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The advantages from combining two insulin sensitizers

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

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 Major progress in the oral treatment of diabetes
1920 1940 1960 1980 2000 ? Glinides NPH Insulin Metformin Gliptins Insulin discovered Insulin pump First sulphonylureas GLP-1 Glitazones Lente Insulins Human Insulin Insulin analogues Acarbose .....But the good glycemic control of the type 2 diabetic patient remains a challenge

4 Metformin -In Europe since 1957 -In USA since 1992
Derived from the plant known as Goat's Rue, French Lilac, Italian Fitch or Professor-weed (Galega officinalis)

5 Remarkable story of metformin
Undisputed first choice! First disappointments New success Discussion of a possible withdrawal UKPDS Commer-cialization FDA metformin Fatal lactic acidosis! New “steady – state” craze progressive disaffection Phenformin Buformin Final withdrawal 1957 1980 1992 1998 2011

6 Oral Antihyperglycemic Monotherapy Maximum Therapeutic Effect on A1C
Nateglinide Acarbose Repaglinide Rosiglitazone Pioglitazone Glimepiride Glipizide GITS Metformin -0.5 -1.0 -1.5 -2.0 Reduction in A1C (%) 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
Improving the Prognosis of Patients with Type 2 Diabetes Slide 26. UKPDS: Any Diabetes Related Endpoint in Metformin Study Kaplan Meier Survival Plot. Overweight patients Conventional Diet 60 Any diabetes-related endpoint Insulin or Sulphonylureas 40 Met v Diet p=0.0023 Metformin  32% Reduction Proportion of patients with events The impact of therapy on clinical outcome measurements, in this case the 21 diabetes related complications, is reported in this slide. The 'survival' curves for each therapy represent the time to occurrence of each complication and are expressed as the cumulative damage over 16 years. For example, approximately 15% of diet treated patients have at least one complication at six years, and this figure increases to 60% of patients after 16 years of follow-up. Patients assigned to intensive blood glucose control with metformin had a significant 32% lower risk of developing any diabetes-related endpoint than patients assigned to conventional treatment (p=0.0023). The metformin group also had significantly greater risk reduction than the group assigned to intensive therapy with a sulphonylurea or insulin (p=0.0034). The outcome benefits with metformin became apparent after about 6 years of treatment, where the three curves diverged. This shows that long-term treatment with metformin is required to maximise the benefits in terms of reducing morbidity or mortality. Met v Sus or Insulin p=0.0034 20 3 6 9 12 16 Time from randomisation (years) Lancet 1998;352:854-65

8 UKPDS: Risk reduction with metformin in overweight patients
N = 4075 with type 2 diabetes Aggregate endpoints P* Favors metformin or intensive Favors conventional All-cause mortality Metformin Intensive Myocardial infarction Stroke 0.021 The United Kingdom Prospective Diabetes Study (UKPDS) randomized patients with newly diagnosed type 2 diabetes to metformin (n = 342; target fasting glucose of 108 mg/dL), other hypoglycemic medication (either chlorpropamide, glibenclamide, or insulin) (n = 951; target fasting glucose of 108 mg/dL), or usual care (n = 411).1 The median duration was 10.7 years. • Relative to usual care, metformin was associated with a 36% relative risk reduction in all-cause mortality (RR, 0.64, 95% CI, 0.45–0.91). The other intensive treatments combined were associated with an 8% relative risk reduction (RR, 0.92; 95% CI, 0.71–1.18) (P = 0.021, comparison between the two intensive-treatment groups).1 • There was no difference between the two intensive-treatment groups in the relative risk reductions in stroke and MI, although the trend was in favor of metformin. • These data suggest that insulin-sensitizing therapy may be associated with greater reductions in CV outcomes than other hypoglycemic therapies. 0.1 1 10 Relative risk reduction (95% CI) *metformin vs intensive therapy UKPDS Group. Lancet. 1998;352: 1. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:

9 Metformin associated with lower mortality
N = 16,417 with diabetes and HF 1.0 0.9 • Another class of insulin sensitizer, metformin, was associated with a 14% relative risk reduction in mortality (HR, 0.86; 95% CI, 0.78–0.97; data not shown).1 0.8 Proportion of patients surviving Metformin (n = 1861) 0.7 13% Relative risk reduction No insulin sensitizer (n = 12,069) 0.6 0.5 50 100 150 200 250 300 350 Time (days) Masoudi FA et al. Circulation. 2005;111: 1. Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: An observational study. Circulation. 2005;111:

10 Metformin and lipid profiles
A double-blind, randomised study in 289 patients with previously diet-treated type 2 diabetes showed that total cholesterol and LDL-cholesterol improved significantly, compared with placebo, after 29 weeks of metformin treatment. Triglycerides were also reduced in the metformin group, and increased in the placebo group, though this comparison did not achieve statistical significance. These improvements in lipid profiles are typical of those observed in dyslipidaemic type 2 diabetic populations after treatment with metformin. DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin dependent diabetes mellitus. N Engl J Med 1995;333:541-9. p=0.001 p=0.019 DeFronzo RA & Goodman AM. NEJM 1995;333:541-9

11 Metformin and body fat composition
Selective loss of visceral fat Weight (kg) Body Mass Index (Kg/m2) Total Body Fat (L) Total Subcutaneous Fat (L) Abdominal Subcutaneous Fat (L) Viscera Fat (L) Lean Body Mass Change from baseline - 3.3 - 1.2 - 2.8 - 2.1 - 0.6 % Decrease from baseline 4% 9% 7% 11% 15% No change p value 0.006 0.014 0.025 0.013 0.01 NS Metformin and body fat composition Recent studies suggest that visceral fat is most strongly associated with insulin resistance and increased cardiovascular risk, while subcutaneous fat is associated with a lower risk of poor cardiovascular outcomes. Seven obese type 2 diabetic patients (mean BMI 29 kg/m2) received their maximally tolerated dose of metformin for 6 months in this study. The amount of visceral and subcutaneous fat was measured in each patient using computed tomography and dual-energy x-ray absorptiometry techniques. On average, body weight was reduced by 3.3 kg (p<0.008). However, a larger decrease in visceral fat was observed, compared with subcutaneous fat (mean reductions of 15.7% [p=0.01] and 7% [p=NS], respectively). Metformin treatment is therefore associated with a redistribution of visceral fat that is consistent with its beneficial effects on insulin resistance and clinical outcomes. Kurukulasuriya R, Banerji MA, Chaiken R, Lebovitz H. Selective decrease in visceral fat is associated with weight loss during metformin treatment in African Americans with type 2 diabetes [abstract]. Diabetes 1999;48: A315. Data are Means. Duration of Treatment: 6 Months. Kurukulasuriya R et al. Diabetes 1999;48:A315

12 Metformin improves endothelial function
400 Metformin mg (3 months) Placebo 350 * 300 • Endothelial function is impaired early in insulin resistance. • Mather et al randomized 44 patients with type 2 diabetes to metformin 1 g or placebo for 12 weeks.1 • Before and after treatment, endothelium-dependent and endothelium-independent vasodilation was assessed by intra-arterial administration of acetycholine or sodium nitroprusside, respectively. • As shown, metformin was associated with a significant improvement in endothelium-dependent vasodilation compared with placebo. • This finding supports a link between insulin resistance and endothelial dysfunction. Increase in forearm blood flow (%) 250 200 * 150 100 * 50 3 10 30 3 10 30 Acetylcholine (g/min) Before treatment After treatment * P = vs placebo Mather KJ et al. J Am Coll Cardiol. 2001;37: 1. Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol. 2001;37:

13 Myocardial Infarction
Improving the Prognosis of Patients with Type 2 Diabetes Slide 29. UKPDS: Myocardial Infarction in Metformin Study. Heart Attacks Coronary Deaths 20 10 p=0.01 p=0.02 NS 8 39% 15 Reduction 50% 6 Reduction Metformin markedly and significantly reduced the incidence of myocardial infarction, by 39% compared with diet alone (p = 0.01). No significant changes were observed with the intensive regimen based on sulphonylureas or insulin. Consistent with the effects on myocardial infarction, metformin also significantly reduced the incidence of coronary deaths, by 50% compared with diet (p = 0.02). No published data on fatal heart attacks have been given for overweight patients assigned to sulphonylureas or insulin. Incidence per 1000 patient years 10 Incidence per 1000 patient years 4 5 2 Conventional Insulin Metformin Conventional Metformin Diet or Diet Sulphonylureas

