Kidney and heart: dangerous liaisons Luis M. RUILOPE (Madrid, Spain)
Type 2 diabetes and renal disease: impact on cardiovascular outcomes
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% 4.1 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;165:1410-1419.
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;26:3160-3167. - Tsao PS, et al. Arterioscler Thromb Vasc Biol. 1998;18:947-953. Hsueh WA, et al. Am J Med. 1998;105(1):4S-14S. - ADA. Diabetes Care. 1998;21:310-314.
Percent chance of CV event in 5 years diabetes 180/105 160/95 140/85 120/75 180/105 160/95 140/85 120/75 180/105 160/95 140/85 120/75 Men Women Nonsmoker Smoker Nonsmoker Smoker Total Chol.:HDL-Chol. Total Chol.:HDL-Chol. 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 Age 70 Age 60 Age 50 >20% 15%-20% 10%-15% 5%-10% 2.5%-5% <2.5%
Renal disease: major complication in type 2 diabetes x2.5 x4 Tonelli M et al. Lancet. 2012;380:807-814.
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 2 1 0.5 8 CV mortality; egfr CV mortality; ACR 4 2 1 0.5 15 30 45 60 75 90 105 120 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;375:2073 81. 2.5 5 10 30 300 3000 (0.3) (0.6) (1.1) (3.4) (33.9) (113.0) ACR (mg/g [mg/mmol])
HR (95% CI) HR (95% CI) 16 8 4 2 1 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) 3.4 33.8 mg/mmol (30-299 mg/g) <3.4 mg/mmol (<30 mg/g) 16 8 4 2 1 CV mortality; ACR studies 0.5 16 8 All-cause mortality; dipstick studies Dipstick urine protein 2+ or more Dipstick urine protein 1+ Dipstick urine protein negative or trace 0.5 16 8 CV mortality; dipstick studies 4 4 2 2 1 1 0.5 0.5 15 30 45 60 75 90 105 120 15 30 45 60 75 90 105 120 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;375:2073 81.
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 <0.22 0.22-0.57 0.58-1.62 >1.62 P for trend Ml, Stroke & CV death 1 0.85 (0.63 1.14) 1.11 (0.86 1.43) 1.89 (1.52 2.63) <0.001 All cause mortality 1 0.86 (0.58 1.28) 1.41 (1.01 1.95) 2.38 (1.80 3.20) <0.001 CHF 1 0.72 (0.32 1.63) 1.83 (0.98 3.43) 3.65 (2.06 6.46) <0.001 Gerstein et al. JAMA. 2001
Evidence for prevention of cardiovascular and kidney disease through controlling diabetes
Effect of Gliclazide intensive strategy on renal events
Prevalence (%) ADVANCE: albuminuria is a risk marker for complications in patients with type 2 diabetes 14 12 10 8 6 4 2 Normoalbuminuria (n=7877) Albuminuria (n=3263) 0 ESRD Macrovascular disease CVD All-cause death HR (95% CI) 1.99 (1.08 3.70) 1.61 (1.42 1.84) 2.07 (1.72 2.50) 1.70 (1.48 1.96) de Galan BE, et al. J Am Soc Nephrol. 2009;20:883-92.
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):761-769.
Gliclazide intensive strategy reduces new-onset end-stage kidney disease Coca S et al. Arch Intern Med. 2012;172(10):761-769.
In the ADVANCE trial A specific kidney protection was observed ADVANCE collaborative group. N Engl J Med. 2008;358(24):2560-2572.
Reduction of CV disease risk in type 2 diabetes: lessons learned from ACCORD and VADT trials
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;358:2545-59. - 2. N Engl J Med. 2009;360:129-39.
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;358:2545-2559. 2. VADT Investigators. N Engl J Med. 2009;360:129-139.
What about? Positive trend for CV deaths reduction trough Gliclazide intensive strategy
Primary outcomes in ADVANCE Major macro- or microvascular events ADVANCE collaborative group. N Engl J Med. 2008;358(24):2560-2572.
ADVANCE: positive trend for reducing cardiovascular death CONTROL Group; Turnbull FM, Abraira C, Anderson RJ, et al. Diabetologia. 2009;52:2288-2298.
Danish nationwide registry study Gliclazide monotherapy: trend towards reduction in CV death Previous Myocardial infarction Schramm T K et al. Eur Heart J. 2011;32:1900-1908.
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:10.1016/s0735-1097(13)61397-2
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 4.2 27 6.4 Glimepiride 3.0 5.4 1.8 Gliclazide MR 50 800 000 16 000 EC 50 : sulfonylurea concentration 50% effective on cloned channels
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 0.8 0.6 0.4 0.2 SUR1 SUR2A G / G c 0.8 0.6 0.4 0.2 SUR1 SUR2A 0 8 7 6 -log 10 {[Gliclazide] (M)} 0 12 11 10 9 8 7 6 5 4 -log 10 {[Glibenclamide] (M)} Gribble FM Diabetologia. 1999;42:845-848.
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