Sulfonylureas

Sulfonylureas were introduced in the 1950s (Schernthaner 2019). The discovery of SH was an accidental finding at the time. During treatment with antibacterially active sulfonamides, a reduction in BG was clinically noticed. As a result, the SH were developed from sulfonamides (Mark 2002).

The sulfonylureas (SH) belong to the group of oral insulinotropic substances. They include:

• Glibenclamide
• Gliclazide
• Glimepiride
• Gliquidone

They are recommended in the German Medical Association algorithm (2021) as a 2nd or 3rd stage option in combination with metformin.

SH are primarily excreted in the urine. An exception is gliriquidone, which is excreted bilaterally by 86% in addition to urinary excretion (Schernthaner 2019).

• 1st generation:
  • Chlorpropamide
  • Tolazamide
  • Tolbutamide

1st generation SH have a relatively long half-life, so hypoglycemia was quite common. There are also multiple drug interactions. For these reasons, 1st generation sulfonylureas are now discontinued.

• 2nd generation:
  • Glibenclamide
  • Gliclazide
  • Gliquidone

The effect is more rapid, the half-life is shorter and the postprandial glucose increase is better covered.

• 3rd generation:
  • Glimepiride

(Kasper 2015)

Pharmacodynamics (action):

SH block the potassium channels of the beta cell. This leads to an influx of calcium into the cell, which in turn releases insulin (Schernthaner 2019).

SH lower fasting blood glucose and postprandial BG (Kasper 2015) and lead to a decrease in hepatic gluconeogenesis (due to improved insulinization of the liver).

(Wehling 2006)

Risk of microvascular events is reduced according to UKPD- study (Herold 2020).

Indications:

• Type 2 DM as far as the therapy goal cannot be reached by diet, exercise and administration of metformin (Herold 2020)
• Type 2 DM that has not been present for a long time (< 5 years) with endogenous insulin production still present (Kasper 2015)
• MODY- patients "Maturity-Onset Diabetes of the Young":

In MODY 1 and MODY 3, the switch from insulin to SH - even after prolonged administration - is usually possible without any problems (Schernthaner 2019)

• normal to slightly overweight patients with type 2 DM
• with contraindication to metformin (Luippold 2012).

Because of the sometimes considerable adverse effects (see below), SH now play only a minor role in Germany.

Dosage and route of administration:

SH should initially be dosed low and then increased every 1 - 2 weeks after appropriate BG self-monitoring.

• Glimepiride 1 mg / d, increasing to 2 mg / d after 1 - 2 weeks. The maximum dose is 6 mg / d (Diederich 2020). At doses of > 6 mg / d, a disproportionate frequency of side effects is found (Herold 2020).
• Glibenclamide: 3.5 - 10.5 mg / d (Luippold 2012).

SH should be taken immediately before a meal.

During the discontinuation phase, it is essential to inform the patient about the restricted participation in road traffic (have it confirmed in writing).

(Herold 2020)

A once daily administration is possible with:

• Glimepiride (1 - 6 mg / d [Luippold 2012]).
• Glipizide (2.5 - 15.0 mg / d [Schernthaner 2019])

[Kasper 2020)

SH are recommended by the German Medical Association (2021) in combination with metformin , as there is then a

• the risk of hypoglycemia is low, provided that NO HbA1c < 7.5 is targeted
• weight gain is minimal
• SH represent a substance that has an established benefit at endpoint studies.

A triple combination should be avoided if possible. If this is not possible, the German Medical Association (2021) recommends:

• Sulfonylureas
• SGLT2 inhibitors such as Gliflozine
• GLP- 1 receptor antagonists such as liraglutide

Adverse effects:

• Hypoglycemia:

According to the German Medical Association (2021) SH have the highest hypoglycemic potential of all oral antidiabetic agents.

