Diabetology is one of the most rapidly evolving disciplines of medicine and encompasses efforts to advance scientific knowledge and implement ever-expanding health knowledge into clinical practice. The biguanide drug, metformin, has been used widely for the treatment of hyperglycemia in patients with type 2 diabetes mellitus (T2DM) since 1957, and is the only biguanide drug still prescribed widely 1. Current guidelines from the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) recommend early initiation of metformin as a first-line drug for monotherapy and combination therapy for patients with T2DM 2.
Metformin is believed to exert its effect by reducing hepatic glucose production, intestinal glucose absorption, and by increasing glucose use by peripheral tissues. Metformin inhibits hepatic gluconeogenesis and suppresses hepatic glucose output, increases fatty acid oxidation in hepatocytes, and inhibits very low-density lipoprotein synthesis in the liver 3. Metformin is believed to exert powerful effects primarily by counteracting postreceptor insulin resistance and by increasing insulin-stimulated glucose uptake in muscle and fat 3.
The intracellular effects of metformin are believed to be mediated mainly by AMP-activated protein kinase (AMPK), a molecule that is a major cellular energy sensor and regulator of energy homeostasis 4,5. AMPK activity is regulated by the AMPK upstream kinase LKB1 6. AMPK activation results in numerous intracellular effects: inhibition of hepatic gluconeogenesis suppression of the activity of mammalian target of rapamycin (mTOR), a signaling pathway with a central role in cell growth signaling 7, promotion of glucose uptake in muscle and liver mostly by increasing the number of GLUT-4 transporters, inhibition of lipid synthesis, and promotion of fatty acid oxidation in the liver.
Despite extensive clinical use, the mechanisms underlying the therapeutic effects of metformin are still not completely understood. Metformin has been well characterized as a substrate of organic cation transporters (OCT), membrane transporters expressed in different target tissues. OCT1, plays an important role in metformin intracellular concentration and reinforces the critical role of the liver as the primary site of action for metformin 8. Other mechanisms, such as passive diffusion and other transporters, may account for a small portion of hepatic and other tissue uptake of metformin. These data strongly suggest that genetic polymorphisms in OCT1 and LKB1 may contribute toward reduced therapeutic response to metformin clinically (Fig. 1) 8.
Dipeptidyl peptidase-4 activity might be inhibited by metformin, resulting in a postmeal increase in glucagon-like peptide (GLP)-1 levels in the plasma derived from intestinal hormone localized in L cells 9.
GLP-1 is an incretin hormone that stimulates glucose-dependent endogenous insulin secretion, decreases glucagon secretion, slows gastric motility and emptying, and reduces appetite and food intake 9,10. Furthermore, native GLP-1 stimulates β-cell proliferation in animal models and inhibits apoptosis in vitro, which may increase β-cell mass and function 10.
Besides the fact that metformin is a well-established first-line T2DM drug, metformin has been shown to be valuable in preventing the development of T2DM in individuals with impaired glucose tolerance and/or impaired fasting glucose.
The Diabetes Prevention Program Research Group conducted a large, randomized clinical trial involving adults in the USA who were at high risk for the development of T2DM 11. The reduction in the average fasting plasma glucose concentration was similar in the lifestyle intervention and metformin groups, but the lifestyle intervention had a greater effect than metformin on glycosylated hemoglobin and weight reduction 11. The incidence of diabetes was reduced by 58% with the lifestyle intervention and by 31% with metformin compared with placebo 11.
Clinical use of metformin HbA1c
The introduction of metformin into therapy should be gradual to avoid side effects. There is a linear dose–effect relationship. The most effective dose in reducing HbA1c is 2000 mg and fasting glucose 1500 mg. In a meta-analysis, MEDLINE, EMBASE, and the Cochrane Library were searched from 1950 to June 2010 for trials of at least 12 weeks’ duration in which diabetic patients were treated with either metformin monotherapy or as an add-on therapy. Data on the change in HbA1c were pooled in a meta-analysis. Metformin monotherapy reduced HbA1c by 1.12% [95% confidence interval (CI) 0.92–1.32; I2=80%] versus placebo. Metformin added to oral therapy reduced HbA1c by 0.95% (95% CI 0.77–1.13; I2=77%) versus placebo added to oral therapy, and metformin added to insulin therapy reduced HbA1c by 0.60% (95% CI 0.30–0.91; I2=79.8%) versus insulin only 12. There was a significantly greater reduction in HbA1c using higher doses of metformin compared with lower doses of metformin, with no significant increase in side effects 12.
