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Home , Acarbose, Alogliptin, Gliclazide, Glimepiride, Linagliptin, Nateglinide

Antihyperglycemic Agents Comparison Chart

Parameter Glitazones (TZD’s) Mechanism of ↓ Hepatic output ↑ secretion ↑ insulin secretion ↑ Peripheral glucose uptake by Action ↑ Peripheral glucose uptake by (both basal & prandial) (primarily prandial) enhancing insulin action enhancing insulin action ↓ Hepatic glucose output Efficacy 1 – 1.5 % 1 – 1.5 % 1 – 1.5 % 1 – 1.5 % (A1c Reduction) 0.6 – 1 % Risk 0 Glyburide ++++ + 0 +++ ++ Weight Change ↓ ↑ ↑ ↑↑ Suitability for use in OK in stable ; OK OK Avoid in all stages of heart failure; heart failure Monitor renal function; consider CDA guidelines state may be used stopping metformin if significant in mild, stable CHF if patient is reduction in GFR (see above) closely monitored by a specialist Metabolism & • Negligible metabolism Sulfonylureas are extensively Repaglinide: : • Excreted 100% as unchanged metabolized primarily via CYP2C9. • Extensively metabolized to • Extensively metabolized to by glomerular filtration plus Excreted primarily as inactive or inactive compounds primarily via inactive compounds primarily via active tubular secretion weakly active metabolites. CYP2C8 & to lesser extent via CYP2C8 & to a lesser extent • Gliclazide: metabolized to 3A4 3A4; (H) inactive compounds • Excreted as inactive metabolites • Excreted as inactive metabolites • Glimepiride: metabolized to primarily in the bile; very little primarily via fecal route inactive compounds excreted as unchanged in urine : • Glyburide: metabolized in part to Nateglinide: • Extensively metabolized to weakly active metabolites that • Extensively metabolized to weakly active compounds may accumulate in renal inactive compounds primarily via primarily via CYP2C8 with minor impairment CYP 2C9 (70%) & to lesser pathway 2C9 extent via 3A4 • Excreted as metabolites in urine • Excreted primarily as metabolites; only 15% as unchanged drug in urine Suitability for use in Caution if GFR 30-60 mL/min; Gliclazide & Glimepiride OK OK OK renal insufficiency Avoid if GFR < 30 Glyburide – caution if GFR < 30

2012 August; Bill Cornish, Drug Information, Sunnybrook Health Sciences Centre 1 Antihyperglycemic Agents Comparison Chart

Parameter Metformin Sulfonylureas Meglitinides Glitazones (TZD’s) Pharmacokinetic ↑ metformin AUC 50% Sulfonylureas: Repaglinide Pioglitazone Drug Interactions (competitive inhibition of active renal tubular secretion) ↑ AUC due to CYP2C9 inhibitor: ↑ AUC due to CYP inhibitor: ↑ AUC due to CYP2C8 inhibitor: Notes: • ↑ glyburide 35% • Clarithromycin 40% (3A4) • 230%; consider (1) None of the • ↑ glimepiride 138% • Cyclosporine 144% (3A4) limiting dose of pioglitazone to antihyperglycemic 15 mg daily • Co-trimoxazole (TMP/SMX) • Gemfibrozil 712% (2C8 and agents is an important • ↓ clearance of 25% OATP1B1); avoid combined use Trimethoprim 42% cause of drug and ↑ half-life 30% with repaglinide interactions (no strong inhibitors or inducers). • 41% (3A4 and ↓ AUC due to CYP2C8 inducer: (2) Most of the ↓ AUC due to CYP2C9 inducer: OATP1B1) • Rifampin 54% pharmacokinetic data • Rifampin ↓ gliclazide 70% • Itraconazole + gemfibrozil 1839% presented here (20-fold increase) (2C8 & 3A4); • Rifampin ↓ glimepiride 34% Rosiglitazone describing alterations avoid combined use of both in the disposition of • Rifampin ↓ glyburide 39% with repaglinide ↑ AUC due to CYP inhibitor: antihyperglycemic • agents caused by 15% (3A4) • Fluvoxamine 21% (2C8) inhibition or induction • Telithromycin 77% (3A4) • Gemfibrozil 130% (2C8); of metabolizing • Trimethoprim 61% (2C8) consider limiting dose of are of rosiglitazone to 4 mg daily unknown clinical • Ketoconazole 47% (3A4) significance. Indeed, ↓ AUC due to CYP inducer: • many are likely of no • Rifampin 32-85% (3A4) Trimethoprim 35% (2C8) clinical significance based on the small ↓ AUC due to CYP inducer: magnitude of the Nateglinide • effect. Exceptions Rifampin 60% (2C8; also 2C9) include those for ↑ AUC due to CYP inhibitor: which it is • Fluconazole 48% (2C9) recommended to • Gemfibrozil + itraconazole 47% “avoid” the (2C8 & 3A4) combination and those for which an alteration in dosage of ↓ AUC due to CYP inducer: antihyperglycemic • Rifampin 24% (2C9 & 3A4) agent is recommended. Products & Dosage • Metformin (Glucophage & • Gliclazide (Diamicron & generics) • Repaglinide (Gluconorm & • Pioglitazone (Actos & generics) Forms generics) 500, 850 mg 80 mg generics) 0.5 mg, 1 mg, 2 mg 15, 30, 45 mg • Glumetza extended release (ER) modified release (MR) 30 mg • Nateglinide (Starlix) • Rosiglitazone (Avandia) 500, 1000 mg • Glimepiride (Amaryl & generics) 60, 120, 180 mg 2, 4, 8 mg Combination products: 1 mg, 2 mg, 4 mg • Avandamet = Rosiglitazone + • • Avandamet – see Glitazones Glyburide (Diabeta & generics) Metformin 1/500 mg, 2/500 mg, 2.5, 5 mg 4/500 mg, 2/1000 mg, 4/1000 mg • Janumet – see DPP-4 Inhibitors

