Mortality and incidence of renal replacement therapy in people with type 1 diabetes mellitus--a three decade long prospective observational study in the Lainz T1DM cohort.

ORIGINAL

ARTICLE

E n d o c r i n e

C a r e

Mortality and Incidence of Renal Replacement Therapy in People With Type 1 Diabetes Mellitus– A Three Decade Long Prospective Observational Study in the Lainz T1DM Cohort Marietta Stadler,* Slobodan Peric,* Hermine Strohner-Kaestenbauer, Reinhard Kramar, Thomas Kaestenbauer, Andreas Reitner, Martin Auinger, Florian Kronenberg, Karl Irsigler, Stephanie A. Amiel, and Rudolf Prager Third Medical Department (M.S., M.A., R.P.), Hietzing Hospital Vienna Wolkersbergenstr. 1, 1130 Vienna, Austria; Diabetes Research Group (M.S., S.A.A.), King’s College London, 10, Cutcombe Road, SE5 9RJ London, United Kingdom; Karl-Landsteiner Institute of Metabolic Diseases and Nephrology (S.P., H.S-K., T.K., R.P.), Hietzing Hospital Vienna, Wolkersbergenstr. 1, 1130 Vienna, Austria; Former Ludwig Boltzmann Institute for Metabolic Diseases and Diabetes (K.I.), 1130 Vienna, Austria; Austrian Dialysis and Transplantation Registry (R.K.), Klinikum Kreuzschwestern, Grieskirchner Strasse 42, 4600 Wels, Austria; Department of Ophthalmology (A.R.), Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria; Department of Medical Genetics (F.K.), Division of Genetic Epidemiology, Innsbruck Medical University, Schöpfst. 41, 6020 Innsbruck Austria

Context and Objective: We investigated long term mortality, requirement for renal replacement therapy (RRT), and incidence of other late diabetic complications in an observational cohort study of 641 people with type 1 diabetes (T1DM). Design: Prospective observational cohort study. Setting: The study was conducted at a Tertiary Diabetes Centre in Vienna, Austria. Patients: A cohort with all people with T1DM (n ⫽ 641, 47% females, 30 ⫾ 11 years) attending their annual diabetes review was created in 1983–1984. Biomedical data were collected. Main Outcome Measures: In 2013 we investigated mortality rates and incidence rates of RRT by record linkage with national registries and incidence of other major diabetes complications by questionnaire. Results: 156 (24%) patients died [mortality rate: 922 (95%CI: 778 –1066) per 100 000 person years]. Fifty-five (8.6%) received RRT [incidence rate: 335 (95%CI: 246 – 423) per 100 000 person years]. The 380 questionnaires (78% return rate) recorded cardiac events, strokes, limb amputations, and/or blindness, affecting 21.8% of survivors. Mortality and incidence of RRT increased in each quartile of baseline HbA1c, with the lowest rates in the quartile with HbA1c ⱕ6.5% (48 mmol/mol) (P ⬍ .05). Conclusions: In people with established type 1 diabetes who were observed for almost three decades, the overall mortality was 24% and the incidence of renal replacement therapy was 8.6%, with a 21.8% combined incidence rate of the other hard endpoints in the surviving people. A clear linear relationship between early glycemic control and the later development of end stage renal disease and mortality has been found. (J Clin Endocrinol Metab 99: 4523– 4530, 2014)

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received June 18, 2014. Accepted September 10, 2014. First Published Online September 23, 2014

doi: 10.1210/jc.2014-2701

* M.S. and S.P. contributed equally to this work. Abbreviations: ESRD, end stage renal disease RRT; HR, hazard ratio; T1DM, type 1 diabetes mellitus; RRT, renal replacement therapy.

J Clin Endocrinol Metab, December 2014, 99(12):4523– 4530

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Mortality and Complications in Type 1 Diabetes

eople with type 1 diabetes mellitus (T1DM) face a number of potentially life-threatening long-term complications due to micro- and macrovascular disease. Among these, diabetic nephropathy causing end-stage renal disease (ESRD) with the need for renal replacement therapy (RRT) is a major contributor to increased mortality (1– 4). After a long disease duration, most of the excess mortality in people with T1DM results from cardiovascular events (5, 6). In the last three decades, therapy for T1DM has advanced. The development of support for better self-management (eg, home glucose monitoring, structured education in the use of multiple daily insulin injection regimens) and the advent of new technologies (eg, insulin analogues, insulin pumps, and glucose sensors) provide cause for optimism that late T1DM-related complications may be delayed/prevented. In the early 1980s, a cohort of people with T1DM was established at Lainz hospital, Vienna, Austria, with the aim of establishing the future need for RRT for patients with this condition. The hospital serves as a large tertiary referral center for people with T1DM and also has a major nephrology unit providing care for people on dialysis and after renal transplantation. In a previous study of the Lainz T1DM cohort, we reported a 13% mortality and 5.6% incidence of RRT after approximately 20 years of followup; both endpoints were associated with poorer glycemic control (2). At enrollment, the patients were, on average, 30 years old with a mean diabetes duration of 15 years (2). Now that the Lainz T1DM cohort has a mean age of 60 years, with 45 years of diabetes duration, it was considered timely to reassess mortality and the incidence of RRT, after an observation time of almost 30 years. We report here on mortality, incidence of RRT in our original cohort. We included in the present assessment the prevalence of diabetic late complications (cardio- and cerebrovascular events, blindness, limb amputation, and end stage renal failure) in the participants that are alive by structured questionnaires.

