Diabeteses nephropathia Tisztelt hallgatók, Előadásomban a k Mucsi István I.sz. Belgyógyászati Klinika és Magatartástudományi Intézet Semmelweis Egyetem

45 éves ffi 8 éve DM2T J.o. térd alatti amputatio B. o. tarsalis amputatio 2 évvel korábban AMI Se kreat 200, 24 ó víz feh 8 g, se albumin 20 Dohányzik, se cholest 6,5, HbA1c 8.5

Diabeteses és veseelégtelenség

A krónikus vesebetegség korai kezelésének jelentősége

A diabetes prevalenciája világszerte 80 70 60 50 40 30 20 10 Prevalence (millions) Year 1995 2000 2025 Slide 2: Worldwide rates of diabetes mellitus: predictions An estimated 135 million people worldwide have diabetes. Type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM) currently accounts for approximately 90% of all cases of diabetes. This figure is expected to more than double to nearly 300 million by the year 2025, with developing countries expected to experience the brunt of the increase with an expected 200% rise. Developed countries can expect to see a rise of 45% in rates of the disease. By the year 2004, it is estimated that up to 1 in 4 adults over age 45 will be diagnosed with diabetes. 1. The World Health Report 1997: Conquering Suffering, Enriching Humanity. Geneva, Switzerland: World Health Organization; 1997. 2. Diabetes A-Z. Diabetes: the facts. http://www.diabetes.ca/atoz/general.htm Canada United States Europe Southeast Asia World Health Organization. The World Health Report 1997. Diabetes A-Z. Diabetes: the facts. http://www.diabetes.ca/atoz/general.htm 2

Diabeteses nephropathia (DNP) Mind I. , mind II. tipusú diabetesben előfordul, lényegében ugyanaz a betegség, hasonló klinikummal és epidemiológiával Korábban a DNP „life-time” kockázata 30-45% volt, ez az utóbbi időben csökken, 15-25% A diabetes betegek 30%-ában a veseelégtelenség, ill proteinuria hátterében nem, vagy nem csak DNP áll Magyarországon a DM-ben szenvedők száma kb 1 millió

A diabeteses nephropathia epidemiológiája I. tipusú diabetesben 20-30 év alatt a DNP kockázata 5-10% II. tipusú diabetesben évente kb 2% vált diagnosztikus csoportot (microalbuminuria, macroalbuminuria, veseelégtelenség) II. tipusú diabetesben 150 mikromól körüli se kreat esetén a dialízisig átlagosan 2-3 év telik el

A diabeteses nephropathia

A DNP klinikai lefolyása

A DNP rizikója

A DNP klinikai lefolyása Eli A. Friedman

Natural history of MAU Years 9 Clinical type 2 diabetes Functional changes • GFR GFR Structural changes Incipient nephropathy Proteinuria Rising serum creatinine Slide 9: Natural history of type 2 diabetic nephropathy: functional changes In contrast to type 1 diabetes, the time of onset of type 2 diabetes is often difficult to determine. Functional changes, exemplified by altered renal hemodynamics (renal vasodilatation, reduced renovascular resistance) and increased glomerular filtration rate (GFR), are present in the majority of patients at the time of onset of type 2 diabetes. Microalbuminuria may already be present at the time of diagnosis. 1. Nelson RG, Knowler WC, Mc Camnce DR, et al. Determinants of end-stage renal disease in Pima Indians with type 2 (non-insulin-dependent) diabetes mellitus and proteinuria. Diabetologia 1993;36:1087-93. 2. Pugh JA, Medina R, Ramirez M. Comparison of the course to end-stage renal disease of type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetic nephropathy. Diabetologia 1993;36:1094-8. End-stage renal failure Cardiovascular death Dx 2 5 10 20 30 Years 9

