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.
nephropathy, type 2 diabetes, treatment.
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. 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
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