Anti-diabetic medicationPrepared for the Medical DepartmentFranco Indian Pharmaceuticals LtdBy Dr. Ashok Moses
Anti-diabetic medicationAnti-diabetic medications treat diabetes mellitusby lowering glucose levels in the blood. With theexceptions of insulin, exenatide, liraglutide andpramlintide, all are administered orally and arethus also called oral hypoglycemic agents or oralanti hyperglycemic agents. There are differentclasses of anti-diabetic drugs, and their selectiondepends on the nature of the diabetes, age andsituation of the person, as well as other factors.
Diabetes mellitus type 1• Diabetes mellitus type 1 (also known as type 1diabetes, or T1DM; formerly insulin dependentdiabetes or juvenile diabetes) is a form ofdiabetes mellitus that results from autoimmunedestruction of insulin-producing beta cells of thepancreas. The subsequent lack of insulin leadsto increased blood and urine glucose. Theclassical symptoms are polyuria (frequenturination), polydipsia (increased thirst),polyphagia (increased hunger), and weight loss.
Diabetes mellitus type 2• Diabetes mellitus type 2 (formerly noninsulin-dependentdiabetes mellitus (NIDDM) or adult-onset diabetes) is ametabolic disorder that is characterized by high bloodglucose in the context of insulin resistance and relativeinsulin deficiency. This is in contrast to diabetes mellitustype 1, in which there is an absolute insulin deficiency dueto destruction of islet cells in the pancreas. The classicsymptoms are excess thirst, frequent urination, andconstant hunger. Type 2 diabetes makes up about 90% ofcases of diabetes with the other 10% due primarily todiabetes mellitus type 1 and gestational diabetes. Obesityis thought to be the primary cause of type 2 diabetes inpeople who are genetically predisposed to the disease.
Diabetes mellitus type 2• Type 2 diabetes is initially managed byincreasing exercise and dietary modification. Ifblood glucose levels are not adequatelylowered by these measures, medications suchas metformin or insulin may be needed. Inthose on insulin, there is typically therequirement to routinely check blood sugarlevels
• Several groups of drugs, mostly given by mouth,are effective in Type II, often in combination. Thetherapeutic combination in Type II may includeinsulin, not necessarily because oral agents havefailed completely, but in search of a desiredcombination of effects. The great advantage ofinjected insulin in Type II is that a well-educatedpatient can adjust the dose, or even takeadditional doses, when blood glucose levelsmeasured by the patient, usually with a simplemeter, as needed by the measured amount ofsugar in the blood.
Insulin• Insulin is usually given subcutaneously, eitherby injections or by an insulin pump. Researchof other routes of administration is underway.In acute-care settings, insulin may also begiven intravenously. In general, there are threetypes of insulin, characterized by the ratewhich they are metabolized by the body. Theyare rapid acting insulins, intermediate actinginsulins and long acting insulins.
Sensitizers• Insulin sensitizers address the core problem inType II diabetes—insulin resistance• Biguanides• Thiazolidinediones
Biguanides• Biguanides reduce hepatic glucose output andincrease uptake of glucose by theperiphery, including skeletal muscle. Although itmust be used with caution in patients withimpaired liver or kidney function, metformin, abiguanide, has become the most commonly usedagent for type 2 diabetes in children andteenagers. Among common diabeticdrugs, metformin is the only widely used oraldrug that does not cause weight gain
Other Biguanides• Phenformin (DBI) was used from 1960sthrough 1980s, but was withdrawn due tolactic acidosis risk.• Buformin also was withdrawn due to lacticacidosis risk.
• Metformin is usually the first-line medicationused for treatment of type 2 diabetes. In general,it is prescribed at initial diagnosis in conjunctionwith exercise and weight loss, as opposed to inthe past, where it was prescribed after diet andexercise had failed. There is an immediate releaseas well as an extended-release formulation,typically reserved for patients experiencing GIside-effects. It is also available in combinationwith other oral diabetic medications.
Thiazolidinediones• Thiazolidinediones (TZDs), also known as"glitazones," bind to PPARγ (PeroxisomeProliferator Receptor gamma), a type of nuclearregulatory protein involved in transcription ofgenes regulating glucose and fat metabolism.These PPARs act on peroxysome proliferatorresponsive elements (PPRE). The PPREsinfluence insulin-sensitive genes, which enhanceproduction of mRNAs of insulin-dependentenzymes. The final result is better use of glucoseby the cells
Thiazolidinediones• Rosiglitazone (Avandia): the EuropeanMedicines Agency recommended inSeptember 2010 that it be suspended fromthe EU market due to elevated cardiovascularrisks.[• Pioglitazone (Actos)• Troglitazone (Rezulin): used in 1990s,withdrawn due to hepatitis and liver damagerisk
Secretagogues• These are the drugs that increase Insulinoutput from Pancreas.• Sulfonylureas• Nonsulfonylurea secretagogues
Sulfonylureas• Sulfonylureas were the first widely used oral anti-hyperglycaemicmedications. They are insulin secretagogues, triggering insulinrelease by inhibiting the KATP channel of the pancreatic beta cells.Eight types of these pills have been marketed in North America, butnot all remain available. The "second-generation" drugs are nowmore commonly used. They are more effective than first-generationdrugs and have fewer side-effects. All may cause weight gain. A2012 study found sulfonylureas raise the risk of death comparedwith metformin.• Sulfonylureas bind strongly to plasma proteins. Sulfonylureas areuseful only in Type II diabetes, as they work by stimulatingendogenous release of insulin. They work best with patients over40 years old who have had diabetes mellitus for under ten years.They cannot be used with type I diabetes, or diabetes of pregnancy.They can be safely used with metformin or -glitazones. The primaryside-effect is hypoglycemia.