A DNP pathogenesise glomerulosclerosis – fokozott intraglomerularis nyomás mesangialis mátrix expanzió – fokozott mesangialis glukóz koncentráció, korai és késői protein glikoziláció (AGEs) A lokális RAS aktiválódása transforming growth factor-beta és egyéb pro-fibrotikus citokinek aktiválódása Epithelialis mesenchymalis transformatio

A DNP pathogenesise

A DNP rizikófaktorai Genetikai tényezők (PIMA: 14% - nincs a családban DM; egy szülő: 23%; két szülő 46% gén-polymorphismusok: ACE DD (?); aldose reductase gén vérnyomás GFR alakulása vércukor kontroll lipidek rassz Obesitas dohányzás

A DNP kezelésének szempontjai fogyás Dohányzás testmozgás vércukor kontroll vérnyomás kontroll RAAS gátlása (ACEI/ARB – COMBO TERÁPIA) lipidek

Cardiovascularis rizikótényezők gyakorisága diabetesben Hypertension - >140/90 mm Hg MAU - 30-300 mg/24 h Hypercholesterolemia - TC > 5.2 mmol/L 100% 80% 60% 40% 20% 0% 90% % of diabetic patients 40% 25% Slide 7: Risk factors: prevalence in diabetes The prevalence of hypertension in diabetes patients ranges between 51% and 93% depending on the blood pressure criteria used and the severity of type 2 diabetes. The JNC-V guidelines found that while as many as 90% of diabetic patients meet the criteria for hypertension, only 41% are currently on an antihypertensive therapy.1,2 Persistent microalbuminuria (> 300 µg/24 h or 200 mg/min) is the hallmark of diabetic nephropathy and its prevalence in diabetes is 25%. However, coexisting hypertension is associated with a doubling of the presence of microalbuminuria, left ventricular hypertrophy, electrocardiographic signs of myocardial ischemia and a prior history of overt cardiovascular events. MAU also advances the atherosclerotic process by 26 years.3-5 The prevalence of dyslipidemia in people with diabetes is as high as 40%. Its role in the development of atherosclerosis and macrovascular disease is well established. With its high prevalence in diabetic patients, 40%, and the increased risk of cardiovascular disease in this population, its importance in diabetes must be considered.6,7 1. Parving H-H, et al. Renal protection in diabetes: an emerging role for calcium antagonists. J Hypertens 1996;14(suppl 4):S21-S25. 2. The Fifth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Institute of Health. 3. Diabetes A-Z. Diabetes: the facts. http://www.diabetes.ca/atoz/general.htm 4. Kaplan NM. Hypertension and diabetes. In: Ellenberg and Rifkin’s Diabetes Mellitus: Theory and Practice. 5th ed. Stamford, CT: Appleton & Lange; 1997: chap 49. 5. Elliot T. Diabetes: A clinical approach. The Canadian Journal of CME 1997:141-53. 6. Canadian Diabetes. Macrovascular Complications of Diabetes Mellitus. http://www.diabetes.ca/prof/candiab/win97/w97art2b.htm 7. NIDDK Home Page. Diabetes statistics. http://www.niddk.nih.gov/DiabetesStatistics/Diabetes Statistics.html Hypertension Microalbuminuria Hypercholesterolemia Parving H-H. J Hypertens 1996;14(suppl 2):S89-S94. JNC VI. National Institute of Health. November 1997. No. 98-4080. 7

