Nep75

NEPHROLOGY 2001; 6, 266–269
Nephropathy in type 2 diabetes: current therapeutic strategies
University of Melbourne Department of Medicine, St. Vincent’s Hospital, Victoria, Australia SUMMARY:
Diabetic nephropathy is currently the commonest cause of end-stage renal failure in most countries with a Western lifestyle. In addition to progressing to end-stage renal disease, patientswith type 2 diabetes and nephropathy are at especially high risk of cardiovascular death. A multi-faceted approach, aiming not only to slow the progression of renal dysfunction but also to reducethe risk of associated complications, particularly cardiovascular disease, is advocated. Current evidence-based guidelines serve a useful adjunctive role in providing target levels for therapeuticintervention.
KEY WORDS:
nephropathy, type 2 diabetes, treatment.
INTRODUCTION
type 2 diabetic patients is not only important for assess-ing risk of overt nephropathy, but also because of the Diabetic nephropathy, currently the commonest cause of close association between microalbuminuria and cardio- end-stage renal failure in most countries with a Western vascular disease,4 the leading cause of death in these lifestyle, has reached catastrophic dimensions.1 In addi- tion to progressing to end-stage renal disease, patients Annual screening for microalbuminuria should com- with type 2 diabetes and nephropathy are at an especially mence at diagnosis in all patients with type 2 diabetes to high risk of cardiovascular death. Strategies for the early permit early intervention and to review associated identification and treatment of diabetic nephropathy conditions, in particular cardiovascular disease and and its associated pathology have been developed and retinopathy.8 In the Microvascular Outcomes in People are constantly being updated in the light of new evidence with Diabetes Mellitus Substudy: of the Heart Out- comes Prevention Evaluation (MICRO-HOPE) Study,angiotensin-converting enzyme (ACE) inhibitor treat-ment provided protection from cardiovascular events EARLY IDENTIFICATION AND
and also reduced progression to overt nephropathy in TREATMENT: MICROALBUMINURIA
patients with type 2 diabetes and microalbuminuria.9Current evidence-based options in patients with type 2 Diabetes is unique as a cause of renal dysfunction in that diabetes would therefore include the use of an ACE its development may be predicted a decade in advance inhibitor in normotensive microalbuminuric patients by the detection of small quantities of urinary albumin to provide cardiovascular protection,9 and the use of termed microalbuminuria.2 While approximately 80% of either an ACE inhibitor or angiotensin receptor blocker patients with type 1 diabetes and microalbuminuria will (ARB) in hypertensive microalbuminuric patients to progress to overt nephropathy over a 10-year period, in slow the progression from microalbuminuria to overt the type 2 diabetic patient only 20–50% of patients will progress.3–7 However, detection of microalbuminuria in BLOOD PRESSURE
Correspondence: Richard E. Gilbert, Associate Professor of Medi- Control of blood pressure (BP) is of paramount impor- cine, University of Melbourne Department of Medicine, St. Vincent’s tance in slowing the progression of diabetic nephropa- Hospital, 41 Victoria Parade, Fitzroy, Victoria, 3065, Australia. E-mail:gilbert@medstv.unimelb.edu.au thy. The US-based Joint National Committee (JNC)-VI Accepted for publication 14 May 2001.
