The role of pioglitazone in the treatment of Type 2 Diabetes - - PowerPoint PPT Presentation

The role of pioglitazone in the treatment of Type 2 Diabetes - Update 2016 Professor Guntram Schernthaner Medical University of Vienna, Austria guntram.schernthaner@meduniwien.ac.at

Optimal Treating of Type 2 Diabetes means treating Hyperglycaemia and the Dysmetabolic Syndrome Good glycaemic control Microvascular & Macrovascular NEED TO Complications TREAT Dysmetabolic syndrome Insulin resistance, obesity, hyperinsulinaemia, hypertension, dyslipidaemia, atherosclerosis, procoagulant state

PPAR γ activation and atherosclerosis Ligand: Activated PPAR γ Endogenous or synthetic (TZDs) Direct Indirect Vascular and inflammatory cells Fat, liver, skeletal muscle cells ↓ Cytokines ↓ FFA Reduces – – ↓ Chemokines ↓ Glucose inflammation ↑ Cholesterol efflux ↑ Insulin sensitivity ↓ Adhesion molecules ↓ Triglycerides ↑ HDL ↓ Atherogenic LDL – – Inhibits Atherosclerosis Plutzky J. Science . 2003

Pow erful HbA1 c Low ering: Sim ilar as Metform in or Exenatide once a w eek

DURATION 4: Effects of Monotherapy of Pioglitazone, Metformin, Sitagliptin or Exenatide once weekly in early Type 2 Diabetes on HbA1c Number of Patients: 1194 Number of Patients: 800 Duration of Diabetes: 3 years Duration of Diabetes: 2 years Duration of Treatment: 12 months Duration of Treatment: 6 months Changes in n=597 n=597 n= 163 n=246 n=248 n=163 HbA 1C (%) 0,0 -0,5 -1,0 -1,5 -1,4 -1,5 -1,5 -1,5 -1,2 -1,6 Exenatide -2,0 Pioglitazone Metformin Pioglitazone Metformin Sitagliptin once a week Weight + 1.9 - 2.5 + 1.8 - 2.2 - 2.3 - 0.8 Change (kG) Russel-Jones et al. Diab Care 2012; 35:252-258 Schernthaner G et al. JCEM 2004, 89:6068

Low Risk of Hypoglycemia

Effects of oral antidiabetic Drugs on HbA1c, Hypoglycemic Events & Weight Gain in 4 randomisied double blind large Studies (Quartet) Weight Weight Number Hypoglycemia HbA1c Change Difference of Patients (%) (%) (kg) (kg) 1 Metformin 597 -2,5 -1,5 1,3 4,4 1 Pioglitazone 597 -1,4 1.5 +1,9 2 SU 626 -1,35 10.1 +1.9 0,9 2 Pioglitazone 624 -1,43 3.5 +2.8 3 Metformin + Pioglitazone 317 -1,5 1.3 +1,5 0,1 3 Metformin + SU -1,4 11.2 +1,4 317 4 SU + Pioglitazone 319 -1,35 10.7 +2,8 3,8 4 SU + Metformin -1,43 14.1 -1,0 320 SU = Sulfonylureas 1 Schernthaner et al; JCEM 2004; 89:6068 2 Charbonell et al; Diabet Med. 2005; 22:399 3 Matthews et al; Diab.Metab Res.Rev.2005; 21:167 4 Hanefeld et al; Diab.Care 2004;27:141

Weight Gain, but significant lowering of Visceral Fat and Hepatic Fat

Waist is not a relevant marker of visceral fat on Pioglitazone due to the fat redistribution shown on Pioglitazone + 42% R.De Fronzo et al: JCEM 2002, 87, 2784

Visceral fat actually decreases on Pioglitazone: the « abdominal obesity » parameter is improved - 25 % R.De Fronzo et al: JCEM 2002, 87, 2784

Progression of Diabetes: HbA 1C - Increase per Year (Two-Year Results from the QUARTET-Studies) Charbonnel B, Schernthaner G, Brunetti P et al (Diabetologia 2005; 48:1093) 1,00 0,89 HbA 1C - per Year (%) Mean Increase of 0,75 0,50 0,33 0,29 0,25 0,06 0,00 Pioglitazone Sulfonylurea Pioglitazone Metformin +Metformin +Metformin Combination-Therapy Studies Mono-Therapy Studies Duration of Diabetes: 6 years Duration of Diabetes: 3 years

Superior to Metformin in Reducing Insulin Resistance

Treatment-induced changes in Insulin-mediated Glucose Uptake (M value) with Metformin and Thiazolidinediones Metformin Thiazolidinediones + 36 % Insulin-mediated glucose uptake 50 + 34 % 40 + 18 % 30 + 11 % (% change) 20 10 0 -10 Open Open Double-blind/ Double-blind/ -20 placebo-controlled placebo-controlled Natali A and Ferrannini E. Diabetologia 2006; 49:434-41

Potential anti-atherogenic Effects of Thiazolidinediones Traditional Risk Factors Non-traditional Risk Factors • Reduction of vascular Inflammation • Decrease of HbA1c, FPG, PRS → Lowering of CRP, IL-6, NFkB, • Lowering of Systolic BP sICAM, sVCAM, MCP-1, MMP-9 • Increase of HDL-Cholesterol • Antiplatelet Effects: sCD40L, P-Selectin • Decrease of Triglycerides • Improvement of Fibrinolysis → lowering of PAI-1 • Decrease of Lp (a) • Improvement of Endothelial Dysfunction → lowering of ADMA • Decrease of small-dense LDL-Particles • Neovascularisation & Neoangiogenesis → Increase of endothelial progenitor cells (EPC)