P

Materials and Methods Study design The study design was a prospective cohort study.

Setting The study was conducted at the Third Department of Medicine and Ludwig Boltzmann Institute for Metabolic Diseases and Diabetes, at the Hietzing Hospital, previously Lainz (a tertiary referral center in Vienna, Austria).


Participants The participants included people with an established diagnosis of T1DM attending their annual review between 1983 and 1984. Consent for use of patient data for research was routinely requested at the presentation to the clinic. For inclusion into this cohort study, T1DM had to have been diagnosed before the age of 30 years, with insulin treatment starting within the first year and continued to date. Six hundred and forty-one subjects consented in writing to the recording and processing of their data. The protocol for the 30-year follow-up was submitted to the Ethics Committee of the Vienna Health Services for review in 2011. The committee decided that this study did not need formal ethics approval due to its purely observational nature. The baseline evaluation, which was part of the routine annual review, included an anthropometric assessment, clinical examination, and routine laboratory examinations, including HbA1c, serum creatinine, and albuminuria measurements from timed overnight urine samples.

Laboratory procedures HbA1c was measured with high-performance liquid chromatography (HPLC) (Diamat, Bio-Rad). Screening for albumin in urine was performed with urine dipsticks (Combur8Test). If the test was positive, then subsequent quantitative analysis was performed to distinguish between micro- and macroalbuminuria. Urine samples containing albumin concentrations between 30 and 299 ␮g/min were considered as microalbuminuric; concentrations ⱖ300 ␮g/min were classified as macroalbuminuric (2). Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease 2 (MDRD 2) formula (7).

Endpoint assessment In 2012–2013, we used a stepwise approach to the follow-up of our patients. First, we performed a record-linkage with the national death register, and searched the Viennese cemetery register, to determine which patients had died. We repeated the exercise with the Austrian dialysis and transplantation registry and the Eurotransplant Registry. Thereafter, we contacted survivors by telephone and used a structured questionnaire to document their current health status and the presence of late diabetes complications. For those participants who were not contacted by telephone, we used the central civil register to find their current names and addresses and sent a paper copy of the questionnaire via the post.

Mortality and incidence of renal replacement therapy Computer-assisted record linkages with the national death register (Statistics Austria), the Austrian Dialysis and Transplantation Registry (ÖDTR, Austria), and the Eurotransplant Registry (http://www.eurotransplant.org) were performed at the beginning of our follow-up in June 2012 and repeated in June 2013. The national death registry notes all deaths, including dates and causes (as per death certificate). The ÖDTR records all patients with ESRD receiving hemodialysis, peritoneal dialysis, and/or kidney transplantation or kidney-pancreas transplantation (http://www.nephro.at/oedtr.htm). Austria is part of the Eurotransplant network, which is responsible for the allocation of donor organs in Austria, Belgium, Croatia, Germany, Hungary,


doi: 10.1210/jc.2014-2701

Luxembourg, the Netherlands, and Slovenia. Eurotransplant records all transplantations within the Eurotransplant network (http://www.eurotransplant.org).

Myocardial infarction, stroke, lower limb amputation, and blindness due to diabetes Telephone interviews were conducted using a prewritten structured paper-based questionnaire by one person (H. S.-K.) to avoid interviewer bias. The questionnaire covered demographic and anthropometric data, anamnestic data regarding T1DM (age at onset, current therapy), and if and when the following end points occurred: myocardial infarction (MI), percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), stroke, lower limb amputation, blindness due to diabetes and renal dialysis or transplantation. All data were anonymized and entered into the database to be analyzed by a different person (M.S.) than the one performing the telephone interviews.

Statistical analysis Overall and gender-specific mortality rates and the RRT incidence per 100 000 person-years follow-up were calculated. To assess the effects of glycemic control, patients were stratified into baseline HbA1c quartiles. Differences between groups were assessed by performing ␹2-tests for categorical variables. Continuous variables were analyzed with ANOVA or Kruskal-Wallis and post hoc testing using the Student-Newman-Keuls test and the Dunn test, respectively. Mortality and the incidence of RRT were analyzed with Kaplan-Meier curves. The log-rank test was used to determine statistical differences between the survival curves with respect to HbA1c quartiles. Fractional polynomial models were used to determine whether there was a threshold of HbA1c beyond which the hazard ratio (HR) levelled off. Multiple Cox proportional hazards regression analysis was used to calculate adjusted risk estimates, based on the data of all T1DM patients whose baseline HbA1c values were available (n ⫽ 494). The model describing mortality risk and RRT used survival time and RRT-free survival as dependent variables, respectively. Baseline characteristics of surviving and deceased patients, and patients with and without RRT, respectively, whose values differed at a P value ⬍.10, were considered for the Cox regression analysis. The final model was verified by backward stepwise Cox regression analysis. All statistical calculations were performed with SPSS® (SPSS Statistics 19, Inc.) computer software. Data are presented as means ⫾ SD unless otherwise indicated. For differences between groups, the level of significance was set at P ⬍ .05.

