Metformin: From Research to Clinical Practice

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Key points

  • Metformin is the first-line glucose-lowering drug to control hyperglycemia in type 2 diabetes mellitus (T2DM); an insulin sensitizer, it decreases hepatic gluconeogenesis and increases glucose disposal in skeletal muscles.

  • Metformin is safe (small risk for hypoglycemia, weight neutral, and some gastrointestinal [GI] adverse events), is inexpensive, reduces microvascular complication risk, and lowers cardiovascular mortality compared with sulfonylurea therapy.

  • Metformin-induced lactic acidosis is

Drug Development

Metformin (dimethylguanidine) has its roots in a plant, Galega officinalis (French lilac, Goat’s rue, or Spanish sainfoin), rich in guanidine. An outline of the events from 1918, when guanidine was shown to lower blood glucose in animals, to its launch as an oral GLD in 1957 and beyond is shown in Table 1.5

The First-Line Oral Glucose-Lowering Drug for Type 2 Diabetes Mellitus

The only approved indication for metformin use is as “an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus.”6 The package insert

Delaying or Preventing the Onset of Type 2 Diabetes Mellitus

The personal and societal burden of T2DM is increasing, with an estimated 415 million people affected globally in 2015.91 Another estimated 318 million people globally have impaired glucose tolerance (IGT).91 One way to reduce the health and economic burden of T2DM is to delay the progression of prediabetes to T2DM. Lifestyle, pharmacotherapy, and bariatric surgery intervention strategies have been reported to be effective.92 Metformin delays the development of or prevents new-onset T2DM (

Metformin Use in Type 2 Diabetes Mellitus Patients with Cancer

Several studies and meta-analyses established an association between diabetes and cancer.126 This association can be explained by hyperinsulinemia, hyperglycemia, and chronic inflammation in T2DM patients, with insulin-stimulating growth of cancerous cells and enhancing mitogenesis. Recently, new observations suggest that metformin may possibly play a role in cancer treatment and prevention.127 Proposed mechanisms for metformin’s anticancer effects includes metformin activation of AMP-activated

Summary

In closing, new knowledge uncovered by research, especially during the past 2 decades, has changed the understanding and use of metformin in the management of T2DM. Although metformin’s cellular and molecular mechanisms of action continue to evolve, how it improves glycemic control is better understood. As the recommended first-line oral GLD to control hyperglycemia in T2DM, and its continued use in combination therapy, metformin is now the most prescribed GLD in the United States. Metformin is

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      Alternatively, several studies aimed at reinforcing the ATP-depleting properties of 2-DG, for example with the use of metformin which is probably the most studied drug in combination with 2-DG. Metformin is a compound widely used for type 2 diabetes treatment which lowers hyperglycemia by inhibiting hepatic lipogenesis and gluconeogenesis and promotes insulin sensitivity (reviewed in [150]). At the cellular level, metformin is a mild mitochondrial complex I inhibitor, leading to decreased ATP levels and AMPK activation, although akin to 2-DG, some consequences of metformin are independent of AMPK [151].

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