Cedars Sinai Diabetes. Michael A. Weber

Transcription

1 Cedars Sinai Diabetes Michael A. Weber

2 Speaker Disclosures I disclose that I am a Consultant for: Ablative Solutions, Boston Scientific, Boehringer Ingelheim, Eli Lilly, Forest, Medtronics, Novartis, ReCor

3 Obesity Trends* Among US Adults: BRFSS, 199, 2, *BMI 3, or about 3 lbs overweight for 5ʹ4ʹʹ person 21 2 Behavioral Risk Factor Surveillance System, CDC. U.S. Obesity Trends. Accessed August 25, 211. No Data <1% 1% 14% 15% 19% 2% 24% 25% 29% 3%

4 Metabolic Syndrome Increases Mortality Risk In US adults 3 to 74 years of age, MetS confers an increased risk of CHD, CVD, and total mortality persons with diabetes and/or pre-existing CVD are at even higher risk. Hazard ratios for age- and gender-adjusted CVD and total mortality in US adults with and without metabolic syndrome, diabetes, and preexisting CVD in the NHANES II Follow-Up Study (n=6255; mean follow-up, 13.3 years) * 2.42* 2.83* x3 1.97* 1.74* Neither MetS nor DM All MetS MetS w/dm Prior CVD x CVD Mortality Total Mortality CVD=cardiovascular disease; DM=diabetes mellitus; MetS=metabolic syndrome. *P<.1; P=.1. Malik S et al. Circulation. 24;11:

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7 Prevalence/Incidence of 25.8 million people in the United States have diabetes 8.3% of total population Diabetes Mellitus In people aged 65 and older, 1.9 million (26.9%) had diabetes in million new cases in 21 in people aged >2 years CDC estimates 79 million Americans aged >2 years have prediabetes Leading cause of kidney failure, non-traumatic lower-limb amputations, and blindness in adults in the US Major cause of heart disease and stroke 7 th leading cause of death in the United States CDC=Centers for Disease Control and Prevention. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: National estimates and general information on diabetes and prediabetes in the United States, 211. Atlanta, GA: US Department of Health and Human Services; Center for Disease Control and Prevention; Accessed May 18, 211.

8 Over Half of Patients Referred to Cardiologists Have Insulin-resistance Syndrome Cardiac Rehabilitation Acute MI Patients with insulinresistance syndrome (%) N=1912 Savage, 25 N=235 Milani, 23 N=85 Curran, 24 Savage PD, et al. Am Heart J. 25;149: Milani RV, Lavie CJ. Am J Cardiol. 23;92:5-54. Curran PJ, et al. J Am Coll Cardiol. 24;43(suppl A):249A.

9 Almost 7% of Patients With First MI Have IGT or Undiagnosed Diabetes 7 66 Patients (%) Undiagnosed diabetes 1 35 Impaired glucose tolerance (IGT) Glucose tolerance test results N=181 consecutive patients admitted to CCU. Norhammar A et al. Lancet. 22;359:

10 The importance of blood pressure control in diabetes for CV, stroke and renal prevention

11 United Kingdom Prospective Diabetes Study (UKPDS): Results Any diabetesrelated end point Glucose control Diabetesrelated Microvascular death end points Any diabetesrelated end point BP control (144/82 vs 154/87 mm Hg) Diabetesrelated death Stroke Microvascular end points % (P<.1) -1% (P=.34) % (P<.1) -25% (P<.5) -32% (P=.19) -44% (P=.13) -37% (P=.9) UKPDS Group 38. BMJ. 1998;317: UKPDS Group 33. Lancet. 1998;352:

12 HOT Study: Significant Benefit From Intensive Treatment in the Diabetic Subgroup 25 Major cardiovascul ar events/1, patientyears p=.5 for trend Target Diastolic Blood Pressure Hansson L et al. Lancet. 1998;351: mm Hg

