A 57 years old lady presents with type-ll diabetes mellitus with symptoms like polyuria, excessive thirst, fatigue and blurred vision. Further investigation reveals insulin resistance. Which one of the following drug is most appropriate for initiating treatment along with diet and exercise?

Answer: b) MetforminCLASSIFICATION OF ANTI-DIABETIC DRUGS* Enhance Insulin secretiono Sulfonylureas (KATP Channel blockers)# First generation: Tolbutamide, chlorpropamide, tolazamide, acetohexamide# Second generation: Glibenclamide (glyburide), Glipizide, Gliclazide, Glimepirideo Glinides/Meglitinides/phenylalanine analogues(KATP Channel blockers/prandial glucose regulators): Repaglinide, Nateglinideo Glucagon-like peptide-1 (GLP-1) receptor agonists (Injectable drugs): Exenatide, Liraglutideo Dipeptidyl peptidase-4 (DPP-4) inhibitors: Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, Linagliptin* Overcome Insulin resistanceo Biguanide (AMPK activator): Metformino Thiazolidinediones (PPARY activator): Pioglitazone* Miscellaneous antidiabetic drugso a -Glucosidase inhibitors: Acarbose, Miglitol, Vogliboseo Amylin analogue: pramlintideo Dopamine-D2 receptor agonist: Bromocriptineo Sodium-glucose cotransport-2 (SGLT-2) inhibitor in kidneys: Dapagliflozin, canagliflozinImprove insulin availabilityOvercome insulin resistance* Exogenous insulin* Sulfonylureas* Meglinitinide/ phenylalanine analogues* Dipeptidyl peptidase-4 inhibitors (DPP-4ls)* Biguanides* Thiazolidinediones* Alpha glucosidase inhibitorsMajor limitations (except for DPP-4ls)Major limitations* Hypoglycaemic episodes* Weight gain* Concern about premature Atherosclerosis d/t hyperinsulinemiaInability to achieve normoglycaemia by themselves in many patients, especially moderate-to-severe casesINSULIN (Discovered by Banting and Best in 1921)Preparations: Conventional preparations are obtained from pork (porcine) and beef (bovine). Addition of zinc makes it long acting. Insulin may be:o Ultra short acting (insulin lispro, glulisine and aspart)o Short acting (regular insulin and semi lente)o Intermediate acting (lente insulin and neutral protamine hagedron).o Long acting (ultra lente and protamine zinc insulin)o Ultra long acting (insulin detemir, glargine, degludec)* Single peak insulin and mono component insulin: less immunogenic.* Rapid-acting and short-acting insulins are clear solutions at neutral pH and contain small amounts of zinc to improve their stability and shelf-life.* All others except insulin glargine are dispensed as turbid suspensions at neutral pH with either protamine in phosphate buffer (neutral protamine Hagedorn insulin) or varying concentrations of zinc in acetate buffer (ultralente and lente insulins).* Insulin glargine is the only soluble, "peakless" ultralong- acting insulin analog.* When lente insulin is mixed with regular insulin, some of the regular insulin may form a complex with the protamine or Zn2+* D/t its acidic pH, insulin glargine cannot be mixed with other insulin preparations that are formulated at neutral pH.* Prevalence of hypoglycemia is reduced by 20-30% with insulin lispro, and glucose control, as assessed by HbAlc, is modestly but significantly improved.* Continuous Subcutaneous Insulin Infusion Devices: most physiologic method of insulin replacement.* Best drug of choice to combine with insulin: metformin.* Major and dose limiting side effect of insulin therapy: Hypoglycemia.* Insulin detemir: not approved in pregnancy.