A DNP kezelése – vércukor kontroll T2DM - UKPDS

A DNP kezelése – vércukor kontroll T1DM - DCCT

A DNP kezelése – vércukor kontroll T2DM - UKPDS

Vérnyomás kontroll és vesefunkció változás veseelégtelenségben 130 134 138 142 146 150 154 170 180 r = 0.69; P < .05 SBP (mmHg) GFR (mL/min/year) Untreated HTN -2 -4 -6 -8 -10 -12 -14 Meta Analysis: Lower Systolic BP Results in Slower Rates of Decline in GFR in Diabetics and Non-Diabetics Talking Points: Like control of mean arterial blood pressure, lower systolic blood pressure results in slower rates of decline in glomerular filtration rate (GFR) in patients with diabetic and non-diabetic renal disease. The beneficial impact from achieved control of systolic blood pressure (SBP) is demonstrated in this slide, which shows a meta-analysis of the 9 major clinical trials in diabetic and non-diabetic renal diseases. The GISEN Group, Klahr, and Moschio studies are those in non-diabetic subjects. The higher the SBP, the faster the GFR declines; the better the control of SBP, the slower the GFR declines.   References: Bakris GL, Mangrum A, Copley JB, Vicknair N, Sadler R. Effect of calcium channel or beta-blocker on the progression of diabetic nephropathy in African Americans. Hypertension. 1997;29(3):744-750. Bakris GL, Siomos M, Richardson D, et al. Comparative effects of an ACE inhibitor and an angiotensin receptor blocker on potassium homeostasis in high risk patients. Kidney Int. (in press). Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, Tuttle K, Douglas J, Hsueh W, Sowers J. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36(3):646-661. Herbert LA, Bain RP, Verme D, Cattran D, Whittier FC, Tolchin N, Rohde RD, Lewis EJ. Remission of nephrotic range proteinuria in type 1 diabetes. Collaborative Study Group. Kidney Int. 1994;46(6):1688-1693. Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, Striker G. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal failure. N Eng J Med. 1994;330(13):877-884. Lebovitz HE, Wiegmann TB, Cnaan A, Shahinfar S, Sica DA, Broadstone V, Schwartz SL, Mengel MC, Segal R, Versaggi JA, et al. Renal protective effects of enalapril in hypertensive NIDDM:Role of baseline albuminuria. Kidney Int Suppl. 1994;Suppl 45:150-155. Parving HH, Hommel E, Damkjaer Nielsen M, Giese J. Effect of captopril on blood pressure and kidney function in normotensive insulin dependent diabetics with nephropathy. BMJ. 1989;299(6698):533-536. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal failure in proteinuric, non-diabetic nephropathy. The GISEN group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997;349(9069):1857-1863. Viberti G, Morgensen CE, Groop LC, Pauls JF. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. JAMA. 1994;271(4):275-279. Parving HH, et al. Br Med J. 1989.Moschio G, et al. N Engl J Med. 1996. Viberti GC, et al. JAMA. 1993. Bakris GL, et al. Kidney Int. 1996. Klahr S, et al. N Eng J Med. 1994. Bakris GL. Hypertension. 1997. Hebert L, et al. Kidney Int. 1994.The GISEN Group. Lancet. 1997. Lebovitz H, et al. Kidney Int. 1994. Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.

Vérnyomás kontroll szerepe Az elért vérnyomás alapján történő elemzés MAP N Final proteinuria % < 500 mg/24 Cr GFR < 92 47 1073 57 +0.14 -5.2 92-99.9 41 1830 27 +0.38 -6.2 100-107 32 4292 6 -11.6 >107 4882 +0.92 -11.0 Lewis JB et al. AJKD 1999; 34: 809-817.

A DNP kezelése - ACEI Eli A. Friedman

A DNP kezelése - ACEI 50%* % death, dialysis or transplant Placebo 40 30 20 10 % death, dialysis or transplant Placebo 50%* Slide 20: Effect of ACE inhibitors on diabetic nephropathy — type 1 diabetes The benefit of ACE inhibitor therapy in type 1 diabetic nephropathy was first identified when the ACE inhibitor captopril was evaluated in 409 type 1 diabetic patients with diabetic retinopathy, proteinuria  500 mg/d and serum creatinine concentrations Š 2.5 mg/dL. Progression to nephropathy was defined as a doubling of serum creatinine concentrations in this study. The use of ACE inhibition reduced the overall risk for doubling serum creatinine by 48%. ACE inhibition also reduced the risk of clinical events such as death, need for dialysis, or transplant by half as compared with placebo. Furthermore, ACE inhibition protected against deterioration in type 1 diabetic nephropathy to a greater degree than would be expected from blood pressure reduction alone. This slide and the next 2 slides focus on the positive effects of ACE inhibition in patients with type 1 and 2 diabetes. 1. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456-62. ACE I 1 2 3 4 Years *p = 0.006 vs. placebo. Adapted from Lewis EJ, et al. N Engl J Med 1993;329:1456–1462. 20

