The True Overall Mortality of Unselected Nephropathic Type 2 Diabetic Patients With Mild to Moderate Renal Insufficiency

Despite significant improvements in therapy over the last decade, the prognosis of nephropathic type 2 diabetic patients continues to be poor (1). In recent antihypertensive intervention studies performed in type 2 diabetic patients with overt nephropathy, the mean 5-year mortality rate was ∼20%. In the irbesartan study published by Lewis et al. (2), the mean death rate after 54 months ranged from 15 (irbesartan group) to 16.3% (placebo group). Similar data were obtained in the losartan study published by Brenner et al. (3). These results might lead to false conclusions concerning the overall mortality of all unselected type 2 diabetic patients with overt nephropathy. In the irbesartan study, major excretion criteria were congestive heart failure (New York Heart Association [NYHA] class III or worse) and cardiovascular events within the last 3 months.

In accordance with the irbesartan study, in 1996 we recruited all nephropathic type 2 diabetic patients who were treated at that time in our hospital and/or in the outpatient care unit and who fulfilled the inclusion criteria of the study (serum creatinine 1.0–3.0 mg/dl in female and 1.3- 3.0 mg/dl in male patients, as well as protein excretion ≥1.0 g/24-h urine), without considering the usual exclusion criteria. We recruited 46 nephropathic type 2 diabetic patients (aged 61 ± 8 years, 26 women and 20 men, diabetes duration 17 ± 4 years), and we prospectively studied their progression of diabetic nephropathy and the 5-year mortality rate.

Cardiovascular disease was present in 43%, while 28% had heart failure (NYHA class III and higher). Of patients, 36% had exclusion criteria according to the irbesartan study. All patients underwent evaluations in our outpatient unit (n = 24) or at the offices of their general physicians in at least 6-month intervals over an observation period of 5 years. The following parameters were routinely measured: creatinine in serum and 24-h urine, creatinine clearance (calculated), protein in 24-h urine, HbA_1c, and blood pressure. The three end points of the study were doubling of serum creatinine levels, end-stage renal disease, or death. Patients were also divided into those with and without heart failure, and 5-year mortality rates were assessed in both groups.

Serum creatinine had doubled in 37% of patients over 60 months, compared with 22% within 54 months in the irbesartan study. The percentage of patients who reached end-stage renal disease was 26% in our patients and 16.7% in the irbesartan study. During the period of observation, mean HbA_1c level in our patients was 7.6 ± 1.0%, while their mean blood pressure was 139 ± 11/80 ± 8 mmHg. In the irbesartan study, the mean blood pressure at visits after baseline was similar, with 140/77 mmHg in the irbesartan group and 144/80 mmHg in the placebo group.

The overall 5-year mortality of all of our diabetic patients was 33%. Five-year mortality rates were 57% in patients with heart failure (NYHA III or IV) and 22% (P < 0.05) in those without heart failure. In comparison with the data of the intervention studies, the mortality of our nephropathic type 2 diabetic patients without heart failure was similar to that of the selected patients in the irbesartan study. In contrast, survival was significantly lower in patients with heart failure, and as a consequence, the overall mortality of all unselected type 2 diabetic patients with overt nephropathy was also higher than that registered in the intervention studies. There were no significant differences at baseline visit in creatinine clearance (139 ± 31 vs. 134 ± 32 ml · min⁻¹ · 1.73 m⁻²) and urinary protein (2.4 ± 1.3 vs. 2.3 ± 1.2 g/24 h) in the groups with and without chronic heart failure, respectively. The mean blood pressure during the observation period was approximately the same in both groups (140 ± 12 vs. 138 ± 11 mmHg). Twenty-eight percent of the patients with and 25% of those without heart failure reached end-stage renal disease. Our results are in agreement with those of Short (4), who found, at a mean follow-up of 5.3 years, a mortality rate of 37% in nephropathic type 2 diabetic patients compared with just 8% in a nonnephropathic group. Multivariate Cox regression analyses confirmed a fivefold excess risk for cardiovascular mortality in type 2 diabetic patients with overt nephropathy. Angiotensin II blockers have shown effective cardiovascular protection in type 2 diabetic patients (5).

In conclusion, the real mortality rate of all unselected type 2 diabetic patients with overt nephropathy and mild-to-moderate renal insufficiency is much higher than the mortality of nephropathic type 2 diabetic patients selected for antihypertensive studies. The difference between outcome in studies versus “real life” is mainly due to the fact that patients with heart failure are excluded from studies, but obviously present in a nonstudy situation.