* Degludec: action lasts for 72 hours. (? Weekly twice dosage)Main types of insulin preparationTypeOnsetPeakDurationCommentsRapid-acting insulin analogue5-15 min30-60 min2-5 hrCan be injected at the start of a mealShort-acting(soluble/ regular insulin)30 min1-3 hr4-8 hrUsually injected 15-30 minutes before a meal. Clear solutionIntermediate or long-actin Insulin1-2 hr(NPH, Lente) 2-3 hr4-8 hr8-12 hr(NPH)Used to control glucose levels between meals. May be combined with(isophane or zinc insulin)(Ultralente)4-8 hr8-24 hr(Ultralente)short-octing insulinLong-acting insulin analogue30-60 minNo pee k16-24 hrUsually taken once dailyRoute of administration* All preparations can be given by S.C. route.* Only regular (crystalline zinc) insulin can be given i.v.* Inhalational route (Exubera), oral insulin, buccal delivery of insulin- under trial.Basal-bolus regimen:* 3-4 daily injections.* A long-acting insulin (glargine) is injected once daily either before breakfast or before bed-time for basal coverage along with 2-3 meal - time injections of a rapid acting preparation (insulin lispro or aspart).Complications of insulin therapy* Most common complication is hypoglycemia.* Lipodystrophy (less with highly purified and recombinant forms)* Allergic reactions can occur with conventional preparation* Short lived edema due to Na+ retention.ORAL HYPOGLYCEMIC AGENTSDRUGS ACTING BY THE RELEASE OF INSULIN* This group includes Sulfonyl ureas and meglitinides. These drugs inhibit ATP sensitive K+ channels and cause depolarization of b cells resulting in the release of insulin.* These drugs are effective only if 30% or more of the b cells in the pancreas are available.* Major limitation of these drugs is hypoglycemia.Sulfonvlureas:* These may be first generation (Tolbutamide, chlorpropamide) or second generation (glibenclamide, glipizide, gliclazide and glimepiride) compounds.* Tolbutamide is the shortest acting whereas chlorpropamide is the longest acting sulfonylurea.* Second generation drugs are most the potent.* They can cause weight gain (less chance with glipizide and gliclazide).* Chlorpropamide has additional actions like dilutional hyponatremia (ADH like action), cholestatic jaundice and disulfiram like reaction (intolerance to alcohol).* Glimepiride: Sulfonylurea of choice, Have beneficial effects in regard to ischemic preconditioningo Enhances GLUT-4 translocation.o Inhibitory effects on platelet aggregation.* Sequestered in beta cells, Higher incidence of hypoglycemia (maximum with glibenclamide)* Glibenclamide: releases duodenal insulin releasing agent (DIRA), responsible for sustained effect* Gliclazide has additional antiplatelet action, beneficial effect on fibrinolysis.* Glipizide: better control of post prandial hyperglycemia.* Chlorpropamide: now used in diabetes insipidus.* Can precipitate Steven Johnson syndrome, but do not exhibit cross reactivity with sulfonamides Meglitinides: Nateglinide and repaglinide (mainly for post prandial hyperglycemia-"treat while you eat")DRUGS ACTING BY OTHER MECHANISMSBiguanides:* Extracted initially from French lilac.* Metformin and phenformin: preferred agents for obese patients (cause weight loss).* Decreases the production (inhibit gluconeogenesis and glycogenolysis) and increasing the utilization (stimulation of glycolysis and tissue uptake of glucose).* Actions of metformino Anorexigenic effecto Decreases glucose absorption in intestineo Decreases hepatic gluconeogenesiso Increases the number of insulin receptorso Increases GLUT-4 transporterso Decreases TGL synthesis in livero Facilitates conversion of atherogenic LDL to non atherogenic LDL.* 1st line drug in the management of diabetes; shown to prevent progression of IGT to diabetes* Only anti-diabetic drug approved for pediatric use in USA.* Lactic acidosis-type-B (more with phenformin) and Megaloblastic anemia (more with metformin) due to vitamin B12 deficiency are the major adverse effects of these drugs.