Albumin Excretion Rate (µg/min) A DNP kezelése - ACEI 90 80 70 60 50 40 30 20 10 Placebo Albumin Excretion Rate (µg/min) 66.7%* ACE I Slide 21: Effect of ACE inhibitors on diabetic nephropathy — type 2 diabetes The efficacy of the ACE inhibitor enalapril in preventing the progression of microalbuminuria to clinical albuminuria was evaluated in 103 normotensive patients with type 2 diabetes, over 5 years. Patients enrolled in this prospective, randomized, single-blind, placebo-controlled study had persistent albumin excretion rates (AER) of 20-200 µg/min and normal renal function. The use of ACE inhibition decreased AER from 55 ± 33 to 20 ± 59 µg/min while those in the placebo group AER increased from 53 ± 31 to 85 ± 90 µg/min (geometric mean ± SD) at year five of the study. Within five years, 7.7% of the ACE inhibitor group and 23.5% of placebo-treated patients progressed to clinical albuminuria as defined by an AER of > 200 µg/min (p < 0.001). This is a risk reduction of 66.7% (p < 0.001) for ACE inhibitor-treated patients. AER increased at annual rate of 12.3% in the placebo group and declined at an annual rate of 16.7% for those treated by ACE inhibition (p < 0.001). Following five years of therapy with an ACE inhibitor, normotensive patients with type 2 diabetes experienced significantly less progression of microalbuminuria to clinical albuminuria and reduced AER when compared to placebo. 1. Ahmad J, Siddiqui MA, Ahmad H. Effective postponement of diabetic nephropathy with enalapril in normotensive type 2 diabetic patients with microalbuminuria. Diabetes Care 1997;20(10):1576-81. 0 1 2 3 4 5 Years *p < 0.001 Ahmad J, et al. Diabetes Care Oct. 1997;20(10):1576-81. 21

A DNP kezelése - ACEI Proteinuria (mg/24 h) Years 22 0 1 2 3 4 5 6 7 420 380 340 300 260 220 180 140 100 60 20 Placebo yrs 1-5, no treatment yrs 6 & 7 Placebo yrs 1-5, ACEI years 6 & 7 Proteinuria (mg/24 h) ACE I yrs 1-7 ACE I yrs 1-5, no treatment years 6 & 7 Slide 22: Effect of ACE inhibitors on diabetic nephropathy — type 2 diabetes This 7-year, randomized, controlled study consisted of two phases: phase 1, double-blinded, and phase 2, open. It examined the long-term renoprotective effects of ACE inhibition in type 2 diabetes. ACE inhibition was found to offer long-term protection against the development of nephropathy in normotensive type 2 diabetic patients with microalbuminuria. It was also found to stabilize renal function in previously untreated patients with impaired renal function. When ACE inhibition treatment was discontinued, renewed progression of nephropathy occurred. The results of this study indicate the antiproteinuric and renoprotective effects of ACE inhibition in type 2 diabetic patients with early and moderately advanced diabetic nephropathy. 1. Ravid M, Lang R, Rachmani R, et al. Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. A 7-year follow-up study. Arch Intern Med 1996;156:286-9. 0 1 2 3 4 5 6 7 Years Ravid M, et al. Arch Intern Med 1996;156:286-9. 22