Results Baseline characteristics The baseline characteristics of this study cohort have been described in detail previously (2). The cohort comprised 641 people with established T1DM. In brief, at inclusion into the study (n ⫽ 641, 47% women), mean age was 30 ⫾ 11 years old, T1DM duration was 15 ⫾ 9 years, and onset of the disease was at age 15 ⫾ 8 years. Mean HbA1c at enrolment was 7.6% ⫾ 1.6% (59 ⫾ 17 mmol/


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mol) (range 4.2–14.8%/22–138 mmol/mol), 12% had microalbuminuria and 16% macroalbuminuria. Blood pressure was significantly higher in men (131 ⫾ 82/82 ⫾ 11 mmHg vs 123 ⫾ 17/79 ⫾ 11 mmHg in women, SD; P ⬍ .01) as was eGFR (98 ⫾ 32 mLmin/1.73 m2 vs 84 ⫾ 21 mL/min/1.73 m2, SD; P ⬍ .02), but age, BMI, HbA1c, prevalence of nephropathy, age at diabetes onset, and diabetes duration did not differ by gender. Follow up data Of the cohort of 641 patients, 156 had died. The remaining 485 had diabetes for an average of 43 ⫾ 8 years and were 57 ⫾ 10 years old at the time of follow up. We obtained questionnaire data from 380 (78%) patients. Of these, 353 (93%) were completed by phone (all of those contacted by phone completed the questionnaire) and 27 (7%) by post. Of the 105 patients not contactable, 80 were alive according to the Austrian civil registry. The remaining 25 (3.9%) were not found in the civil, death, or RRT registries, and were assumed to be alive when the analysis was conducted. At the time of the interviews, participants (49% females) were, on average, 57.4 ⫾ 9.8 years old and had a BMI of 26.6 ⫾ 9.6 kg/m2 and a diabetes duration of 43.3 ⫾ 8.5 years. Mortality Mean follow-up duration was 26.0 years (median 29.5, range 0.7–29.5 years), totaling 16921 patient years of observation, giving a mortality rate of 24% (n ⫽ 156) or 922 per 100 000 person years; 95% CI: 778 –1066. There was a trend towards a higher mortality in men [male mortality ratio of 1055 per 100 000 person years (95% CI: 840 –1269) vs 781 per 100 000 person years in women; 95% CI: 590 –971; P ⫽ .07 ␹2-test]. The main causes of death were cardio- and cerebrovascular events (31%), “diabetes related” (19%); renal insufficiency (14%, of which 61% were reported to have died due to “diabetes with renal complications”), and malignant neoplasm (14%) (Table 1). Incidence of renal replacement therapy Fifty-five participants (8.6%) started RRT during the observation period, resulting in an incidence rate of 335 per 100 000 person years (95% CI: 246 – 423). The vast majority (51/55) were receiving dialysis (17/51 peritoneal; 34/51 hemodialysis), with four patients having received pre-emptive combined pancreas-kidney transplantation as their first RRT. There were no sex-related differences in RRT incidence rates, which were 342 per 100 000 person years (95% CI: 218 – 475) in men and 327 per 100 000 person years (95% CI: 201– 452) in women (P ⫽ NS).


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Table 1. The Underlying Causes of Death as Documented on the Death Certificates for the Total Cohort of Women and Men Cause of Death According to Death Certificate Circulatory system Ischemic heart disease Cerebrovascular disease Heart diseases Others Diabetes associated Diabetes mellitus Diabetic coma Hypoglycemic coma Renal insufficiency Diabetes with renal complication Renal insufficiency Malignant neoplasm Stomach, intestine, and mouth Liver Lung Breast Others Other causes Asthma, pneumonia, suffocation Renal insufficiency, chronic nephritis Liver cirrhosis, skull fracture

Total (f/m) (%) 48 (20/28) (30.7%) 32 (10/22) 6 (4/2) 8 (5/3) 2 (1/1) 29 (13/16) (18.6%) 31 (12/19) 4 (2/2) 2 (2/0) 21 (10/11) (13.5%) 13 (7/6) 8 (3/5) 22 (5/17) (14.1%) 9 (1/8) 3 (1/2) 4 (0/4) 2 (2/0) 4 (3/1) 36 (16/20) (23.1%)

