Академический Документы
Профессиональный Документы
Культура Документы
Metformin in 2019
James Flory, MD, MSCE; Kasia Lipska, MD, MHS
Metformin is the first-line pharmacologic treatment for type 2 dia- metformin causes subclinical increases in lactic acid and appears to
betes and the most commonly prescribed drug for this condition cause lactic acidosis in extreme overdose. Metformin use has been
worldwide, either alone or in combination with insulin or other glu- discouraged in patients with risk factors for lactic acidosis, includ-
cose-lowering therapies. Metformin is a biguanide, a drug class of ing hepatic impairment, heart failure, and chronic kidney disease
herbal origin that has been widely used to treat diabetes since the (CKD). But ongoing experience with metformin indicates that its use
1950s.1,2 Two other biguanides were withdrawn from clinical use be- is unsafe only for a relatively small subset of patients with severe liver,
cause they caused lactic acidosis. Metformin was also taken off the heart, or kidney dysfunction.3,9
US market due to concerns over lactic acidosis, but it subsequently
has been proven safe and effective in lowering glucose levels and Figure. Suggested Starting Regimen for Metformin, Common Obstacles
was reintroduced in 1995. Optimal metformin use requires clear un- to Use, and Alternatives
derstanding of its effects, dosing, safety, and alternatives.
First-line metformin treatment for type 2 diabetes
Mechanism of Action Begin treatment Optional approach
Animal and human studies have shown that metformin acts in the liver, Start with initial dose Consider extended-release form to minimize risk
of 500 mg daily of gastrointestinal (GI) adverse effects
where it inhibits gluconeogenesis by blocking a mitochondrial redox
shuttle. However, a full understanding of metformin’s mechanism of Adjust dose Approach for GI side effects
Increase dose gradually to Try extended-release form and consider using highest
action remains elusive, and the drug’s effects are likely pleiotropic. For 2000 mg daily if tolerated dose tolerable rather than stopping medication
instance, metformin has also been shown to be an insulin sensitizer
and to likely act in the gut lumen through multiple mechanisms.1 Common obstacles to using metformin
Condition Suggested approach
Clinical Use GI intolerance Reduce dose until adverse effects resolve
Metformin is indicated for treatment of hyperglycemia in type 2 dia- Consider use of extended-release form
betes (Figure) and improves glycemic control without inducing Impaired Use freely if eGFR ≥45 mL/min
kidney function
hypoglycemia or weight gain.3,4 Metformin’s use is supported by a Use with caution if eGFR 30-45 mL/min
Do not use if eGFR <30 mL/min
randomized clinical trial of intensive vs standard glycemic control
among patients with newly diagnosed type 2 diabetes. This trial Heart failure Acceptable to use with stable, chronic heart failure
Do not use with acute heart failure
found lower rates of myocardial infarction (7% absolute risk reduc- and evidence of end-organ hypoperfusion
tion; P = .01) and mortality (7.1% absolute risk reduction; P = .01) in Liver disease Acceptable to use with chronic liver disease (including
a subgroup of overweight patients randomly assigned to metfor- mildly elevated liver enzymes, but intact liver function)
Do not use with functional hepatic failure or acute liver injury
min (n = 342) compared with conventional (diet) therapy (n = 411).5
This evidence for cardiovascular and mortality benefits is now re-
Noninsulin alternatives to metformin
garded as weak given the small subgroup size and because the trial was
Medication Pros Cons Potential risks
conductedbetween1977and1991(meaningitsresultsmaynotpertain
Sodium-glucose Cardiovascular High cost Amputations
to current clinical conditions). Furthermore, the trial included another cotransporter 2 (CV) benefit Genitourinary Fractures