14 Improving the Prognosis of Patients with Type 2 Diabetes
Stroke Slide 30. UKPDS: Stroke in Metformin Study. P=0.13(NS) P=0.032 14% The beneficial cardiovascular effects of metformin, compared with insulin/sulphonylurea based intensive management, also extend to the reduction in risk of stroke. There was a 41% reduction in the risk of stroke in the metformin group which proved to be significantly superior to the 14% increased risk in the insulin/sulphonylurea intensive therapy group (p=0.032). Due to the small number of stroke events there were no significant differences between intensive therapies and the diet alone group. 41% Conventional Diet Metformin Metformin Insulin or Sulphonylureas Insulin or Sulphonyl

15 Survival in Overweight Group
Improving the Prognosis of Patients with Type 2 Diabetes Survival in Overweight Group Slide 32. UKPDS: Mortality Figures in Metformin Study. Diabetes Related Deaths 3 6 9 12 15 Incidence (Deaths per 1000 Patient Years) All Cause Mortality 5 10 15 20 25 Incidence (Deaths per 1000 Patient Years) p=0.017 p=0.011 NS NS p=0.021 42% Reduction 36% Reduction In the study in overweight patients, therapy outcomes for survival (measured as the death rate per 1000 patient years) paralleled their effects on myocardial infarction. Patients allocated to metformin treatment had significantly reduced diabetes- related deaths or deaths from all-causes. The magnitude of the risk reductions were 42% (p = 0.02) and 36% (p = 0.011) respectively, compared with the conventional diet-based policy. The insulin/sulphonylurea regimen was without significant effect on either measure of mortality. Conventional Diet Insulin Conventional Insulin Metformin Metformin or Diet or Sulphonylureas Sulphonylureas

16 Mechanisms of vascular protection
Reduce insulin resistance Improved lipid profiles Adiposity Improved hemostasis Inhibition of glycoxidation Inhibition of inflammation

17

18 Metformin ;effect on cancer risk and mortality

19 Diabetes Prevention Program (DPP)
20 40 60 DIET + EXERCISE METFORMIN TROGLITAZONE % 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
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. 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

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%
National Health and Nutrition Examination Survey (NHANES), 37.2% >8% 63% 7% 7.8% 25.8% 37.0% 17.0% 12.4% 1 in 5 Have A1c > 9% A1C % of Subjects n = 404 Saddinne JB, Cadwell B, Gregg EB, Engelgau MM, Vinicor F, Imperatore G, Narayan KMV, (2006), Improvements In Diabetes Processes Of Care And Intermediate Outcomes: United States, , Ann Intern Med 144: Only 7% of adults attained: A1c <7%, BP 130/80, and Total Cholesterol <200mg/dL

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 complications1 up to 50% of -cell function has already been lost2 Current management: two-thirds of patients do not achieve target HbA1c3,4 majority require polypharmacy to meet glycaemic goals over time5 1UKPDS Group. Diabetologia 1991; 34:877–890. 2Holman RR. Diabetes Res Clin Prac 1998; 40 (Suppl.):S21–S25. 3Saydah SH et al. JAMA 2004; 291:335–342. 4Liebl A et al. Diabetologia 2002; 45:S23–S28. 5Turner RC et al. JAMA 1999; 281:2005–2012.

25 Stepwise approach: delays control and leaves patients at risk of complications
OAD monotherapy uptitration OAD + multiple daily insulin injections Diet and exercise OAD monotherapy OAD combination OAD + basal insulin 10 Complications2 9 Mean HbA1c (%)1 8 7 6 Duration of diabetes 1Adapted from Del Prato S et al. Int J Clin Pract 2005; 59:1345– Stratton IM et al. BMJ 2000; 321:405–412.

26 Early, intensive intervention: reach glycaemic goals and reduce the risk of complications
OAD monotherapy 10 OAD combination OAD uptitration 9 OAD + multiple daily insulin injections OAD uptitration OAD + basal insulin HbA1c (%)1 8 Complications2 Mean 7 6 Duration of diabetes 1Adapted from Del Prato S et al. Int J Clin Pract 2005; 59:1345– Stratton IM et al. BMJ 2000; 321:405–412.