During the observation period, 37/55 patients (67%) received kidney transplants, of whom 21 received one (or more) pancreas transplants: 15 patients had simultaneous combined kidney-pancreas, 5 pancreas after kidney, 1 kidney after pancreas, 14 kidney only, and 2 combined heartkidney transplantations. Of these, 8 patients received a second and one a third kidney transplant, and three received a second pancreas transplant. These consecutive organ transplants were not counted as “endpoints” in the RRT free survival analyses. Five patients were listed on the Eurotransplant waiting list, but died before they could be transplanted and one patient is currently listed. Thirty-six of the patients who received RRT died during the follow-up (65.5% vs 20.5% in those who had not received RRT); in half of them the cause of death was “renal insufficiency,” or “diabetes and renal complication” (n ⫽ 18). In the remaining patients, cardio- or cerebrovascular causes, diabetes associated causes, or malignant neoplasms were noted as the cause of death on their death certificate. Combined endpoint RRT or death The combined endpoint (either RRT or death) occurred in 177 participants, resulting in an incidence rate of 1103 per 100 000 person years (95% CI: 942–1265) in the total cohort. There was a trend towards men having a higher incidence rate [1262 per 100 000 person years (95% CI:


1021–1503)] than women [936 per 100 000 person years (95% CI: 722–1149), P ⫽ .06]. Diabetes related hard endpoints assessed with questionnaires According to the 380 completed questionnaires, 83 patients (21.8%) had suffered one or more events, 41 (10.8%) having had one or more cardiac events (24 MI, 22 bypass surgery, 19 PTA/stent), 24 (6.3%) strokes, and 20 (5.2%) needed RRT. Thirteen participants had had a nontraumatic limb amputation and nine stated that they were blind due to their diabetes. No sex-related differences in the incidence of these events were noted. HbA1c quartile subgroup analysis We divided the entire baseline cohort into quartiles of their baseline HbA1c values. Table 2 shows the data by quartile of HbA1c at enrollment. There were no significant differences between quartiles in BMI, gender distribution, blood pressure (BP), age of diabetes onset, or eGFR. The participants in the highest HbA1c quartile were younger and had shorter diabetes duration compared to the second quartile. The prevalence of both micro- and macroalbuminuria was approximately twofold higher in the highest than in the lowest HbA1c quartile (each P ⬍ .03) at baseline. Mortality was 17.5% in the lowest HbA1c quartile (HbA1c ⱕ 6.5%/49 mmol/mol), increased in the second and third quartiles, and was greatest at 31.7% in the highest HbA1c quartile (HbA1c ⱖ 8.4/68 mmol/mol) (Table 2; P ⬍ .01). This increase in mortality starting from the second HbA1c quartile was also reflected in the KaplanMeier analyses (Figure 1A; P ⬍ .04). The incidence of RRT was 4% in the lowest HbA1c quartile and was 14.3% in the highest HbA1c quartile (Table 2, P ⬍ .01). The corresponding Kaplan-Meier analysis showed an increased incidence rate in the second and third HbA1c quartiles and the highest rates in the fourth quartile (Figure 1B, P ⫽ .02). The combined endpoint (RRT or death) occurred most frequently in the fourth HbA1c quartile and the fewest cases were noted in the first quartile (Table 2, P ⬍ .01 first vs fourth quartile; Figure 1C, P ⫽ .02). Multiple Cox proportional hazards regression analysis for survival and incidence of RRT Surviving and deceased patients differed in baseline variables: gender, age, BP, HbA1c, BMI, eGFR, incidence of RRT, and prevalence of micro- and macroalbuminuria. These variables were considered for the Cox proportional Hazards regression analyses. The final model was verified by stepwise backwards regression and included the re-


doi: 10.1210/jc.2014-2701


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Table 2. Baseline Patient Characteristics, Mortality, and the Incidence of RRT by Baseline HbA1c Quartiles HbA1c Quartiles First

Second

Third

Fourth

Diabetes duration (y) Diabetes onset (y) BMI (kg/m2)

126 (25.5) 30.4 ⫾ 10.4 45/55 5.9 ⫾ 0.5% 41 ⫾ 6 mmol/mol 4.2– 6.5% 22– 47 mmol/mol 14.9 ⫾ 8.5 16.4 ⫾ 8.0 23.7 ⫾ 3.4

134 (27.1) 31.8 ⫾ 10.8 47/53 7.0 ⫾ 0.3% 53 ⫾ 3 mmol/mol 6.6 –7.4% 49 –57 mmol/mol 16.1 ⫾ 9.4 16.6 ⫾ 7.8 23.8 ⫾ 3.1

108 (21.9) 30.0 ⫾ 11.2 40/60 7.9 ⫾ 0.3% 63 ⫾ 3 mmol/mol 7.5– 8.3% 58 – 67 mmol/mol 16.5 ⫾ 8.7 14.4 ⫾ 8.1 24.2 ⫾ 4.0

126 (25.5) 27.2 ⫾ 11.8 50/50 9.6 ⫾ 1.3% 82 ⫾ 15 mmol/mol 8.4 –14.8% 68 –138 mmol/mol 13.5 ⫾ 8.5 14.4 ⫾ 8.1 23.4 ⫾ 4.1