2012 August; Bill Cornish, Drug Information, Sunnybrook Health Sciences Centre 2 Antihyperglycemic Agents Comparison Chart

Parameter Metformin Sulfonylureas Meglitinides Glitazones (TZD’s) Dosage To improve GI tolerability, start Most of the benefit of a Meglitinides are to be taken Before increasing dose, allow with a low dose and increase is achieved in most within 30 min prior to a meal and 8-12 weeks to assess full benefit slowly every 3-5 days patients at half the max daily only if patient will be eating. • Pioglitazone is taken once daily • Metformin is taken 2-3 times per dose listed below If a meal is delayed or will not be without regard to mealtimes; start day with or after meals; • Gliclazide is taken twice daily eaten, the dose should usually with 15 or 30 mg daily; max 45 Start with 500 once or twice daily; before breakfast & supper; start be delayed or omitted. mg/day increase by 500 mg/day as with 80 mg BID; max 160 mg BID • Repaglinide: start with 0.5 to • Rosiglitazone is taken once daily tolerated; max 2.5 g /day • Glimepiride is taken once daily 1 mg TID; max 12 mg/day without regard to mealtimes; start • Glumetza is taken once daily with before breakfast; start with 1 mg • Nateglinide: start with 120 mg with 4 mg daily; max 8 mg/day evening meal; start with 1 g and daily; increase every 1-2 weeks; TID; max 540 mg/day increase by 500 mg at weekly max 8 mg daily intervals; max 2 g/day • Glyburide is taken once daily or twice daily if the dose/day exceeds 10 mg; start with 2.5 to 5 mg daily; increase every 1-2 weeks; max 20 mg/day Cost per month for Metformin $ Gliclazide $ Repaglinide $$ Pioglitazone $$$ most common dose Glumetza $$$ Gliclazide MR $ Nateglinide $$$ Rosiglitazone $$$$ < $15 $ Glimepiride $$ Avandamet $$$$ to $$$$$ $16-35 $$ Glyburide $ $36-70 $$$

$71-100 $$$$

> $100 $$$$$

Coverage by public Metformin YES Gliclazide YES NO NO drug plan (ODB) Glumetza NO Glyburide YES Glimepiride NO Advantages • Efficacy (major A1c reduction) • Efficacy (major A1c reduction) • Efficacy: A1c reduction with • Efficacy (major A1C reduction) • More durable glycemic control • Well tolerated Repaglinide is similar to • More durable glycemic control sulfonylureas (but less with than sulfonylurea • than sulfonylurea OK in renal insufficiency (caution: Nateglinide) • No hypoglycemia glyburide) • No hypoglycemia • Less hypoglycemia than • • • No weight gain; possible modest Once-daily dosing possible sulfonylureas (especially in OK in renal insufficiency weight loss • Low cost generics patients who may miss meals) • Well tolerated • Possible CV benefit • ODB coverage for some • Well tolerated • Once-daily dosing • Best oral agent for use with (glyburide & gliclazide) • OK in renal insufficiency insulin (less weight gain; lower insulin dose) • Low cost generics • ODB coverage

