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Comprehensive Overview of Oral Antidiabetic Agents for Type 2 Diabetes Management

Detailed insights into oral antidiabetic drugs, their classifications, mechanisms, dosing, adverse effects, and strategies for effective type 2 diabetes treatment.

Health & Medicine◦
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ORAL ANTIDIABETIC AGENTS Dr Abdullah Al Maruf MD (E&M) Student, BIRDEM
ORAL ANTIDIABETIC AGENTS (OAA)  Oral antidiabetic drugs are used to treat type 2 DM when dietary modification and exercise can not achieve the glycemic goals  OAA like Metformin and TZDs prevent DM in prediabetic patients and used to treat insulin resistant conditions like NAFLD and PCOS  Metformin may also be used in type 1 DM to reduce the dose of insulin
Classification of OAA Class Drugs Biguanides Metformin Sulfonylurea Glibenclamide/Glyburide Glipizide Gliclazide Glimepiride Meglitinides (glinides) Repaglinide Nateglinide TZDs Pioglitazone Rosiglitazone DPP-4 inhibitors Sitagliptin Vildagliptin Saxagliptin Linagliptin
Classification of OAA (Cont.) Class Drugs α-Glucosidase inhibitors Acarbose Miglitol SGLT2 inhibitors Canagliflozin Dapagliflozin Empagliflozin Dopamine-2 agonists Bromocriptine Bile acid sequestrant Colesevelam
Biguanides  Metformin is the only biguanide available in Bangladesh  Phenformin and buformin remain available in some countries
Metformin  Metformin reduce hepatic glucose production  Usually taken at least twice daily. Extended release formulation can be given once daily.  Extended release metformin is associated with less severe upper GIT symptoms.  Daily dose: 500-2000 mg  Adverse Effect: nausea, diarrhea, crampy abdominal pain, dysgeusia, Vit B12 deficiency
Metformin (Cont.)  Contraindication: circulatory shock, dehydration, acidosis, hepatic and renal failure  Can be used if eGFR up to 30 ml/min/1.73m²  Max dose is 1000 mg when eGFR is between 30 to 45 ml/min  Safe in pregnancy (pregnancy category B)
Sulfonylurea  First generation sulfonylurea: Tolbutamide, tolazamide, acetohexamide and chlorpropamide.  Second generation sulfonylureas: Glybenclamide(glyburide), glipizide, gliclazide and glimepiride
Mode of Action of Sulfonylurea Sulfonylureas activate sulfonylurea receptor on the – β cells Closer of the K⁺ ATP channel, reducing the efflux of K⁺ Membrane depolarization Opening of Ca channels, increasing Ca influx Exocytotic release of insulin granules
Sulfonylurea (Cont.)  Adverse Effect: Hypoglycaemia, weight gain (rarely idiosyncratic reaction: skin rash, leukopenia, thrombocytopenia)  Contraindication: Severe kidney and liver impairment, pregnancy and lactation
Sulfonylurea (Dose Range) Drug Tablet size Dose Range Duration of Action(hr) Glibenclamide/ glyburide (Gluconil ®) 1.25, 2.5 and 5 mg 1.25-20 mg Up to 24 Glipizide 5 and 10 mg 2.5-40 mg 6-12 Glipizide XL 2.5, 5 and 10 mg Up to 20 mg Up to 24 Glyclazide 80 mg 40-320 mg 12 Glimepiride 1, 2 and 4 mg 1-4 mg Up to 24
Meglitinides (glinides)  These are rapid acting secretagogues  Acts by binding to the sulfonylurea receptor  Adverse Effect: hypoglycemia and weight gain  Causes less hypoglycemia than sulfonylurea  Useful in renal impairment and elderly person  Taken 15 min before each meal
Meglitinides (glinides) Drug Tablet size Dose Range Duration of Action(hr) Repaglinide (Nomopil®) 0.5, 1 and 2 mg 0.5-40 in three divided doses 3 Nateglinide (Sterlix®) 120 mg 60-180 mg in three divided doses 2
Advantages of Nateglinide  It has quicker onset and shorter duration of action than repaglinide  Advantage: less hypoglycemia  Disadvantages: It lower postprandial plasma glucose but repaglinide lower both fasting and postprandial plasma glucose  Useful when FPG is modestly elevated in early diabetes or in combination with insulin sensitizers or long acting evening insulin
Thiazolidinediones  Insulin sensitizers of peripheral tissue  Mode of action: activation of PPAR-ϒ  Adverse Effect: water retention, decreased BMD, anaemia, wt gain  Contraindication: heart failure (NYH grade III & IV), active liver disease  Dose: rosiglitazone 4 to 8 mg/d and pioglitazone 15 to 45 mg/d
Dipeptidyl Peptidase-4 Inhibitors Mechanism of Action: enhance endogenous incretin activity by preventing the degradation of the GIP and GLP-1. Incretin causes: 1. Enhance glucose dependant insulin secretion 2. Suppress glucagon secretion 3. Create satiety 4. Slow gastric emptying  Advantages: No hypoglycemia, wt neutral  Adverse Effect: GI upset, pancreatitis, upper RTI
Sitagliptin vs Vildagliptin Sitagliptin Vildagliptin Doses 100 mg/d in the morning 50 mg twice daily Max daily dose 100 mg 100 mg Moderate renal insufficiency (CCR ≥ 30 to < 50 mL/min) Sitagliptin 50 mg Contraindicated Severe renal insufficiency (CCR< 30 mL/min) or with ESRD requiring dialysis Sitagliptin 25 mg Contraindicated Mild or moderate impairment of liver function Can be used Contraindicated Linagliptin can be used in CKD