guidelines suggest a target blood pressure of < 130/85 in NEPHROLOGY
patients with type 2 diabetes.12 However, in the presence Appropriate adjunctive therapy should be guided by of nephropathy with > 1 g/day proteinuria, a target BP of patient considerations but could include b-blockers, < 125/75 is advocated. Similarly, the US National CCBs, diuretics and ARBs as these agents have been Kidney Foundation, has suggested that on the basis of shown to reduce proteinuria and/or cardiovascular recent evidence, a target blood pressure of 130/80 is A role for b-blockers in the diabetic patient, parti- cularly those at high cardiovascular risk has emerged following the recent findings of the UK Prospective Diabetes Study (UKPDS) in which both ACE inhibitors CHOICE OF ANTIHYPERTENSIVE DRUG
and b-blockers were shown to have cardioprotectiveeffects beyond that due to blood pressure reduction Evidence from large, well conducted, double-blind, placebo-controlled, clinical trials has repeatedly shown While the use of CCBs in patients with diabetes, par- the efficacy of blockade of the renin-angiotensin-aldos- ticularly the dihydropyridines, has been the subject of terone system as a key therapeutic strategy in reducing controversy, several recent studies indicate that these the progression of diabetic nephropathy. In patients with agents reduce cardiovascular events in the hypertensive nephropathy and type 1 diabetes, captopril treatment diabetic patient.18–20 However, when compared directly was associated with a 50% reduction in the risk of the with ACE inhibitors, as in the Appropriate Blood Pres- combined endpoints of death, dialysis and transplanta- sure Control in Diabetes (ABCD) study21 and Fosinopril tion that was independent of the small disparity in blood vs. Amlodipine Cardiovascular Events Trial (FACET) pressure between the groups.14 In type 2 diabetic patients Trial,22 dihydropyridine CCBs provide less cardiovascu- with nephropathy, two recent trials have shown that the lar protection, although a post hoc analysis of FACET angiotensin II receptor blockers (ARBs) are also effec- suggested a favourable response to a combination of ACE tive as renoprotective agents. In the Irbesartan Diabetic Nephropathy Trial (IDNT), 1715 patients were ran- The combination of an ACE inhibitor with an ARB domized to receive either the ARB, irbesartan, the may also be useful in the diabetic patient as suggested in calcium channel blocker (CCB), amlodipine, or placebo.
the Candesartan And Lisinopril in Microalbuminuria All patients also received additional conventional anti- (CALM) trial, showing an additive effect on blood pres- hypertensive medication (non-ACE, non-ARB, non- CCB) as required to control blood pressure. Patientsrandomized to receive irbesartan were 20% less likely(P = 0.02) to reach a composite endpoint of progression GLYCAEMIC CONTROL
of renal disease or death when compared with placebo,and 23% (P = 0.006) less likely when compared with There is a clear relationship between glycaemic control amlodipine.15 Similarly, in the Reduction of Endpoints and both the development, and the progression of dia- in Non-Insulin-Dependent Diabetes Mellitus with the betic nephropathy in type 1 and type 2 diabetes.23 Gly- Angiotensin II Antagonist Losartan (RENAAL) Study, caemic control should be optimized, aiming for a target 1513 patients with type 2 diabetes and nephropathy were haemoglobin A1c of 7.0% in most patients. In addition randomized to receive either the ARB, losartan, or to sulphonylureas, metformin and acarbose, new oral placebo, with conventional blood pressure medication hypoglycaemic agents have recently become available (non-ACE, non-ARB) added as necessary to control which should assist with attaining good glycaemic hypertension. After an average of 3.4 years, patients control. These agents include the insulin-sensitizing, randomized to receive losartan were 16% less likely PPARg agonist thiazolidendiones (rosiglitazone and (P = 0.02) to reach a composite endpoint of doubling of pioglitazone) as well as nonsulphonylurea, insulin secre- serum creatinine, end-stage renal disease (ESRD) or tagogues such as repaglinide and neteglinide.24 Further- death.16 Neither IDNT nor RENAAL included an ACE more, the development of insulin analogs with more inhibitor treatment arm. Thus, the relative efficacy of predictable profiles and the advent of inhaled insulin are ACE inhibitors and ARBs in type 2 diabetic nephropa- likely to make attaining target HbA1c levels easier with Second-line antihypertensive agents
In clinical practice, achieving recommended blood pres- Many patients with type 2 diabetes and nephropathy will sure targets will frequently necessitate the use of multi- have significant coronary artery disease, although this ple antihypertensive drugs, with participants in clinical will often be clinically silent. Indeed, most patients with trials requiring an average of 3.2 different medications.13 type 2 diabetes and nephropathy will die from cardio- NEPHROLOGY
vascular disease rather than from renal failure per se.
reduce the risk of associated complications, particularly Optimization of all cardiovascular risk factors such as cardiovascular disease. Current evidence-based guide- dyslipidaemia is therefore an important aspect in the lines serve a useful adjunctive role in providing target management of patients with diabetic nephropathy. As levels for therapeutic intervention.
