Mortality Risk Quantified for Diabetes Plus Kidney Disease
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By Todd Neale, Senior Staff Writer, MedPage Today
Published: February 22, 2012
· This meta-analysis found that the presence of chronic kidney disease strongly predicted mortality risk in patients with type 2 diabetes.
· Note that, on average, patients in the trials with the highest mortality rates -- versus those in trials with the lowest rates -- were older, had a longer diabetes duration, and had a higher systolic blood pressure, serum creatinine, and proteinuria prevalence.
Chronic kidney disease more than doubles mortality risk in patients with type 2 diabetes, researchers found.
In an analysis of nearly two dozen randomized controlled trials involving diabetic patients, the highest mortality rates were observed in those trials that required the inclusion of patients with renal disease, according to Marc Pfeffer, MD, PhD, of Brigham and Women's Hospital in Boston, and colleagues.
Trials that selected for patients with elevated serum creatinine or impaired estimated glomerular filtration rate (eGFR) had mortality rates of 5.9 to 8.2 per 100 patient-years, whereas the rest of the trials had rates no higher than 3.3, the researchers reported in the online Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease.
"Risk stratification by evidence of kidney disease, determined by renal function or proteinuria, should be emphasized in diabetic subjects, given its major impact on morbidity and mortality," they wrote.
Pfeffer and colleagues examined 22 randomized trials of at least 1,000 patients with type 2 diabetes and a follow-up duration of at least one year, looking for relationships between specific inclusion and exclusion criteria and all-cause mortality. They excluded trials that selected patients with acute coronary syndromes or end-stage renal disease.
The trials included a total of 91,742 patients, of whom 7.5% died.
After intervention and control arms were combined, mortality rates among the trials ranged widely, from 0.28 to 8.24 per 100 patient-years.
Six trials had a mortality rate of less than 1 per 100 patient-years, 10 had a rate of 1 to less than 2, and three each had rates of 2 to less than 4 and 4 to less than 10.
On average, patients in the trials with the highest mortality rates -- versus those in trials with the lowest rates -- were older (64.2 versus 59), had a longer diabetes duration (15.2 versus 7.2 years), and had a higher systolic blood pressure (145 mm Hg versus 136 mm Hg), serum creatinine (1.8 versus 0.9 mg/dL), and proteinuria prevalence (100% versus 9%).
Both the average LDL cholesterol level and prevalence of current smoking decreased across the increasing mortality categories.
"While the lower prevalence of smoking is probably related to the inclusion criteria, reports from cohorts of chronic kidney disease and heart failure demonstrated that lower cholesterol correlates with higher mortality -- what is described as 'reverse epidemiology' in other populations of patients with advanced disease," the authors wrote.
Selection for hypertension was common across trials in all four of the mortality categories, ranging from 69% to 97% of patients. Hypertension was not a strong predictor of mortality, but rates were lowest in primary prevention trials and those in which hypertension was the only additional inclusion criterion.
Mortality rates were higher in trials selecting for prior cardiovascular disease compared with those for which cardiovascular disease was simply permitted but not required (2.0 to 2.5 versus 0.9 to 2.0 per 100 patient-years).
The highest rates, however, occurred in the three trials that required the presence of chronic kidney disease -- defined as either elevated serum creatinine or eGFR less than 60 mL/min/1.73 m2 with or without the presence of proteinuria.
The authors acknowledged that the study was limited by the lack of individual patient data, of information on the effects of medications and therapeutic interventions during the trials, and of information on the effects of the randomized treatment arms and their relationships with mortality.
Mortality Rates in Trials of Subjects With Type 2 Diabetes
Background-In randomized controlled trials (RCTs) of subjects with type 2 diabetes mellitus, mortality rates vary substantially. We sought to examine the inclusion and exclusion criteria of these RCTs to explore relationships with mortality.
Methods and Results-MEDLINE database was searched from August 1980 through March 2011. Selection criterion included published RCTs of adults with type 2 diabetes mellitus of at least 1000 patients, reporting all-cause mortality and having follow-up duration of at least 1 year. Twenty-two trials were eligible. Annualized mortality rates were derived. Inclusion and exclusion criteria were tabulated for each trial. Trials were categorized in 4 groups according to annual mortality rates: <1, ≥1 to <2, ≥2 to <4, and ≥4 per 100 patient-years. The analysis cohort included 91842 patients and 6837 deaths. Mortality rates ranged from 0.28 to 8.24 per 100 patient-years. Patients enrolled in the highest mortality category were more likely to be older and had longer diabetes duration and higher blood pressure. The selection for hypertension was common in the low- as well as high-mortality trials. Although the mortality rates were higher in RCTs with prior cardiovascular morbidity, the selection for chronic kidney disease-defined by either higher serum creatinine or lower estimated glomerular filtration rate and/or the presence of proteinuria-was associated with the highest mortality rates.