Alpha-glucosidase Inhibitors (AGI)  Drugs: acarbose and miglitol  Mechanism of Action: Inhibit intestinal brush border α- glucosidases and thereby delay the absorption of carbohydrate  Given with each meal (first mouthful of food ingested)  Advantages: No hypoglycemia or wt gain  Adverse effect: Flatulence, diarrhoea
Doses of α-glycosidase inhibitor Start with a low dose just once daily to increase tolerance Drug Tablet size Dose Range Duration of Action(hr) Acarbose (Sugatrol® 50, 100 mg) 50 and 100 mg 75-300 in three divided doses 4 Miglitol (Diaset®25, 50 mg) 25, 50 and 100 mg 75-300 in three divided doses 4
SGLT2 inhibitors  Drugs: canagliflozin (Invokana®), dapagliflozin, empagliflozin  Mechanism of Action: Inhibits SGLT2 in the proximal nephron, increasing glucosuria  Dose: 100 mg/day taken before the first meal of the day, may increase dose to 300 mg/day  Adverse Effects: Genitourinary infections, polyuria, volume depletion/hypotention/dizziness
Novel Agents  Colesevelam: Bile acid sequestrant  Bromocriptine (quick release formulation): Dopamine-2 agonists  Pramlintide (injectable): Amylinomimetic
Colesevelam  Mechanism of glycemic effect is unknown  Advantage: No hypoglycemia, decrease LDL-C  Disadvantase: Generally modest HbA1C reduction, constipation, increases TG, may decrease absorption of other medications
Bromocriptine  Quick-release formulation of Bromocriptine is administered within 2 hour of rising in the morning  Improves insulin sensitivity  Modest HbA1c improvement  Nausea is the most common adverse effect
Strategies of using OAA  Minimal Cost Strategy  Minimal Weight Gain Strategy  Minimal Progressive Beta-Cell Loss Strategy  Minimal Injection Strategy  Minimal Insulin Resistance Strategy  Minimal Effort Strategy  Hypoglycemia Avoidance Strategy  Postprandial Targeting Strategy
Minimal Cost Strategy  Start with a sulfonylurea or metformin or both  Progress to the addition of bedtime NPH insulin
Minimal Weight Gain Strategy  Dietary modification and exercise  Metformin is initial therapy.  GLP1 receptor agonists are second-line drugs  DPP4 inhibitors, AGIs, colesevelam, and bromocriptine are all weight neutral
Minimal Progressive Beta-Cell Loss Strategy  Thiazolidinedione with metformin as initial therapies  Avoid sulfonylurea
Minimal Injection Strategy  Metformin + thiazolidinediones + sulfonylureas/DPP4 inhibitors
Minimal Insulin Resistance Strategy  Use metformin and thiazolidinedione
Minimal Effort Strategy  Once-a-day medications: metformin XR, sulfonylurea, DPP4 inhibitor, or thiazolidinediones  Basal insulin or liraglutide injection may be considered
Hypoglycemia Avoidance Strategy  GLP1 receptor agonists, DPP4 inhibitors, and metformin are not associated with hypoglycaemia  Secretagogues would be added last, their dose minimized, and glybenclamide avoided  Nateglinide is the preferred secretagogues  Basal insulin are preferred than prandial insulin  Insulin detemir is preferred than NPH insulin and insulin glargine
Postprandial Targeting Strategy  DPP-4 inhibitors & GLP-1 receptor agonists  AGIs  Nateglinide and repaglinide  Rapid-acting insulin analogues
FPG & PPG lowering effect of OAA  Fasting plasma glucose lowering agents: Metformin, Sulfonylurea, TZDs, basal insulin  Prandial plasma glucose lowering agents: Acarbose, Exenetide, bolus insulin  Both FPG and PPG lowering agents: DPP-4 inhibitor, liraglutide, repaglinide
HbA1c Reduction Drug HbA1c Reduction % Metformin 1-2 Glitazones 0.5-2 Sulfonylureas 1-2 Repaglinide 1-2 Nateglinide 0.5-1 Exenetide ̴ 1 DPP-4 inhibitor 0.5-1.4 α-Glucosidase inhibitors 0.5-1 Colesevelam 0.5 Bromocriptine <1 Insulin >2
Euglycaemic and Hypoglycaemic OAA Euglycaemic drugs Hypoglycaemic drugs • Metformin • DPP-4 inhibitors • GLP-1 receptor agonists • TZDs • α-glucosidase inhibitors • Sulfonylureas • Meglitinides • Insulins
OAA Combinatioins  Any OAA can be used in combination with other OAA or insulin  GLP 1 receptor agonists are not used in combined with DPP 4 inhibitors  Secretagogues are usually not used in combined with insulin  Metformin and sitagliptin is the most popular combination  Metformin and TZDs used in combined to decreases insulin resistance
Prospect of Oral Insulin  Oral insulin product would provide insulin in a more physiologic manner [than injectable insulin], with a resultant decrease in peripheral insulin concentrations, and that it would more adequately 'insulinize' the liver  Oral insulin is safe, well tolerated, more effective than placebo, and as effective as subcutaneous regular insulin at controlling postprandial glycemia
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