27 4/14/2017 3:48 PM Metformin Lowers Plasma Glucose by Lowering Hepatic Glucose Production and by Improving Insulin Sensitivity ↓ Gluconeogenesis ↓ Glycogenolysis ↑ Glycogen synthesis ↓Glucose production reduced by1–4: Liver Metformin Blood glucose Purpose: To describe the MOA of metformin. Takeaway: Metformin lowers plasma glucose primarily by reducing hepatic glucose output. It also increases insulin sensitivity, which leads to increased glucose uptake in muscle and adipose tissue. ↑Glucose uptake in muscle and fat by increasing insulin sensitivity5 Metformin Lowers Plasma Glucose by Lowering Hepatic Glucose Production and by Improving Insulin Sensitivity Speaker Notes The glucose-lowering effects of metformin are primarily a consequence of reduced hepatic glucose output. Metformin also increases insulin sensitivity, which leads to increased insulin-stimulated glucose uptake in skeletal muscle and adipocytes.1 Reduced hepatic glucose production: Primarily a result of decreased gluconeogenesis1,2 Secondarily through the acute inhibition of glycogenolysis1,3 Increased insulin sensitivity Increased glucose disposal (mainly in muscle) has been demonstrated using hyperinsulinemic, euglycemic, and hyperglycemic clamp procedures in patients with type 2 diabetes.4 Muscle Adipose tissue Liver 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. References: 1. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med. 2002;137:25–33. 2. Hundal RS, Krssak M, Dufour S, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000;49:2063–2069. 3. Chu CA, Wiernsperger N, Muscato N, et al. The acute effect of metformin on glucose production in the conscious dog is primarily attributable to inhibition of glycogenolysis. Metabolism. 2000;49:1619–1626. 4. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334:574–579.

28 Major Pathophysiologic Defects in Type 2 DM
4/14/2017 3:48 PM Major Pathophysiologic Defects in Type 2 DM Islet-cell dysfunction Glucagon (alpha cell) Pancreas Insulin resistance Glucose uptake in muscle and fat Insulin (beta cell) Hepatic glucose output Major Pathophysiologic Defects in Type 2 Diabetes Speaker Notes This diagram depicts the impact of type 2 diabetes on the feedback loop that regulates glucose homeostasis. In type 2 diabetes, insulin resistance is increased and insulin secretion is impaired.1 Most patients with type 2 diabetes have insulin resistance. Pancreatic beta cells attempt to increase insulin secretion to compensate for insulin resistance. However, when beta-cell function is impaired, hyperglycemia develops.1 By the time diabetes is diagnosed, beta-cell function has already decreased substantially and continues to decline over time.1 Once insulin secretion is impaired, an imbalance between insulin and glucagon can develop. Elevated glucagon levels lead to an increase in hepatic glucose production.1 Likewise, with decreased secretion of insulin, less glucose is taken up by the muscle and adipose tissue.2 Purpose: To explain the 3 core pathophysiologic defects of type 2 diabetes. Takeaway: Insulin resistance, beta-cell dysfunction, and elevated hepatic glucose production each contribute to hyperglycemia in type 2 diabetes. Hyperglycemia Liver Muscle Liver Adipose tissue 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. References: 1. Del Prato S, Marchetti P. Beta- and alpha-cell dysfunction in type 2 diabetes. Horm Metab Res. 2004;36:775–781. 2. Porte D Jr, Kahn SE. The key role of islet dysfunction in type 2 diabetes mellitus. Clin Invest Med. 1995;18:247–254.

29 Complementary Mechanisms of Action
4/14/2017 3:48 PM Complementary Mechanisms of Action Combining Pioglitazone and Metformin Complementary Mechanisms of Action: Combining Sitagliptin and Metformin