* Lactic acidosis is more likely to occur in the presence of hepatic and renal impairment or alcohol ingestion.* Used in PCOD & it is the only drug that reduces macrovascular complications in type-II DM.Thiazolidinediones;* Troglitazone, pioglitazone and rosiglitazone act as agonists of peroxisome proliferator activated receptor gamma (PPARy). These drugs increase HDL. (favorable lipid profile)* These drugs are used to reverse insulin resistance in type II DM.* Troglitazone was withdrawn due to serious hepatotoxicity and monitoring of hepatic function is recommended for other glitazones also.* Glitazones are avoided in CHF due to the risk of edema (fuid retention), increases the risk of osteoporotic fractures.* Usually not combined with insulin (d/t weight gain)* Stimulant of ovulation.* Rosiglitazone is associated with increased incidence of Ml & Pioglitazone with bladder Ca.* Increases subcutaneous fat with decreased visceral fat* Thiazolidinedione paradox: improves insulin sensitivity despite increasing subcutaneous adiposity.a-Glucosidase inhibitors:* Inhibitors of a glucosidase (voglibose, acarbose and miglitol) decrease carbohydrate absorption from the GIT.* Not as potent as other oral agents in lowering the A1C but is unique because it reduces the postprandial glucose rise even in individuals with type 1 DM.* Most specific agent for sucrose and maltase enzymes: Voglibose* Major adverse effect - flatulence due to fermentation of unabsorbed carbohydrates.GLP-1 AGONISTS* Exenatide: a recombinant glucagon like peptide (GLP) analogue.o GLP is normally secreted (in GIT) when food enters the stomach and it stimulates release of insulin.o GLP is normally metabolized by dehydro peptidyl peptidase 4 (DPP-4),o Exenatide is a GLP analogue resistant to DPP-4 and can be used for the treatment of DM.o Major adverse effect: lifr threatening pancreatitis* Liraglutide:o Long-acting GLP-1 agonist, closely related to the native peptide but its tight binding to plasma proteins extends t1/2to > 12 hours and duration of action to >20 hours,o MC adverse effects: nausea and diarrhea.o Use of liraglutide- weight loss & being evaluated as an antiobesity drug even for nondiabetics.o Carries a black box warning because of an increased risk of thyroid C-cell tumors in rodents,o Contraindicated in medullary carcinoma of the thyroid and MEN syndromes.o Hypoglycaemia is rare with exenatide/liraglutide mono-therapy.* Recent drugs: albiglutide, dulaglutide and semaglutide.DPP-4 INHIBITORS* Sitagliptin, Vildagliptin, Linagliptin & Saxagliptin: It is a DPP-4 inhibitor and thus decreases the metabolism of endogenous GLP.* Sitagliptin achieves peak concentrations within 1-4 hours, and has a half-life of 12 hours.* Linagliptin: no dose adjustement needed in renal failure.* The usual dosage is 100 mg orally once daily.* Sitagliptin can be used as monotherapy and in combination with metformin, sulfonylureas, and Tzds.* Therapy with sitagliptin has resulted in HbA lc reductions of between 0.5% and 1.0%.* Boosts post prandial insulin release & decreases glucagon secretion.* Nasopharyngitis & cough can occur d/t prevention of Substance-P degradation.* Pancreatitis is rare.* Recent drugs: alogliptin, teneligliptinNEWER DRUGS* Pramlintide, an analogue of amylin: given parenterally, delays gastric emptying and suppresses glucagon secretion. Reduce postprandial glycemic excursions in type 1 and type 2 diabetic patients taking insulin.* Bromocriptine mesylate: alter insulin resistance by acting on hypothalamus & bromocriptine targets D-2 receptors.