Conclusions-In this analysis of RCTs of type 2 diabetes mellitus, a 29-fold difference in annualized mortality was observed. In these RCTs, selection for renal disease, defined by either decline in renal function or presence of proteinuria, portends important mortality risk.
Type 2 diabetes mellitus (T2DM) increases the risk of premature morbidity and mortality in the community and cardiovascular disease (CVD) is the leading cause of death in individuals with diabetes.1,2 The burden of diabetes-related CVD is likely to continue to expand with the increasing incidence of diabetes in the population.3
It is clear from epidemiologic studies that concomitant diabetes augments the hazard associated with other risk factors for developing CVD, including hypertension, hyperlipidemia, and renal impairment.4,5 Similarly, in patients with established CVD, diabetes portends a greater risk of worse outcomes especially when associated complications such as nephropathy, retinopathy, and, possibly, neuropathy are present. Conversely, in patients whose only risk factor is diabetes, the population attributable risk of death may not be very high.6
In contrast to epidemiologic studies, which provide the most accurate assessment of disease burden in population, randomized controlled trials (RCTs) use inclusion and exclusion criteria to target a specific subpopulation and provide an insight to contributions of comorbidities on mortality in a selected population. Although the specific selection criteria distort the disease proportion in the population, including patients who fulfill specific selection criteria can augment the overall morbidity and mortality risk. Across trials, the selection or exclusion of a specific risk profile offers a diverse sample that extends from low mortality to those with the extreme hazard.
In RCTs of T2DM patients, while any cardiovascular or renal diseases increase mortality in diabetes, patients without evidence of such would be expected to experience fewer complications.7 Furthermore, annualized death rates can characterize the risk in diabetes populations across trials. We used data from recent RCTs in T2DM to further examine the relationship between cardiovascular risk factors and renal disease and its complications and how this interplay augments the risk of death.
Our analysis included 91742 patients and 6837 deaths (7.5%). The overall mortality rate in the entire population was 1.83 deaths per 100 patient-years and varied widely from 0.28 to 8.24 deaths per 100 patient-years across the selected trials (Figure 2 and Table 2).
All RCTs included additional risk factors other than diabetes in their inclusion criteria. Hypertension was a common inclusion criterion for low- and high-mortality trials. Mortality rates were the lowest in primary prevention trials and those for which hypertension was the only additional inclusion criterion (BENIDICT, DIRECT, JPAD, and ROADMAP). These trials, excluding JPAD, shared an exclusion criterion of proteinuria at baseline. Studies selecting for the presence of CVD other than hypertension (DAVID, PROACTIVE, and BARI2D) had higher mortality than those permitting CVD in their inclusion criteria (RECORD, ACCORD, FIELD, UKPDS, ADVANCE, and VADT). Moreover, trials in which inclusion required elevated serum creatinine values (mostly >1.5 mg/dL) or estimated glomerular filtration rate<60, or/and evident proteinuria (DIABHYCAR, IDNT, RENAAL, and TREAT) showed the highest mortality rates.
Mortality, across trials, was associated with certain characteristics: serum creatinine, proteinuria prevalence, age, diabetes duration, and systolic blood pressure averages (Table 3). Furthermore, subjects in the lower mortality category were younger (59 years), had lower serum creatinine averages (0.9 mg/dL), and proteinuria prevalence (9%). Conversely, subjects enrolled in the highest mortality trials were more likely to be older (64.2 years); have longer diabetes duration (15.2 years); and have higher systolic blood pressure (145 mmHg), serum creatinine averages (1.8 mg/dL), and proteinuria prevalence (100%).
Lower low-density lipoprotein averages and current smoking status were observed with higher mortality rates (126, 117, 107, 99 mg/dL and 16%, 15%, 14%, and 9%, respectively, along the categories). In addition, we observed variation in body mass index and glycated hemoglobin averages across mortality and were highest in the trials with CVD trials. Moreover, hypertension prevalence was highest in the highest mortality trials category (97%) and ranged 69% to 73% across all other mortality categories. Similarly, reporting retinopathy varied in consistency across mortality groups with higher presence in the highest mortality category. Gender type was not associated with mortality in our analysis.
