Metformin

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Ther Adv Endocrinol Metab. 2021 Jan 13;12:2042018820980225. doi: 10.1177/2042018820980225

Should metformin remain the first-line therapy for treatment of type 2 diabetes?

Chelsea Baker 1,✉, Cimmaron Retzik-Stahr 2, Vatsala Singh 3, Renee Plomondon 4, Victoria Anderson 5, Neda Rasouli 6

        Abstract

Metformin is a biguanide that is used as first-line treatment of type 2 diabetes mellitus and is effective as monotherapy and in combination with other glucose-lowering medications. 

        Results It is generally well-tolerated with minimal side effects and is affordable.1 Although the safety and efficacy of metformin have been well-established, there is discussion regarding whether metformin should remain the first choice for therapy in all patients as other anti-hyperglycemic medications have proven to have additional benefits in certain populations. It is important to understand the risks and benefits of metformin and other anti-hyperglycemic medications before making any change in clinical practice.

Historical overview of metformin

1Chemical origins of metformin

Guanidine-based remedies were originally derived from the perennial plant Galega officinalis (Figure 1A) and have been used

 medicinally for centuries.

2 Commonly known as Goat’s Rue or French Lilac ,the herb ,

was used to treat frequent urination and increased thirst, symptoms now known to be associated with hyperglycemia.

3 Of the common biguanide-based medications, including phenformin and buformin, metformin (dimethyl-biguanide, Figure 1B) eventually stood out for its comparative advantage in both safety and efficacy.

A) Galega officinalis, commonly known as French lilac; 

it is rich in galegine, a substance with blood 

glucose-lowering activity and the foundation for the discovery of metformin. (B) The chemical structure of 1,1-dimethylbiguanide hydrochloride or metformin hydrochloride.

Metformin in the 21st century

By the end of the 20th century, metformin’s ability to safely lower glucose levels in patients with diabetes had been well-documented on a global scale. In 2002, metformin became the most commonly prescribed oral anti-hyperglycemic medication.³

 In 2005, the International Diabetes Foundation published guidelines recommending metformin as a first-line treatment for type 2 diabetes.⁹

 Nearly 50 years after the rediscovery of metformin, the World Health Organization added metformin to its list of essential medications in 2011.¹⁰ 

Numerous clinical trials in the last decade have thoroughly assessed concerns regarding the risk of metformin-induced lactic acidosis in patients with comorbidities such as renal and hepatic dysfunction or congestive heart failure. Results from such trials continue to support metformin as a safe and effective medication for the vast majority of patients.¹¹ 

In fact, the restriction for using metformin in patients with impaired kidney function has recently been relaxed.¹²

Metformin mechanism of action

Since metformin was discovered from a plant source and was not originally synthesized to bind to a specific target, some of its actions remain unknown. However, metformin has been shown to improve glycemic control through several mechanisms (Figure 2A). It inhibits hepatic gluconeogenesis, reduces absorption of glucose from the intestines and increases glucose uptake by tissue. 

The UKPDS suggested there might be cardiovascular benefits with metformin use. In that trial, 753 patients with newly diagnosed type 2 diabetes were assigned to usual care (diet, with sulfonylurea, insulin, and/or metformin added for marked hyperglycemia) or open-label metformin. Drug treatment was added in 44% of usual care patients. Compared with usual care, metformin was associated with fewer deaths [relative risk (RR) 0.64, p = 0.01] and myocardial infarctions (RR 0.61, p = 0.01) with non-significant reductions in stroke and peripheral artery disease events.26 However, the sample size was small, and the study was not powered to prove cardiovascular benefits of metformin.26 The UKPDS results, including glycemic-lowering efficacy, the weight benefits, the low risk for hypoglycemia, and the reduction in macrovascular complications, led to metformin becoming the preferred first-line therapy for treatment of type 2 diabetes. The 10-year follow-up of the UKPDS reported continued benefit after metformin therapy among overweight patients.31

Metformin therapy also showed a reduction in cardiovascular events compared with glipizide in the SPREAD-DIMCAD trial.32 While both groups achieved A1c targets, metformin therapy resulted in a 12% absolute risk reduction of major adverse cardiovascular events whereas the glipizide group experienced more episodes of hypoglycemia and weight gain compared with the metformin group.32