subgroupofpatientsalreadytakingsulfonylureawhowererandomized (SGLT-2) inhibitors Weight loss infections Euglycemic
to intensification of therapy with metformin (n = 268) and found 11.2% diabetic
ketoacidosis
absolutehighermortalityinthemetformingroup(P = .04).5 Theauthors
Glucagon-like CV benefit High cost Pancreatitis
havearguedthatthesefindingswerelikelyduetochance.Meta-analyses peptide 1 (GLP-1) Weight loss Requires injections
receptor agonists
and other small studies have overall shown no increased risk of mortal- GI adverse effects
ity from metformin, but further research, ideally large clinical trials, Dipeptidyl Few side effects High cost Pancreatitis
is needed to confirm the limited evidence for benefit.5,6 peptidase 4 Modest effect Heart failure
(DDP-4) inhibitors on glucose levels (alogliptin,
Among high risk patients with prediabetes, metformin re- No CV benefit saxagliptin)
duces the risk of developing diabetes (7.2% absolute risk reduc-
Sulfonylureas Low cost Weight gain
tion; P < .001) and is associated with modest weight loss.7 There is Hypoglycemia
also evidence supporting use of metformin in the management of No CV benefit
polycystic ovarian syndrome and gestational diabetes.8 Interest in Thiazolidinediones Low cost Weight gain Bladder cancer
metformin for other uses, such as cancer prevention and to delay Possible CV Edema
benefit after Heart failure
some processes of aging, is not yet supported by clinical evidence.1 stroke
Fractures
ARTICLE INFORMATION REFERENCES 6. Griffin SJ, Leaver JK, Irving GJ. Impact of
Author Affiliations: Endocrinology Service, 1. Rena G, Hardie DG, Pearson ER. The mechanisms metformin on cardiovascular disease:
Division of Subspecialty Medicine, Memorial Sloan of action of metformin. Diabetologia. 2017;60(9): a meta-analysis of randomised trials among people
Kettering Cancer Center, New York, New York 1577-1585. with type 2 diabetes. Diabetologia. 2017;60(9):
(Flory); Section of Endocrinology, Department of 1620-1629.
2. Inzucchi SE. Is it time to change the type 2
Internal Medicine, Yale School of Medicine, diabetes treatment paradigm? no! Diabetes Care. 7. Knowler WC, Barrett-Connor E, Fowler SE, et al.
New Haven, Connecticut (Lipska). 2017;40(8):1128-1132. Reduction in the incidence of type 2 diabetes with
Corresponding Author: James Flory, MD, MSCE, lifestyle intervention or metformin. N Engl J Med.
3. FDA. Label information: glucophage tablets and 2002;346(6):393-403.
885 Second Ave, Room 1012, New York, NY 10017 glucophage XR extended-release tablets. https://
(floryj@mskcc.org). www.accessdata.fda.gov/drugsatfda_docs/label/ 8. Sinai Talaulikar V, Tang T, Yasmin E. Role of
Published Online: April 22, 2019. 2017/020357s037s039,021202s021s023lbl.pdf. metformin in women’s health. Obstet Gynecol Surv.
doi:10.1001/jama.2019.3805 Accessed April 16, 2019. 2016;71(5):307-317.
Conflict of Interest Disclosures: Dr Flory reported 4. American Diabetes Association. Pharmacologic 9. Crowley MJ, Diamantidis CJ, McDuffie JR, et al.
receiving grants from AHRQ, a contract from PCORI, approaches to glycemic treatment: Standards of Clinical outcomes of metformin use in populations
and personal fees from Eli Lilly and Genentech Medical Care in Diabetes-2019. Diabetes Care. with chronic kidney disease, congestive heart
outside the submitted work. Dr Lipska reported 2019;42(suppl 1):S90-S102. failure, or chronic liver disease. Ann Intern Med.
receiving grants from NIA, support to develop and 2017;166(3):191-200.
5. UK Prospective Diabetes Study (UKPDS) Group.
evaluate publicly reported quality measures from Effect of intensive blood-glucose control with 10. Bonnet F, Scheen A. Understanding and
CMS, and personal fees from Health Services metformin on complications in overweight patients overcoming metformin gastrointestinal intolerance.
Advisory Group outside the submitted work. with type 2 diabetes (UKPDS 34). Lancet. 1998; Diabetes Obes Metab. 2017;19(4):473-481.
352(9131):854-865.