Nonsulfonylurea secretagogues• Meglitinides help the pancreas produce insulin and are often called"short-acting secretagogues." They act on the same potassiumchannels as sulfonylureas, but at a different binding site. By closingthe potassium channels of the pancreatic beta cells, they open thecalcium channels, thereby enhancing insulin secretion.• They are taken with or shortly before meals to boost the insulinresponse to each meal. If a meal is skipped, the medication is alsoskipped.• Typical reductions in glycated hemoglobin (A1C) values are 0.5–1.0%.• Repaglinide (Prandin)• Nateglinide (Starlix)• Adverse reactions include weight gain and hypoglycemia.
Alpha-glucosidase inhibitors• Alpha-glucosidase inhibitors are "diabetes pills"but not technically hypoglycemic agents becausethey do not have a direct effect on insulinsecretion or sensitivity. These agents slow thedigestion of starch in the small intestine, so thatglucose from the starch of a meal enters thebloodstream more slowly, and can be matchedmore effectively by an impaired insulin responseor sensitivity. These agents are effective bythemselves only in the earliest stages of impairedglucose tolerance, but can be helpful incombination with other agents in type 2 diabetes.
Alpha-glucosidase inhibitors• Miglitol (Glyset)• Acarbose (Precose/Glucobay)• Voglibose• These medications are rarely used in the United Statesbecause of the severity of their side-effects (flatulenceand bloating). They are more commonly prescribed inEurope. They do have the potential to cause weightloss by lowering the amount of sugar metabolized.• Research has shown that the culinary mushroommaitake (Grifola frondosa) has a hypoglycemic effect,possibly due to the mushroom acting as a natural alphaglucosidase inhibitor
Injectable Glucagon-like peptideanalogs and agonists• Incretins are insulin secretagogues. The two maincandidate molecules that fulfill criteria for beingan incretin are glucagon-like peptide-1 (GLP-1)and gastric inhibitory peptide (glucose-dependent insulinotropic peptide, GIP). BothGLP-1 and GIP are rapidly inactivated by theenzyme dipeptidyl peptidase-4 (DPP-4).• Glucagon-like peptide (GLP) agonists bind to amembrane GLP receptor. As a consequence,insulin release from the pancreatic beta cells isincreased. Endogenous GLP has a half-life of onlya few minutes, thus an analogue of GLP wouldnot be practical.
Injectable Glucagon-like peptideanalogs and agonists• Exenatide (also Exendin-4, marketed as Byetta) is the first GLP-1agonist approved for the treatment of type 2 diabetes. Exenatideis not an analogue of GLP but rather a GLP agonist. Exenatide hasonly 53% homology with GLP, which increases its resistance todegradation by DPP-4 and extends its half-life. Typical reductionsin A1C values are 0.5–1.0%.• Liraglutide, a once-daily human analogue (97% homology), hasbeen developed by Novo Nordisk under the brand name Victoza.The product was approved by the European Medicines Agency(EMEA) on July 3, 2009, and by the U.S. Food and DrugAdministration (FDA) on January 25, 2010.• Taspoglutide is presently in Phase III clinical trials with Hoffman-LaRoche.• These agents may also cause a decrease in gastric motility,responsible for the common side-effect of nausea, and is probablythe mechanism by which weight loss occurs
Gastric inhibitory peptide analogs• None are FDA approved
Dipeptidyl Peptidase-4 Inhibitors• GLP-1 analogs resulted in weight loss and had more gastrointestinalside-effects, while in general DPP-4 inhibitors were weight-neutral andincreased risk for infection and headache, but both classes appear topresent an alternative to other antidiabetic drugs. However, weight gainand/or hypoglycaemia have been observed when DPP-4 inhibitors wereused with sulfonylureas; effect on long-term health and morbidity ratesare still unknown.• Dipeptidyl peptidase-4 (DPP-4) inhibitors increase blood concentrationof the incretin GLP-1 by inhibiting its degradation by dipeptidylpeptidase-4.• Examples are:• vildagliptin (Galvus) EU Approved 2008• sitagliptin (Januvia) FDA approved Oct 2006• saxagliptin (Onglyza) FDA Approved July 2009• linagliptin (Tradjenta) FDA Approved May 2, 2011• allogliptin• septagliptin
Injectable Amylin analogues• Amylin agonist analogues slow gastric emptyingand suppress glucagon. They have all theincretins actions except stimulation of insulinsecretion. As of 2007[update], pramlintide is theonly clinically available amylin analogue. Likeinsulin, it is administered by subcutaneousinjection. The most frequent and severe adverseeffect of pramlintide is nausea, which occursmostly at the beginning of treatment andgradually reduces.
Natural substances• Plants• A number of medicinal plants have been studied for the treatment ofdiabetes, however there is insufficient evidence to determine theireffectiveness. Cinnamon has blood sugar-lowering properties, howeverwhether or not it is useful for treating diabetes is unknown. Researchersfrom Australias Swinburne University have found extracts from AustralianSandalwood and Indian Kino tree slows down two key enzymes incarbohydrate metabolism. Bioassay-directed fractionation techniques led toisolation of isoorientin as the main hypoglycemic component in Gentianaolivieri.• Elements• While chromium supplements have no beneficial effect on healthy people,there might be an improvement in glucose metabolism in individuals withdiabetes, although the evidence for this effect remains weak. Vanadylsulfate, a salt of vanadium, is still in preliminary studies. There is tentativeresearch that thiamine may prevent some diabetic complications howevermore research is needed.