Antihyperglycemic Agents Comparison Chart PDF

Antihyperglycemic Agents Comparison Chart
Parameter Metformin Sulfonylureas Meglitinides Glitazones (TZDs)

Mechanism of Hepatic glucose output insulin secretion insulin secretion Peripheral glucose uptake by
Action (both basal & prandial) (primarily prandial) enhancing insulin action
Peripheral glucose uptake by
enhancing insulin action Hepatic glucose output
Efficacy 1 1.5 % 1 1.5 % Repaglinide 1 1.5 % 1 1.5 %
(A1c Reduction) Nateglinide 0.6 1 %
Hypoglycemia Risk 0 Glyburide ++++ + 0
Glimepiride +++
Gliclazide ++
Weight Change
Suitability for use in OK in stable heart failure; 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: Pioglitazone:
Excretion Excreted 100% as unchanged metabolized primarily via CYP2C9. Extensively metabolized to Extensively metabolized to
drug 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 Rosiglitazone:
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
Pharmacokinetic Cimetidine 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: Clarithromycin glyburide 35% Clarithromycin 40% (3A4) Gemfibrozil 230%; consider
(1) None of the Fluconazole 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 tolbutamide 25% OATP1B1); avoid combined use Trimethoprim 42%
cause of drug
and half-life 30% with repaglinide
interactions (no strong
inhibitors or inducers). Itraconazole 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); Rosiglitazone
describing alterations Rifampin glimepiride 34% avoid combined use of both
in the disposition of Rifampin glyburide 39% drugs with repaglinide AUC due to CYP inhibitor:
antihyperglycemic
Ketoconazole 15% (3A4) Fluvoxamine 21% (2C8)
agents caused by
inhibition or induction Telithromycin 77% (3A4) Gemfibrozil 130% (2C8);
of metabolizing Trimethoprim 61% (2C8) consider limiting dose of
enzymes 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
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 sulfonylurea 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
than sulfonylurea sulfonylureas (but less with 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
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 vitamin B12 glyburide > glimepiride > Nateglinide A1C modest (8-12 wks)
may result in anemia gliclazide Higher cost than sulfonylureas Many precautions or
Many precautions or Weight gain contraindications:
No ODB coverage
contraindications (risk factors for Efficacy declines over time more - Fluid retention, edema
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 myocardial infarction by 30-
40%
- Pioglitazone doubles risk of
bladder cancer
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
Parameter DPP-4 Inhibitors GLP-1 Agonists Insulin Acarbose
Mechanism of Enhance incretin activity Enhance incretin activity Corrects insulin deficiency Alpha-glucosidase inhibitor
Action Insulin secretion (primarily Insulin secretion (primarily Peripheral glucose uptake Slows digestion of carbohydrate,
prandial) prandial) Hepatic glucose output thereby slowing postprandial
Glucagon 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% Exenatide 0.5 1.0% Variable 0.5 1%
(A1C Reduction ) Liraglutide 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)
Metabolism & Linagliptin: 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
Sitagliptin:
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%)
Vildagliptin:
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
Saxagliptin 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
Pharmacokinetic Saxagliptin No known pharmacokinetic drug No known pharmacokinetic drug Digestive enzyme products
Drug Interactions interactions interactions containing amylase may reduce
AUC due to CYP3A4 inhibitor: the effect of acarbose; avoid
Diltiazem 109% concomitant administration (H)
Note: most of the
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 Alogliptin
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 (regular insulin)
Janumet (sitagliptin 50 mg +
metformin 500, 850, or Intermediate-acting insulin
1000 mg) (NPH insulin)
Long-acting analogues
(detemir, glargine)
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
supper. Start with 5 mcg SC BID eaten, dose should be omitted.
Saxagliptin 5 mg once daily or
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
Liraglutide is injected once daily slowly every 3-5 days
Sitagliptin 100 mg 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)
the glitazones failure rate) OK in renal insufficiency
No hypoglycemia
Once daily dosing anytime and Prompt improvement in blood
Dose-related weight loss glucose
no dosage titration required
ODB coverage (most products) Well tolerated
Cost of therapy can be
reasonable (if regimen is simple
and/or human insulin is used)
ODB coverage
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 (thyroid cancer?) intolerance (10-35%), particularly
Self-monitoring of blood glucose
Long-term efficacy and safety Pancreatitis: avoid use of GLP-1 is a requirement initially, requiring slow upward
unknown agonists in patients with risk dosage titration
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
factors: very high triglycerides; Vision and dexterity problems 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 drug class
No ODB coverage
Place in Therapy Third-line agents for addition in Role not yet well established Type 2 diabetes: 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 hyperglycemia
insulin injections (trauma, surgery, infection, MI)
References:
1. Holstein A, Beil W. Oral antidiabetic drug metabolism: pharmacogenomics 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 thiazolidinediones. 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. Pharmacokinetics 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.

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Parameter Metformin Sulfonylureas Meglitinides Glitazones (TZDs)

Coverage by public Metformin YES Gliclazide YES NO NO

Sitagliptin (Januvia) 100 mg Liraglutide (Victoza) 18 mg per Short-acting insulin

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