* Dapagliflozin/canaglifozin: produces round-the-clock glycosuria and lowers blood glucose levels. Resulting glycosuria can predispose to urinary and genital infections, electrolyte imbalance and increased urinary frequency. Contraindicated in renal failureNOTE:* Colesevelam hydrochloride: Initially developed as a bile acid sequestrant and cholesterol- lowering drug, is now approved as an antihyperglycemic therapy for persons with type 2 diabetes who are taking other medications or have not achieved adequate control with diet and exercise.* Epalrestat:o Sorbitol is a minor metabolite of glucose generated by the enzyme aldose reductase,o In diabetics, excess sorbitol is deposited in nerves and other tissues diabetic neuropathy and other complications.o Epalrestat is an aldose reductase inhibitor - delays sorbitol accumulation & delays progression of diabetic neuropathy.o Nausea, vomiting and elevation of liver enzymes are the adverse effects.Important facts:* Glucose-lowering agents other than insulin (with the exception of amylin analogue and a- glucosidase inhibitors) are ineffective in type 1 DM.* Glucagon is suppressed by: incretin analogues & DPP-IV inhibitors.* All others are used only in type 2 DM.* Injectable drugs for DM: Insulin, Exenatide, Pramlinitide, Liraglutide.* The only bile acid binding resin approved for type 2 DM is cholesevelam.* D2 agonist approved for type 2 DM is Bromocriptine* Weight gain is seen with--Insulin, insulin secretagogues (sulfonyl ureas, meglinitinides), thiazolidinediones* Weight reduction is seen with - Metformin, pramlintide,GLP-l agonist* Weight neutral- DDP4 inhibitors* Alpha glucosidase inhibitor will reduce the progression of IGT to type 2 DM MOAHbAlC Reduction (%)AdvantagesDisadvantagesContraindicationsBiguanides| Hepatic glucose production1-2Weight neutral, Do not cause hypoglycemia, inexpensiveDiarrhea, nausea, lactic acidosisSerum creatinine >1.5, CHF, radiographic contrast studies, seriously ill patients, acidosisa-Glucosidase inhibitors| GI glucose absorption0.5-0.8| postprandial glycemiaGl flatulence, liver function testsRenal/liver diseaseDipeptidyl peptidase IV inhibitorsProlong endogenous GLP-1 action0.5-0.8Do not cause hypoglycaemia Reduce dose with renal diseaseInsulin secretagogues: Sulfonylurea| Insulin secretion1-2InexpensiveHypoglycemia, weight gainRenal/liver diseaseInsulin secretagogues: Non- sulfonylureas| lnsulin secretion1-2Short onset of action, lower postprandial glucoseHypoglycemiaRenal/liver diseaseThiazolidinedi onesb| lnsulin resistance, '|glucose utilization0.5-1.4Lower insulin requirementsPeripheral edema, CHF, weight gain, fractures, macular edema; rosiglitazone may increase cardiovascular riskCHF, liver disease;Bile acid sequestrantsBind bile acids; mechanism of glucose lowering not known0.5 Constipation, | triglycerides, interfere with absorption of other drugs, intestinal obstructionElevated plasma triglycerideslnsulinb'c| Glucose utilization, | Hepatic glucose production,Not limitedKnown safety profileInjection, weight gain, hypoglycemia GLP-1 receptor agonistsb| lnsulin, | glucagon, slow gastric emptying, satiety0.5-1.0Weight loss, do not cause hypoglycemiaInjection, nausea, 'brisk of hypoglycemia with insulin secretagogues, pancreatitis, renal failureRenal disease, agents that also slowGI motility;Amylin agonistsb,cSlow gastric emptying, | glucagon0.25- 0.5Reduce postprandial glycemia; weight lossInjection, nausea, 'brisk of hypoglycemia with insulinAgents that also slow Gl motilityMedical nutrition therapy and physical activityb,c| Insulin resistance, | insulin secretion1-3Other health benefitsCompliance difficult, long-term success low * aAiC reduction (absolute) depends partly on starting AiC.* bUsed for treatment of type 2 diabetes.* cUsed in conjunction with insulin for treatment of type 1 diabetes