13 Major Outcomes by Achieved Systolic Blood Pressure Category in ACCOMPLISH Primary Endpoint* 32 Patients With Diabetes p-values versus >14 32 Patients Without Diabetes p-values versus >14 Events per 1, patient-years Events per 1, patient-years to <12 n=83 12 to <13 n= to <14 n=23 * CV Death or Non-fatal MI or Non-fatal Stroke >14 n=1429 Systolic Blood Pressure Category (mmhg) 4 11 to <12 n= to <13 n= to <14 n=1426 >14 n=925 Systolic Blood Pressure Category (mmhg) Weber et al. J Clin Hypertens 216; in press.

14 Major Outcomes by Achieved Systolic Blood Pressure (SBP) Category in ACCOMPLISH Patients With Diabetes Achieved SBP (mmhg) 11 to <12 12 to <13 13 to <14 >14 Patients Without Diabetes Achieved SBP (mmhg) 11 to <12 12 to <13 13 to <14 >14 Events per 1, patient-years Events per 1, patient-years Total Stroke Total Myocardial Infarction p-values versus >14 Events per 1, patient-years Events per 1, patient-years Total Stroke 16 p-values versus >14 p-values versus > Total Myocardial Infarction p-values versus > < Weber et al. J Clin Hypertens 216; in press.

15 Major Outcomes by Achieved Systolic Blood Pressure Category in ACCOMPLISH Increased Serum Creatinine (>5% from baseline) 7 p-values versus >14 Events per 1, Patient-Years Patients with diabetes Patients without diabetes 1 p-values versus >14 11 to <12 12 to <13 13 to <14 >14 Achieved Systolic Blood Pressure (mmhg) Weber et al. J Clin Hypertens 216; in press.

16 Kaplan-Meier curves for progression of chronic kidney disease for the intention-to-treat population Bakris GL et.al. Lancet 21, Feb 18th

17 Principles of Kidney Protection in Diabetes Control BP to < 14/9 mmhg ---- maybe lower? Block the renin angiotensin system Is RAS blocker + CCB optimal 2- drug combination? Treat other CV risk factors e.g. statins if indicated

18 Effects of ARBs on Progression to ESRD in diabetic nephropathy 3 RENAAL p=.6 3 p<.1 IDNT p=.3 Doubling of serum creatinine concentration (% of patients) Losartan Placebo Irbesartan Amlodipine Placebo Brenner et al. N Engl J Med 21;345: Lewis et al. N Engl J Med 21;345:851 86

19 New-Onset Diabetes Prevention With ACEIs or ARBs ALLHAT ANBP 2 CAPPP LIFE SCOPE STOP-HYPERTENSION 2 VALUE HOPE PEACE CHARM-Alternative CHARM-Preserved Total Odds Ratio (95% CI) Absolute risk reduction = 1.7% (95% CI, ).78 (.73,.83) Favors ACEI or ARB Favors control Adapted from Gillespie EL et al. Diabetes Care. 25;28: Thomson PPS

20 Network Meta-analysis: New Diabetes ARB (n=14,185) ACE-I (n=23,351) Placebo (n=24,767) CCB (n=38,89) ß-blocker (n=36,15) Diuretic (n=2,678) Elliott WJ. Lancet. 27;269: Odds ratio for incident diabetes Incoherence= ( ) P<.1.67 ( ) P<.1.75 ( ) P=.1.79 ( ) P=.4.93 ( ) P=.43 Referent

21 RENAAL: Post hoc Composite of ESRD/MI/Stroke/Cardiovascular Death % Patients with an event Risk reduction: 21.2% (7., 33.2) P=.5 P L n at Risk Months Pbo Los

22 Effects of BMI on Treatment Responses Previous epidemiologic studies as well as outcomes trials in hypertension have established that lean patients have higher CV event rates than heavier patients This phenomenon has been reported with SHEP (chlorthalidone, but not the placebo group), in LIFE and in INVEST. Most or all the patients in these trials in whom this occurred were receiving thiazide therapy