SBP (mmHg) DBP (mmHg) eGFR (ml/min/1.73 m2) Normoalbuminuria (%)

127 ⫾ 19 80 ⫾ 11 90 ⫾ 26 98 (80)

128 ⫾ 18 80 ⫾ 12 89 ⫾ 32 93 (72)

129 ⫾ 19 82 ⫾ 10 92 ⫾ 28 74 (72)

127 ⫾ 19 81 ⫾ 13 94 ⫾ 29 69 (58)

Microalbuminuria (%) Macroalbuminuria (%)

10 (8) 14 (11)

20 (15) 17 (13)

11 (11) 18 (18)

19 (16) 32 (26)

22 (17.5%) 627 (366 – 889)

30 (22.4%) 858 (552–1163)

29 (26.9%) 1040 (664 –1418)

40 (31.7%) 1280 (886 –1674)

⬍.01 (first vs fourth)

5 (4.0%) 146 (18 –274)

11 (8.2%) 323 (132–514)

8 (7.4%) 294 (91– 498)

18 (14.3%) 605 (327– 884)

⬍.01 (first vs fourth)

25 (19.8%)

35 (26.1%)

32 (29.6%)

46 (36.5%)

743 (453–1034)

1051 (705–1398)

1193 (782–1604)

1569 (1119 –2018)

⬍.01 (first vs fourth) ⬍0.05 (second vs fourth) .06 (first vs third)

Baseline characteristics N (%) Age (y) Female/Male (%) HbA1c HbA1c range

Mortality and the incidence of RRT Deceased (n) Mortality rate per 100 000 person-years (95% CI) RRT (n) Incidence of RRT per 100 000 person-years (95% CI) Combined endpoint death and incidence of RRT (n) Incidence rate of RRT/death per 100 000 person-years (95% CI)

P Value

⬍.01 (second vs fourth) n.s. ⬍.0001

⬍0.1 (third vs fourth) n.s. n.s. n.s. n.s. n.s. ⬍.02 (fourth vs first ⫹ second; second vs third) ⬍.03 (first vs fourth) ⬍.005 (fourth vs first ⫹ second)

Data are presented as means ⫾ SD, absolute numbers of cases, percentage of cases, and rates per 100 000 person-years. BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate.

maining factors: HbA1c, systolic BP, eGFR, age, and micro-/macrolbuminuria status (Table 3A). The mortality risk increased by 22% with each percentage-point increase of HbA1c, by 27% if microalbuminuria was present and was 3.8-fold higher if macroalbuminuria was present at baseline. Mortality risk rose with increased age and higher systolic BP and with lower GFR (Table 3A). As the prevalence of albuminuria and eGFR could not be considered independent parameters (both reflecting renal function), a separate model was designed without the variable albuminuria. In this model the proportional hazards estimates remained almost the same (Table 3B). Participants with and without RRT differed in baseline variables: diabetes duration, age at diabetes onset, BP, HbA1c, eGFR, and prevalence of albuminuria. These variables were considered for the Cox proportional hazards analyses. In the final model, each 1% point higher HbA1c was related to a 35% higher risk, prevalence of microalbuminuria with 1.8-fold and macroalbuminuria with 6.9fold increased risk for RRT (Table 3C). In the model without albuminuria, HbA1c and eGFR remained in the model with similar hazard estimates (Table 3D). Examination of fractional polynomial Cox proportional hazards regressions showed no threshold of HbA1c beyond which the HR levelled off, and for mortality, RRT and the combined endpoint the fractional

polynomial models did not fit statistically significantly better than linear models (P ⫽ .244, P ⫽ .950, and P ⫽ .589, respectively).

Discussion This report describes data derived from a cohort of patients with established T1DM followed for almost 30 years in a tertiary referral hospital. Overall mortality was 24%, with an incidence of RRT of 8.6%. The combined incidence of other hard endpoints (cardio- and cerebrovascular events, end-stage renal failure, blindness, and limb amputations) assessed in the surviving participants was 21.8%. Further, subgroup analysis indicated a clear linear relationship between initial glycemic control and the subsequent risk of both mortality and the requirement for RRT. Mortality and causes of mortality Comparison of mortality rates between studies is problematic due, at least in part, to differences in average age, duration of disease at enrollment, and total duration of observation. In our study, the mean duration of diabetes at inclusion was 15 years and, in those patients still alive in 2012/2013, mean duration of di-


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cidence study (8). It should be noted, however, that in the later reports, the patients were younger and were observed for a shorter period of time (8, 9). Incidence of end stage renal disease Although the incidence of ESRD in T1DM has been falling (probably as a consequence of improvements in diabetes and BP management), many epidemiological studies in people with T1DM confirm that diabetic nephropathy still is a major predictor of mortality and endstage complications (1, 11, 12). The incidence of end stage renal disease was higher in the Allegheny cohort than in the Lainz group, despite the longer diabetes duration in our study (13). Our rate of RRT with a diabetes duration of over 40 years was similar to that observed in a Finnish study of 30 years diabetes duration (14). Although the presence of micro- or macroalbuminuria at baseline was a strong predictor of the subsequent incidence of ESRD, the total incidence of RRT was low (8.6%), indicating (in line with previous reports) that an individual with micro- or macroalbuminuria will not inevitably progress to ESRD (15).