suggested by the recent consensus conference of theAmerican Heart Association, patients with diabetesshould be managed as a coronary disease equivalent with ACKNOWLEDGEMENTS
regard to the treatment of risk factors.25 This is especiallythe case for patients with nephropathy, where an optimal Richard Gilbert is the recipient of a Career Development lipid profile should be sought including a suggested target Award and Darren Kelly is the recipient of a Post Doc- toral Fellowship, both from Juvenile Diabetes Founda- Furthermore, some pilot experimental and clinical studies have also suggested that the HMGCoA reductaseinhibitors may also have favourably influence the courseof diabetic nephropathy, independent of their effects oncirculating lipoproteins.26 REFERENCES
1. Ritz E, Rychlik I, Locatelli F, Halimi S. End-stage renal failure in type 2 diabetes: a medical catastrophe of worldwide dimensions.
Am. J. Kidney Dis., 1999; 34: 795–808.
2. Mogensen CE, Christensen CK. Predicting diabetic nephropathy The American Diabetes Association (ADA) has recom- in insulin-dependent diabetic patients. N. Engl. J. Med., 1984; mended that patients with diabetes who are at high risk 311: 89–93.
of cardiovascular disease,27 such as those with nephropa- 3. Haneda M, Kikkawa R, Togawa M et al. High blood pressure is a thy, should receive prophylactic low-dose aspirin risk factor for the development of microalbuminuria in Japanese therapy, provided that there are no contraindications subjects with non-insulin-dependent diabetes mellitus. J. Diabetes such as actively bleeding retinopathy.
Complications, 1992; 6: 181–5.
4. Mogensen C E. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N. Engl. J. Med., 1984; 310: 356–60.
5. John L, Rao PS, Kanagasabapathy AS. Rate of progression of albu- minuria in type II diabetes. Five-year prospective study from south Smoking promotes both the onset and progression of dia- India. Diabetes Care, 1994; 17: 888–90.
betic nephropathy as well as providing yet an other factor 6. Cooper ME, Frauman A, O’Brien RC, Seeman E, Murray RM, which accelerates cardiovascular disease in patients Jerums G. Progression of proteinuria in type 1 and type 2 diabetes [published erratum appears in Diabet. Med., 1988 5: 422]. Diabet.
Med., 1988; 5: 361–8.
7. Ravid M, Savin H, Lang R, Jutrin I, Shoshana L, Lishner M. Pro- OTHER COMPLICATIONS
teinuria, renal impairment, metabolic control, and blood pressurein type 2 diabetes mellitus. A 14-year follow-up report on 195 Background diabetic retinopathy eventually develops in patients. Arch. Intern. Med., 1992; 152: 1225–9.
all patents with diabetes. However, patients with dia- 8. Mogensen CE, Keane WF, Bennett PH et al. Prevention of diabetic betes and nephropathy are at high risk of developing renal disease with special reference to microalbuminuria. Lancet,
1995; 346: 1080–4.
vision threatening retinal complications, clinically sig- 9. Heart Outcomes Prevention Evaluation Study Investigators.
nificant macular oedema and proliferative diabetic Effects of ramipril on cardiovascular and microvascular outcomes retinopathy.29 Regular ophthalmological assessment is in people with diabetes mellitus. Results of the HOPE study and therefore another important aspect of managing the MICRO-HOPE substudy. Lancet, 2000; 355: 253–9.
patient with diabetic nephropathy. Similarly, patients 10. Ravid M, Savin H, Jutrin I, Bental T, Katz B, Lishner M. Long- with nephropathy are more likely to suffer form neu- term stabilizing effect of angiotensin-converting enzyme inhibition ropathy and peripheral vascular disease such that foot on plasma creatinine and on proteinuria in normotensive type II care is an important part in the overall management of diabetic patients. Ann. Intern. Med., 1993; 118: 577–81.
the patients with diabetes and renal disease.
11. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Ander- sen S, Arner P. The effect of irbesartan on the development of dia-
betic nephropathy in patients with type 2 diabetes. N. Engl. J.
Med., 2001; 345: 870–8.
