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Editorial |
Barbara Davis Center for Childhood Diabetes Department of Pediatrics University of Colorado Health Sciences Center Aurora, Colorado 80045-6511
Address all correspondence and requests for reprints to: Dr. David Maahs, University of Colorado Health Sciences Center, Barbara Davis Center for Childhood Diabetes, Department of Endocrinology, Aurora, Colorado 80045. E-mail: david.maahs{at}uchsc.edu.
In this issue of the journal, Stadler et al. (1) provide prospective, 20-yr longitudinal data on mortality, renal disease, and their risk factors in a cohort of patients with type 1 diabetes mellitus. Renal disease has long been a dreaded complication for persons with type 1 diabetes, often a harbinger of rapid demise (2), and historically the leading cause of mortality (3, 4). Diabetes (all types) is the most common cause of end-stage renal disease (ESRD), accounting for approximately 40% of new cases in the United States. The estimated cost of diabetic ESRD in the United States was $15.6 billion in 1997 (5), including an estimated $1.9 billion in 2001 specifically for ESRD in type 1 diabetes (6). Of concern is the reported increase in the incidence of type 1 diabetes. Furthermore, though not a topic of the paper by Stadler et al. (1), type 2 diabetes is rapidly increasing, and renal complications may be more common in youth with type 2 than type 1 diabetes (7, 8).
The Diabetes Control and Complications Trial (DCCT) has clearly shown the importance of glycemic control in reducing microvascular complications, including renal disease (9, 10). Despite significant advances in the care of type 1 diabetes since the initiation of the Lainz study (1) in 1983–1984, 13% of the 684 patients in this relatively young cohort (30 ± 11 yr at inception with type 1 diabetes duration of 15 ± 9 yr) died over 20 yr, with 5.6% receiving renal replacement therapy. Of note, the leading cause of death in this cohort was cardio- and cerebrovascular disease (38%), followed by diabetes-associated deaths with and without renal complications (29%) accounting for over two thirds of the cohort’s deaths. These deaths, in part, should be considered preventable and should rouse clinicians and their patients to greater efforts to improve diabetic care to prevent complications and limit premature mortality. These data are of importance to the endocrine community as a reminder that kidney disease and premature death remain all too frequent among persons with type 1 diabetes. A particular strength of this paper was the inclusion of all eligible patients at the time of enrollment and the ability to use nationwide databases to completely ascertain renal replacement therapy and mortality over a 20-yr period.
The authors also place their data in historical context, which is important to compare the results convincingly with those of previously published studies from the 1970s and 1980s, which have reported a much higher rate of renal disease and mortality (3, 4, 11), although comparing different cohorts must be done cautiously. More recently, data from the Steno clinic have suggested reduced nephropathy after 20 yr of type 1 diabetes duration in successive 5-yr cohorts from 31.1% (1965–1969) to 13.7% (1979–1984) (P = 0.015). This positive trend coincided with more antihypertensives started, lower blood pressure and HbA1c, and less smoking in later cohorts (12). Similarly, after 30 yr of duration, a decline in successive 5-yr cohorts from 32.1% (1961–1965) to 10.8% (1966–1970) (P = 0.005) (13) has been reported in the Linkoping Study. By 35 yr duration, the reported cumulative incidence of 21.3% (14) is an apparent decrease from previous estimates from the Joslin clinic (15). Population-based estimates have reported ESRD of 2.2% at 20 yr and 7.8% at 30 yr in patients diagnosed in Finland between 1965 and 1999 (16). In this Finnish population-based study, cumulative mortality was 6.8% and 15.0% at 20 and 30 yr after the diagnosis of type 1 diabetes, respectively (16). More data supporting improved outcomes over time come from the Pittsburgh Epidemiology of Diabetes Complications Study, which documents decreased mortality and renal failure, though not coronary artery disease, in each progressive cohort diagnosed in subsequent time periods from 1950–1959 to 1975–1980 (17).