Figure 1. Survival (A), RRT free survival (B) and cumulative survival to the combined endpoint (RRT or death). (C) From the baseline examination to the end of the study are analyzed with Kaplan-Meier curves for baseline HbA1c quartiles [HbA1c quartiles 1 (Q1, black squares), 2 (Q2, white triangles), 3 (Q3, black triangles), and 4 (Q4, white squares)].

abetes was 43 years. As with other cohort studies (8 –10) the main causes of death were cardio- and cerebrovascular events, followed by diabetes-associated causes and malignant neoplasms. Overall mortality in our patients was similar to the Allegheny T1DM cohort (USA) (10), but was almost threefold higher than in a Finnish population-based T1DM cohort (9) and a Japanese in-

Glycemic control and mortality and morbidity In comparison to our previous report of the Lainz cohort after approximately 20 years of follow-up (2), the impact of HbA1c on mortality is much clearer 10 years later. There was an increased risk of death and need for RRT even in the second quartile with HbA1c ⬎6.5%; previously, it has been suggested that there could be an HbA1c threshold above which the risk of developing renal damage increases significantly (16). Our 20-year follow up supported this, with an apparent threshold above 8.5% relevant for the development of end stage renal disease (2). After almost three decades of observation of the same cohort, the evidence suggests that the risk increases linearly with increasing HbA1c. The Diabetes Control and Complications Trial (DCCT), together with its long term observational follow up, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, have provided strong randomized controlled trial (RCT) evidence for the beneficial effects of good glycemic control on the subsequent incidence of micro- and macrovascular complications (17, 18). The almost three decade follow up of the DCCT cohorts in EDIC cohort shows that the intervention (intensively-treated) group had a strikingly better cardiovascular (18, 19) and renal (20) outcome than the control (conventionallytreated) group. The HbA1c during or at the end of the DCCT intervention was a strong predictor for subsequent outcome during observational follow-up, even though the HbA1c values in the (original) intervention and control


doi: 10.1210/jc.2014-2701


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Table 3. Association of Different Variables With All-Cause Mortality and The Incidence of Renal Replacement Therapy Using Multiple Cox Proportional Hazards Regression Models Variable (increment) Predictors of survival With albuminuria in the model (n ⫽ 397)a Age (1 y) HbA1c (1%) eGFR (1 ml/min) Systolic blood pressure (1 mmHg) No albuminuria Microalbuminuria Macroalbuminuria Without albuminuria in the model (n ⫽ 492)b Age (1 y) HbA1c (1%) eGFR (1 ml/min) Systolic blood pressure (1 mmHg) Gender (reference ⫽ men) Predictors of RRT-free survival With albuminuria in the model (n ⫽ 396)c eGFR (1 ml/min) HbA1c (1%) No albuminuria Microalbuminuria Macroalbuminuria Without albuminuria in the model (n ⫽ 406)d eGFR (1 mL/min) HbA1c (1%) Systolic blood pressure (1 mmHg)

Hazard Ratio (95% CI)

P Value

1.07 (1.05–1.09) 1.22 (1.07–1.39) 0.99 (0.98 –1.00) 1.010 (0.998 –1.021)

⬍.0001 .003 .03 .089

0.311 0.235

46.2 8.6 4.63 2.88 33.82 0.583 32.35

1.27 (0.69- 2.33) 3.81 (2.40 – 6.03)

.445 ⬍.0001

0.055 0.245 ⫺0.023 0.012 ⫺0.409

0.010 0.065 0.005 0.006 0.215

30.0 14.28 17.31 4.596 3.633

1.056 (1.036 –1.077) 1.28 (1.13–1.45) 0.978 (0.967– 0.988) 1.012 (1.001–1.023) 0.66 (0.44 –1.01)

⬍.0001 ⬍.0001

⫺0.042 0.300

25.44 10.14

0.96 (0.94 – 0.97) 1.35 (1.12–1.62)

0.597 1.934

0.008 0.094 26.72 0.543 0.388

1.209 24.884

1.82 (0.63- 5.26) 6.920 (3.236 –14.797)

⬍.0001 .001 ⬍.0001 .272 ⬍.0001

⫺0.052 0.362 0.018

0.009 0.93 0.008

34.47 15.14 4.756

0.95 (0.93– 0.97) 1.44 (1.20 –1.72) 0.95 (0.93– 0.97)

⬍.0001 ⬍.0001 .029

Coefficient

SEM

0.069 0.196 ⫺0.011 0.010

0.010 0.067 0.005 0.006

0.237 1.337

Wald ␹2

.032 .057

0, no albuminuria; 1, microalbuminuria; 2, macroalbuminuria; HR, micro- and macroalbuminuria vs no albuminuria. a