30 Major Targeted Sites of Oral Drug Classes
4/14/2017 3:48 PM Major Targeted Sites of Oral Drug Classes Beta-cell dysfunction Pancreas Sulfonylureas Muscle and fat Meglitinides Liver Hepatic glucose overproduction DPP-4 inhibitors GLP-1 Insulin resistance ↓Glucose level Major Targeted Sites of Various Oral Drug Classes Speaker Notes The various therapeutic agents available for the treatment of type 2 diabetes act on different pathways to control hyperglycemia.1,2 Sulfonylureas act in the pancreas, stimulating insulin release by binding to the sulfonylurea receptor of beta-cell membranes.1 Meglitinides, another class of short-acting insulin secretagogues, also act in the pancreas, stimulating insulin release by binding to several sites on the beta cells. They are used to control postprandial hyperglycemia.1 TZDs (thiazolidinediones) are selective peroxisome proliferator-activated receptor gamma agonists and act in the muscle. They also exert effects in the liver and adipose tissue. These agents reduce insulin resistance and decrease hepatic glucose output.1,2 Alpha-glucosidase inhibitors lower postprandial blood glucose concentrations by inhibiting disaccharidase enzymes in the gut, thereby delaying carbohydrate absorption. This action retards glucose entry into the systemic circulation.1 Biguanides (metformin) act primarily in the liver by decreasing hepatic glucose output through a mechanism that has not been fully elucidated. Metformin also enhances insulin sensitivity in muscle and decreases intestinal absorption of glucose.1,3,4 Based on their different mechanisms of action, these drugs may be used in combination, as noted in the prescribing information for each product. The dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of treatment for type 2 diabetes. These agents prevent the enzyme DPP-4 from degrading and inactivating GLP-1 and GIP, incretin hormones that are produced in the gut and help regulate insulin production and secretion.5 This glucose-dependent mechanism targets 2 key defects: insulin release and hepatic glucose production. Purpose: To provide a broad overview of the key mechanisms and targeted sites of available antihyperglycemic classes and to introduce the concept that DPP-4 inhibitors have an effect on both the pancreas and the liver. Takeaway: Different drug classes with different but complementary mechanisms may be suitable for combination therapy to address multiple pathophysiologies and improve A1C control. The glucose-dependent mechanism of DPP-4 inhibitors targets 2 key defects: insulin release and unsuppressed hepatic glucose production. Biguanides Gut Glucose absorption TZDs TZDs Biguanides Alpha-glucosidase inhibitors DPP-4 inhibitors Biguanides 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. References: 1. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303. 2. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals America, Inc; 2004. 3. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483. 4. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004. 5. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patient with type 2 diabetes. J Clin Endocrinol Metab. 2006;9:4612–4619.

31 Alpha-Glucosidase Inhibitors1,2
4/14/2017 3:48 PM No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies Alpha-Glucosidase Inhibitors1,2 Meglitinides3 SUs4,5 TZDs6,7 Metformin8 DPP-4 Inhibitors Insulin deficiency Insulin resistance Excess hepatic glucose output Major Pathophysiologies Purpose: To examine the key pathophysiologies targeted by each class of oral antihyperglycemic agent. Takeaway: No one class targets all key pathophysiologies of type 2 diabetes. No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies Speaker Notes No single-agent monotherapy has an MOA that addresses all key pathophysiologies of type 2 diabetes. Alpha-glucosidase inhibitors decrease intestinal absorption of glucose.1,2 Meglitinides and sulfonylureas stimulate insulin secretion.3–5 TZDs are insulin sensitizers that also lower hepatic glucose output.6,7 Metformin, a biguanide, lowers hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity.8 DPP-4 inhibitors improve insulin synthesis and release and lower hepatic glucose production, both through suppressing glucagon production and release, and by improving insulin synthesis and release. Each class of oral antihyperglycemic agent does not address at least 1 key pathophysiology of type 2 diabetes. Intestinal glucose absorption 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; 2004. References: 1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004. 3. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007. 4. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 5. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004. 7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005. 8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.

32 Trends in Antidiabetic Therapy
1995 2000

33 Effects of Pioglitazone and Metformin on FBG and HbA1c
0.2 5 0.2 -5 0.0 -5 FBG (mg/dL) change from baseline HbA1c (%) change from baseline -15 -0.2 -25 -0.4 -35 * -0.6 -45 -38 -55 -0.8 -0.8 * Placebo + metformin Pioglitazone 30 mg + metformin *P0.05 for comparison with placebo Egan J et al. Diabetes. 1999;47(suppl 1):A117. Abstract.

34 Early Addition of Rosiglitazone 8 mg/day to 1 g Metformin: More Patients Reach A1c Goal* vs. MET Monotherapy (2 g) 55% 45% Goal‡ <7% Goal‡ <6.5% *ADA A1c goal <7%, AACE A1C goal 6.5%. †P<0.05. ‡Patients received Avandia® 8 mg/day plus metformin 1 g/day (n=322; baseline A1c 8.05%) versus maximum dose metformin (n=313; baseline A1c 7.95%) in a 24-week, randomized, double-blind, parallel-group, multicenter study.

