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Commentary on: Ruospo M, Saglimbe VM, Palmer SC, et al. Glucose targets for preventing diabetic kidney disease and its progression. Cochrane Database Syst Rev 2017;6:CD010137.
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Randomised controlled trials (RCTs) suggest that intensive glycaemic control reduces progression of albuminuria, but effects on later DKD stages and cardiovascular outcomes are less clear. This systematic review evaluated the benefits and harms of intensive versus standard glycaemic control on the onset and progression of DKD and mortality.
This meta-analysis of published tabular data included RCTs assigning patients with diabetes (type 1 or 2) with and without kidney disease to intensive (glycated haemoglobin (HbA1c) <7% or fasting blood glucose (FBG) <6.6 mmol/L) or standard glycaemic control (HbA1c ≥7% or FBG ≥6.6 mmol/L). Primary outcomes were doubling of serum creatinine, ESKD, and death or non-fatal myocardial infarction or stroke. Secondary outcomes included measures of albuminuria, serum creatinine, measures of glomerular filtration rate (GFR), hypoglycaemia, glycaemic control and lipid profile.
The meta-analyses included 29 141 patients from 11 trials, of average duration of 56.7 months. Trials of multifactorial interventions such as the Steno-2 and Microalbuminuria Education and Medication Optimisation (MEMO) trials were included. Intensive compared with standard glycaemic control did not reduce doubling of serum creatinine (Relative risk (RR) 0.84, 95% CI 0.64 to 1.11, I2=73%; low certainty evidence), development of ESKD (RR 0.62, 95% CI 0.34 to 1.12, I2=52%; low certainty evidence), all-cause mortality (RR 0.99, 95% CI 0.86 to 1.13, I2=50%; moderate certainty evidence), cardiovascular mortality (RR 1.19, 95% CI 0.73 to 1.92, I2=85%; low certainty evidence) or sudden death (RR 0.82, 95% CI 0.26 to 2.57, I2=85%; very low certainty evidence). However, intensive control reduced risk of non-fatal myocardial infarction (RR 0.82, 95% CI 0.67 to 0.99, I2=46%), and onset (RR 0.82, 95% CI 0.71 to 0.93, I2=61%) and progression of microalbuminuria (RR 0.59, 95% CI 0.38 to 0.93, I2=75%; all moderate certainty evidence). There was moderate to considerable heterogeneity in the effects on outcomes studied.
This meta-analysis of published tabular data does not clarify the effects of intensive glycaemic control on renal or cardiovascular outcomes. The authors’ certainty in the treatment effects on doubling of serum creatinine, ESKD and cardiovascular mortality was low. Additionally, inclusion of data from trials studying multifactorial interventions may have affected the validity of the findings. The moderate to substantial heterogeneity in the treatment effects, unexplained by age, kidney function or study quality, supports the premise that included trials differed substantively.
The authors’ conclusion of little or no effect of intensive control on clinically important renal endpoints appears premature. The absence of clear evidence for an effect differs from the absence of an effect, especially given the potential for large benefits as reported by the Diabetes Control and Complications Trial (DCCT), the United Kingdom Prospective Diabetes Study (UKPDS) and the Action in Diabetes and Vascular Disease Preteraaax and Diamicron Controlled Evaluation (ADVANCE) trial and their long-term post-trial follow-ups.1–4 Supporting this is a recent meta-analysis of individual participant data from the UKPDS, Veteran Affairs Diabetes Trial (VADT), Action to Control Cardiovascular Risk in Diabetes (ACCORD) and ADVANCE trials, reporting that intensive control resulted in a 20% risk reduction for the composite of ESKD, renal death and development of an estimated GFR (eGFR) <30 mL/min or macroalbuminuria.5 Given the rarity of and the time taken to develop ESKD, trials with longer term follow-up or conducted with high-risk groups are warranted.
The effect of intensive control on cardiovascular endpoints and mortality remains controversial. While short-term trials have not shown benefit, or even harm,6 7 long-term follow-up (greater than 10 years) in younger people with diabetes suggests a reduction in major cardiovascular events including cardiac mortality3 and death from any cause.4 Unfortunately, most trials in this meta-analysis had a short follow-up. Understanding the effects on cardiovascular endpoints by diabetes duration is of interest, but these analyses were not provided.
Implications for practice
While intensive glycaemic control reduces onset and progression of albuminuria, effects on ESKD and cardiovascular mortality are less clear. Trials of patients with later stage DKD and with longer follow-up may clarify these effects. Nonetheless, prevention and management of early DKD are clinically important. Early DKD provides important prognostic information and the opportunity to minimise disease progression. As per international guidelines, a general glycaemic goal of <7% for prevention of microvascular complications should be targeted and individualised according to diabetes duration and comorbidities.
CL and SZ contributed equally.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.