Vascular effects of metformin
Vasculoprotective properties of metformin therapy, in addition to enhancing insulin sensitivity and lowering blood glucose, have been attributed to improvement in lipid profiles, prothrombotic and proinflammatory factors, endothelial function, and chronic blood vessel inflammation. Metformin has been used in the treatment of metabolic syndrome, with favorable effects on atherogenic dyslipidemia, characterized by high triglyceride and low high-density lipoprotein cholesterol levels, reduction of thrombotic factor concentrations including the antifibrinolytic plasminogen activator inhibitor 1, and an inhibitory effect on platelet aggregation 13.
Insulin sensitizer therapy can also improve cardiovascular risk factors while improving insulin sensitivity and reducing adiposity.
Beneficial effects of metformin on cardiovascular outcomes were shown in the United Kingdom Prospective Diabetes Study (UKPDS), suggesting a role in the primary prevention of cardiovascular disease 14. A continued reduction in death from any cause was observed during 10 years of post-trial follow-up among overweight patients on initial metformin monotherapy 15. Overweight and obese patients randomized to initial monotherapy with metformin experienced significant reductions in myocardial infarction and diabetes-related deaths. Patients allocated to metformin, compared with the conventional treatment group, showed risk reductions of 32% at any diabetes-related endpoint and up to 42% for diabetes-related death 15.
Holman et al. 15, in a 10-year follow-up of patients with T2DM on intensive glucose therapy, showed a so-called legacy effect associated with intensive glucose control. In the metformin group, significant risk reductions persisted for myocardial infarction (33%, P=0.005) and death from any cause (27%, P=0.002) 15.
A post-hoc analysis of diabetic patients undergoing coronary interventions was carried out in diabetic patients in the Prevention of Restenosis with Tranilast and its Outcomes (PRESTO) trial 16. The use of metformin in diabetics undergoing coronary interventions (n=887) compared with patients without metformin therapy (n=1110) appeared to decrease rates of major adverse clinical events, especially rates of death and myocardial infarction, which was three times lower 16. In the PRESTO study, 40% of patients had a previous myocardial infarction in contrast with UKPDS (1% patients with previous myocardial infarction at inclusion) 16.
Metformin use and mortality among patients with diabetes and atherothrombosis was assessed in the study of Roussel et al. 17, whose aim was to assess whether metformin use was associated with a difference in 2-year mortality among 19 691 patients with diabetes with established coronary artery disease, cerebrovascular disease, or peripheral arterial disease or patients with at least three atherothrombotic risk factors in 44 countries.
Mortality was lower among patients taking metformin with moderately reduced kidney function (glomerular filtrate rate 30–<60 ml/min), patents younger than 65 years old, or those aged 65–80 years. Mortality was also decreased among metformin users older than 80 years, but not significantly 17.
In a substudy of the Sibutramine Cardiovascular Trial Outcomes trial (SCOUT), the association between hypoglycemic treatment regimens with cardiovascular adverse events and mortality in a large population of overweight and obese T2DM patients (n=8192) at increased cardiovascular risk was assessed 18. The population was grouped according to baseline use of the following hypoglycemic therapies: insulin as monotherapy, metformin as monotherapy, sulfonylureas as monotherapy, diet only, sulfonylureas plus insulin, sulfonylureas plus metformin, and sulfonylureas plus metformin plus insulin. The results of the study showed that, compared with insulin monotherapy, treatment with metformin monotherapy or diet alone was associated with a decreased risk of primary cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) in obese T2DM patients with diabetes with known or increased risk of cardiovascular disease 18.
Metformin as an adjunctive therapy for type 1 diabetes
The aim of the Hamilton study was to determine whether the addition of metformin to standard diabetes care in teens with type 1 diabetes and insulin resistance would improve insulin sensitivity, lower HbA1c, fasting glucose, insulin dosage (U/kg/day), and BMI 19. This was a randomized, placebo-controlled 3-month trial of metformin therapy in 27 adolescents, 12–17 years old, with type 1 diabetes, high-insulin dosage (>1 U/kg/day), and HbA1c more than 8%, with measurements of insulin sensitivity, HbA1c, insulin dosage, and BMI at the onset and end of treatment 19. At the end of the study, HbA1c was 0.6% lower in the metformin group than in the placebo group (P<0.05). This was achieved at lower daily insulin dosages (metformin group −0.14±0.1) with no significant change in BMI. Long-term studies will determine whether these improvements are sustained and whether certain subgroups accrue greater benefit from this therapy.
