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Dr. Nizar ALBACHE Aleppo University- Diabetes Research Unit President of Syrian Endocrine Society Vice President of Mediterranean Group for Study of Diabetes.

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Presentation on theme: "Dr. Nizar ALBACHE Aleppo University- Diabetes Research Unit President of Syrian Endocrine Society Vice President of Mediterranean Group for Study of Diabetes."— Presentation transcript:

1 Dr. Nizar ALBACHE Aleppo University- Diabetes Research Unit President of Syrian Endocrine Society Vice President of Mediterranean Group for Study of Diabetes PIOGLIT-MET The advantages from combining two insulin sensitizers

2 Diabetes Mellitus in Syria 2006 (>25 year) Epidemiology of Type 2 diabetes mellitus in Aleppo, Syria N. ALBACHE, R. ALI, S. RASTAM, F. M. FOUAD, F. MZAYEK,. W. MAZIAK; Journal of Diabetes 2 (2009) 1–7

3 First sulphonylureas Metformin Glitazones Acarbose Gliptins ? Major progress in the oral treatment of diabetes Lente Insulins NPH Insulin discovered Insulin pump Human Insulin GLP-1 Insulin analogues Glinides.....But the good glycemic control of the type 2 diabetic patient remains a challenge

4 Metformin Derived from the plant known as Goat's Rue, French Lilac, Italian Fitch or Professor-weed (Galega officinalis) -In USA since In Europe since 1957

5 craze First disappointments Discussion of a possible withdrawal Final withdrawal progressive disaffection New success New “steady – state” Remarkable story of metformin Undisputed first choice ! Commer- cialization Fatal lactic acidosis ! metformin UKPDS FDA Phenformin Buformin

6 Oral Antihyperglycemic Monotherapy Maximum Therapeutic Effect on A1C Nateglinide Reduction in A1C (%) Glipizide GITS Glimepiride Repaglinide Pioglitazone Acarbose Metformin Rosiglitazone Diabetes Care. 2000;23: ; Precose (acarbose) package insert; Drugs. 1995;50: ; J Clin Endocrinol Metab. 2001;86: ; Diabetes Care. 2000;23: ; Diabetes Care. 1996; 19: ; Diabetes Care. 1997;20: ; Am J Med. 1997;102:

7 UKPDS: Global Clinical Outcomes Overweight patients Met v Sus or Insulin p= Met v Diet p= Proportion of patients with events Time from randomisation (years) Insulin or Sulphonylureas Metformin Conventional Diet Any diabetes-related endpoint  32% Reduction Lancet 1998;352:854-65

8 UKPDS: Risk reduction with metformin in overweight patients N = 4075 with type 2 diabetes UKPDS Group. Lancet. 1998;352: Favors metformin or intensive Favors conventional All-cause mortality Metformin Intensive Myocardial infarction Metformin Intensive Stroke Metformin Intensive Aggregate endpointsP* *metformin vs intensive therapy Relative risk reduction (95% CI)

9 Metformin associated with lower mortality Masoudi FA et al. Circulation. 2005;111: N = 16,417 with diabetes and HF Metformin (n = 1861) No insulin sensitizer (n = 12,069) Time (days) % Relative risk reduction Proportion of patients surviving

10 Metformin and lipid profiles DeFronzo RA & Goodman AM. NEJM 1995;333:541-9 p=0.001 p=0.019

11 Kurukulasuriya R et al. Diabetes 1999;48:A315 Data are Means. Duration of Treatment: 6 Months. Weight (kg) Body Mass Index (Kg/m 2 ) Total Body Fat (L) Total Subcutaneous Fat (L) Abdominal Subcutaneous Fat (L) Viscera Fat (L) Lean Body Mass Change from baseline % Decrease from baseline 4% 9% 7% 11% 15% No change p value NS Selective loss of visceral fat Metformin and body fat composition

12 Mather KJ et al. J Am Coll Cardiol. 2001;37: * P = vs placebo Before treatmentAfter treatment Metformin 1000 mg (3 months) 3 Increase in forearm blood flow (%) Acetylcholine (  g/min) 100 * Placebo * * Metformin improves endothelial function

13 Myocardial Infarction Heart Attacks Incidence per 1000 patient years Coronary Deaths Conventional Diet Insulin or Sulphonylureas Metformin p= % Reduction Conventional Diet Metformin p= % Reduction NS Incidence per 1000 patient years