Diabetes duration, gender (each P ⬎ .2).

b

Diabetes duration (each P ⬎ .48).

c


d


groups were almost identical (0.1% absolute difference) at the conclusion of the EDIC observation period. The authors proposed the hypothesis that a “metabolic memory” for good glycemic control could have a favorable impact on subsequent outcomes (21). Our data are consistent with this hypothesis. Strengths and limitations The strengths of our study include the long duration of follow-up, access to anthropometric and biochemical data at baseline which could be included into the risk analyses, the high percentage of completed outcome questionnaires and the availability of quality of data via robust, wellmanaged national and European registries. Further, all participants had access to the best diabetes care available at the time. In the early 1980s, when this study was launched (2), our center was offering structured patient education for an intensified insulin therapy called “near normal glycemic insulin substitution” (22), and 117 patients were already using insulin pump therapy. This level of support is reflected in the relatively low mean HbA1c

of our cohort as a whole and the favorably low mortality and RRT incidence rates considering the age and disease duration. The study has obvious limitations, however. The data do not include details of whether patients moved from one HbA1c quartile to another during follow up, nor the extent to which they could have been moved by a more aggressive treatment policy. Recruited in a specialist center, our cohort is not directly comparable to a populationbased incidence registry, and endpoints occurring shortly after diabetes diagnosis may have been missed. The study participants were Caucasians, so our report cannot be used to infer outcomes in other patient groups (eg, African Americans); and data on family history of cardiovascular disease and nephropathy are not available. Although autopsy rates in Austria are high (between 1984 –1990 were 35%, between 1991–2000 were 29%, and 2001–2011 18%, from the WHO/Europe, European HFA database, July 2013), outcomes derived from death certifications have inherent limitations.


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In conclusion, while accepting that a cohort study cannot provide robust evidence for causality, data from this group of T1DM patients treated at a tertiary center show a clear linear relationship between glycemic control and mortality and the need for RRT. The data are in keeping with the hypothesis that achieving near-normoglycemia early in the evolution of T1DM has major benefits in terms of risk reduction of these outcomes over three decades of follow-up. Assuming it can be done safely, this would appear to be a worthwhile goal.


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Acknowledgments 10.

We thank Mr. J.P. Bestwick for his expert statistical assistance. Address all correspondence and requests for reprints to: Priv. Doz. Dr. Marietta Stadler, Clinical Lecturer in Diabetes, Hon Specialist Registrar Endocrinology and Diabetes, King’s College London, Diabetes Research Group, Denmark Hill, London SE5 9RS. E-mail: [email protected]; [email protected]. This work was in part supported by a grant from the Austrian Diabetes Association to M.S. (2006) and a grant from the Mayor of Vienna Funds to R.P. (2011). Author contributions and declarations. Researched data: M.S., S.P., H.S.-K., A.R.; statistical analysis: M.S., F.K., T.K.; database comparison, data entry, and control: H. S.-K, T.K. R.K.; conception of design: M.S., R.P., K.I., F.K.; supervision, funding: R.P., K.I., S.A.A.; wrote manuscript: M.S. All authors critically revised and edited the manuscript. M.S. is the guarantor for the article. Disclosure Summary: The authors have nothing to disclose.

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References 1. Orchard TJ, Secrest AM, Miller RG, Costacou T. In the absence of renal disease, 20 year mortality risk in type 1 diabetes is comparable to that of the general population: a report from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia. 2010; 53:2312–2319. 2. Stadler M, Auinger M, Anderwald C, et al. Long-term mortality and incidence of renal dialysis and transplantation in type 1 diabetes mellitus. J Clin Endocrinol Metab. 2006;91:3814 –3820. 3. Rossing P, Hougaard P, Borch-Johnsen K, Parving HH. Predictors of mortality in insulin dependent diabetes: 10 year observational follow up study. BMJ. 1996;313:779 –784. 4. Rossing P, Hougaard P, Parving HH. Risk factors for development of incipient and overt diabetic nephropathy in type 1 diabetic patients: a 10-year prospective observational study. Diabetes Care. 2002;25:859 – 864. 5. Deckert T, Poulsen JE, Larsen M. Prognosis of diabetics with dia-

18.

19.

20.

21.

