CONTROLLO GLICEMICO E RISCHIO CARDIOVASCOLARE. AGOSTINO CONSOLI DMSI - Università d Annunzio CHIETI ITALY. sul Paziente ad alto rischio CV*

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1 CONTROLLO GLICEMICO E RISCHIO CARDIOVASCOLARE AGOSTINO CONSOLI DMSI - Università d Annunzio CHIETI ITALY sul Paziente ad alto rischio CV*

2 Does reducing hyperglycemia protect against cardiovascular risk? Does reducing hyperglycemia protect against cardiovascular risk in High Risk Patients?

3 Fatal and Non-Fatal Myocardial Infarction-UKPDS Primary Prevention 5 P< Hazard ratio 1 14% decrease per 1% decrement in HbA 1c Updated mean HbA 1c Stratton IM, et al. UKPDS 35. BMJ 321: , 2000

4 Effect of glucose control on diabetes macrovascular complications Stettler et al Am Heart J 2006

5 Does reducing hyperglycemia protect against cardiovascular risk? Does reducing hyperglycemia protect against cardiovascular risk in High Risk Patients?

6 PROactive: Time to Secondary Composite Endpoint (Death from any cause, non-fatal myocardial infarction, or stroke) Lancet 366: , 2005

7 ACCORD: Inclusion Criteria T2DM > 3 months HbA1c 7,5 11,0 % AGE if CVD present AGE if no CVD High Risk for CVD events

8 ACCORD : Outcome N Engl J Med 2008;358:

9 N Engl J Med 2008;358: ACCORD : Outcome

10 VADT Trial: Characteristics of Subjects INTENSIVE STANDARD HbA1c (%) 9,4 9,4 Diabetes since (yrs) 11,5 11,5 Previous CVD (%) BMI 31,3 31,2 Duckworth et al, NEJM 2009

11 VADT Results Duckworth et al, NEJM 2009

12 Predictors of CVD mortality in VADT Predictors HR P value Hypoglycemia Prior history of CVD 3.00 < 0.01 Age 2.09 <0.01 HbA1c at baseline HDL-C at baseline

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14 2,2 MI Risk 2 1,8 VADT 8.4 vs 6.9 1,6 1,4 1,2 ACCORD 7.5 vs 6.4 ADVANCE 7.3 vs 6.5 UKPDS 7.0 vs 7.9 PROACTIVE 7.0 vs , HbA1c

15 2,4 2,2 VADT 8.4 vs 6.9 CV Death Risk 2 1,8 ACCORD 7.5 vs 6.4 1,6 1,4 PROACTIVE 7.0 vs 7.6 UKPDS 7.0 vs 7.9 1,2 ADVANCE 7.3 vs , HbA1c

16 Adjusted hazard ratios for all cause mortality by HbA1c deciles in people given oral combination and insulin based therapies Metformin + Sulphonylureas Insulin Based Regimens Published online January 27, 2010

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18 Does reducing hyperglycemia protect against cardiovascular risk? Are specific anti hyperglycemic agents particularly effective in reducing increasing cardiovascular risk in diabetic subjects?

19 DRUGS: glimepiride repaglinide metformin rosiglitazone acarbose glargine, ACCORD Therapeutic Regimens NPH and premixed insulins Aspart and regular insulin Exenatide (since 2007) ALL COMBINATIONS OF DRUGS WERE PERMITTED

20 ACCORD Therapeutic Regimens DRUGS: glimepiride repaglinide metformin rosiglitazone acarbose glargine, NPH and premixed insulins Aspart and regular insulin Exenatide (since 2007) WEIGHT GAIN CV RISK? HYPO GLYCEMIA

21 New Drugs not associated with hypoglycemia or weight gain

22 GLP-1 Cardiovascular Effects Risk area Normal area GLP-1 Improves LVEF Following AMI Control P<0.01 NS Single-center pilot study (N=21) GLP1- Treated Infarcted area (tetrazolium negative) Bose AK, Diabetes 2005 Control Nikolaidis LA, Circulation 2004 Effect of GLP-1 on endothelial function in T2DM patients with stable coronary artery disease P<0.05 Glucagon-Like Peptide 1 Induces Natriuresis in Healthy Subjects P= flow-mediated vasodilation (%) Sodium excretion (mmol/180 min) Saline GLP-1 Nystrom T, Am J Physiol Endocrinol Metab 2004 Control GLP-1 (1.5 pmol/kg x min) Gutzwiller et al. J Clin Endocrinol Metab 2004