ACEI és diabeteses retinopathia 30% 25% 20% 15% 10% 5% 0% 54%* % progressors Slide 23: Effect of ACE inhibition on other diabetic complications: diabetic retinopathy Diabetes is the leading cause of new blindness in adults 20-74 years of age. Every year, up to 24,000 new cases of blindness due to diabetic retinopathy are diagnosed. All patients with type 1 diabetes for longer than 5 years and all patients with type 2 diabetes within 6 months of diagnosis, should be examined by an ophthalmologist. While several studies have evaluated the effects of ACE inhibitors on diabetic nephropathy, less focus has been placed on their effects on retinopathy. The EUCLID study aimed to fill this gap by examining the effect of an ACE inhibitor on the progression of retinopathy. The EUCLID study is a 2 year, multicentre, randomized, controlled clinical trial of lisinopril versus placebo in patients with type 1 diabetes, with normo or microalbuminuria, aged 20-59 years. In the placebo group, 26% were progressors while only 12% of those in the ACE I-treated group were progressors (p = 0.002). The risk of progression was therefore, 0.41 (95% CI, 0.23-0.74, p = 0.003) in the ACE I versus placebo group. ACE inhibitors appear to have beneficial effects on diabetic retinopathy, even in patients with little or no renal disease and minimal retinopathy that cannot be fully accounted for by effects on blood pressure. 1. The EUCLID Study Group. The effect of lisinopril on retinopathy in people with insulin dependent diabetes mellitus (IDDM). Diabetologia 1997;40(suppl 1):A500. Placebo ACE inhibitor *p = 0.002 vs placebo. The Euclid Study Group. Diabetologia 1997;40(suppl 1): A 500. 23

IRMA 2 Primary Endpoint Development of Overt Proteinuria A DNP kezelése - ARB IRMA 2 Primary Endpoint Development of Overt Proteinuria RRR=70% P<0.001 14 18 16 12 10 8 6 4 2 RRR=39% P=0.08 14.9 Incidence of diabetic nephropathy (%) 9.7 5.2 The event rates for the primary endpoint are approximately 15%, 10%, and 5% in the control (placebo in addition to other nonexcluded antihypertensive therapies), irbesartan 150 mg, and irbesartan 300 mg groups, respectively.1 This corresponds to relative risk reductions of 39% for irbesartan 150 mg vs. the control group (p=0.08), and 70% for irbesartan 300 mg vs. the control group (p<0.001). Two important secondary endpoints in IRMA 2 include change in overnight urinary albumin excretion rate (AER) and change in creatinine clearance. AER was reduced in the two irbesartan groups throughout the study (-24% and -38% at 24 months, compared with baseline, in the irbesartan 150 mg and 300 mg groups, respectively). AER remained unchanged in the control group (-2% at 24 months compared with baseline), p<0.001 for the comparison between the control group and the two irbesartan groups combined. Creatinine clearance remained in the normal range in all three groups throughout the study. 1 Parving et al, 2001a. Control (n=201) 150 mg (n=195) 300 mg (n=194) Irbesartan Parving H-H, et al. N Engl J Med 2001;345:870-878.

IRMA 2 Normalization of Urinary Albumin Excretion Rate (<30 mg/day) A DNP kezelése - ARB IRMA 2 Normalization of Urinary Albumin Excretion Rate (<30 mg/day) 35 45 40 30 25 20 15 10 5 P=0.006 34 Subjects (%) 24 21 Regression to normoalbuminuria (< 20 g/min, or < 30 mg/day) at the last visit was more frequent in the patients treated with irbesartan 300 mg than in the control (placebo in addition to other nonexcluded antihypertensive therapies) group (34% vs. 21%, respectively, p=0.006).1 1 Parving et al, 2001a. Control (n=201) 150 mg (n=195) 300 mg (n=194) MAU Reductions 2% 24% 38% Irbesartan Parving H-H, et al. N Engl J Med 2001;345:870-878.

A DNP kezelése – ACEI + ARB COOPERATE Trial NB: BP is the same in all 3 arms Nakao N et al. Lancet 361: 117-124; 2003.

A DNP kezelése – ACEI + ARB COOPERATE Trial Endpoint = time to doubling of SCr or ESRD Nakao N et al. Lancet 361: 117-124; 2003.

