Diabete: terapia nei pazienti a rischio cardiovascolare

Diabete: terapia nei pazienti a rischio cardiovascolare Giorgio Sesti Università Magna Graecia di Catanzaro

Cardiovascular mortality in relation to diabetes mellitus and a prior MI: A Danish Population Study of 3.3 Million People Schramm et al. Circulation 117:1945-54, 2008

Survival (%) Survival Post-MI in Diabetic and Nondiabetic Men and Women: Minnesota Heart Survey 100 MEN 100 WOMEN No diabetes No diabetes 80 80 n=1628 n=568 60 Diabetes 60 40 n=228 40 Diabetes n=156 0 0 0 20 40 60 Months Post-MI 80 0 20 40 60 80 Months Post-MI Sprafka JM et al. Diabetes Care 14:537-543, 1991

OUTLINE 1. Can intensive glucose lowering treatment reduce the risk for CV events? 2. What are the benefits of intensified multiple risk factor intervention on morbidity and mortality? 3. What is the most powerful component in the intensified multifactorial approach to reduce complications and mortality?

Selvin et al. Ann Intern Med :141:421-431, 2004 Meta-Analysis: HbA1c and Cardiovascular Disease in Diabetes EVERY 1% reduction in HbA 1c Reduced Risk* Number of patients Number of studies Cardiovascular disease -18% 7435 10 Coronary heart disease -13% 6684 6 1% Fatal coronary heart disease -16% 3042 5 Stroke -17% 5962 3 Peripheral arterial disease -28% 3748 3 *P<0.0001

Landmark studies in Type 2 diabetes: intensive glucose control on CV outcomes UKPDS ACCORD ADVANCE VADT

UKPDS, ACCORD, ADVANCE, and VADT Study Characteristics UKPDS ACCORD ADVANCE VADT Protocol Characteristics A1C goals, % FPG <108 mg/dl (I vs S) a vs. best achievable FPG with diet alone <6.0 vs 7.0-7.9 6.5 vs based on local guidelines <6.0 (action if >6.5) vs planned separation of 1.5 Protocol for glycemic control (I vs. S) a Sulfonylurea or insulin vs. diet alone Multiple drugs in both arms Multiple drugs added to gliclazide vs multiple drugs with no gliclazide Multiple drugs in both arms Management of other risk factors Embedded blood pressure trial Embedded blood pressure and lipid trials Embedded blood pressure trial Protocol for intensive treatment in both arms a Medication rates for ACCORD are for any use during the study. I = intensive glycemic control; S = standard glycemic control. Turnbull FR, et al. Diabetologia 52:2288 2298, 2009

UKPDS, ACCORD, ADVANCE, and VADT Results Outcomes HbA1c (Intensive vs. Standard) Definition of primary outcome HR for primary outcome UKPDS ACCORD ADVANCE VADT 7.0 vs. 7.9% 6.5 vs. 7.3% 6.4 vs. 7.5% 6.9 vs. 8.4% 21 clinical endpoints 16% (MI) (P=0.052) Nonfatal MI, nonfatal stroke, CVD death 10% (P=0.16) Microvascular plus macrovascular (nonfatal MI, nonfatal stroke, CVD death) outcomes 10% (P=0.01); 6% CV outcome (P=0.32) Nonfatal MI, nonfatal stroke, CVD death, hospitalization for heart failure, revascularization 12% (P=0.14) HR for mortality findings 6% (P=0.44) 22% (P=0.04) 7% (P=0.28) 7% (P=0.62) Turnbull FR, et al. Diabetologia 52:2288 2298, 2009

Intensive glycaemic control may reduce risk of myocardial infarction Meta-analysis of ACCORD, ADVANCE, VADT and UKPDS suggests intensive glucose control reduces the risk of myocardial infarction by 15% Study Number of events (annual event rate, %) More intensive Less intensive Difference in HbA 1c (%) Favours intensive therapy Favours less intensive therapy Hazard ratio (95% CI) ACCORD 198 (1.18) 245 (1.51) 1.01 0.77 (0.64, 0.93) ADVANCE 310 (1.18) 337 (1.28) 0.72 0.92 (0.79, 1.07) UKPDS 150 (1.20) 76 (1.40) 0.66 0.81 (0.62, 1.07) VADT 72 (16.5) 87 (1.99) 1.16 0.83 (0.61, 1.13) Overall 730 745 0.88 0.85 (0.76, 0.94) 0.5 0 2.0 Turnbull FR, et al. Diabetologia 52:2288 2298, 2009

How can we explain the reported negative results in clinical outcomes observed so far in trials affessing the effect of intensive glucose control on CV outcomes?