23 Clinical Adverse Experiences with Incidence 2% Recent Pooled Analysis Adverse Experience Sitagliptin 100 mg N = 3415 Non-Exposed N = 2724 n (%) n (%) Difference between Sitagliptin and Non-Exposed % (95% CI) Constipation 79 (2.3) 47 (1.7) 0.6 (-0.1, 1.3) Diarrhea 170 (5.0) 144 (5.3) -0.3 (-1.4, 0.8) Dyspepsia 70 (2.0) 40 (1.5) 0.6 (-0.1, 1.2) Nausea 85 (2.5) 70 (2.6) -0.1 (-0.9, 0.7) Peripheral Edema 62 (1.8) 54 (2.0) -0.2 (-0.9, 0.5) Bronchitis 135 (4.0) 83 (3.0) 0.9 (-0.0, 1.8) Gastroenteritis 68 (2.0) 48 (1.8) 0.2 (-0.5, 0.9) Influenza 145 (4.2) 127 (4.7) -0.4 (-1.5, 0.6) Nasopharyngitis 244 (7.1) 162 (5.9) 1.2 (-0.1, 2.4) Sinusitis 80 (2.3) 60 (2.2) 0.1 (-0.6, 0.9) BMC Endocrine Disorders 8: 14 (2008)

24 Clinical Adverse Experiences with Incidence 2% Adverse Experience Recent Pooled Analysis Sitagliptin 100 mg N = 3415 Non-Exposed N = 2724 n (%) n (%) Difference between Sitagliptin and Non-Exposed % (95% CI) Upper Respiratory Tract Infection 265 (7.8) 228 (8.4) -0.6 (-2.0, 0.8) Urinary Tract Infection 134 (3.9) 100 (3.7) 0.3 (-0.7, 1.2) Hypoglycemia 117 (3.4) 296 (10.9) -7.4 (-8.8, -6.1) Arthralgia 113 (3.3) 92 (3.4) -0.1 (-1.0, 0.8) Back Pain 142 (4.2) 108 (4.0) 0.2 (-0.8, 1.2) Pain in Extremity 84 (2.5) 53 (1.9) 0.5 (-0.2, 1.2) Dizziness 86 (2.5) 63 (2.3) 0.2 (-0.6, 1.0) Headache 169 (4.9) 129 (4.7) 0.2 (-0.9, 1.3) Cough 88 (2.6) 73 (2.7) -0.1 (-0.9, 0.7) Hypertension 110 (3.2) 89 (3.3) -0.0 (-1.0, 0.8) BMC Endocrine Disorders 8: 14 (2008)

25 Sitagliptin Cardiovascular Safety Pooled Analysis of 12 phase II/III studies, 3415 exposed vs 2724 non expose patients, mean exposure 294 days Overall incidences of ischemia-related adverse experiences 2.0% in the sitagliptin group 2.3% in the non-exposed group Between-group difference = 0.2% [95% CI, -1.0, 0.5] Incidences of serious ischemia-related adverse experiences 1.1% in the sitagliptin group 1.5% in the non-exposed group Between-group difference = 0.4% [95% CI, -1.0, 0.2] Fatal ischemic events 3 patients (0.09%) in the sitagliptin group (2 with ischemic stroke and 1 with myocardial infarction) 7 patients (0.26%) in the non-exposed group (4 with myocardial infarction, 1 with myocardial ischemia, and 2 with sudden cardiac death) BMC Endocrine Disorders 8: 14 (2008)

26 Is it dangerous to aggressively pursue tight glucose control by using hypoglycemic agents in high risk patients? YES Is it safe to aim for good glucose control by using normoglycemic agents in high risk patients? Probably YES

27 Natural History of poorly treated T2DM subjects Before Intensive Treatment After Intensive Treatment Del Prato, Diabetologia 2009

28 Principiis obsta! Sero medicina paratur, cum mala per longas moras convaluere! Ovidio, Remedia Amoris