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Diabetic nephropathy is the commonest cause of end-stage renal disease (ESRD)1 making the prevention of its onset and progression, critically important. While epidemiological studies have linked hyperglycaemia to diabetic nephropathy, randomised controlled trials (RCTs) to date have reported the beneficial effects of intensive glycaemic control on early stages of nephropathy, that is, albuminuria levels but not ESRD. On the basis of this evidence, guidelines have recommended a glycated haemoglobin (HbA1c) of <7% to prevent renal outcomes. This systematic review specifically examines whether intensive glycaemic control improves a range of early and advanced renal outcomes in patients with type 2 diabetes (T2DM).
RCTs meeting the pre-specified inclusion criteria (randomisation of patients with T2DM to intensive or standard glucose-lowering therapy; and reporting of renal outcomes) were included in the meta-analysis. Primary clinical endpoints were doubling of serum creatinine, ESRD and death from renal disease. Surrogate endpoints were the development of microalbuminuria or macroalbuminuria.
28 065 patients from seven trials, with a mean serum creatinine of 0.9–1 mg/dl, and median HbA1c of 7–9.4% were followed for a median of 2–10.7 years. The mean duration of T2DM at baseline was 6.5–12 years. Glucose-lowering interventions were heterogeneous across the trials. The median achieved HbA1c was 6.4–7.4%. Four studies achieved HbA1c differences of ≥1% between treatment groups. The overall cumulative incidence of long-term renal endpoints (death from renal disease <0.5%, ESRD <1.5% and doubling of serum creatinine <4%) was low compared to short-term surrogate endpoints (microalbuminuria 23% and macroalbuminuria 5%). Compared to the standard therapy, intensive glycaemic therapy significantly reduced the risk of microalbuminuria (RR 0.86, 95% CI 0.76 to 0.96) and macroalbuminuria (RR 0.74, 95% CI 0.65 to 0.85) but not doubling of serum creatinine (RR 1.06, 95% CI 0.92 to 1.22), ESRD (RR 0.69, 95% CI 0.46 to 1.05) or death from renal disease (RR 0.99, 95% CI 0.55 to 1.79). On metaregression, median year of enrolment, years since diabetes diagnosis and duration of randomised treatment were associated with doubling of serum creatinine level, largely due to UKPDS 33.2 Furthermore, the larger the HbA1c difference between treatment groups, the greater the reduction in albuminuria.
This meta-analysis is consistent with findings from previous studies that intensive glycaemic control significantly reduces the onset and progression of albuminuria but not the risk of more advanced renal endpoints.
A trend to benefit for ESRD was reported, with the 95% CI of the point estimate including a potentially large relative risk reduction. This effect may have reached statistical significance with longer follow-up of trial patients. Diabetic nephropathy is commonly considered to progress from microalbuminuria to ESRD over a period of 20 years.3 ,4 All the trials in the meta-analysis had relatively short follow-up periods (2–11.1 years). This may indicate insufficient time for the expected biological effects to emerge.
The long-term follow-up of patients in the UKPDS5 and DCCT (EDIC) 6 ,7 studies suggests that patients receiving a prior period of intensive glycaemic control demonstrate long-term benefits on cardiovascular and microvascular complications: the legacy effect. This is despite convergence in the glycaemic levels of those previously assigned to intensive and standard glucose-lowering therapy. Ten year post-trial follow-up of those receiving intensive therapy in the UKPDS study reported maintained benefits on microvascular endpoints including renal failure.5 Twenty-two years of additional follow-up in the DCCT/EDIC study demonstrated a 55% reduced risk of renal impairment (glomerular filtration rate<60) in the intensive group.7 These data support a long-term renoprotective effect of intensive glycaemic control beyond reduced albuminuria. Moreover, the prevention and regression of albuminuria in the short term may putatively explain the prevention of cardiovascular disease and metabolic memory in the long term.4
This study has a number of limitations. Data from several trials studying a heterogeneous group of patients of different ages, duration of diabetes and baseline glycaemic levels, were pooled. In addition, outcome definitions differed substantially across the trials. While the authors attempted to account for heterogeneity between studies via sensitivity analyses and metaregression, these were limited by available published data.
To conclude that intensive glycaemic control does not reduce renal endpoints such as ESRD would seem premature. Long-term follow-up of contemporary RCTs comparing intensive versus standard methods of glycaemic control will help address this issue. In the meantime, as per international guidelines, glycaemic targets should be individualised, with the general glycaemic target of <7% for renoprotection.
Competing interests S Zoungas has received speaker honoria and travel grants from Servier, MSD, Novartis, Novo Nordisk, Boehringer Ingleheim, Astra Zenica and BMS. She has also served on external advisory boards for MSD, Novo Nordisk and Boerhinger Ingleheim. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.