1. Higher weight gain in the intensive-therapy than the standard-therapy group;

Kg Differences in body weight between intensive and standard therapy groups 9,00 8,00 Standard Therapy Intensive Therapy 8,1 7,00 6,00 5,6 5,00 4,00 3,5 4,05 3,00 2,5 2,00 1,00 0,00-1,00 0,4-0,1-1 UKPDS ACCORD ADVANCE VADT

1. Higher weight gain in the intensive-therapy than the standard-therapy group; 2. Higher rates of hypoglycemia in the intensive-therapy than the standard-therapy group;

Annual event rates per 100 patients of severe hypoglycemia Differences in hypoglycemic events that requires third-party assistance between intensive and standard therapy groups 14,00 12,00 Standard Therapy Intensive Therapy 12 10,00 8,00 6,00 4,00 4,6 4 2,00 1,5 0,00 0,2 0,71 0,3 0,56 UKPDS ACCORD ADVANCE VADT Ismail-Beigi F et al. Ann Intern Med 154:554-559, 2011

Correlation between risk of severe hypoglycemia and cardiovascular death associated with intensive treatment: ACCORD, ADVANCE, PROACTIVE, UKPDS and VADT meta-analysis VADT ACCORD PROACTIVE ADVANCE UKPDS Mannucci E. et al. Nutr Metab Cardiovasc Dis 19:604-612, 2009

1. Higher weight gain in the intensive-therapy than the standard-therapy group; 2. Higher rates of hypoglycemia in the intensive-therapy than the standard-therapy group; 3. Long duration of diabetes;

Correlation between duration of diabetes and cardiovascular death associated with intensive treatment: ACCORD, ADVANCE, PROACTIVE, UKPDS and VADT meta-analysis ACCORD VADT UKPDS PROACTIVE ADVANCE Mannucci E. et al. Nutr Metab Cardiovasc Dis 19:604-612, 2009

1. Higher weight gain in the intensive-therapy than the standard-therapy group; 2. Higher rates of hypoglycemia in the intensive-therapy than the standard-therapy group; 3. Long duration of diabetes; 4. Metabolic memory or legacy effect.

UKPDS Post-Trial Monitoring: Patients 1997 # in survivor cohort 2002 2007 # with final year data 2,118 Sulfonylurea/Insulin Clinic Questionnaire 1,010 Sulfonylurea/Insulin P 880 Conventional Clinic Questionnaire 379 Conventional P 279 Metformin Clinic Questionnaire 136 Metformin Mean age 62±8 years Mortality 44% (1,852) Lost-to-follow-up 3.5% (146) UKPDS 80. N Eng J Med 359, 2008

UKPDS: Post-Trial Changes in HbA 1c UKPDS results presented Mean (95%CI) Holman R.R. et al. N Engl J Med 359:1577-1589, 2008

Extended effects of improved glycemic control in patients with newly diagnosed type 2 diabetes After median 8.5 years post-trial follow-up Aggregate Endpoint 1997 2007 Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040 Microvascular disease RRR: 25% 24% P: 0.009 0.001 Myocardial infarction RRR: 16% 15% P: 0.052 0.014 All-cause mortality RRR: 6% 13% P: 0.44 0.007 RRR = Relative Risk Reduction, P = Log Rank Holman R.R. et al. N Engl J Med 359:1577-1589, 2008

HbA1c (%) Hypothetical representation of the natural history of the diabetic patients recruited in the VADT 9,5 9,0 8,5 Before entering VADT intensive treatment arm Generation of a bad glycemic legacy After entering VADT intensive treatment arm Drive risk for complications 8,0 7,5 7,0 6,5 6,0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 TIME (years since diagnosis) Del Prato S Diabetologia 52:1219 1226, 2009

The floor effect, i.e., a diminishing ability of intensive treatments to lower risk further when one risk factor is reduced to near normal levels and the other risk factor is reasonably well controlled ACCORD ADVANCE VADT On-Study Characteristics On statin at study end, % (I vs S) 88 vs 88 a 46 vs 48 85 vs 83 On aspirin at study end, % (I vs S) 76 vs 76 a 57 vs 55 88 vs 86 Smokers at study end, % 10 8 8 Mean LDL (mg/dl) Intensive glycemic control arm 105* 103 80 Standard glycemic control arm 105* 103 80 Mean blood pressure at study end, mm Hg Intensive glycemic control arm 126/67 136/74 127/68 Standard glycemic control arm 127/68 138/74 125/69 a Medication rates for ACCORD are for any use during the study. *Values at Baseline. I = intensive glycemic control; S = standard glycemic control. Skyler JS et al. J Am Coll Cardiol. 53:298-304, 2009