• weight gain of approx.1.9 kg according to QUARTET studies
• all-cause mortality increases by 26% with SH compared with other antihyperglycemic drugs, according to a meta-analysis by Schramm et al. (2011). An exception was gliclazide, where the hazard ratio (HR)was 0.65
• Cardiovascular mortality increased by as much as 46% with the exception of gliclazide, where the HR without a history of infarction was 1.05 and with a history of infarction was 0.87 l (Schernthaner 2019).
• Gastrointestinal complaints
• Alcohol intolerance
• cholestatic jaundice (Boeckh 2002)
• rarely occurring blood count changes (Herold 2020)

Contraindications:

• Patients who have already had severe hypoglycaemia
• advanced renal insufficiency
• manifest cardiovascular disease
• diabetics on insulin
• patients with dementia (because of the increased risk of hypoglycemia) (Schernthaner 2019)
• Very old patients with reduced food intake (risk of hypoglycemia as shown in the 2016 Schloot study) (Bahrmann 2018)
• type 1 diabetes
• diabetic coma or pre-coma
• Hepatic insufficiency
• Anaesthesia
• Surgeries
• Sulfonamide allergy
• Thyroid disease
• Infections
• Pregnancy
• Lactation
• diabetic gangrene (Herold 2020)
• relative contraindication in obesity grade I = BMI 30 - 40 kg / m² (Luippold 2012)

Interactions:

Drug interactions exist with drugs that are strongly bound to proteins, as these enhance the effect of SH by displacing SH from plasma protein binding. These drugs include:

• Coumarins
• non-steroidal anti-inflammatory drugs
• Sulfonamides (Luippold 2012).

A relatively high risk of hypoglycemiaalso exists with:

• ACE inhibitors
• Acetylsalicylic acid
• Alcohol
• Beta-receptor blockers
• Clarithromycin
• coumarin derivatives
• beta antagonists:

The simultaneous administration of beta-receptor antagonists prevents the glucose-mobilizing effect of adrenaline and thus increases the risk of protracted hypoglycemia (which may be lethal) (Luippold 2012).

An attenuation of the SH effect can occur with the following drugs:

• Diuretics
• Glucocorticoids
• Contraceptives
• Thyroid hormones
• Sympathomimetics (Luippold 2012)
• Diazoxide
• Progestin
• Glucagon
• Nicotinic acid derivatives
• Estrogen
• Phenothiazine derivatives
• Saluretics

The risk of severe hypoglycemia with sulfonylureas is particularly high with:

• physical exertion
• cerebrovascular diseases
• cardiac diseases
• hepatic dysfunction
• renal dysfunction
• diarrhoea
• age > 70 years
• irregular food intake
• alcohol (Herold 2020)

1. Bahrmann A et al. (2018) S2k- Guideline Diagnosis, therapy and follow-up of diabetes mellitus in old age. 2nd edition AWMF register number: 057-017
2. Boeckh M et al. (2002) Original examination questions with commentary: GK2 General pharmacology and toxicology. Georg- Thieme Verlag Stuttgart - New York 447
3. German Medical Association (2021) National health care guidelines: type 2 diabetes. AWMF- Register- No. nvl-001
4. Diederich S et al (2020) Reference endocrinology and diabetology. Georg Thieme Verlag Stuttgart 491
5. Frölich J C et al (2000) Practical drug therapy. Springer Verlag 478
6. Herold G et al (2020) Internal medicine. Herold Publishers 734 - 735
7. Kasper D L et al (2015) Harrison's Principles of Internal Medicine. Mc Graw Hill Education 2413
8. Mark M (2002) Sulfonylureas and glinides: from chemotherapeutic agents to antidiabetic agents.https://doi.org/10.1002/1615-1003(200205)31:3<252::AID-PAUZ252>3.0.CO;2-P
9. Luippold G (2012) Casebook pharmacology: 100 cases. Georg Thieme Verlag Stuttgart
10. Schernthaner G et al (2019) Sulfonylureas: place of gliclazide in modern therapy. Instrinsic Activity 7 (1) e2 doi:10.25006/IA.7.1-e2
11. Schramm T K et al. (2011) Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J, 32 (15) 1900-1908
12. Wehling M et al (2006) Clinical pharmacology. Thieme Verlag 267 - 268