Timed collection (µg/min) Spot collection (mg/g)* Microalbuminuria Timed collection (µg/min) Dipstick for protein 24-hour protein (mg) 24-hour albumin (mg) Spot collection (mg/g)* Normal – < 150 < 30 < 20 < 30 Micro-albuminuria – < 500 30 - 300 20 - 200 30 - 300 Slide 10: Definition of microalbuminuria Microalbuminuria is defined by a range of values within the continuum of urinary albumin excretion. Patients with microalbuminuria are negative for protein on usual dipstick testing and often have normal amounts of protein excreted on the 24-hour urine collections done for protein. However, these patients have abnormally elevated urinary albumin excretion at 20-200 µg/min or 30-300 mg/24 hours. Many patients with microalbuminuria go on to develop overt nephropathy, However, once a patient has overt proteinuria there is no reason to measure urinary albumin excretion, as a test for proteinuria is already positive. The goal is to identify nephropathy and MAU in the early stages, and to institute treatment before it is too late. 1. Parving H-H, et al. Renal protection in diabetes: an emerging role for calcium antagonists. J Hypertens 1996;14(suppl 4):S21-S25. Overt nephropathy +  500 > 300 > 200 > 300 * Spot collection: albumin/creatinine ratio (mg/g). Parving H-H. J Hypertens 1996;14(suppl 2):S89-S94. 10

Diabetes + MAU MAU as a predictor of morbidity and mortality Retinopathy Neuropathy Diabetes + MAU Left ventricular dysfunction Nephropathy Non-fatal cardiovascular disease Slide 11: MAU as a predictor of morbidity and mortality Microalbuminuria has been found to independently predict cardiovascular morbidity and all-cause mortality in essential hypertension and diabetes mellitus. Microalbuminuria is associated with numerous complications, cardiovascular disease risk factors and also factors such as hyperinsulinemia, insulin resistance and dyslipoproteinemia. As well, patients with microalbuminuria also show an increased incidence of left ventricular hypertrophy (LVH) and retinal microvascular lesions. While the connection between microalbuminuria and death from cardiovascular disease is not yet clear, several theories have been postulated. One such theory is that as microalbuminuria is a marker of widespread endothelial dysfunction, the link may be the opportunity for increased penetration of atherogenic lipoprotein particles in the arterial wall, which is a marker of established cardiovascular disease. 1. Parving H-H. Microalbuminuria in essential hypertension and diabetes mellitus. J Hypertens 1996;14(suppl 2):S89-S94. All-cause mortality Peripheral/autonomic neuropathy Parving H-H. J Hypertens 1996;14(suppl 2):S89-S94. 11

MAU as a predictor of morbidity and mortality 10 8 6 4 2 10.02 6.52 Odds Ratio 3.20 2.32 Slide 12: MAU as a predictor of morbidity and mortality Microalbuminuria was found to be the leading independent predictor of coronary heart disease mortality (odds ratio of 10.02, 95% C.I, 4.28-23.47) in a multivariate analysis. Microalbuminuria was followed by smoking, diastolic blood pressure and serum cholesterol as primary predictors of CHD mortality. Microalbuminuria is a potent, independent risk factor for total and cardiovascular mortality. It also interacts with other risk factors such as, arterial blood pressure, dyslipidemia, smoking habits and is a hallmark of vascular endothelial vulnerability. It is thought that perhaps the increase in vascular vulnerability leads to increased permeability to atherogenic lipoprotein particles in the arterial wall in diabetic patients, and may account for the increased rate of cardiovascular disease in this population. 1. Parving H-H. Microalbuminuria in essential hypertension and diabetes mellitus. J Hypertens 1996;14(suppl 2):S89-S94. 2. Eastman RC, Keen H. The impact of cardiovascular disease on people with diabetes: the potential for prevention. Lancet 1997;350(suppl 1):29-32. Microalbuminuria Smoking Hypertension Cholesterol Eastman RC, Keen H. Lancet 1997;350(suppl 1):29-32. 12