A limitation of the study by Stadler et al. (1) is that the analyses are based solely on the baseline data and they are unable to report on how therapeutic advances may have influenced changes in risk factor levels. For instance, glycemic control has improved significantly with home blood glucose monitoring, multiple daily injections, insulin analogs, continuous sc insulin infusion, and more recently continuous glucose monitoring. The authors’ data affirm the importance of glycemic control (although HbA1c was only available in a subset of 500 subjects) and its importance on reducing renal complications and mortality and also affirm that renal disease (both micro- and macroalbuminuria) predicts mortality. Unfortunately, the authors do not have data on blood-pressure-lowering medication usage—a standard of care for type 1 diabetes patients with hypertension or albuminuria—and therefore they are unable to comment on the effect of these medications for renal protection and reduction in mortality. Studies have demonstrated that angiotensin-converting enzyme/angiotensin receptor blocker treatment slows progression to diabetic nephropathy in type 1 diabetes and suggest an additional beneficial effect on cardiovascular disease (CVD)—independent of blood pressure lowering—in persons with diabetes (18, 19). Other important risk factors such as smoking and lipids and their treatment are not reported. Although type 1 patients have been reported to have relatively better lipids (20), elevated lipids remain a risk factor for macro- (21) and microvascular (22) disease. Current guidelines consider type 1 diabetes as a CVD risk equivalent, and the goal for low-density lipoprotein cholesterol is 100 mg/dl, with an even lower goal of 70 mg/dl in individuals with overt CVD (23).
Although proteinuria has been known to dramatically elevate risk of CVD mortality (24), the authors quote data from the 1970s (3) and 1980s (4) and state that most of the excess mortality in the first 20 yr of type 1 diabetes is attributable to renal failure and that after this period CVD becomes the more prominent cause of mortality. More recent data suggest that renal disease and CVD share risk factors and develop in parallel (25, 26). An extensive body of literature exists on renal disease as a CVD risk factor (27), and this concept has long been accepted in the type 1 diabetes literature.
In the Lainz data (1), each 1% increase in HbA1c increased the risk of death by 21%, and the highest quartile of HbA1c increased risk of renal replacement therapy. Absence of data on other risk factors and lack of repeated measures of HbA1c precludes appropriate analysis and novel information concerning relative contribution of hyperglycemia to renal failure and mortality. Although men had higher mortality rates than women, no gender-related difference was found for renal replacement therapy or for CVD mortality, so that the relative protection for females compared with males for CVD is lost in type 1 diabetes, consistent with previous reports (24, 26).
Although further study of the pathophysiology of type 1 diabetes complications is warranted, much can be done currently in the clinical setting to prevent renal failure and reduce premature mortality in this population. Attainment of current goals for glycemic control, though a daily challenge, is more readily achievable with modern tools of diabetic management than in the past. Early screening for diabetic complications can identify early microvascular disease such as albuminuria and allow for intensive management of risk factors. Pharmacological intervention with angiotensin-converting enzymes has been demonstrated to be effective in reducing development of diabetic nephropathy (28). Following the ABCs (hemoglobin A1c, Blood pressure, and Cholesterol) to screen and reach target with more intensive therapeutic and lifestyle interventions should be the basis for primary prevention of CVD in persons with type 1 diabetes. However, data indicate that all too often these goals are not being met and that more needs to be done by healthcare providers and patients to meet these goals (20, 29, 30). Access to care as well as economic and psychosocial aspects of type 1 diabetes also present barriers to achieving these goals. Current screening recommendations for diabetic kidney disease emphasize measuring albumin excretion in timed urine samples (23), although novel markers of renal function such as cystatin c (31) hold promise to improve detection of early diabetic kidney disease.
Glycemic control is the cornerstone of diabetes care, and numerous advances since the start of the Lainz cohort (1) may make these data inappropriate to apply to recently diagnosed persons with type 1 diabetes. Of note, in this cohort the average type 1 duration was 15 ± 9 yr at inception, therefore with an approximate date of diagnosis of 1970, well before current diabetes care modalities. We have reason to hope that these advances in care will lead to fewer diabetic complications in more recently diagnosed patients. However, not all persons with type 1 diabetes either have access to state of the art care or are able to perform such intensive management required for tight glycemic control. These data provide further prospective evidence for the importance of hyperglycemia in development of renal disease and mortality in type 1 diabetes. Unfortunately, this work does not offer any novel ideas on how to intervene. Although progress has been made over time, more remains to be done to prevent diabetic complications and improve the lives of our patients with type 1 diabetes. Attaining treatment goals requires sustained dedication of patient, family, and healthcare providers while awaiting advances in diabetic care and possible cures, which remain tantalizingly on the horizon.
Footnotes
Abbreviations: CVD, Cardiovascular disease; ESRD, end-stage renal disease.
Received August 9, 2006.
Accepted August 11, 2006.
References
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