmacology

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 type 2 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 type 2 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 (C_max) 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 (pK_a) of 2.8 and 11.5, so it exists very largely as the hydrophilic cationic species at physiological pH values. The metformin pK_a 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 pK_a 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.

Derivatives

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

History

Galega officinalis is a natural source of galegine.

The biguanide class of antidiabetic medications, which also includes the withdrawn agents phenformin and buformin, originates from the French lilac or goat's rue (Galega officinalis), a plant used in folk medicine for several centuries. G. officinalis itself does not contain any of these medications, but isoamylene guanidine; phenformin, buformin, and metformin are chemically synthesized compounds composed of two guanidine molecules, and are more lipophilic than the plant-derived parent compound.

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 type 2 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.

Society and culture

Environmental

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

Generic metformin 500-mg tablets, as sold in the United Kingdom

The name "Metformin" is the BAN, USAN, and INN for this medication, and is sold under several trade 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 to the market, and all but the liquid form have generic equivalents. Metformin IR (immediate release) is available in 500-, 850-, and 1000-mg tablets, while Metformin XR (extended release) is available in 500-, 750-, and 1000-mg strengths (also sold as Fortamet, Glumetza, and Glucophage XR in the US). Also available is liquid metformin (sold as Riomet in the US), where 5 mL of solution contains the same amount of drug as a 500-mg tablet.

Combination with other medications

When used for type 2 diabetes, metformin is often prescribed in combination with other medications.

Several are available as fixed-dose combinations, with the potential to reduce pill burden, decrease cost, and simplify administration.

Thiazolidinediones (glitazones)

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.

By 2009, it had become 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. 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, along with the Philippines as Tri-Senza.

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

Impurities

See also: Ranitidine § 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.

Research

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

While metformin may reduce body weight in persons with fragile X syndrome, whether it improves neurological or psychiatric symptoms is uncertain. Metformin has been studied in vivo (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.

There is also some research suggesting that although metformin prevents diabetes, it does not reduce the risk of cancer and cardiovascular disease and thus does not extend lifespan in non-diabetic individuals. Furthermore, some studies suggest that long-term chronic use of metformin by healthy individuals may develop vitamin B12 deficiency.

 

さらに読む

• Markowicz-Piasecka M, Huttunen KM, Mateusiak L, Mikiciuk-Olasik E, Sikora J (2017). "Is Metformin a Perfect Drug? Updates in Pharmacokinetics and Pharmacodynamics". Current Pharmaceutical Design. 23 (17): 2532–2550. doi:10.2174/1381612822666161201152941. PMID 27908266.
• McCreight LJ, Bailey CJ, Pearson ER (March 2016). "Metformin and the gastrointestinal tract". Diabetologia. 59 (3): 426–35. doi:10.1007/s00125-015-3844-9. PMC 4742508. PMID 26780750.
• Moin T, Schmittdiel JA, Flory JH, Yeh J, Karter AJ, Kruge LE, Schillinger D, Mangione CM, Herman WH, Walker EA (October 2018). "Review of Metformin Use for Type 2 Diabetes Prevention". American Journal of Preventive Medicine. 55 (4): 565–574. doi:10.1016/j.amepre.2018.04.038. PMC 6613947. PMID 30126667.
• Rena G, Hardie DG, Pearson ER (September 2017). "The mechanisms of action of metformin". Diabetologia. 60 (9): 1577–1585. doi:10.1007/s00125-017-4342-z. PMC 5552828. PMID 28776086.
• Sanchez-Rangel E, Inzucchi SE (September 2017). "Metformin: clinical use in type 2 diabetes". Diabetologia. 60 (9): 1586–1593. doi:10.1007/s00125-017-4336-x. PMID 28770321.
• Zhou J, Massey S, Story D, Li L (September 2018). "Metformin: An Old Drug with New Applications". International Journal of Molecular Sciences. 19 (10): 2863. doi:10.3390/ijms19102863. PMC 6213209. PMID 30241400.
• Zhou T, Xu X, Du M, Zhao T, Wang J (October 2018). "A preclinical overview of metformin for the treatment of type 2 diabetes". Biomedicine & Pharmacotherapy. 106: 1227–1235. doi:10.1016/j.biopha.2018.07.085. PMID 30119191. S2CID 52031602.

外部リンク

• "Nitrosamine impurities in medications: Guidance". Health Canada. 4 April 2022.