Calcium channel blockers The effects of antihypertensive agents on albuminuria 0.2 - 0.2 - 0.4 - 0.6 † Change Slide 13: The effects of antihypertensive agents on albuminuria In a meta-analysis of 100 clinical studies, authors reported that ACE inhibitors demonstrated a superior effect on reducing protein excretion. In fact, ACE inhibitors were associated with reductions in proteinuria and albuminuria and improvements in glomerular filtration rates which were independent of blood pressure changes. Of note is the superiority of ACE inhibitors over calcium channel blockers as to their respective effects on albuminuria (42% greater decrease). 1. Kasiske et al. Ann Intern Med 1993;118:129-38. ACE inhibitors Calcium channel blockers Beta-blockers Control † p < 0.05 vs. control Kasiske, et al. Ann Intern Med 1993;118:129-38. 13

A MAU kezelése és monitorozása diabetesben MAU szűrés Évente Vérnyomás cél < 120-130/80-85 Hgmm A lehető legszorosabb kontroll Vércukor HTN és MAU Slide 14: MAU management guidelines for diabetics The blood pressure goal is Š 120-130/80-85 mm Hg, however, should MAU persist, it is important to continue/adjust ACE inhibitor therapy in the attempt to normalize MAU levels. Due to their positive effects on microalbuminuria, recommendations suggest the use of ACE inhibitors as treatment for hypertensive and normotensive patients with microalbuminuria. 1. Bennet PH, et al. Am J Kidney Dis 1995;25:107-12. 2. Consensus Development Conference on the diagnosis and management of nephropathy in patients with diabetes mellitus. Diabetes Care 1994;17:1357-61. 3. Report of a WHO study group. WHO Tech Rep Ser 844. Geneva: WHO, 1994;55-59. 4. Viberti GC, et al. In: Morgensen CE, ed. The kidney and hypertension in diabetes mellitus, 2nd ed. Boston: Dordrecht/London: Kluwer, 1994:515-27. 5. Striker GE. Nephrol Dial Transplant 1995;10:290-2. 6. Jerums G, et al. Med J Aust 1994;161:265-8. ACEI vagy ARB Norm. RR + MAU ACEI vagy ARB 14

Cholesterol And Recurrent Events trial (CARE) 40 35 30 25 20 15 10 5 40 35 30 25 20 15 10 5 DIABETIC NON-DIABETIC Placebo 27% Placebo 22% % with CV event % with CV event Pravastatin Pravastatin Slide 37: Secondary prevention in patients with ‘normal’ cholesterol: CARE Study A five-year secondary prevention study using pravastatin, CARE (Cholesterol And Recurrent Events) was conducted in post-MI patients without elevated cholesterol levels (< 240 mg/dL and LDL 115-174 mg/dL). The CARE patient population had a large group of patients with overt diabetes or impaired GTT in whom the effects of lipid lowering using pravastatin could be examined. The patient group contained 976 diabetics, 492 of whom received pravastatin (40 mg o.d.) and 484 of whom received placebo. The risk reduction for coronary events (CHD death, nonfatal MI, CABG or PTCA) in diabetic patients taking pravastatin as compared to placebo was 27% (p = 0.001; 7.0% to 42.9%). This is comparable to the risk reduction of 22% seen in non-diabetic patients (n = 3,183), indicating that diabetic patients with CHD and ‘normal’ cholesterol as well as those without diabetes can benefit from the cardioprotective effects of statins. 1. Goldberg R, Sacks F, Howard B, et al. Diabetic response to pravastatin during the CARE Study (abstract). Circulation 1996;94(8 suppl): 3159. 0 1 2 3 4 5 0 1 2 3 4 5 Years Years Goldberg R, et al. Circulation 1996;94(8 suppl):3159. 37

