Comparison of OADs: Action on insulin secretion and on insulin resistance 3-6
   
  Amaryl®
  Conventional Sulfonylureas
  Glinides
  Biguanides
  Glitazones
  a-Glucosidase Inhibitors
  Glucagon-Like Peptide Analogues
  DiPeptidyl Peptidase IV Inhibitors
Action on insulin
secretion
+
+
+
-
-
-
+
+
Action on insulin
resistance
+
-
-
+
+
+
-
-
In vitro studies of Amaryl® and their significance for its in vivo action7-8
  • Amaryl® associates with the sulfonylurea receptor 2.5 - 3 times faster than glibenclamide.
  • Amaryl® dissociates from its binding protein 8-9 times faster than glibenclamide.
  • The amount of insulin released from human islets after Amaryl® treatment is drug dose-dependent.
  • The amount of insulin released from human islets after Amaryl® treatment is glucose concentration dependent.
Amaryl® augments first and second phase of insulin secretion9
Euglycemic and hyperglycemic clamp studies in 11 obese patients with T2DM with good glycemic control before and after 4 months treatment with Amaryl® to assess effect of Amaryl® on insulin secretion
Amaryl® Achieves greater reductions in glucose than placebo10
  • Amaryl® decreased FPG by 46 mg/dL more than placebo (p < 0.001).
  • Amaryl® decreased PPG by 72 mg/dL more than placebo (p < 0.001).
  • Amaryl® decreased HbA1c by 1.4% more than placebo (p < 0.001).
Prospective, randomized, double-blind, placebo-controlled, dose-titration study. T2DM patients received Amaryl® (n=123) or placebo (n=126) for a 10-week dosetitration period and then the optimal dose (1 to 8 mg) for 12 weeks. 54% of patients on active treatment received <4 mg/day Amary®
Amaryl® has proven extrapancreatic action on insulin resistance11
  • Significant reduction in HOMA-IR, an increase in MCR-g, and a reduction in HbA1c without changing extrapancreatic beta-cell function and urine CPR found with Amaryl®.
  • Increased plasma adiponectin and decreased plasma TNF-alpha may underlie the improvement of insulin resistance with glimepiride.
N = 17 elderly patients with type 2 diabetes, duration: 12 weeks of treatment with glimepiride. Homeostasis assessment model of insulin resistance (HOMA-IR), homeostasis assessment model of beta-cell function, HbA1c, Cpeptide in 24-h pooled urine (urine CPR), and plasma concentrations of 8-epi-PGF2alpha, tumor necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor type 1, and adiponectin were measured at various times. The metabolic clearance rate of glucose (MCR-g) was also assessed by a hyperinsulinaemiceuglycaemic clamp.
Comparison of Amaryl® with other drugs12-21
  • Amaryl®: similar effect on HbA1c and FPG vs. glibenclamide
  • Amaryl® and metformin are equally effective at lowering blood glucose
  • Amaryl® is at least as effective as gliclazide MR
Amaryl® stimulates physiological insulin release in response to meals22
  • Amaryl® once daily stimulates insulin production primarily after meals when plasma glucose concentrations are highest, and controls blood glucose throughout the day.
15-week randomized, placebocontrolled, crossover study in 161 patients with T2DM to compare fasting, 24-hours and postprandial plasma insulin and glucose concentrations. Patients received either glimepiride 3 mg twice daily or glimepiride 6 mg once daily for 4 weeks. After a 3-week placebo washout period, once-daily and twicedaily regimens were crossed over for a further 4 weeks.
In vitro evidence of extrapancreatic effect of Amaryl® 23
  • Rate limiting step for glucose utilisation is glucose uptake via GLUT4 transporter
  • Amaryl® translocation of GLUT4 transporters from low-density microsomes to plasma membrane of insulin-resistant fat and muscle cells
  • Amaryl® appears to H peripheral glucose uptake and to mimic the action of insulin
Comparison of extrapancreatic action of Amaryl® and other sulfonylureas24
  • Amaryl® has greatest extrapancreatic activity among sulfonylureas
Sulfonylureas tested in fasted male beagle dogs to determine ratios of mean plasma insulin release/blood glucose decrease
Increase of peripheral insulin sensitivity: equivalent glucose control with less insulin secretion25
  • Amaryl® induces blood sugar decrease with significantly lower insulin release than antidiabetic sulfonylurea drugs.
  • This is a consequence of Amaryl®’s insulin sensitization effect at peripheral tissues, which improves the underlying problem of insulin resistance.
Summary of Amaryl® efficacy
  • Amaryl® is the first and only OAD that reduces hyperglycaemia by increasing insulin secretion and improving insulin resistance.
  • The binding property of Amaryl® to the ß-cell sulfonylurea receptor account for its higher blood sugar lowering efficacy, while its glucose leveldependent insulinotropic action might explain its lower incidence of hypoglycaemia compared with other sulfonylureas.