Vella and colleagues carried out a systematic review of 197 clinical trials that showed that adding metformin to insulin therapy in type 1 diabetes was associated with reductions in insulin dose (6.6 U/day, P<0.001), but no significant reduction in HbA1c (0.6–0.9%), weight (1.7–6.0 kg in three of six studies), and total cholesterol (0.3–0.41 mmol/l in three of seven studies). No reported trials included cardiovascular outcomes and it is unclear whether there are benefits for cardiovascular and other key clinical outcomes 20.
Metformin and cancer
In general, there is evidence that T2DM alters the risk of developing a variety of cancers 21–25, especially pancreatic cancer, and that cancer mortality is increased 26. For example, the risk for colon cancer seemed to be increased in patients using insulin 27. There is increasing evidence of potential efficacy metformin as an anticancer drug. The first observational study with a prospective design found (after a median follow-up time of 9.6 years) that metformin use at baseline was associated with less cancer-related mortality 28.
Metformin decreases insulin resistance and indirectly reduces the insulin level, which is a beneficial effect because insulin promotes cancer cell growth. The antineoplastic action of metformin was shown for several cancers in animal models and in-vitro experiments on several cancer cell lines. Depending on cell lines, the mechanism of action of metformin and its sensitivity toward this agent are different. Metformin activates the AMPK pathway in normal and cancer cells 4. The potentially beneficial effects of metformin against cancer are believed to be mediated mainly by AMPK, which is a major player in the regulation of metabolism and growth, for both normal and cancer cells 4.
With respect to the anticarcinogenic effects of metformin in cancer cells, the major energy sensor pathway of the cell, the AMPK/mTOR axis, plays a central role, suggesting that metformin interferes with the energetic metabolism of the cell and protein synthesis. The AMPK/mTOR pathway is under the control of LKB1. LKB1 is a serine–threonine kinase acting as a tumor suppressor 6.
AMPK has the ability to regulate protein metabolism, cell polarity, growth, and apoptosis.
AMPK activation by metformin is achieved by two distinct mechanisms (Fig. 1).
- Metformin hampers the respiratory chain complex I in hepatocytes, reducing ATP synthesis and leading to AMPK activation 29,30.
- Metformin exerts its antitumorigenic effects by activating AMPK, which, in turn, suppresses the activity of mTOR in cancer cells. mTOR upregulates many energy-consuming cellular processes and plays a central role in regulating cell growth by controlling mRNA translation and ribosome biogenesis 7.
Metformin exerts a strong and consistent antiproliferative action on several cancer cell lines including breast, colon, ovary, pancreas, lung, and prostate cancer cells.
Metformin also induces p53-dependent autophagy and can interfere with some receptors by decreasing the oncoprotein level of Her2 (erbB-2) or epidermal growth factor receptor in breast and pancreatic cancer cells, respectively 31 (Fig. 2).
The cancer stem cell hypothesis suggests that, unlike most cancer cells within a tumor, cancer stem cells resist chemotherapeutic drugs and can regenerate the various cell types in the tumor, thereby causing relapse of the disease 33. Thus, drugs that selectively target cancer stem cells offer great promise for cancer treatment, particularly in combination with chemotherapy. Metformin, a standard drug for diabetes, inhibits cellular transformation and selectively kills cancer stem cells in four genetically different types of breast cancer 34. The combination of metformin and doxorubicin, a well-defined chemotherapeutic drug, kills both cancer stem cells and nonstem cancer cells in culture, and reduces tumor mass and prolongs remission much more effectively than either drug alone in a xenograft mouse model 34. The combination of metformin and chemotherapeutic drugs might improve the treatment of patients with breast (and possibly other) cancers.
Metformin, unless there are explicit contraindications, notably marked impairment of renal function, remains the most widely used first-line drug for the treatment of T2DM. Metformin is used in addition to lifestyle changes designed to impact an individual’s physical activity levels and food intake. Metformin can prevent T2DM in patients with impaired glucose tolerance and/or impaired fasting glucose; however, metformin is not licensed for the prevention of T2DM. Indications for metformin continue to expand from prediabetes, metabolic syndrome, T2DM, adjuvant therapy in type 1 diabetes, nonalcohol fatty liver disease, polycystic ovarian syndrome, and cardiovascular prevention (primary and secondary). Metformin has recently received increased attention because of its potentially beneficial effects against cancer. However, data from randomized trials are currently lacking, and further research is required to explore cellular mechanisms and provide additional evidence supporting metformin’s anticancer effect.
Conflicts of interest
There are no conflicts of interest.
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