22.

betes onset before the age of thirty-one. II. Factors influencing the prognosis. Diabetologia. 1978;14:371–377. Dorman JS, Laporte RE, Kuller LH, et al. The Pittsburgh insulindependent diabetes mellitus (IDDM) morbidity and mortality study. Mortality results. Diabetes. 1984;33:271–276. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461– 470. Morimoto A, Onda Y, Nishimura R, Sano H, Utsunomiya K, Tajima N. Cause-specific mortality trends in a nationwide populationbased cohort of childhood-onset type 1 diabetes in Japan during 35 years of follow-up: the DERI Mortality Study. Diabetologia. 2013; 56:2171–2175. Harjutsalo V, Forsblom C, Groop P-H. Time trends in mortality in patients with type 1 diabetes: nationwide population based cohort study. BMJ. 2011;343:d5364. Secrest AM, Becker DJ, Kelsey SF, LaPorte RE, Orchard TJ. Allcause mortality trends in a large population-based cohort with longstanding childhood-onset type 1 diabetes: the Allegheny County type 1 diabetes registry. Diabetes Care. 2010;33:2573–2579. Mühlhauser I, Overmann H, Bender R, Jörgens V, Berger M. Predictors of mortality and end-stage diabetic complications in patients with Type 1 diabetes mellitus on intensified insulin therapy. Diabet Med. 2000;17:727–734. Hovind P, Tarnow L, Rossing K, et al. Decreasing incidence of severe diabetic microangiopathy in type 1 diabetes. Diabetes Care. 2003; 26:1258 –1264. Nishimura R, Dorman JS, Bosnyak Z, Tajima N, Becker DJ, Orchard TJ. Incidence of ESRD and survival after renal replacement therapy in patients with type 1 diabetes: a report from the Allegheny County Registry. Am J Kidney Dis. 2003;42:117–124. Finne P, Reunanen A, Stenman S, Groop PH, Grönhagen-Riska C. Incidence of end-stage renal disease in patients with type 1 diabetes. JAMA. 2005;294:1782–1787. Bakris GL, Molitch M. Microalbuminuria as a risk predictor in diabetes: the continuing saga. Diabetes Care. 2014;37:867– 875. Krolewski M, Eggers PW, Warram JH. Magnitude of end-stage renal disease in IDDM: a 35 year follow-up study. Kidney Int. 1996; 50:2041–2046. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 342:381–389. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643–2653. Lachin JM, Orchard TJ, Nathan DM. Update on cardiovascular outcomes at 30 years of the diabetes control and complications trial/ epidemiology of diabetes interventions and complications study. Diabetes Care. 2014;37:39 – 43. de Boer IH. Kidney disease and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care. 2014;37:24 –30. Nathan DM. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care. 2014;37:9 –16. Waldhäusl W, Howorka K, Derfler K, et al. Failure and efficacy of insulin therapy in insulin dependent (type I) diabetic patients. Acta Diabetol Lat. 1985;22:279 –294.


Dysnatremia, its correction, and mortality in patients undergoing continuous renal replacement therapy: a prospective observational study.

Incidence of end stage renal disease among type 1 diabetes: a nationwide cohort study in Taiwan.

Diabetes. Excess mortality in well-controlled T1DM without renal disease.

Long-term outcome in ICU patients with acute kidney injury treated with renal replacement therapy: a prospective cohort study.

Inhospital Mortality in Patients with Type 2 Diabetes Mellitus: A Prospective Cohort Study in Lima, Peru.

Long-term mortality after community-acquired pneumonia--impacts of diabetes and newly discovered hyperglycaemia: a prospective, observational cohort study.

Type 2 diabetes and incidence of a wide range of cardiovascular diseases: a cohort study in 1·9 million people.

Biochemical variables and survival of patients with type 1 diabetes on renal replacement therapy.

Mortality in chronic kidney disease and renal replacement therapy: a population-based cohort study.

Effectiveness of sulphonylureas in the therapy of diabetes mellitus type 2 patients: an observational cohort study.

Is Long-Term Low-Dose Aspirin Therapy Associated with Renal Dysfunction in Patients with Type 2 Diabetes? JPAD2 Cohort Study.

Ethnicity and long-term vascular outcomes in Type 2 diabetes: a prospective observational study (UKPDS 83).

CRRTnet: a prospective, multi-national, observational study of continuous renal replacement therapy practices.

Mortality trends among people with type 1 and type 2 diabetes in Australia: 1997-2010.

Long-term outcomes of survivors of ICU acute kidney injury requiring renal replacement therapy: a 10-year prospective cohort study.

Fracture risk in adult patients treated with growth hormone replacement therapy for growth hormone deficiency: a prospective observational cohort study.

Novel Tubular Biomarkers Predict Renal Progression in Type 2 Diabetes Mellitus: A Prospective Cohort Study.

Changes in proteinuria and the risk of myocardial infarction in people with diabetes or pre-diabetes: a prospective cohort study.

Incidence of renal replacement therapy for diabetic nephropathy in the Netherlands: Dutch diabetes estimates (DUDE)-3.

Depression and Mortality in People with Type 2 Diabetes Mellitus, 2003 to 2013: A Nationwide Population-Based Cohort Study.

Association between hypoglycaemia and impaired hypoglycaemia awareness and mortality in people with Type 1 diabetes mellitus.

Arterial lactate levels in an emergency department are associated with mortality: a prospective observational cohort study.

Mortality trends among people with type 1 and type 2 diabetes in Australia: 1997-2010. Diabetes Care 2014;37:2579-2586.

Dietary Diversity, Diet Cost, and Incidence of Type 2 Diabetes in the United Kingdom: A Prospective Cohort Study.