CONCLUSION
12. Joint National Committee on Prevention Detection, Evaluation, Treatment of High Blood Pressure. The sixth report of the Joint In conclusion, the treatment of diabetic nephropathy National Committee on Prevention, Detection, Evaluation, and should include a multifaceted approach, aiming not only Treatment of High Blood Pressure. Arch. Intern. Med., 1997; 157:
to slow the progression of renal dysfunction but also to NEPHROLOGY
13. Bakris GL, Williams M, Dworkin L et al. Preserving renal function China (Syst-China) Collaborative Group. Arch. Intern. Med., in adults with hypertension and diabetes: a consensus approach.
2000; 160: 211–20.
National Kidney Foundation Hypertension and Diabetes Execu- 21. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford SL, tive Committees Working Group. Am. J. Kidney Dis., 2000; 36:
Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent 14. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, for the Collabora- diabetes and hypertension. N. Engl. J. Med., 1998; 338: 645–52.
tive Study Group. The effect of angiotensin-converting-enzyme 22. Tatti P, Pahor M, Byington R P et al. Outcome results of the fos- inhibition on diabetic nephropathy. N. Engl. J. Med., 1993; 329:
inopril versus amlodipine cardiovascular events randomized trial (FACET) in patients with hypertension and NIDDM. Diabetes 15. Lewis EJ, Hunsicker LG, Clarke WR et al. .Renoprotective effect Care, 1998; 21: 597–603.
of the angiotensin-receptor antagonist irbesartan in patients with 23. Gilbert RE, Tsalamandris C, Bach L et al. Glycemic Control and nephropathy due to type 2 diabetes. N. Engl. J. Med., 2001; 345:
the Rate of Progression of Early Diabetic Kidney Disease. Kidney Int., 1993; 44: 855–9.
16. Brenner BM, Cooper ME, de Zeeuw D et al. Effects of losartan on 24. DeFronzo RA Pharmacologic therapy for type 2 diabetes mellitus.
renal and cardiovascular outcomes in patients with type 2 diabetes Ann. Intern. Med., 1999; 131: 281–303.
and nephropathy. N. Engl. J. Med., 2001; 345: 861–9.
25. Smith SC Jr, Greenland P, Grundy SMAHA. Conference Pro- 17. Adler AI, Stratton IM, Neil HA et al. Association of systolic blood ceedings. Prevention conference V. Beyond secondary prevention: pressure with macrovascular and microvascular complications of Identifying the high-risk patient for primary prevention: executive type 2 diabetes (UKPDS 36): prospective observational study [see summary. American Heart Association. Circulation, 2000; 101:
comments]. BMJ, 2000; 321: 412–19.
18. Staessen JA, Fagard R, Thijs L et al. Randomised double-blind 26. Jandeleit-Dahm K, Cao Z, Cox AJ, Kelly DJ, Gilbert RE, Cooper comparison of placebo and active treatment for older patients with ME. Role of hyperlipidemia in progressive renal disease: focus on isolated systolic hypertension. The Systolic Hypertension in diabetic nephropathy. Kidney Int. Supplement, 1999; 71: S31–
Europe (Syst-Eur) Trial Investigators [see comments]. Lancet, 1997; 350: 757–64.
27. Statement P. Asprin therapy in diabetes. Diabetes Care, 2000; 23:
19. Hansson L, Zanchetti A, Carruthers SG et al. for the HOT Study Group. Effects of intensive blood-pressure lowering and low-dose 28. Ritz E, Ogata H, Orth SR. Smoking: a factor promoting onset and aspirin in patients with hypertension: principal results of the progression of diabetic nephropathy. Diabetes Metab., 2000; 26
Hypertension Optimal Treatment (HOT) randomised trial. Lancet, 1998; 351: 1755–62.
29. Gilbert RE, Tsalamandris C, Allen TJ, Colville D, Jerums G.
20. Wang JG, Staessen JA, Gong L, Liu L. Chinese trial on isolated Evolving nephropathy and vision-threatening retinal disease in systolic hypertension in the elderly. Systolic Hypertension in type I diabetes. J. Am. Soc. Nephrol., 1998; 9: 85–9.

Source: http://i.0dxy.cn/upload/2004/09/21/54584796.pdf