Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: systematic review and meta-analysis intensive glucose control in type 2 diabetes

Abstract

Background: Aggressive glycemic control has been hypothesized to prevent renal disease in patients with type 2 diabetes mellitus. A systematic review was conducted to summarize the benefits of intensive vs conventional glucose control on kidney-related outcomes for adults with type 2 diabetes.

Methods: Three databases were systematically searched (January 1, 1950, to December 31, 2010) with no language restrictions to identify randomized trials that compared surrogate renal end points (microalbuminuria and macroalbuminuria) and clinical renal end points (doubling of the serum creatinine level, end-stage renal disease [ESRD], and death from renal disease) in patients with type 2 diabetes receiving intensive glucose control vs those receiving conventional glucose control.

Results: We evaluated 7 trials involving 28 065 adults who were monitored for 2 to 15 years. Compared with conventional control, intensive glucose control reduced the risk for microalbuminuria (risk ratio, 0.86 [95% CI, 0.76-0.96]) and macroalbuminuria (0.74 [0.65-0.85]), but not doubling of the serum creatinine level (1.06 [0.92-1.22]), ESRD (0.69 [0.46-1.05]), or death from renal disease (0.99 [0.55-1.79]). Meta-regression revealed that larger differences in hemoglobin A1c between intensive and conventional therapy at the study level were associated with greater benefit for both microalbuminuria and macroalbuminuria. The pooled cumulative incidence of doubling of the serum creatinine level, ESRD, and death from renal disease was low (<4%, <1.5%, and <0.5%, respectively) compared with the surrogate renal end points of microalbuminuria (23%) and macroalbuminuria (5%).

Conclusions: Intensive glucose control reduces the risk for microalbuminuria and macroalbuminuria, but evidence is lacking that intensive glycemic control reduces the risk for significant clinical renal outcomes, such as doubling of the serum creatinine level, ESRD, or death from renal disease during the years of follow-up of the trials.

Figure 1. Literature search and selection

Figure 2. Pooled Risk Ratios, with 95% CI, by trial for end-points of micro and macroalbuminuria

Footnote: Data on the incidence of micro- and macroalbuminuria from UKPDS 33 was reported in 3 year intervals. Due to the marked drop-off of patients with outcomes reported at 9 years and beyond, the data from the 6 year time-point was chosen for the endpoints of micro- and macroalbuminuria. The incidence of microalbuminuria at 9, 12, and 15 years were 19.2%, 23.0%, and 27.1% in the intensive group and 25.4%, 34.2%, and 39% in the conventional group. The incidence of macroalbuminuria at 9, 12, and 15 years was 4.4%, 6.5%, and 7.9% in the intensive group and 6.5%, 10.3%, and 12.6% in the conventional group. Intensive therapy was stopped earlier than planned in ACCORD. Data on renal outcomes were reported at transition to standard therapy (median follow-up 3.5 years) and at study end (median follow-up 5 years). The incidence of outcomes was taken from study end for the main analyses. Utilization of data from transition did not change the results for macroalbuminuria (pooled RR 0.83, 95% CI 0.72–0.95, I² = 68%) or macroalbuminuria (pooled RR 0.74, 95% CI 0.65–0.84, I² = 17%).

Figure 3. Pooled Risk Ratios, with 95% CI, by trial for clinical renal endpoints (doubling of serum creatinine and ESRD)

Footnote: Data on the incidence of doubling of serum creatinine from UKPDS 33 was reported in 3 year intervals. Due to the marked drop-off of patients with outcomes reported at 9 years and beyond, the data from the 6 year time-point (n= 3,045) was chosen for inclusion in the summary data above. There was no difference in the magnitude or direction of effect at 9 and 12 years. At 9 years (n= 2,172), 0.71% vs. 1.76% (RR 0.40, 95% CI 0.14–1.20), and at 12 years (n=1,054), 0.91% and 3.5% (RR 0.25, 95% CI 0.07–0.91)had doubling of serum creatinine in the intensive vs. conventional groups. At 15 years (n=170), 3.52% in the intensive group and 2.8% in the convention group had doubling of serum creatinine (RR 1.25, 95% 0.16–9.55). Data on the incidence of ESRD and Death from Renal Disease are reported from the end of the study period. Intensive therapy was stopped earlier than planned in ACCORD. Data on renal outcomes were reported at transition to standard therapy (median follow-up 3.5 years) and at study end (median follow-up 5 years). The incidence of outcomes was taken from study end for the main analyses. Utilization of data from transition did not change the results for doubling of serum creatinine (pooled RR 1.08, 95% CI 0.95–1.23, I² = 19%) or ESRD (pooled RR 0.70, 95% CI 0.45–1.08, I² = 45%).