Cardiovascular outcomes in primary prevention: Fosinopril Amlodipine Cardiovascular Event Trial (FACET) PROBE design with 380 type 2 diabetic patients with hypertension Follow-up time: 3.5 years Primary objectives: Serum lipids and diabetes control Secondary: Cardiovascular events: stroke, AMI, or hospitalised angina Blood pressure Renal function Slide 29: Cardiovascular outcomes in primary prevention: Fosinopril Amlodipine Cardiovascular Event Trial (FACET) FACET, the first of its kind, was a one-year trial compared fosinopril and amlodipine in 380 hypertensive diabetic patients. The study followed the PROBE design: prospective, randomized, open-label with blinded end points. A strict randomization procedure was used to allocate patients to different treatment regimens. Patients were randomized to receive fosinopril 20 mg/day (n = 189) or amlodipine 10 mg/day (n = 191). Should blood pressure not be controlled, the other study drug was added to either regimen. The PROBE design is gaining popularity as it effectively creates a clinical experience and is currently regarded as equal to double-blind randomized trials in regard to randomization. The primary end point was to assess treatment related differences in serum lipids and diabetes control. Predefined cardiovascular disease events, blood pressure control, and renal function were also monitored as secondary outcomes. The results were confirmed/validated by a blinded ad hoc committee using strict definitions of clinical outcomes to allow for an unbiased comparison of therapies and evaluation of the study results. 1. Tatti et al, Diabetes Care April, 1998. Tatti P, et al. Diabetes Care April, 1998. 29

FACET: probability of stroke, AMI, or hospitalised angina 20 16 12 8 4 0 Amlo n = 191 51%* % Probability Fos n = 189 Slide 31: FACET: probability of stroke, AMI, or hospitalised angina Despite similar blood pressure control, in FACET, fosinopril reduced the risk of having a cardiovascular event by 51% as compared with amlodipine (p = 0.03). Prespecified cardiovascular events included fatal and nonfatal myocardial infarction, fatal and nonfatal stroke, and hospitalised angina. The beneficial effect of fosinopril over amlodipine became apparent within 1.5 to 2 years and continued through the entire 3-5 year follow-up period. At the final visit, patients receiving fosinopril were 51% less likely to have experienced cardiovascular events compared with patients receiving amlodipine (p = 0.03). It is suggested that a benefit could be attributed to fosinopril rather than a risk induced by amlodipine. These findings have also been replicated in a similar trial, the ABCD trial, that compared an ACE I to a CCB. These results demonstrate the benefits of an ACE I, such as fosinopril, as optimal antihypertensive treatment in diabetic primary prevention of cardiovascular events. 1. Tatti et al, Diabetes Care April, 1998. 1 2 3 3.5 Follow-up (y) *p = 0.03 Tatti P, et al. Diabetes Care April, 1998. 31

Steno 2: Intensive Therapy NB: combined cardio/renal protection Multidisciplinary team (MD, nurse, dietician) Diet Exercise 30 minutes 3 – 5x/wk Smoking cessation courses ACEI/ARB independent of BP Vitamin – mineral supplement ASA Glycemic control BP control Lipid control Gaede P et al. NEJM 2003; 348: 383-393

Steno 2: Outcomes Gaede P et al. NEJM 2003; 348: 383-393 Hazard ratio = 0.47 in favor of intensive group (.24 - .73, p=0.008) Absolute RR = 20% NNT 5 patients to prevent one CV event in 7.8 years Gaede P et al. NEJM 2003; 348: 383-393

Étrend (sószegény, növényi, etc) ACEI/ARB BP 130/80 alatt Aspirin 62 éves ffi, szűrés során vc 9.2 BMI 30 Dohányzik, RR 140/80, se cholest 5,8, HbA1c 7.5 Se kreat 80, MAU 250 mg/24 ó ? Fogyás, testmozgás Dohányzás Étrend (sószegény, növényi, etc) ACEI/ARB BP 130/80 alatt Aspirin Diabetes Statins/ezetimibe