23 Rates for Primary Endpoint* for the Pooled ACCOMPLISH Cohort Events per 1 patient-years * CV death or non-fatal MI or stroke p =.66 (24.6) (19.5) Normal Overweight Obese BMI Categories p (overall) =.25 (17.2)

24 Differing Effects of the Thiazide and Amlodipine Combinations on Primary Event Rates in BMI Categories Events per 1 patient-years % risk reduction p =.37 (18.2) (3.7) Benazepril+Hydrochlorothiaz Benazepril+Amlodipine (21.9) p (overall) =.34 24% risk reductio n p =.369 (16.9) N S (18.2) Normal Overweight Obese BMI Categories (16.5)

25 Lancet Diabetes Endocrinol 215. November 24 [epub ahead of print]

26 Effects of Dapagliflozin on Systolic BP in Diabetic Patients Receiving RAAS Blockers Plus One Other BP Drug Overall Subgroups Treatment Group n Baseline mean seated SBP, mmhg (SD) Difference vs Pbo (95% CI) Placebo (Pbo) (6.8) Dapagliflozin (7.9) (-6.54, -2.2)* Beta blocker Pbo (6.9) Dapagliflozin (7.3) Calcium Channel Blocker Pbo (6.4) Dapagliflozin (7.4) Diuretic Pbo (6.9) Dapagliflozin (8.6) (-1.28, -1.23) (-9.47, -.79) (-6.16, 1.4) * SBP=systolic blood pressure Seated diastolic blood pressure showed no relevant differences between the antihypertensive subgroups -2-1 Adjusted mean change (mmhg) Difference vs Pbo (mmhg) *p=.2 Weber MA, et al. Lancet Diabetes Endocrinol 215. November 24 [epub ahead of print]

27 Steno-2: Intensive Multiple Risk Factor Management Cardiovascular Events 8 Cumulative incidence of any cardiovascular event (%) Conventional therapy Intensive therapy HR=.41; P<.1 Absolute RR= 29% HR for Total Mortality:.54; P=.2 Absolute RR= 2% Years of follow-up No. at Risk Intensive therapy Conventional therapy Gaede P et al. NEJM. 28;358:

28 Changes in Selected Risk Factors During the Interventional Study and Follow-up Period (13.3 yrs) Glycosylated hemoglobin (%) 11 Conventional therapy Intensive therapy Total cholesterol (mg/dl) 35 3 Conventional therapy Intensive therapy Systolic blood pressure (mm Hg) Conventional therapy Intensive therapy LDL cholesterol (mg/dl) Conventional therapy Intensive therapy Diastolic blood pressure (mm Hg) Conventional therapy Intensive therapy Triglycerides (mg/dl) 35 3 Conventional therapy Intensive therapy Years of follow-up Years of follow-up Patients (%) P=.31 P=.35 P=.5 P=.27 P=.14 Intensive therapy Conventional therapy Glycosylated hemoglobin <6.5% Cholesterol <175 mg/dl Triglycerides <15 mg/dl Systolic blood pressure <13 mm Hg Diastolic blood pressure <8 mm Hg Gæde P et al. N Engl J Med. 28;358:

29 Steno-2 Trial: End of Follow-Up years 6.% 5.% Intensive Conventional 4.% 3.% 2.% 1.%.% All-cause mortality CV mortality Overt DN ESRD Gæde P et al. N Engl J Med. 28;358:

30 Diabetes and Hypertension Best stroke protection at SBP <12 mmhg Best CV protection at <13 mmhg Best renal protection at <14 mmhg (not lower) RAS blocker-based therapy is basis of treatment, but RAS + CCB appears superior to RAS + thiazide for CV protection, particularly in non-obese patients Newer diabetes agents like GLPs and SGLT2 inhibitors can reduce BP: could the SGLT2 agents replace thiazides in combination BP therapy?