Patients with diabetes mellitus enrolled in RCTs do not represent a homogenous population.31 Different inclusion criteria, according to study aim, influence baseline characteristics of the enrolled subjects and subsequently the risk profile and observed outcomes. As a result, the heterogeneity of this population is translated into a wide range of death rates. The term "diabetes risk" in and of itself does not differentiate those with the highest death risk in the spectrum.
Our report highlights the risk of death in subjects with diabetes, with an approximately 30-fold difference in annualized mortality rate across the range of trials we examined. Hypertension was not associated with higher mortality rate and selection for hypertension specifically did not discriminate those at higher risk of death. Furthermore, in RCTs of subjects with diabetes, the selection for increased urinary protein excretion or/and elevated serum creatinine was particularly and closely associated with increased risk of death.
Our study is consistent with prior reports describing the risk associated with nephropathy in diabetes. UKPDS 64 data described mortality rates similar to our data with a stepwise increase in death rate on the progression from normoalbunimura to albuminuria to decline in kidney function.32 Although multiple studies demonstrated that baseline characteristics affect mortality in diabetic subjects33,34, our descriptive report shows that chronic kidney disease (CKD) in diabetes is associated with major mortality risk.
In addition to diabetes and CKD, TREAT also required hemoglobin level ≤11.0 g/dL as an inclusion criterion. This additional eligibility requirement would be expected to be associated with a greater risk of death.35 Additionally, other detectable serum cardiac biomarkers were shown to be associated with even higher risk of death36 and could potentially be used for further risk stratification and/or selection of specific populations for clinical trials.37
The Emerging Risk Factors Collaboration showed that diabetes increases the risk of vascular and nonvascular mortality causes.38 The report also demonstrated that the risk of death increased with estimated glomerular filtration rate decline. Our study illustrates that any degree of proteinuria in diabetes is associated with a higher death rate. Risk stratification by evidence of kidney disease, determined by renal function or proteinuria, should be emphasized in diabetic subjects given its major impact on morbidity and mortality.39
Most clinical trials, by design, augment the studied risk in clinical trials and eventually increase endpoint rates. In our cohort of all subjects with type 2 diabetes, each trial contains an attributed risk in its inclusion. Although hypertension is an element of the cardiovascular continuum risk profile in diabetes, its mortality augmentation was not evident in our cohort especially in the absence of proteinuria and did not provide further risk discrimination. Recent analysis concluded the similar finding.40 Although the diagnosis of hypertension was common across all morality categories, the actual weighted systolic blood pressure average was greater in the highest mortality trials.
Within our cohort of subjects with T2DM participants in RCTs, we did not observe an increase of other "traditional" risk factors along with increasing mortality.41 Moreover, variation of certain characteristic risk factors was seen across the selected trials; for example, body mass index and glycated hemoglobin weighted average values showed a disparity across the arbitrary categories and likely due to the selection processes in these trials. Notably, current smoking and low-density lipoprotein weighted averages were lower in higher mortality categories. Although the lower prevalence of smoking is probably related to the inclusion criteria, reports from cohorts of CKD and heart failure demonstrated that lower cholesterol correlates with higher mortality what is described as "reverse epidemiology" in other population of patients with advanced disease.42 Moreover, the presence of CKD matched higher presence of hypertension and retinopathy. This matching increase is probably explained by the bidirectional influence between the vasculature and the kidney along with the end-organ damage of both systems simultaneously.43
Our report was limited by the lack of individual patient data to allow detailed analyses of baseline characteristics and risk of death. Baseline characteristics were obtained from the publication as averages; not all baseline characteristics were reported in every trial; we also used overall prevalence of CVDs in our analysis and not its subtypes. Furthermore, we did not account for the medications and therapeutic interventions during trials. We examined overall mortality in the analyzed trials and did not take into account randomized treatment arms and treatment effects on mortality, albeit these were generally neutral. Although we also did not account for potential secular decline in mortality rates over time, 21 of our 22 trials in our analysis were published in the past 10 years. The strength of this report includes the review of numerous baseline demographics and examination of a large cohort. Moreover, the extensive literature search that was performed makes publication selection bias less likely. Our report focuses on comparing the exclusion and inclusion criteria and demonstrating the contrast in the clinical trials population as selective cohort to supplement for epidemiologic studies, which have critical estimates of demographics. Furthermore, the truncated distribution of the population demographics was dictated by the trials selection criteria and probably resulted in a less pronounced relationship between demographics and outcomes.
Mortality has a broad range of representation in trials of type 2 diabetes subjects. Moreover, diabetes trials with nephropathy selection had the highest death rates. We conclude that the selection for CKD, defined by either decline in renal function or presence of proteinuria, augmented the death risk in diabetes.