Sulfonylureas orsulphonylureas are a class oforganic compounds used inmedicine andagriculture. The functional group consists of asulfonyl group (-S(=O)2) with its sulphur atom bonded to a nitrogen atom of aureylene group (N,N-dehydrourea, a dehydrogenated derivative ofurea). The side chains R1 and R2 distinguish various sulfonylureas. Sulfonylureas are the most widely used herbicide.[1]
Many sulfonylureas are used asherbicides, because they can interfere with plantbiosynthesis of certainamino acids.[2]
Asherbicides sulfonylureas function by interfering with biosynthesis of the amino acids valine, isoleucine, and leucine, specifically viaacetolactate synthase inhibition. Compounds in this class includeamidosulfuron,azimsulfuron,bensulfuron-methyl,chlorimuron-ethyl,chlorsulfuron,ethametsulfuron-methyl,cinosulfuron,cyclosulfamuron,ethoxysulfuron,flazasulfuron,flupyrsulfuron-methyl-Na,foramsulfuron,halosulfuron,imazosulfuron,iodosulfuron,mesosulfuron,metsulfuron-methyl,nicosulfuron,oxasulfuron,primisulfuron-methyl,prosulfuron,pyrazosulfuron-ethyl,rimsulfuron,sulfometuron-methyl,sulfosulfuron,thifensulfuron-methyl,triasulfuron,tribenuron-methyl,trifloxysulfuron,triflusulfuron-methyl andtritosulfuron.[3][4][5] These are broad-spectrum herbicides that kill plants weeds or pests by inhibiting the enzymeacetolactate synthase. In the 1960s, more than 1 kg/ha (0.89 lb/acre) crop protection chemical was typically applied, while sulfonylureates allow as little as 1% as much material to achieve the same effect.[6][7]
They are widely used asantidiabetic drugs in the management ofdiabetes mellitus type 2. They act by increasingsecretion ofinsulin from thebeta cells in thepancreas.[8]
Sulfonylureas are ineffective where there is absolute deficiency of insulin production such as in type 1 diabetes or post-pancreatectomy.[9]
Sulfonylureas can be used to treat some types ofneonatal 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.[10]
A 2011Cochranesystematic review evaluated the effects on treatment ofLatent Autoimmune Diabetes in Adults (LADA) and found that Sulfonylureas did not improve metabolic control ofglucose at 3 and 12 months, even worseningHbA1c levels in some cases, when compared to insulin.[11] The same review did not find improvement of fasting C-peptide following treatment with sulfonylurea.[11] Still, it is important to highlight that the studies available to be included in this review presented considerable flaws in quality and design.[11]
While prior sulfonylureas were associated with worse outcomes, newer agents do not appear to increase the risk of death, heart attacks, or strokes.[12] This is further reinforced by a 2020 Cochranesystematic review which did not find enough evidence of reduction of all-cause mortality, serious adverse events, cardiovascular mortality, non-fatalmyocardial infarction, non-fatalstroke or end-stage renal disease when comparingmetformin monotherapy to sulfonylureas.[13] This same review also did not find improvement in health-related quality of life.[13]
In individuals withimpaired-glucose tolerance, a 2019 systematic review only found one suitable trial comparing the effects of Sulphonylurea withmetformin in reduction or delay of risk of developing type 2 diabetes, however this trial did not report patient-relevant outcomes.[14] Anothersystematic review completed in the same year suggested that there is limited evidence if the combined used 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 andmicrovascular complications.[15] Combined Metformin and Sulphonylurea therapy did appear to lead to higher risk ofHypoglycemia.[15]
Sulfonylureas are also used experimentally to inhibit release ofinterleukin 1 beta from theNALP3 (or NLRP3)inflammasome.[16][17]
Sulfonylureas – as opposed tometformin, thethiazolidinediones,pramlintide and other newer treatments – may inducehypoglycemia as a result of excesses in insulin production and release. Hypoglycemia appears to happen more often with sulfonylureas than compared to other treatments.[18] 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.
Likeinsulin, 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 andhypersensitivity 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.[19] Impairment of liver or kidney function increase the risk of hypoglycemia, and are contraindications. Since otherantidiabetic drugs cannot be used either under these circumstances, insulin therapy is typically recommended during pregnancy and in liver andkidney failure, although some of the newer agents offer potentially better options.
