Metformin

Biguanides, to which metformin belongs, were already used in the Middle Ages in Southern and Eastern Europe for the treatment of diabetes in the form of the plant galega officinalis (yarrow), which is rich in guanidine. Watanabe was the first to demonstrate its blood sugar-lowering effect in 1918 (Mehnert 2003).

In 1929, metformin was first described as a hypoglycemic biguanide in animals by Slotta and Tscheche in what was then Germany (now Poland), but it was not until 1950 that clinical trials in diabetics were underway in France by Sterne, Duval and colleagues.

Metformin was patented in France in 1957 under the auspices of Aron Laboraties. It was approved in France in 1958 (Rea 2018). In Germany, metformin was launched in 1968 (Häussler 2012) and has been approved for monotherapy and combination therapy in Germany since 1994 (Kirch 2013).

Classification: Metformin belongs to the non-insulinotropic substances (substances with low or no risk of hypoglycemia [Bahrmann 2018]) and belongs to the biguanide group (Herold 2020).

Metformin does not bind to plasma; it is excreted unchanged by the kidneys. The half-life is between 1.7 - 4.5 h. Within 12 h, 90% of the substance is excreted.

Action: The mechanism of action of metformin is now largely understood:

• hepatic gluconeogenesis is inhibited by antagonizing glucagon, which can generate cAMP in hepatocytes (Kasper 2015)
• the absorption of glucose from the intestine is delayed
• the uptake of glucose into the muscles is increased (Bahrmann 2018)
• insulin sensitivity is increased (Kasper 2015).

Other effects include:

• appetite is discreetly decreased
• cancer mortality decreases (Herold 2020)
• reduction in the incidence of basal cell carcinoma
• the insulin resistance improves (Bahrmann 2018)
• the risk of cardiovascular morbidity and mortality decreases
• the risk of hypoglycemia is low because insulin secretion is not affected (Diederich 2020)
• the fasting blood level is lowered
• the lipid profile is improved (Kasper 2015)

Side effects:

• gastrointestinal discomfort (common side effect).
• vitamin B12 deficiency (during treatment, the level is lowered by about 30% [Kasper 2015])
• If contraindications are disregarded, there is a risk of lactic acidotic coma with high lethality (rare side effect) (Herold 2020)

Indications: According to the guideline, metformin is the drug of choice for overweight type 2 diabetics, provided there are no contraindications (Herold 2020). It is the most commonly prescribed oral antidiabetic drug worldwide. Still the best evidence from studies is provided by the "UK Prospective Diabetes Study" (UKPDS) from 1998 (Bahrmann 2018 / Kellerer 2013).

Contraindications:

• Severe renal insufficiency with persistent eGFR < 30 ml / min.
• Conditions predisposing to tissue hypoxia such as respiratory failure, circulatory shock, severe heart failure (Mehnert 2003)
• decompensated heart failure
• severe liver dysfunction
• Fasting
• reduction diet
• alcoholism
• consumptive diseases
• acute and severe diseases
• gastrointestinal infections
• pregnancy
• 48 h before and after a pyelography with contrast media, otherwise there is a risk of lactic acidosis
• before and after surgery (see also diabetes and surgery)

Dosage recommendation:

Metformin should be dosed up slowly at the beginning, as this can reduce gastrointestinal side effects (Bahrmann 2018).

It is recommended to start with a small dose of 250 - 500 mg and then increase the dose every 2 - 3 weeks after BG measurements in self-monitoring (Kasper 2015).

The maximum dose is 2,000 mg / d. With a higher dose, no additional effect can be achieved, but the side effects can be increased (Herold 2020).

Metformin can be given 1 - 2 x / d, with the evening dose being the more important (Herold 2020).

The guidelines recommend doses of 1 x / d for monotherapy and 2 x / d doses in combination therapy (Bahrmann 2018).

If the patient has diabetic nephropathy with an eGFR between 33 - 44 ml / min, a maximum dose of 1,000 mg / d should not be exceeded. This is recommended - under regular GFR- controls - to be divided into 2 doses per day .

Metformin can be combined with other oral antidiabetics such as sulfonylureas, alpha-glucosidase inhibitors, glitazones or with insulin (Mehnert 2003).

In the above-mentioned UKPD study (see "Indications"), therapy with sulfonylurea after the addition of metformin showed an increase in total mortality of 6% within 6.6 years (Arzneimitteltelegramm 1998). However, only 268 patients on this combination therapy were included in this study. At the 2013 EASD- Congress, the combination of metformin and sulfonylureaswas also a topic of discussion (Kellerer 2013) and is still the subject of controversy (Müller 2018).

In mid-2021, first results of the GRADE- study on dual combinations with metformin were presented. However, no conclusive assessment is possible at present, as the evaluation of cardiovascular events in particular has not yet been completed (Barnard 2021).

Controls:

In patients with an eGFR between 30 - 59 ml / min, the risk of lactic acidosis should be initially assessed before starting therapy (Herold 2020).

Renal function should initially be checked every 3 - 6 months in newly recruited patients (Bahrmann 2018) and later every 6 months with checks of creatinine levels, blood count (Mehnert 2003) and Vit. B 12- levels (Kasper 2015).

Metformin should be discontinued or paused in situations where there is a risk of acute deterioration of renal function, such as during:

• Operations under general anesthesia
• Examinations with X-ray contrast media
• Exsiccosis
• gastrointestinal infections
• febrile diseases (Herold 2020)

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