14 Stroke 41% 14% P=0.13(NS)P=0.032 MetforminConventional Diet Insulin or Sulphonyl MetforminInsulin or Sulphonylureas

15 Survival in Overweight Group Diabetes Related Deaths Incidence (Deaths per 1000 Patient Years) All Cause Mortality Incidence (Deaths per 1000 Patient Years) Conventional Diet Insulin or Sulphonylureas Metformin p= % Reduction p= % Reduction Conventional Diet Insulin or Sulphonylureas Metformin p=0.021 NS

16 Mechanisms of vascular protection 1.Reduce insulin resistance 2.Improved lipid profiles 3.Adiposity 4.Improved hemostasis 5.Inhibition of glycoxidation 6.Inhibition of inflammation

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18 Metformin ;effect on cancer risk and mortality

19 Diabetes Prevention Program (DPP) DIET + EXERCISE METFORMINTROGLITAZONE % decrease IGT  T2DM 58% 31% 23% DPP, NEJM 2002; 346:

20 Early metformin therapy to delay menarche and augment height in girls with precocious pubarche Early metformin therapy to delay menarche and augment height in girls with precocious pubarche Lourdes Ibáñez M.D., Ph.D. a,,, Abel Lopez-Bermejo M.D, Abstract – selected,Fertility and Sterility,Article in Press aFertility and Sterility Conclusion) Early metformin therapy (age 8–12 years) suffices Delay menarche Augment postmenarcheal height Reduce total, visceral, and hepatic adiposity Curb the endocrine-metabolic course of LBW-PP girls away from adolescent PCOS.

21 Contraindications for metformin treatment Decrease renal function Congestive heart failure Patients > 80 years of age Liver disease Chronic alcohol disease Sepsis or other acute illnesses with decreased tissue perfusion During intavenous radiographic contrast administration(+-)

22 Oral Antihyperglycemic Monotherapy Maximum Therapeutic Effect on A1C Metformin associated with lower mortality Metformin and lipid profiles Decrease Visceral Fat Metformin improves endothelial function Decrease Myocardial Infarction Decrease Stroke Decrease risk of Cancers Decrease the risk of Developing Diabetes(DPP)

23 63% of Patients With Diabetes are Not At ADA A1C Goal <7% 37.2% >8% 63%  7% 7.8% 25.8% 37.0% 17.0% 12.4% % of Subjects n = 404 A1C National Health and Nutrition Examination Survey (NHANES), % Only 7% of adults attained: A1c <7%, BP 130/80, and Total Cholesterol <200mg/dL 1 in 5 Have A1c > 9%

24 Need for an early and intensive approach to type 2 diabetes management 30% of MD2 undiagnosed At Diagnosis of type 2 diabetes: 50% of patients already have complications 1 up to 50% of  -cell function has already been lost 2 Current management: two-thirds of patients do not achieve target HbA 1c 3,4 majority require polypharmacy to meet glycaemic goals over time 5 1 UKPDS Group. Diabetologia 1991; 34:877– Holman RR. Diabetes Res Clin Prac 1998; 40 (Suppl.):S21–S25. 3 Saydah SH et al. JAMA 2004; 291:335– Liebl A et al. Diabetologia 2002; 45:S23–S28. 5 Turner RC et al. JAMA 1999; 281:2005–2012.

25 Stepwise approach: delays control and leaves patients at risk of complications 1 Adapted from Del Prato S et al. Int J Clin Pract 2005; 59:1345– Stratton IM et al. BMJ 2000; 321:405–412. Duration of diabetes HbA1c (%) Diet and exercise OAD monotherapy OAD combination OAD + basal insulin OAD monotherapy uptitration OAD + multiple daily insulin injections Mean Complications 2

26 Early, intensive intervention: reach glycaemic goals and reduce the risk of complications 1 Adapted from Del Prato S et al. Int J Clin Pract 2005; 59:1345– Stratton IM et al. BMJ 2000; 321:405–412. Duration of diabetes HbA1c (%) Complications 2 OAD monotherapy OAD combination OAD uptitration OAD + basal insulin OAD + multiple daily insulin injections Mean OAD uptitration

27 Metformin Lowers Plasma Glucose by Lowering Hepatic Glucose Production and by Improving Insulin Sensitivity Metformin Blood glucose ↑Glucose uptake in muscle and fat by increasing insulin sensitivity 5 1. Kirpichnikov D et al. Ann Intern Med. 2002;137:25– Setter SM et al. Clin Ther. 2003;25:2991– Hundal RS et al. Diabetes. 2000;49:2063– Chu CA et al. Metabolism. 2000;49:1619– Bailey CJ et al. N Engl J Med. 1996;334:574–579. Muscle Adipose tissue Liver ↓ Gluconeogenesis ↓ Glycogenolysis ↑ Glycogen synthesis ↓Glucose production reduced by 1–4 : Liver

