Biguanide

Biguanides 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" (flagellum or 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.

In 1956, phenformin was developed by Krall and Camerini- Davalos in the USA, buformin by Walter Seitz and Hellmut Mehnert in Germany and metformin by J- Sterne in France (Häussler 2012).

Biguanides are oral antidiabetic drugs. They include phenformin, buformin and metformin (Paumgartner 2013).

The biguanides were first admitted to Germany in 1957. By 1977, 330 patients experienced biguanide-induced lactic acidosis: 85% from phenformin, 10% from buformin, and 5% from metformin (Schatz 2014). For this reason, phenformin and buformin were withdrawn from the market in Germany in 1978. Since then, only one biguanide, metformin, has been approved in Germany (Huismans 2005). In addition to monotherapy, this has also been approved for combination therapy in Germany since 1994 (Kirch 2013).

Pharmacodynamics (Action):

The mechanism of action of biguanides is now largely understood:

• hepatic gluconeogenesis is inhibited by antagonizing glucagon, which can produce cAMP in hepatocytes (Kasper 2015)
• the absorption of glucose from the intestine is delayed
• the absorption 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)
• 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)

Indications:

According to the guideline, biguanides represent the drug of choice in 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 provides the "UK Prospective Diabetes Study" (UKPDS) from 1998 (Bahrmann 2018 / Kellerer 2013).

Dosage and route of administration:

Biguanides 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 metformin of 250 - 500 mg and then increase the dose every 2 - 3 weeks after BG measurements in self-monitoring (Kasper 2015).

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

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

(Herold 2020)

In the guidelines, biguanides are recommended in doses of 1 x / d for monotherapy and 2 x / d doses in combination therapy (Bahrmann 2018).

Provided that 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 distributed over 2 doses per day (Herold 2020).

Biguanides 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 a biguanide 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 EASD- Congress 2013, the combination of metformin and sulfonylureas was 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 biguanides were presented. However, no final assessment is possible at present, as the evaluation of cardiovascular events in particular has not yet been completed (Barnard 2021).

Adverse effects:

• Gastrointestinal discomfort (common side effect).
• Vitamin B12 deficiency (levels are reduced by about 30% during treatment [Kasper 2015]).
• If contraindications are disregarded, there is a risk of lactic acidotic coma with high lethality (rare side effect)

[Herold 2020)

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
• gravidity
• 48 h before and after a pyelography with contrast media, as otherwise there is a risk of lactic acidosis
• before and after surgery (see also diabetes and surgery)

(Herold 2020)

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

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

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

• operations under general anaesthesia
• examinations with X-ray contrast media
• Exsiccosis
• gastrointestinal infections
• febrile diseases

(Herold 2020)

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