2012 August; Bill Cornish, Drug Information, Sunnybrook Health Sciences Centre 3 Antihyperglycemic Agents Comparison Chart

Parameter Metformin Sulfonylureas Meglitinides Glitazones (TZD’s) Disadvantages or • Dose-related GI intolerance • Hypoglycemia • Compliance may be a challenge • Slow onset of maximal glucose- Factors Limiting Use initially (5-20%) • Risk ranking highest to lowest: (TID ac dosing) lowering effect • Malabsorption of B12 glyburide > glimepiride > • Nateglinide A1C ↓ modest (8-12 wks) • may result in anemia gliclazide • Higher cost than sulfonylureas Many precautions or • • contraindications: Many precautions or Weight gain • No ODB coverage contraindications (risk factors for • Efficacy declines over time more - Fluid retention, lactic acidosis) than metformin or glitazones - Risk of new or worsened heart - Renal impairment failure is double that of other - Hepatic disease agents - Alcoholism - Contraindicated in any stage of heart failure - Severe heart failure - Weight gain can be significant - Severe respiratory disease - Fracture risk is doubled - Rosiglitazone may increase risk of by 30- 40% - Pioglitazone doubles risk of • Moderately expensive • No ODB coverage Place in Therapy • Drug of choice for all patients as • Second line therapy, for addition • Useful in patients who require an • Glitazones are less commonly monotherapy or combination to metformin or for initial use insulin secretagogue but who are used now (DPP-4 inhibitors have therapy, especially insulin- when metformin is not an option at risk of sulfonylurea-induced become preferred third-line requiring patients hypoglycemia (especially that agents, particularly since which may be due to an irregular coverage by public drug plan meal schedule) [ODB] was introduced) • Pioglitazone is the preferred agent in class • Rosiglitazone is rarely used, and only if all other therapies are deemed to be unsuitable

2012 August; Bill Cornish, Drug Information, Sunnybrook Health Sciences Centre 4 Antihyperglycemic Agents Comparison Chart

Parameter DPP-4 Inhibitors GLP-1 Agonists Insulin Mechanism of Enhance activity Enhance incretin activity Corrects insulin deficiency Alpha-glucosidase inhibitor Action ↑ Insulin secretion (primarily ↑ Insulin secretion (primarily ↑ Peripheral glucose uptake Slows of , prandial) prandial) ↓ Hepatic glucose output thereby slowing postprandial ↓ secretion ↓ Glucagon secretion glucose absorption These actions occur only when These actions occur only when blood glucose levels are elevated; blood glucose levels are elevated; they do not cause hypoglycaemia they do not cause hypoglycaemia or impair ability to recover from or impair ability to recover from hypoglycemia hypoglycemia Efficacy 0.5 - 1% 0.5 – 1.0% Variable 0.5 – 1% (A1C Reduction ) 0.8 – 1.5% (1.5 – 3.5 %) Hypoglycemia 0 0 +++++ 0 Weight Change 0 ↓↓ (dose-related) ↑↑↑ (dose-related) 0 Suitability in heart OK OK OK OK failure (Caution: ↑ risk of HF if used in combination with a glitazone)

2012 August; Bill Cornish, Drug Information, Sunnybrook Health Sciences Centre 5 Antihyperglycemic Agents Comparison Chart

Parameter DPP-4 Inhibitors GLP-1 Agonists Insulin Acarbose Metabolism & : Exenatide: Exogenous insulin is cleared Acarbose is metabolized to Excretion • Minimal metabolism • Minimal metabolism primarily by the kidneys inactive compounds in GI tract and < 2% reaches systemic circulation • Excreted primarily as unchanged • Excreted renally unchanged

drug (85%) via fecal route Liraglutide:

Saxagliptin: • Extensively metabolized to • Extensively metabolized via inactive compounds by CYP3A4/5 (1 active metabolite) endogenous endopeptidases • Excreted primarily as inactive • Excreted as inactive metabolites metabolites; 24% as unchanged drug; 26% as active metabolite : • Minor metabolism via CYP3A4 & 2C8 to inactive compounds • Excreted primarily as unchanged drug in urine (80%) Alopgliptin: • Minimal metabolism • Excreted primarily as unchanged drug in urine (95%) : • Extensively metabolized (55%) to inactive compounds via non- CYP hydrolysis • Excreted primarily as inactive metabolites (21-33% as unchanged drug) Suitability for use in • Linagliptin not renally excreted; • Exenatide contraindicated if OK OK renal insufficiency but still “not recommended” if GFR < 30; caution if GFR (Health Canada GFR < 30 (based on a lack of 30-50 approvals) experience in these patients) • Liraglutide “not recommended” if • approved at 2.5 mg GFR < 50 (based on a lack of daily for GFR 10-50 mL/min experience in these patients) • Sitagtliptin ““not recommended” if GFR < 50 (based on a lack of experience in these patients) • Janumet: see metformin

2012 August; Bill Cornish, Drug Information, Sunnybrook Health Sciences Centre 6 Antihyperglycemic Agents Comparison Chart

Parameter DPP-4 Inhibitors GLP-1 Agonists Insulin Acarbose Pharmacokinetic Saxagliptin No known pharmacokinetic drug No known pharmacokinetic drug Digestive products Drug Interactions interactions interactions containing amylase may reduce ↑ AUC due to CYP3A4 inhibitor: the effect of acarbose; avoid concomitant administration (H) Note: most of the • 109% pharmacokinetic data • Ketoconazole 145%; consider presented here reducing dose of saxagliptin by describing alterations 50% (to 2.5 mg daily) in the disposition of ↓ AUC due to CYP3A4 inducer: antihyperglycemic agents caused by • Rifampin 76% inhibition or induction of metabolizing Linagliptin enzymes are of No significant metabolic drug unknown clinical interactions significance. Indeed, many are likely of no clinical significance Sitagliptin based on the small No significant metabolic magnitude of the interactions effect. Exceptions include those for which it is No metabolic drug interactions recommended to “avoid” the Vildagliptin combination and No metabolic drug interactions those for which an alteration in dosage of antihyperglycemic agent is recommended. Products & Dosage • Linagliptin (Trajenta) 5 mg • Exenatide (Byetta) 1.2 mL or • Rapid-acting analogues Acarbose (Glucobay) Forms • Saxagliptin (Onglyza) 2.5, 5 mg 2.4 mL prefilled disposable pens (aspart, glulisine, lispro) 50, 100 mg • • • Sitagliptin (Januvia) 100 mg Liraglutide (Victoza) 18 mg per Short-acting insulin 3 mL prefilled disposable pen (“”) • Janumet (sitagliptin 50 mg + • metformin 500, 850, or Intermediate-acting insulin 1000 mg) (NPH insulin) • Long-acting analogues (detemir, glargine)

2012 August; Bill Cornish, Drug Information, Sunnybrook Health Sciences Centre 7 Antihyperglycemic Agents Comparison Chart

Parameter DPP-4 Inhibitors GLP-1 Agonists Insulin Acarbose Dosage DPP-4 inhibitors are taken once GLP-1 agonists must be injected Variable • Acarbose must be taken with the daily without regard to subcutaneously. first bite of a meal (if taken after mealtimes • Exenatide is injected twice daily meal, efficacy is significantly • Linagliptin 5 mg once daily 0-60 min before breakfast & reduced). If no meal is to be eaten, dose should be omitted. • Saxagliptin 5 mg once daily or supper. Start with 5 mcg SC BID • 2.5 mg once daily if GFR 10-15 for first month; if tolerated, may To improve GI tolerability, start mL/min increase to 10 mg SC BID with a low dose and increase • slowly every 3-5 days • Sitagliptin 100 mg once daily Liraglutide is injected once daily without regard to mealtimes. • • Start with 25 mg 1-2 times/day; Janumet (sitagliptin + metformin) Start with 0.6 mg SC once daily increase dose by 25-50 mg/day if is taken BID with or after meals for at least first week; if tolerated, tolerated every 3-5 days; usual increase to 1.2 mg SC once max 150 mg/day (higher doses daily; max 1.8 mg/day are poorly tolerated)