28 Hepatic glucose output Insulin resistance Glucose uptake in muscle and fat Glucagon (alpha cell) Insulin (beta cell) Hyperglycemia Islet-cell dysfunction Major Pathophysiologic Defects in Type 2 DM Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254. Pancreas Liver Adipose tissue Liver Muscle

29 Complementary Mechanisms of Action Combining Pioglitazone and Metformin

30 Glucose absorption Hepatic glucose overproduction Beta-cell dysfunction Insulin resistance Major Targeted Sites of Oral Drug Classes DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones. DeFronzo RA. Ann Intern Med. 1999;131:281–303. Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483. Pancreas ↓Glucose level Muscle and fat Liver Biguanides TZDsBiguanides Sulfonylureas Meglitinides TZDs Alpha- glucosidase inhibitors Gut DPP-4 inhibitors GLP-1 DPP-4 inhibitors Biguanides

31 No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies Alpha- Glucosidase Inhibitors 1,2 Meglitinides 3 SUs 4,5 TZDs 6,7 Metformin 8 DPP-4 Inhibitors Insulin deficiency Insulin resistance Excess hepatic glucose output Major Pathophysiologies 1. Glyset [package insert]. New York, NY: Pfizer Inc; Precose [package insert]. West Haven, Conn: Bayer; Prandin [package insert]. Princeton, NJ: Novo Nordisk; Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; Glucotrol [package insert]. New York, NY: Pfizer Inc; Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; Intestinal glucose absorption

32 Trends in Antidiabetic Therapy

33 Effects of Pioglitazone and Metformin on FBG and HbA 1c Egan J et al. Diabetes. 1999;47(suppl 1):A117. Abstract Placebo + metforminPioglitazone 30 mg + metformin *P  0.05 for comparison with placebo * * C FBG (mg/dL) change from baseline HbA 1c (%) change from baseline

34 *ADA A 1c goal <7%, AACE A 1C goal  6.5%. †P<0.05. ‡ Patients received Avandia ® 8 mg/day plus metformin 1 g/day (n=322; baseline A 1c 8.05%) versus maximum dose metformin (n=313; baseline A 1c 7.95%) in a 24-week, randomized, double-blind, parallel-group, multicenter study. Early Addition of Rosiglitazone 8 mg/day to 1 g Metformin: More Patients Reach A 1c Goal* vs. MET Monotherapy (2 g) 45% 55% Goal ‡ <6.5% Goal ‡ <7% †

35 Insulin sensitizers vs other glucose- lowering agents following AMI 8872 acute MI patients, mean age 76.4 years, discharged on glucose-lowering medication MetforminTZDBoth Mortality0.92 (0.81–1.06) 0.92 (0.80–1.05) 0.52 (0.34–0.82) Myocardial infarction readmission 1.02 (0.86–1.20) 0.92 (0.77–1.10) 0.88 (0.56–1.37) Heart failure readmission 1.06 (0.95–1.18) 1.17 (1.05–1.30) 1.24 (0.94–1.63) All-cause readmission 1.04 (0.96–1.13) 1.09 (1.00–1.20) 1.06 (0.87–1.30)

36 Neutral effect of PPAR  activation and metformin on hospital readmission All-causeHF TZD1.04 (0.99–1.10)1.06 (1.00–1.12) Metformin0.94 (0.89–1.01)0.92 (0.86–0.99) N = 16,417 with diabetes and HF Hospital readmission TZD = thiazolidinedione

37 Mortality benefit with combined insulin-sensitizing therapy 8872 acute MI patients, mean age 76.4 years, discharged on glucose-lowering medication No insulin sensitizer (n = 6641) Thiazolidinediones (n = 1273) Metformin (n = 819) TZD + MET (n = 139) 48% Relative risk reduction Days from discharge Proportion of patients surviving 150

38 Fixed-dose combination tablets may help to increase patient compliance and improve efficacy

39 Patient compliance can be a difficult obstacle to overcome Among newly DM2=53.8% adhered to their treatment regimen Compliance problems result in higher A1C levels 10% increase in drug adherence  decreased A1C 0.16% optimal compliance vs the group with the worst compliance = 1.4% difference in A1C

40 Patient compliance is influenced by the frequency of doses taken Patient compliance is dependent on two behavioral aspects: Dose taking : QD dosing is 98.7% BID dosing is 83.1% TID dosing is 65.8% Dose timing: QD dosing is 79.1% BID dosing is 65.6% TID dosing is 38.1% QD dosing regimens are associated with higher rates of adherence than BID or TID regimens.