Comparison of HRs for CHD by long-term average concentrations of fasting blood glucose, total (and non-hdl) cholesterol, and systolic blood pressure FPG concentrations are non-linearly and moderately associated with risk of CHD, total (or non-hdl-) cholesterol levels and systolic blood pressure are more strongly associated with such risk and show a near log-linear relationship The Emerging Risk Factors Collaboration. Lancet 375:2215 2222, 2010

Incidence of the UKPDS primary composite any diabetes related endpoint by intention-to-treat in the 887 patients randomised in a factorial design 87 P for trend 0.024 155 231 414 Stratton IM et al. Diabetologia 49: 1761 1769, 2006

ADVANCE: Joint effects of routine blood pressure lowering and intensive glucose control Cardiovascular death BP arm Hazard ratios Favours Per-Ind Favours Placebo Relative risk reduction (95% CI) All participants 18% (2 to 32) 1.3 Annual event rate % RRR 24%, P=0.04 Standard 22% (0 to 40) Intensive 14% (-11 to 34) 0.5 1.0 2.0 Hazard ratio 1.1 1.14 1.02 Glucose arm Favours Favours Intensive Standard Relative risk reduction (95% CI) 0.9 0.89 All participants 7% (-11 to 23) Placebo 11% (-14 to 30) Perindopril-Indapamide 2% (-28 to 25) 0.5 1.0 2.0 0.7 Standard Glucose 0.87 Intensive Per-Ind Placebo BP Hazard ratio P for interaction=0.62 Zoungas S et al- Diabetes Care * in 32:2068 2074, most patients 2009

Steno-2: treatment conditions Conventional group Aim: to modify CV risk factors to conventional targets: Systolic BP < 160 Diastolic BP < 95 HbA 1c < 7.5% Fasting serum total cholesterol: 250 mg/dl Fasting serum triglycerides: 195 mg/dl Aspirin for those with known ischaemia Intensive group Aim: to modify CV risk factors to strict targets: Systolic BP < 140 Diastolic BP < 85 HbA 1c < 6.5% Fasting serum total cholesterol 190 mg/dl Fasting serum triglycerides 150 mg/dl Aspirin for those with known ischaemia or peripheral vascular disease Automatic treatment with ACE inhibitor Steno-2: Lancet 353:617 22, 1999

Composite Endpoint of Death from CV Causes, Nonfatal MI, CABG, PCI, Nonfatal Stroke, Amputation, or Surgery for PAD: STENO-2 Primary Composite Endpoint (%) Hazard ratio = 0.47 (95% CI, 0.24 0.73; P=0.008) Conventional Therapy Intensive Therapy 0 12 24 36 48 60 72 84 96 Months of Follow-up Gæde P et al. N Engl J Med 348:383-393, 2003

Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with Microalbuminuria): Steno-2 Patients Reaching Intensive- Treatment Goals at Mean 7.8 y, (%) Intensive Therapy Conventional Therapy 80 70 P<0.001 P=0.21 60 P=0.19 P=0.001 50 40 30 20 P=0.06 10 0 Glycosylated hemoglobin <6.5% Cholesterol <175 mg/dl Triglycerides <150 mg/dl Systolic BP <130 mm Hg Diastolic BP <80 mm Hg Gæde P et al. N Engl J Med 348:383-393, 2003

Percent of Total Calculated Risk Reduction in CVD Events Lipid-Lowering Therapy Accounted for Over 70% of Cardiovascular Risk Reduction in Patients With Diabetes* 80 60 40 20 0 Lipids HbA 1c Systolic Blood Pressure *Analysis of Steno-2 data based on United Kingdom Prospective Diabetes Study risk engine Adapted from Gaede P, Pedersen O. Diabetes 53 (suppl 3):S39 S47, 2004

BP Control Yields Greater CV Risk Reduction Than Glycemic Control in Type 2 Diabetic Patients Tight glucose control (HbA1c <7.0%) Tight BP control (<150/85 mmhg) 20 Fatal MI Nonfatal MI 17 Fatal stroke Nonfatal stroke Heart failure Diabetesrelated deaths 10 7 0-10 -6-10 -9-10 -20-21 -30-40 -28-32 -50-44 -60-58 -56 UKPDS 33. Lancet 352:837-853, 1998 UKPDS 38. BMJ 317:703-713, 1998

