Regression in Albuminuria is Associated with Reduction in All-Cause Mortality in Insulin-Treated T2DM Patients

Table of Content

Background

Overt albuminuria (urinary albumin-creatinine ratio > 300 mg/g) is known to increase the risk for progression of nephropathy and total mortality in type-2 diabetes mellitus (T2DM) patients. It is however not known if a reduction in ACR would translate into a reduced mortality and/or cardiovascular (CV) events among T2DM patients, particularly those treated with insulin.

Aim

To determine the impact of ACR reduction on mortality and CV events in T2DM patients treated with insulin

Patient Profile

  • Adult T2DM patients on insulin therapy and having nephropathy (ACR ≥ 300 mg/g; n=11074; mean age: 62.3 years; males: 53%)

Methods

Study Design

  • Observational study

Follow-up

  • Study subjects (T2DM patients treated with insulin and having ACR ≥ 300mg/g) were followed up from baseline to 1 year
  • Post-1 year, patients were grouped into 2 groups as per the latest ACR estimates as:
    • Albuminuria regression: Current ACR levels < 300 mg/g
    • Nonregression of albuminuria: Current ACR ≥300 mg/g
  • Study subjects were then followed-up until occurrence of the primary or secondary endpoint, or loss to follow-up, or discontinuation of insulin therapy, or until the end of the 5-year follow-up period.

Endpoints

Primary Endpoints

  • All-cause mortality
  • CV events (a composite of nonfatal myocardial infarction and stroke)

Secondary Endpoint

  • A 3-composite of major adverse CV events (MACE) that included all-cause mortality or nonfatal MI or stroke, and the component parts of non-fatal MI and stroke

Results

  • Mean glycosylated hemoglobin (HbA1c) of the study population was 8.7%.
  • During a follow-up period of 43,393 person-years, 682 deaths were recorded. This corresponded to a crude mortality rate of 15.7 per 1,000 person-years (95% confidence interval 14.6–17.0).
  • Patients with albuminuria regression had a 31% decrease in risk of all-cause mortality vs. patients with albuminuria nonregression (Table 1).  
  • Patients with albuminuria regression had a 27% decrease in risk of CV events vs. patients with nonregression of albuminuria (aHR 0.73, 95% CI 0.54-0.98, p=0.041) (Table 1).
  • The risk of MACE was 27% lower amongst those with regression of albuminuria vs. those with nonregression of albuminuria (aHR 0.737, 95% CI 0.59-0.89, p=0.002) (Table 1).
  • Although the risk of nonfatal MI did not significantly differ between the groups (aHR 0.66, 95% CI 0.26-1.70, p=0.387), patients with albuminuria regression had a 28% reduction in the risk of stroke vs. those with albuminuria nonregression (aHR 0.72, 95% CI 0.52-0.97, p=0.032) (Table 1).
Table 1: Event Rates in the study groups

Endpoints

Patients with albuminuria regression (ACR <300 mg/g)

Patients with  albuminuria nonregression (ACR ≥300 mg/g)

Adjusted* hazard ratio, along with 95% CI

Risk reduction

P value

All-cause Mortality

9.7 per 1000 person years (PY)

16.7 per 1000 PY

0.69 (0.52-0.91)

31%

0.008

CV events

9.0 per 1000 PY

13.4 per 1000 PY

0.73 (0.54-0.98)

27%

0.041

MACE

19.9  per 1000 PY

32.5 per 1000 PY

0.73 (0.59-0.89)

27%

0.002

Stroke

7.9 per 1000 PY

11.1 per 1000 PY

0.72  0.52-0.97)

28%

0.032

*Results were adjusted for various covariates including; age, gender, socioeconomic status, alcohol and smoking status; important clinical measures such as body weight, height, systolic blood pressure, and diastolic pressure; biochemical parameters like; baseline HbA1c, lipid-profile, use of other medications including other glucose lowering therapies; comorbidity status, duration of diabetes treatment, and duration of insulin use.

Conclusions

  • Albuminuria is an independent marker of subsequent CV events and all-cause mortality in insulin-treated T2DM patients.
  • Regression of albuminuria through appropriate interventions was associated with a reduction in the risk of all-cause mortality and CV events including stroke.
  • Thus, albuminuria should not only be considered as a marker of renal and CV disease but must be treated as an independent target for therapy.

Am J Nephrol. 2019; 49:146–155.