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Combination Therapy

Rationale for combination therapy

  • In the UKPDS, 50% patients at 3 years and 75% patients at 9 years needed combination therapy.1
  • Up-titrating monotherapy to the maximum recommended dose may not provide benefit.2
  • Delays often occur between stepping up from monotherapy to combination therapy.3

Most patients with Type 2 diabetes may fail to attain A1c goal with conventional treatment paradigm

Amaryl-13

OAD = oral antihyperglycemic drug.

Potential advantages of early combination therapy

  • Earlier achievement of therapeutic goals.
  • Potential reduction in risk of side effects if you combine drugs at lower doses versus up-titration of single dose.
  • Opportunity to combine oral antidiabetic drugs with complementary modes of action.
  • Potential to delay disease progression.

Global Partnership for Effective Diabetes Management recommends: Use combinations of OADs with complementary mechanisms of action

Earlier and more aggressive intervention may improve treating to target compared with conventional therapy

 

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Efficacy as a combination therapy

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Biguanides (METFORMIN): Mode of action

 

Mode of action

  • Stimulation of glucose uptake
  • Suppression of excessive hepatic glucose production
  • Reduced intestinal glucose absorption

Metformin characteristics

  • Corrects a primary pathophysiologic impairment: insulin resistance
  • High initial response rate
  • Long record of relative safety
  • No weight gain or modest weight loss
  • Advantageous lipid profile

Modes of action of Glimepiride-Metformin combination

  • Sulfonylureas and biguanides act complementary to each other.1
  • Both compounds have a synergistic antihyperglycaemic effect without increasing the adverse effects of either pharmacological class.2
  • Glimepiride acts via stimulating beta cells of pancreas to release insulin and also increases peripheral sensitivity of insulin.3
  • Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilisation.4

The combination of Glimepiride and Metformin addresses the 2 core defects of Type 2 diabetes in a complementary manner

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Efficacy of Amaryl® + Metformin combination on HbA1c

  • Combination therapy was more efficient in reducing HbA1c than Metformin or Amaryl® alone

Mean (+SEM) change in HbA1c at week 20 according to treatment

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Prospective, multicentre, randomised, double-blind, double-dummy parallel group study of 372 T2DM patients inadequately controlled by Metformin 850 mg tid. Patients received Metformin, Amaryl® or both for 20 weeks.

Efficacy of Amaryl®+Metformin combination on FBG

  • Superior glycaemic control with Metformin+Amaryl® than with Metformin or Amaryl® alone

Evolution in FBG over time according to treatment

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Prospective, multicentre, randomised, double-blind, double-dummy parallel group study of 372 T2DM patients inadequately controlled by Metformin 850 mg tid. Patients received Metformin, Amaryl® or both for 20 weeks.

Efficacy of Amaryl®+Metformin combination on PBG

  • Combination therapy was more efficient in reducing postprandial blood glucose than Metformin or Amaryl® alone

Mean (+SEM) change in PBG at week 20 according to treatment

Amaryl-25

Prospective, multicentre, randomised, double-blind, double-dummy parallel group study of 372 T2DM patients inadequately controlled by Metformin 850 mg tid. Patients received Metformin, Amaryl® or both for 20 weeks.

Amaryl® M achieves equivalent glycaemic control compared to a free combination of Amaryl® and Metformin

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  • Lowering of HbA1c in both groups equivalent
  • Above picture for illustration only.

Achieve better glycaemic control with a combination of Sulfonylurea and Metformin

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UKPDS 28: To access the efficacy over 3 years of the addition of Metformin to maximum Sulfonylurea therapy in T2DM.
Multicentre randomised open-controlled trial, where Metformin was administered to 591 subjects showing poor glycaemic control with maximum doses of Sulfonylurea

  • 3 years after starting patients on combination therapy of Sulfonylurea and Metformin, both FPG and HbA1c were significantly improved

Occurrence rate of symptomatic hypoglycaemia in Amaryl® M equivalent to a free combination of Amaryl® and metformin

Amaryl-28

Phase II, open, randomised, multi-centre study was conducted to compare the efficacy and safety of a fixed dose combination and a free combination of Glimepiride and Metformin.
N = 286 T2DM
Pre-meal administration of Glimepiride and Metformin twice a day for 16 weeks for both groups of fixed dose combination and free combination therapy.

Advantages of FDC

  • Better compliance
  • Improved efficacy
  • E.g.: FDC of hypertension, respiratory diseases and postmenopausal hormone replacement therapy shown significant improvement in compliance as much as 30% compared to separate component usage.

Achieve better adherence to therapy with fixed-dose combination

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Comparison of adherence in free combination therapy and administration of fixed-dose combination
This study examined medication adherence among patients with DM receiving antidiabetic monotherapy, free combination therapy, or fixed-dose combination therapy.
Retrospective database analysis of pharmacy claims, adherence rate was defined as the sum of days of medication obtained by patient during FU period, divided by the total number of days in the designated FU period (180 days)

  • With an oral antidiabetic agent taken for a long time, the increased convenience of a fixed-dose combination can raise the adherence rate of a person.

ADA & EASD consensus guidelines

  • Many patients can be managed effectively with monotherapy
    • But disease is progressive
  • Will require use of combination therapy in many, if not in most patients over time to maintain glycaemia in target range
  • When adding second drug, synergy of particular combination and other interactions should be considered
  • Antihyperglycaemic agents with different mechanisms of action will have greatest synergy

References:

Turner RC, et al. UKPDS 49. JAMA 1999; 281: 2005-2012.
Garber AJ, et al. Am J Med 1997; 103: 491-497.
Brown JB, et al. Diab Care 2004; 27: 1535-1540.
Del Prato S, et al. Int J Clin Pract 2005; 59: 1345-1355.
AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocrine Practice 2007; 13: 3-68.
Hundal RS and Inzucchi SE. Drugs 2003; 63 (18): 1879-1894.
Charpentier G. Diabetes Metab Res Rev 2002; 18 (Suppl 3): S70-S76.
Riddle M. Am J Med 2000; 108 (Suppl 6a): 15S-22S.
Raptis SA and Dimitriadis GD. Exp Clin Endocrinol Diabetes 2001; 109 (Suppl 2): S265-S287.
Hundal RS and Inzucchi SE. Drugs 2003; 63 (18): 1879-1894.
Charpentier G, et al. Diabet Med 2001; 18: 828-834.
Baik S, et al. J Med Asso Thai 2005; 88 (Suppl 6): PP120.
U.K. Prospective Diabetes Study Group. Diab Care 1998; 21: 87-92.
Baik S, et al. J Med Asso Thai 2005; 88 (Suppl 6): PP120.
Bell DS and Wyne KL. Postgrad Med 2006; 119: 8-14.
Melikian C, et al. Clin Ther 2002; 24 (3): 460-467.
Nathan et al, ADA EASD consensus Guidelines, Diabetologia, 2006; 49: 1711-1721.

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