The epidemiological and interventional relationships of cholesterol, blood pressure and HbA1c with cardiovascular disease Variable Cholesterol (1mmol/l o 39 mg/dl) CHD (fatal and non-fatal MI and sudden death Epidemiological (%) -30 Intervention (%) -23 Cardiovascular disease NNT for 5 years 59.2 44.4 Blood pressure (10/5 mmhg) Epidemiological (%) -25 Intervention (%) -22 NNT for 5 years 61.8 33.6 Glycemia (HbA1c 0.9%) Epidemiological (%) -12 Intervention (%) -9.7 NNT for 5 years 140.3 118.5 NNT= number needed to treat Yudkin JS et al. Diabetologia 53:2079 2085, 2010

ACCORD Therapeutic regimen DRUGS: Glimepiride Repaglinide Metformin Rosiglitazone Acarbose Glargine NPH and Premixed Insulins Aspart and Regular Insulin Exenatide (since 2007) WEIGHT GAIN CV RISK? HYPO GLYCEMIA

Cardiovascular outcomes trials for GLP-1, DPP4i and SGLT2i products SUSTAIN 6 (Semaglutide, GLP-1) n=3,260; duration ~2.8 yrs end Q1 2016 NCT01703208 (Omarigliptin, QW DPP4i) n=4,000; duration ~3 yrs end Q4 2017 REWIND (Dulaglutide, QW GLP-1) n=9,622; duration ~8 yrs end Q2 2019 CANVAS (Canagliflozin, SGLT2i) n=4,414; duration 4+yrs end Q2 2018 EXAMINE (Alogliptin, DPP4i) n=5,380; follow-up ~1.5 yrs end Q2 2013 - RESULTS ELIXA (Lixisenatide, GLP-1) n=6,000; duration ~4 yrs end Q3 2014 EMPA-REG OUTCOME (Empagliflozin, SGLT2) n=7,000; duration ~4 yrs end Q1 2018 FREEDOM-CVO (ITCA 650, GLP-1 in DUROS) n=2-3,000; duration ~2 yrs end Q3 2018 SAVOR TIMI-53 (Saxagliptin, DPP4i) n=16,492; follow-up ~2 yrs end Q2 2013 - RESULTS LEADER (Liraglutide,GLP-1) n=9,340; duration 3.5-5 yrs end Q1 2016 EXSCEL (Exenatide QW GLP-1) n=9,500; duration ~5.5 yrs end Q1 2017 DECLARE-TIMI-58 (Dapagliflozin, SGLT2i) n=17,150; duration~6 yrs end Q2 2019 ORIGIN (Glargine, basal insulin) n=12,500; duration >5yrs end Q4 2011 - RESULTS TECOS (Sitagliptin, DPP4i) n=14,000; duration ~4-5yrs end Q4 2014 CARMELINA (Linagliptin, DPP4i) n= 8,300; duration ~4 yrs end Q1 2018 CAROLINA (Linagliptin, DPP4i vs SU) n= 6,000; duration ~8 yrs end Q3 2018 2011 2012 2013 2014 2015 2016 2017 2018 2019 Pre-approval Pre + post approval Post-approval Other Source: ClinicalTrials.gov (October 2013) and LLY Investor call ADA 2013

Saxagliptin and cardiovascular outcomes in patients with T2DM SAVOR-TIMI 16,492 patients, median followup 2.1 years Scirica BM et al. N Engl J Med 2013

Alogliptin after acute coronary syndrome in patients with T2DM EXAMINE 5380 patients, median follow-up 18 months White WB et al. N Engl J Med 2013

Management of hyperglycemia in T2DM: a patient-centered approach. Position statement of ADA and EASD Most Intensive Less Intensive Least Intensive 6.0% 7.0% 8.0% Disease Duration Newly diagnosed Long Long standing Life expentancy Short Comorbidities None Few/Mild Severe Established Vascular Complications Absent Few/Mild Severe Hypoglycemia Risk Low Moderate High Highly Motivated, Adherent, Excellent Self-Care Capacities Patient attitude Less motivated, non-adherent, poor self-care capacities Resources, support system Readily available Limited Adapted from Inzucchi SE et al. Diabetes Care 38:140 149, 2015