35 Insulin sensitizers vs other glucose-lowering agents following AMI
8872 acute MI patients, mean age 76.4 years, discharged on glucose-lowering medication Metformin TZD Both • Patients prescribed thiazolidinediones (alone or in combination with metformin) had a higher risk of readmission for heart failure probably due to drug-related peripheral edema.1 • Increases in heart failure readmissions were not associated with increased mortality. Mortality 0.92 (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) 1. Inzucchi SE, Masoudi FA, Wang Y, Kosiborod M, Foody JM, Setaro JF, et al. Insulin-sensitizing antihyperglycemic drugs and mortality after acute myocardial infarction: Insights from the National Heart Care Project. Diabetes Care. 2005;28:

36 Neutral effect of PPAR activation and metformin on hospital readmission
N = 16,417 with diabetes and HF Hospital readmission • There were no differences in the risk for all-cause readmission among patients discharged on a thiazolidinedione or metformin Rx compared with those not receiving either drug.1 • There was a modestly higher risk (of borderline significance) for heart failure readmission with a thiazolidinedione Rx and a significantly lower risk with a metformin Rx. • The investigators concluded, “This observational study suggests that thiazolidinediones and metformin are not associated with increased mortality and may improve outcomes in older patients with diabetes and heart failure.” All-cause HF TZD 1.04 (0.99–1.10) 1.06 (1.00–1.12) Metformin 0.94 (0.89–1.01) 0.92 (0.86–0.99) TZD = thiazolidinedione 1. Masoudi FA, Inzucchi S, Wang Y, Havranek EP, Foody JM, Krumholz HM. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure. Circulation. 2005;111:

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) 1.00 • Inzucchi et al conducted a retrospective cohort study of 8872 Medicare beneficiaries with diabetes.1 Subjects were discharged after hospitalization with MI between April 1998 and March 1999 or July 2000 to June 2001; 819 with a thiazolidinedione Rx, 1273 metformin Rx, and 139 receiving both drugs. • Metformin or thiazolidinediones had a neutral effect on mortality compared with treatment that did not include an insulin sensitizer: o Metformin: Hazard ratio (HR) 0.92 (0.81–1.06) o Thiazolidinediones: HR 0.92 (0.80–1.05) • Mortality risk was nearly 50% lower in patients receiving both drugs: o Metformin + thiazolidinediones: HR 0.52 (0.34–0.82). 0.95 Proportion of patients surviving 0.90 48% Relative risk reduction 0.85 0.80 50 100 150 200 250 300 350 Days from discharge 1. Inzucchi SE, Masoudi FA, Wang Y, Kosiborod M, Foody JM, Setaro JF, et al. Insulin-sensitizing antihyperglycemic drugs and mortality after acute myocardial infarction: Insights from the National Heart Care Project. Diabetes Care. 2005;28:

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

39 Patient compliance can be a difficult obstacle to overcome
4/14/2017 3:48 PM 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 Dosing flexibility may be key to tight control Patient compliance increases as complexity decreases

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

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%** A1C 7.6 – 9.0% A1C > 9.0% 45 Monotherapy
Drug Naive Under Treatment Symptoms No Symptoms Monotherapy Dual Therapy 8 MET † DPP4 1 GLP-1 TZD 2 AGI 3 MET + GLP-1 or DPP4 1 or TZD 2 SU or Glinide 4,5 INSULIN ± Other Agent(s) 6 MET + GLP-1 or DPP4 1 ± SU 7 TZD 2 ± TZD 2 INSULIN ± Other Agent(s) 6 2 - 3 Mos.*** Dual Therapy MET + GLP-1 or DPP4 1 TZD 2 Glinide or SU 5 TZD GLP-1 or DPP4 1 Colesevelam AGI 3 2 - 3 Mos.*** Triple Therapy 9 * 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 1 DPP4 if  PPG and  FPG or GLP-1 if  PPG 2 TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD) 3 AGI if  PPG 4 Glinide if  PPG or SU if  FPG 5 Low-dose secretagogue recommended 6 a) Discontinue insulin secretagogue with multidose insulin b) Can use pramlintide with prandial insulin 7 Decrease secretagogue by 50% when added to GLP-1 or DPP-4 8 If A1C < 8.5%, combination Rx with agents that cause hypoglycemia should be used with caution 9 If A1C > 8.5%, in patients on Dual Therapy, insulin should be considered MET + GLP-1 or DPP4 1 + TZD 2 + SU 7 TZD 2 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 2 - 3 Mos.*** Triple Therapy 2 - 3 Mos.*** MET + GLP-1 or DPP4 1 + TZD 2 Glinide or SU 4,7 INSULIN ± Other Agent(s) 6 2 - 3 Mos.*** INSULIN ± Other Agent(s) 6 Available at © AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE 45

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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 thanks nizar-albache.com


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