Treatment of type 2 diabetes They are widely used as
antidiabetic drugs in the management of
diabetes mellitus type 2. They act by increasing
secretion of
insulin from the
beta cells in the
pancreas. Sulfonylureas are ineffective where there is absolute deficiency of insulin production such as in type 1 diabetes or post-pancreatectomy. Sulfonylureas can be used to treat some types of
neonatal diabetes. Historically, people with hyperglycemia and low blood insulin levels were diagnosed with type 1 diabetes by default, but it has been found that patients who receive this diagnosis before 6 months of age are often candidates for receiving sulfonylureas rather than insulin throughout life. A 2011
Cochrane systematic review evaluated the effects on treatment of
Latent Autoimmune Diabetes in Adults (LADA) and found that Sulfonylureas did not improve metabolic control of
glucose at 3 and 12 months, even worsening
HbA1c levels in some cases, when compared to insulin. The same review did not find improvement of fasting C-peptide following treatment with sulfonylurea. This is further reinforced by a 2020 Cochrane
systematic review which did not find enough evidence of reduction of all-cause mortality, serious adverse events, cardiovascular mortality, non-fatal
myocardial infarction, non-fatal
stroke or end-stage renal disease when comparing
metformin monotherapy to sulfonylureas. This same review also did not find improvement in health-related quality of life. Another
systematic review completed in the same year suggested that there is limited evidence if the combined use of Metformin with Sulphonylurea compared to the combination of Metformin plus another glucose-lowering intervention, provides benefit or harm in mortality, severe adverse events,
macrovascular and
microvascular complications. Combined Metformin and Sulphonylurea therapy did appear to lead to higher risk of
Hypoglycemia.
Side effects Sulfonylureas – as opposed to
metformin, the
thiazolidinediones,
pramlintide and other newer treatments – may induce
hypoglycemia as a result of excesses in insulin production and release. Hypoglycemia appears to happen more often with sulfonylureas than compared to other treatments. This typically occurs if the dose is too high, and the patient is fasting. Some people attempt to change eating habits to prevent this, however it can be counterproductive. Like
insulin, sulfonylureas can induce weight gain, mainly as a result of their effect to increase insulin levels and thus use of glucose and other metabolic fuels. Other side-effects are: gastrointestinal upset,
headache and
hypersensitivity reactions. The safety of sulfonylurea therapy in pregnancy is unestablished. Prolonged hypoglycemia (4 to 10 days) has been reported in children borne to mothers taking sulfonylureas at the time of delivery. Impairment of liver or kidney function increase the risk of hypoglycemia, and are contraindications. Since other
antidiabetic drugs cannot be used either under these circumstances, insulin therapy is typically recommended during pregnancy and in liver and
kidney failure, although some of the newer agents offer potentially better options. A 2011 Cochrane review found evidence that treatment of
LADA using sulfonylureas lead to earlier insulin dependence in approximately 30% of cases. An earlier review by the same group found a statistically significant increase in the risk of cardiovascular death for first generation sulfonylureas relative to placebo (RR 2.6) but there was not enough data to determine the relative risk of first generation sulfonylureas relative to insulin (RR 1.4). Likewise it was not possible to determine the relative mortality risk of second generation sulfonylureas relative to metformin (RR 1.0), insulin (RR 1.0), or placebo. The FDA requires sulfonylureas to carry a label warning regarding increased risk of cardiovascular death. Similarly, ACCORD (Action to Control Cardiovascular Risk in Diabetes) and the VADT (Veterans Affairs Diabetes Trial) studies showed no reduction in heart attack or death in patients assigned to tight glucose control with various drugs.
Interactions Drugs that potentiate or prolong the effects of sulfonylureas and therefore increase the risk of hypoglycemia include
acetylsalicylic acid and derivatives,
allopurinol,
sulfonamides, and
fibrates. Drugs that worsen
glucose tolerance, contravening the effects of antidiabetics, include
corticosteroids,
isoniazid,
oral contraceptives and other
estrogens,
sympathomimetics, and
thyroid hormones. Sulfonylureas tend to interact with a wide variety of other drugs, but these interactions, as well as their clinical significance, vary from substance to substance. == Structure ==