A 2011 Cochrane review found evidence that treatment ofLADA using sulfonylureas lead to earlier insulin dependence in approximately 30% of cases.[11]
A 2014 Cochrane review found tentative evidence that people treated with sulfonylureas have fewer non-fatal cardiovascular events than those treated with metformin (RR 0.7) but a higher risk of severe hypoglycemia (RR 5.6). There was not enough data available to determine the risk of mortality or of cardiovascular mortality.[20] 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.[21] The FDA requires sulfonylureas to carry a label warning regarding increased risk of cardiovascular death.[19]
A 2020Cochranesystematic review comparingmetformin monotherapy to sulfonylureas did not find enough evidence of reduction of all-cause mortality, serious adverse events, cardiovascular mortality, non-fatalmyocardial infarction, non-fatalstroke orend-stage renal disease.[13]
Second-generation sulfonylureas have increased potency by weight, compared to first-generation sulfonylureas.[22] Similarly, ACCORD (Action to Control Cardiovascular Risk in Diabetes)[23] and the VADT (Veterans Affairs Diabetes Trial)[24] studies showed no reduction in heart attack or death in patients assigned to tight glucose control with various drugs.
Drugs that potentiate or prolong the effects of sulfonylureas and therefore increase the risk of hypoglycemia includeacetylsalicylic acid and derivatives,allopurinol,sulfonamides, andfibrates. Drugs that worsenglucose tolerance, contravening the effects of antidiabetics, includecorticosteroids,isoniazid,oral contraceptives and otherestrogens,sympathomimetics, andthyroid 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.[25][26]
Sulfonylureas contain a centralS-arylsulfonylurea structure with ap-substituent on the phenyl ring (R1) and various groups terminating the ureaN′ end group (R2). Chemically, this functionality can be easily installed by reactingarylsulfonamides (R1—C6H4—SO2NH2) withisocyanates (R2—NCO).
Sulfonylureas are divided into 3 classes on basis of therapeutic efficiency of their antidiabetic action:
They includeacetohexamide,carbutamide,chlorpropamide,glycyclamide (tolcyclamide),metahexamide,tolazamide andtolbutamide.
They includeglibenclamide (glyburide),glibornuride,gliclazide,glipizide,gliquidone,glisoxepide andglyclopyramide.
They includeglimepiride, although it is sometimes considered a second-generation drug.[27][28]
Sulfonylureas bind to and closeATP-sensitive K+ (KATP) channels on the cell membrane of pancreaticbeta cells, which depolarizes the cell by preventing potassium from exiting. Thisdepolarization opens voltage-gatedCa2+ channels. The rise in intracellular calcium leads to increased fusion ofinsulin granules with the cell membrane, and therefore increasedsecretion of mature insulin.[29]
There is some evidence that sulfonylureas also sensitize β-cells to glucose, that they limit glucose production in theliver, that they decrease lipolysis (breakdown and release offatty acids byadipose tissue) and decrease clearance of insulin by the liver.[30]
The KATP channel is an octameric complex of theinward-rectifier potassium ion channel Kir6.x andsulfonylurea receptor SUR which associate with astoichiometry of 4:4.[29]
Furthermore, it has been shown that sulfonylureas interact with the nucleotide exchange factorEpac2.[31][32] Mice lacking this factor exhibited a decreased glucose-lowering effect upon sulfonylurea treatment.
Sulfonylureas were discovered in 1942, by the chemistMarcel Janbon and co-workers in France,[33] who were studyingsulfonamideantibiotics and discovered that the compound sulfonylurea inducedhypoglycemia in animals.[34]
Research and development (translational research and commercial application development) for sulfonylureas as pharmaceuticals (as diagnostic and therapeutic agents in prediabetes and diabetes) happened in the 1950s and 1960s, as explored atTolbutamide § History.
Research and development (translational research and commercial application development) for sulfonylureas as herbicides happened in the 1970s and 1980s, as explored for example in a volume of the Sloan Technology Series focusing on the sociotechnological aspects of agriculture (Canine 1995);[35] theDuPont Experimental Station led this development.[35]
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