Superior to Metformin in Reducing Microalbuminuria

Significant lowering of urinary albumin/creatinine ratio by treatment with Pioglitazone in type 2 diabetic patients Change of urinary albumin/creatinine ratio 10 SU +Metformin Pioglitazone (n=313) Metformin PIO (n=597) +SU (n=320) +Metformin Metformin PIO (n=317) (n=597) +SU (n=319) after 52 weeks (%) 0 +6 +2 -1 -10 -10 -15 p<0.017 p<0.027 -20 -19 p<0.002 Schernthaner et al Hanefeld et al Matthews et al JCEM 2004; Diab.Care 2004; Diab.Metab Res.Rev. 89:6086 28:141 2005; 21:167-174

Serafidis & Bakris. Kidney International 2006; 70:1223-33

Significant Increase of HDL-Cholesterol, which is a strong predictor of CV Mortality in Patients with Type 2 Diabetes

Benefits of Pioglitazone: Lipid Metabolism • Pioglitazone improves diabetic dyslipidaemia – Decreases triglyceride levels – Increases high-density lipoprotein (HDL) cholesterol levels Corrected for Comparator Dormandy JA et al. Lancet 2005;366:1279- Mazzone T et al.,JAMA 2006; 296: 2572 Nicholls et al. J Am Coll Cardiol 2008; 52:255-62.

Which Studies do we have indicating that Pioglitazone has antiatherogenic and cardioprotective effetcs? • Four Randomized Controlled Trials PROactive CHICAGO PERISCOPE IRIS • Several Metaanalyses • ThreeLarge Observational Studies from UK

PROactive

PROactive Study Design Pioglitazone + existing therapy Forced titration up to 45 mg/day Existing therapy Diet and Glucose-lowering Placebo agents, Antihypertensives, + existing therapy Lipid-altering agents, Antithrombotic agents… Patient management throughout study to be according to the 1999 International Diabetes Federation (Europe) Guidelines

Overlap of Previous Macrovascular Events Previous stroke n=984 Previous 662 82 Myocardial Infarction 763 145 n=2445 95 1505 Other 1904 macrovascular criteria Previous Macrovascular Disease n=3649* 50% Myocardial Infarction 25% Stroke * - including 1043 with peripheral arterial obstructive disease 25% Peripheral Vascular Disease

PROACTIVE (Lancet 2005; 366: 1279-1289) Time to Primary Composite Endpoint * Pioglitazone (514 / 2605) Placebo (572 / 2633) 0,25 Kaplan-Meier Event Rate 0,2 0,15 0,1 0,05 HR 95 % CI p value Pioglitazone 0.904 0.802, 1.018 0.0951 * vs Placebo 0 N at Risk: 5238 5018 4786 4619 4433 4268 693 (228) 0 6 12 18 24 30 36 Time from Randomisation (months) * Death from any cause, non-fatal myocardial infarction (including silent MI), stroke, acute coronary syndrome, leg ampuation, coronary revascularisation, bypass surgery/revascularisation of the leg

Significant Reduction of the combined Clinical Outcome of Death, Myocardial Infarction & Stroke Pioglitazone : Events 301 / 2605 (12.3%) Kaplan-Meier Event Rate Placebo : Events 358 / 2633 (14.4%) 0,15 - 16% - at 3-year (p=0.0237) 0,1 0,05 HR 95 % CI p value Pioglitazone 0.841 0.722, 0.981 0.0237 * vs Placebo 0 N at Risk: 5238 5102 4991 4877 4752 4651 786 (256) 0 6 12 18 24 30 36 Time from Randomisation (months) Dormandy G et al (Lancet 2005; 366: 1279-1289)

Primary Composite Endpoint – CV Death, Myocardial Infarction and Stroke • ACCORD • ORIGIN • SAVOR • EXAMINE • PROactive (secondary primary endpoint*) • SAVOR, EXAMINE, TECOS • EMPA REC OUTCOME • LEADER, SUSTAIN-6 In March, 2005, the steering committee identified this endpoint as the intended main secondary endpoint. The final version was signed and released on May 13, 2005. A copy of the plan was registered as received by the US Food and Drug Administration on May 17, 2005. The study database was formally locked on May 25, 2005 and statistical analysis of unblinded data started only after that date. (Lancet March 25 th , 2006

Pioglitazone’s effect on recurrent stroke in patients with previous stroke Kaplan-Meier event rate 0.12 Pioglitazone (27 / 486) 0.10 Placebo (51 / 498) - 47% 0.08 0.06 0.04 0.02 HR 95% CI p value pioglitazone vs placebo 0.53 0.34, 0.85 0.008 0.00 N at Risk: 984 952 926 903 877 849 132 0 6 12 18 24 30 36 Time from Randomisation (months) Wilcox R et al. STROKE 2007; 38: 865-873

Pioglitazone’s effect on recurrent MI in patients with previous MI Kaplan-Meier Event Rate 0.10 Pioglitazone (65 / 1230) 0.08 Placebo (88 / 1215) -28 % 0.06 0.04 0.02 HR 95 % CI p-Value Pioglitazone vs Placebo 0.72 0.52, 0.99 0.045 0.0 N. at risk:2455 2387 2337 2293 2245 2199 399(139) 0 6 12 16 24 30 36 Time from Randomisation (months) Erdmann E. et al. JACC 2007; 49: 1772-1780