Kidney and heart: dangerous liaisons. Luis M. RUILOPE (Madrid, Spain)

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1 Kidney and heart: dangerous liaisons Luis M. RUILOPE (Madrid, Spain)

2 Type 2 diabetes and renal disease: impact on cardiovascular outcomes

3 The "heavyweights" of modifiable CVD risk factors Hypertension Cholesterol LDL HDL Diabetes Smoking Global CVD risk CVD=cardiovascular disease; HDL=high-density lipoprotein; LDL=low-density lipoprotein

Diabetes increases risk of major cardiovascular events and death in hypertensive patients Major cardiovascular events Cardiovascular death 20% 17.3 8% 7.6 15% 6% 10% 10.7 4% 4.

4 Diabetes increases risk of major cardiovascular events and death in hypertensive patients Major cardiovascular events Cardiovascular death 20% % % 6% 10% % 4.1 5% 2% 0% Hypertension (N=107,605) Hypertension and diabetes (N=34,148) 0% Hypertension (N=107,605) Hypertension and diabetes (N=34,148) BPLTTC. Arch Intern Med. 2005;165:

5 The Continuum of CV risk in type 2 diabetes Genetic Susceptibility Environmental factors Nutrition Obesity Physical inactivity Diabetes Onset Complications Disability Insulin Resistance IGT Ongoing Hyperglycemia Death Hyperinsulinemia HDL-C Triglycerides Atherosclerosis Hypertension Atherosclerosis Hyperglycemia Hypertension Retinopathy Nephropathy Neuropathy Blindness Renal failure CHD Amputation Adapted from ADA. Diabetes Care. 2003;26: Tsao PS, et al. Arterioscler Thromb Vasc Biol. 1998;18: Hsueh WA, et al. Am J Med. 1998;105(1):4S-14S. - ADA. Diabetes Care. 1998;21:

6 Percent chance of CV event in 5 years diabetes 180/ /95 140/85 120/75 180/ /95 140/85 120/75 180/ /95 140/85 120/75 Men Women Nonsmoker Smoker Nonsmoker Smoker Total Chol.:HDL-Chol. Total Chol.:HDL-Chol Age 70 Age 60 Age 50 >20% 15%-20% 10%-15% 5%-10% 2.5%-5% <2.5%

7 Renal disease: major complication in type 2 diabetes x2.5 x4 Tonelli M et al. Lancet. 2012;380:

8 HR (95% CI) HR (95% CI) HRs and 95% CIs for all-cause and CV mortality according to spline egfr and ACR 8 4 All-cause mortality; egfr All-cause mortality; ACR CV mortality; egfr CV mortality; ACR egfr (ml/min/1.73m 2 ) HRs and 95% CIs (shaded areas) according to egfr and ACR adjusted for each other, age, sex, ethnic origin, history of CV disease, SBP, diabetes, smoking, and total cholesterol. The reference (diamond) was egfr 95 ml/min/1.73 m 2 and ACR 5 mg/g, respectively. Circles represent statistically significant and triangles represent not significant. ACR=albumin-to-creatinine ratio; CV=cardiovascular; egfr=estimated glomerular filtration rate; HR=hazard ratio; SBP=systolic blood pressure Chronic Kidney Disease Prognosis Consortium. Lancet. 2010;375: (0.3) (0.6) (1.1) (3.4) (33.9) (113.0) ACR (mg/g [mg/mmol])

9 HR (95% CI) HR (95% CI) HRs and 95% CIs for all-cause and CV mortality according to spline egfr and categorical albuminuria All-cause mortality; ACR studies 33.9 mg/mmol ( 300 mg/g) mg/mmol ( mg/g) <3.4 mg/mmol (<30 mg/g) CV mortality; ACR studies All-cause mortality; dipstick studies Dipstick urine protein 2+ or more Dipstick urine protein 1+ Dipstick urine protein negative or trace CV mortality; dipstick studies egfr (ml/min/1.73m 2 ) egfr (ml/min/1.73m 2 ) Shaded areas represent 95% CIs. Models included spline egfr, categorical albuminuria, and their interaction terms as well as adjustment for age, sex, ethnic origin, history of CV disease, SBP, diabetes, smoking, and total cholesterol. The reference (diamond) was egfr 95 ml/min/1.73 m² plus ACR less than 3.4 mg/mmol (30 mg/g) or dipstick test result negative or trace. Circles represent statistically significant and triangles represent not significant. Chronic Kidney Disease Prognosis Consortium. Lancet. 2010;375:

10 Relative risk of CVD and mortality in 3498 DM by quartile of albuminuria ACR (mg/mmol) quartiles RR (95% Cl) 1st 2nd 3rd 4th Variable < >1.62 P for trend Ml, Stroke & CV death ( ) 1.11 ( ) 1.89 ( ) <0.001 All cause mortality ( ) 1.41 ( ) 2.38 ( ) <0.001 CHF ( ) 1.83 ( ) 3.65 ( ) <0.001 Gerstein et al. JAMA. 2001