  • The ability to augment the first-phase of insulin secretion makes Amaryl® unique among second-generation sulfonylureas.
  • In in vitro studies, Amaryl®’s extrapancreatic effect is evident from increased peripheral glucose uptake.
  • In in vivo studies, Amaryl® has shown the greatest extrapancreatic activity among sulfonylureas. It induces blood sugar decrease with significantly lower insulin release than other sulfonylurea drugs.
Safety in special populations26-28
  • No special risk: elderly, hepatic and renal impairment
    • ↑plasma elimination with decreasing kidney function explainable on the basis of altered protein binding with an ↑ in unbound drug
    • Safety in elderly (65-85 yrs old T2DM patients) similar to glibenclamide
  • No intrinsic difference in oral clearance of glimepiride in obese patients compared with non-obese patients. No special dose consideration required for the use of glimepiride in the treatment of obese patients with type 2 diabetes.
Cardiovascular Safety: Coronary Artery Disease29
  • Amaryl® reduces ischemia during angioplasty in patients with coronary artery disease
The ST segment shift was measured 80 ms after the J-point. ECG recordings were started 30 s before each dilatation and were obtained every 15s during balloon inflation. After deflation, recordings were obtained every 15s for another 60s and a final tracing was taken after 3 min.
Cardiovascular Safety: Ischaemic Preconditioning30
  • Amaryl® maintains and glibenclamide blunts the anti-anginal effect of ischaemic preconditioning
Mean (SD) chest pain scores during angioplasty  
  Non-diabetic group Diabetic group
Control(n=7) Glib(n=6) Amaryl®(n=7) Glib (n=6) Amaryl®(n=5) Glib + Nic (n=6) Amaryl® + Nic (n=6)
Inflation 1 5.9 ± 0.9 5.2 ± 1.5 6.2 ± 0.8 5.8 ± 0.8 6.2 ± 0.8 3.2 ± 0.8 4.4 ± 1.5
Inflation 2 2.4 ± 0.5* 5.3 ± 1.5 3.2 ± 0.8* 5.5 ± 1.5 3.4 ± 0.9* 2.7 ± 0.8 4.0 ± 1.2
Myocardial responses were assessed following coronary angioplasty in diabetic and nondiabetic subjects receiving Amaryl® (2 mg or usual dose) or glibenclamide (10 mg or usual dose).
*p<0.05 vs. inflation 1 within same group. † p<0.05 vs. Glib group alone at same time. Glib = glibenclamide; Nic = nicorandil.

Cardiovascular Safety: Myocardial Infarction31
  • Antidiabetic treatment is associated with a better post-MI prognosis than no treatment
The 28-day mortality was analyzed using a logistic model with sulfonylurea, metformin and insulin as covariates. In this model, each odds ratio was adjusted for the prescription of the other antidiabetic drugs, patients receiving several antidiabetic drugs being taken into account in this model.
Summary of Cardiovascular Safety of Amaryl® 32-34
  • Glimepiride appears to improve insulin resistance and atherosclerotic disorders.
  • Amaryl® has less effect on blood pressure than glibenclamide in endotoxin-shock rats.
  • Amaryl® has the most potent antithrombotic effect among sulfonylureas in vitro.
Safety: Hypoglycaemia35,36
  • Despite being prescribed more frequently, fewer episodes of severe hypoglycaemia with Amaryl® vs. glibenclamide (6 vs. 38 episodes).
  • Lower incidence of hypoglycaemia with Amaryl® vs. glibenclamide during first month of treatment; trend maintained throughout treatment.
Safety: Weight37,38
  • Treatment with Amaryl® resulted in significant and stable weight loss.
  • Treatment of newly diagnosed T2DM patients with Amaryl® resulted in greater decrease in body weight and body mass index than treatment with glibenclamide over 12 months.
  Mean (±SD)change in BMI (kg/m²) Mean (±SD)change in weight (kg)   Multicenter, retrospective analysis of data from case reports for
520 newly diagnosed T2DM patients treated with Amaryl® or
glibenclamide for 12 months.
Amaryl® (n=251) -0.71 ± 1.38 -2.04 ± -3.99  
Glibenclamide (n=269) -0.20 ± -1.28 -0.58 ± -3.65  
P value for between group differences <0.001 <0.001  
Summary of Amaryl® Safety
  • Amaryl® is safe for use in special populations.
  • Amaryl® is associated with cardioprotective effects, and has lower incidence of cardiovascular events compared to other OADs.
  • Amaryl® maintains and glibenclamide blunts the anti-anginal effect of ischaemic preconditioning
  • There was a lower incidence of hypoglycaemia with Amaryl® than glibenclamide and glyburide in T2DM patients.
  • Amaryl®, unlike other sulfonylureas, does not induce weight gain.
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