Cost per month for $$$$ $$$$$ Varies by product & dosage $$ most common dose Initial basal insulin regimen: < $15 $ • NPH daily at bedtime (50 units) $16-30 $$ $$$ $31-70 $$$ • Detemir or Glargine once daily $71-100 $$$$ (50 units) > $100 $$$$$ $$$$ Coverage by oublic Linagliptin NO NO YES YES drug plan (ODB) Saxagliptin YES Sitagliptin YES Janumet YES Advantages • No hypoglycemia • Efficacy: A1c reduction with • Greatest potential A1c reduction • No hypoglycemia • No weight gain (neutral effect) Liraglutide may be similar to • Uniquely effective when oral • Weight neutral metformin, sulfonylureas, • agents prove inadequate • Well tolerated glitazones (greater than DPP-4 No systemic toxicity (negligible • • Fewer safety concerns than with inhibitors and exenatide) Consistently effective (lower absorption) failure rate) • the glitazones • No hypoglycemia OK in renal insufficiency • • Prompt improvement in blood Once daily dosing “anytime” and • Dose-related weight loss no dosage titration required glucose • • ODB coverage (most products) Well tolerated • Cost of therapy can be reasonable (if regimen is simple and/or human insulin is used) • ODB coverage

2012 August; Bill Cornish, Drug Information, Sunnybrook Health Sciences Centre 8 Antihyperglycemic Agents Comparison Chart

Parameter DPP-4 Inhibitors GLP-1 Agonists Insulin Acarbose Disadvantages or • A1C ↓ somewhat less than • Long-term efficacy unknown • Hypoglycemia • A1C ↓ modest Factors Limiting Use metformin, sulfonylureas, and • Long-term safety unknown • Weight gain (dose-related) • Major dose-related GI glitazones ( cancer?) • Self-monitoring of blood glucose intolerance (10-35%), particularly • Long-term efficacy and safety • : avoid use of GLP-1 is a requirement initially, requiring slow upward unknown dosage titration agonists in patients with risk • Dosage adjustments are usually • • Pancreatitis: avoid use of DPP-4 factors: very high triglycerides; required Compliance may be a challenge inhibitors in patients with risk alcoholism; history of pancreatitis (must be taken with first bite of • Vision and dexterity problems factors: very high triglycerides; • meals) Renal insufficiency: exenatide is may limit use alcoholism; history of pancreatitis contraindicated if GFR < 30; • • Expensive caution for both agents if GFR < Low acceptance among many 50 patients and perhaps also health care providers • Must be injected (not attractive to • patients with aversion to needle) Can be expensive (intensive regimens using analogues) • Major dose-related GI intolerance (30-50%) primarily during initial month • Most expensive • No ODB coverage Place in Therapy • Third-line agents for addition in • Role not yet well established Type 2 : • Limited role as an alternative patients not controlled on • May be considered for patients in • Usually added when patients fail when other agents are deemed metformin + a secretagogue whom weight loss is a primary to achieve target A1c despite use unsuitable • Alternative to basal insulin when goal and avoidance of of 2-3 agents • Most useful when A1c is near hypoglycemia and/or weight gain hypoglycaemia is important • Also used temporarily in patients target, and/or main problem is are concerns or patient refuses with severe metabolic stress postprandial insulin injections (trauma, surgery, infection, MI)

References: 1. Holstein A, Beil W. Oral antidiabetic : and drug interactions. Expert Opin Drug Metab Toxicol 2009;5:225-41. 2. Scheen AJ. Dipeptidylpeptidase-4 inhibitors (Gliptins): focus on drug-drug interactions. Clin Pharmacokinet 2010;49:573-88. 3. Scheen AJ. Pharmacokinetic interactions with . Clin Pharmacokinet 2007;46:1-12. 4. Scheen AJ. Drug-drug and food-drug pharmacokinetic interactions with new insulotropic agents repaglinide and nateglinide. Clin Pharmacokinet 2007;46:93-108. 5. Scheen AJ. of dipeptidylpeptidase-4 inhibitors. Diabetes Obes Metab 2010;12:648-58. 6. Baetta R, Corsini A. Pharmacology of dipeptidyl peptidase-4 inhibitors: similarities and differences. Drugs 2011;71:1441-67. 7. Scheen AJ. Drug interactions of clinical importance with antihyperglycemic agents: an update. Drug Safety 2005;28:601-31. 8. Fichtenbaum CJ, Gerber JG. Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet 2002;41:1195-1211.

2012 August; Bill Cornish, Drug Information, Sunnybrook Health Sciences Centre 9