11 Evidence for prevention of cardiovascular and kidney disease through controlling diabetes

12 Effect of Gliclazide intensive strategy on renal events

13 Prevalence (%) ADVANCE: albuminuria is a risk marker for complications in patients with type 2 diabetes Normoalbuminuria (n=7877) Albuminuria (n=3263) 0 ESRD Macrovascular disease CVD All-cause death HR (95% CI) 1.99 ( ) 1.61 ( ) 2.07 ( ) 1.70 ( ) de Galan BE, et al. J Am Soc Nephrol. 2009;20:

14 ADVANCE: kidney protection at all stages Microalbuminuria Macroalbuminuria End-stage kidney disease UKPDS 33 1 NS NS NS VADT 2 NS NS NS ACCORD 3-12% RR,0.88 [95% CI, 0.76 to 0.96] ADVANCE 4-8% RR,0.92 [95% CI, 0.86 to 0.98] -44% RR,0.56 [95% CI, 0.33 to 0.96] -21% RR,0.79 [95% CI, 0.67 to 0.93] NS -65% RR,0.35 [95% CI, 0.18 to 0.70] Adapted from Coca S et al. Arch Intern Med. 2012;172(10):

15 Gliclazide intensive strategy reduces new-onset end-stage kidney disease Coca S et al. Arch Intern Med. 2012;172(10):

16 In the ADVANCE trial A specific kidney protection was observed ADVANCE collaborative group. N Engl J Med. 2008;358(24):

17 Reduction of CV disease risk in type 2 diabetes: lessons learned from ACCORD and VADT trials

18 ACCORD and VADT: does intensive glucose control reduce risk for CV disease in type 2 diabetes? ACCORD 1 VADT 2 Number 10,251 1,791 Primary CVD endpoint Mortality (overall) 10% (p=0.16) 22% (p=0.04) 13% (p=0.12) 6.5% (p=ns) CV mortality 39% (p=0.02) 25% (p=ns) 1. N Engl J Med. 2008;358: N Engl J Med. 2009;360:

19 Lessons from ACCORD 1 and VADT 2 Intensive glucose control : does not reduce cardiovascular disease mortality in type 2 diabetes, and may increase risk of coronary heart disease, especially in patients with preexisting coronary heart disease. 1. Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med. 2008;358: VADT Investigators. N Engl J Med. 2009;360:

20 What about? Positive trend for CV deaths reduction trough Gliclazide intensive strategy

21 Primary outcomes in ADVANCE Major macro- or microvascular events ADVANCE collaborative group. N Engl J Med. 2008;358(24):

22 ADVANCE: positive trend for reducing cardiovascular death CONTROL Group; Turnbull FM, Abraira C, Anderson RJ, et al. Diabetologia. 2009;52:

23 Danish nationwide registry study Gliclazide monotherapy: trend towards reduction in CV death Previous Myocardial infarction Schramm T K et al. Eur Heart J. 2011;32:

24 Danish nationwide registry study Sulfonylurea-metformin combination therapies: mortality and CV risk * * MI, stroke and CV mortality Mogensen et al. J Am Coll Cardiol. 2013;61(10_S):. doi: /s (13)

Differential selectivity of SUs (cloned K ATP channels): no impairment of ischemic preconditioning -CELL (SUR-1) EC 50 (nmol/l) HEART (SUR-2A) EC 50 (nmol/l)

25 Differential selectivity of SUs (cloned K ATP channels): no impairment of ischemic preconditioning -CELL (SUR-1) EC 50 (nmol/l) HEART (SUR-2A) EC 50 (nmol/l) PANCREAS/HEART SELECTIVITY RATIO Glibenclamide Glimepiride Gliclazide MR EC 50 : sulfonylurea concentration 50% effective on cloned channels

26 Selectivity for ß-cell K ATP channel 10 m M Gliclazide 100 nm Glibenclamide Kir6.2/SUR1 ( -cell) 1 na Kir6.2/SUR2A (cardiac) 30 s 1 1 G / G c SUR1 SUR2A G / G c SUR1 SUR2A log 10 {[Gliclazide] (M)} log 10 {[Glibenclamide] (M)} Gribble FM Diabetologia. 1999;42:

27 Conclusions Cardiovascular disease outcomes are more frequent in type 2 diabetic patients with renal impairment Intensive strategy based on Gliclazide reduces nephropathy and CV outcomes ADVANCE is the reference study with regard to simultaneous renal and cardiovascular protection Protect the kidney to save the heart

CARDIO-RENAL SYNDROME

CARDIO-RENAL SYNDROME Luis M Ruilope Athens, October 216 DISCLOSURES: ADVISOR/SPEAKER for Astra-Zeneca, Bayer, BMS, Daiichi-Sankyo, Esteve, GSK Janssen, Lacer, Medtronic, MSD, Novartis, Pfizer, Relypsa,