41 Advantages of combination therapy The side effects and toxicities ; not altered by combination dose related in individual patients lower doses in combination better tolerated Patient compliance increases as complexity decreases Dosing flexibility may be key to tight control

42 ADA/EASD Revised Consensus Statement(2009) David Nathan Diabetes Care 2009; 32: Tier 1 : Well-validated core therapies At diagnosis: Lifestyle + Metformin Step 1 Lifestyle + Metformin + Intensive Insulin Step 3 Lifestyle + Metformin + Pioglitazone No hypglycemia Oedema/CHF Bone loss Lifestyle + Metformin + GLP-1 agonist b No hypglycemia Weight loss Nausea/Vomitting Lifestyle + Metformin + Pioglitazone + Sulphonylureas Lifestyle + Metformin + Basal insulin Tier 2 : Less well-validated core therapies Lifestyle + Metformin + Basal Insulin Lifestyle + Metformin + Sulphonlyureas a Step 2

43 Evidence vs. opinion based guidelines for the management of type 2 diabetic patients Diabetologia July; 53(7): 1258–1269

44 Debate on The ADA and EASD algorithm(Nathan) Deficiencies in the algorithm Not evidence based approach Not offer the best quality of treatment – on the basis of our understanding of the multifactorial pathophysiology of type 2 diabetes or the need for individualised therapy Based more on an outdated expert opinion Priorities for treatment –on the benefits of all available classes of glucose-lowering agents – In favouring initial use of metformin monotherapy followed by sulfonylurea, an approach known to fail Does not offer appropriate selection – of options to individualise and optimise care Diabetologia July; 53(7): 1258–1269

45 A1C 6.5 – 7.5% ** Monotherapy MET + GLP-1 or DPP4 1 TZD 2 Glinide or SU 5 TZD + GLP-1 or DPP4 1 MET + Colesevelam AGI Mos. *** Dual Therapy MET + GLP-1 or DPP4 1 + TZD 2 Glinide or SU 4,7 A1C > 9.0% No Symptoms Drug Naive Under Treatment INSULIN ± Other Agent(s) 6 Symptoms INSULIN ± Other Agent(s) 6 INSULIN ± Other Agent(s) 6 Triple Therapy AACE/ACE Algorithm for Glycemic Control Committee Cochairpersons: Helena W. Rodbard, MD, FACP, MACE Paul S. Jellinger, MD, MACE Zachary T. Bloomgarden, MD, FACE Jaime A. Davidson, MD, FACP, MACE Daniel Einhorn, MD, FACP, FACE Alan J. Garber, MD, PhD, FACE James R. Gavin III, MD, PhD George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Edward S. Horton, MD, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, MACE Etie S. Moghissi, MD, FACP, FACE Stanley S. Schwartz, MD, FACE * May not be appropriate for all patients ** For patients with diabetes and A1C < 6.5%, pharmacologic Rx may be considered *** If A1C goal not achieved safely †Preferred initial agent 1DPP4 if  PPG and  FPG or GLP-1 if  PPG 2TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD) 3AGI if  PPG 4Glinide if  PPG or SU if  FPG 5Low-dose secretagogue recommended 6a)Discontinue insulin secretagogue with multidose insulin b)Can use pramlintide with prandial insulin 7Decrease secretagogue by 50% when added to GLP-1 or DPP-4 8If A1C < 8.5%, combination Rx with agents that cause hypoglycemia should be used with caution 9If A1C > 8.5%, in patients on Dual Therapy, insulin should be considered MET + GLP-1 or DPP4 1 ± SU 7 TZD 2 GLP-1 or DPP4 1 ± TZD 2 A1C 7.6 – 9.0% Dual Therapy Mos. *** Triple Therapy 9 INSULIN ± Other Agent(s) 6 MET + GLP-1 or DPP4 1 or TZD 2 SU or Glinide 4,5 MET + GLP-1 or DPP4 1 + TZD 2 GLP-1 or DPP4 1 + SU 7 TZD 2 MET † DPP4 1 GLP-1TZD 2 AGI 3 Available at © AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

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48 Take home messages Guidelines changing now, we expect the new one to be release soon We have many choices to initiate oral TT Combination of 2 Sensitizers looks a good one With adding Piogl. To Metf. You add the benefits: Increase patients adherence More redaction on A1c Improve Lipid profile Increase cardiac protection Decrease the cancer risk

49 nizar-albache.com


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