Among examined participants with data available for all complications of interest at 35 years of diabetes duration, only 15.3% were complication free. More than 18.0% were diagnosed as having a single vascular complication, while the majority (66.3%) was diagnosed with two or more complications. In this subgroup, the observed number with any two complications co-occurring was greater than would be expected under a null hypothesis of no association (Supplemental Table 1, Supplemental digital content 1, http://links.lww.com/CAEN/A18). Particularly striking is the high χ2-statistic for the co-occurrence of ON and PR.
In time-dependent Cox proportional hazards models, allowing for baseline duration, sex, and repeated measurements over time of BMI, current smoking status, HbA1c, systolic blood pressure, hypertension medication use, and non-HDL cholesterol, evidence for an improvement in complication-free survival for the 1975–1980 diagnosis cohort was observed only for DSP and PR, although findings did not reach statistical significance (Table 2). Using year of T1D diagnosis as the main independent variable in these analyses produced similar results, with the exception of a marginal improvement in the incidence of ON with a more recent diagnosis (hazard ratio=0.72, 95% confidence interval: 0.51–1.02).
Given the suggestion of a marginal improvement in complication-free survival after adjustment for risk factor trajectories, we further evaluated whether risk factor levels differed post study baseline. Among all examined participants, a significant increase in the adoption of intensive therapy (from 5.1% in 1986–1988 to 63.0% in 2012–14, Ptrend<0.0001) was observed, which was accompanied by a decline in HbA1c (8.9% in 1986–1988 vs. 8.2% in 2012–14, Ptrend<0.0001). These trends were similar across diagnosis cohorts for HbA1c (Pinteraction=0.93), but not for intensive insulin therapy, where a significant time by diagnosis cohort interaction was observed (Pinteraction=0.04): intensive therapy was higher in the 1975–1980 diagnosis cohort until the late 1990s, and became similar across cohorts by 2004. Nevertheless, as at each given time point, the more recent diagnosis cohorts would have a shorter diabetes duration compared with their more distantly diagnosed counterparts, assessing differences in risk factor trajectories by follow-time fails to provide a clear picture of what differences may or may not exist at similar diabetes durations. We, thus, further assessed trends in intensive insulin therapy and HbA1c by diabetes duration and diagnosis cohort. Analyses were restricted to those individuals with a diabetes duration between 17 and 37 years, to assure participants across all three cohorts were studied at comparable durations. The overall proportion of adopting intensive therapy increased significantly (P<0.0001), whereas HbA1c declined across diabetes durations postbaseline (Fig. 3a); these trends were, however, similar across diagnosis cohorts (intensive therapy Pinteraction=0.36 and HbA1c Pinteraction=0.11).
During the same period, levels of BMI increased (P<0.0001), current smoking declined (P<0.0001), the proportion diagnosed with hypertension increased significantly from 9.2% (across all cohorts) in 1986–1988 to 38.5% in 2012–2014 (Ptrend<0.0001), and the concentration of non-HDL cholesterol fell (across all cohorts) (P<0.0001). BMI increased by the duration of diabetes postbaseline (BMI P<0.0001; Fig. 3b), as did hypertension (P<0.0001), whereas the proportion of current smokers (P<0.0001) and non-HDL cholesterol concentration declined (P=0.0008; Fig. 3c). Once again, no significant ‘diabetes duration by diagnosis cohort interactions’ were observed (BMI Pinteraction=0.55, current smoking Pinteraction=0.12, hypertension Pinteraction=0.15, and non-HDL cholesterol Pinteraction=0.12).
In a cohort representative of the T1D population in Allegheny County, Pennsylvania, USA, univariately, all-cause, cardiovascular and renal mortality over 35 years duration significantly declined in those with more recent onset. However, restricting analyses to examined participants, no differences in mortality were observed with a more recent diagnosis. Generally, no significant univariate differences in complication-free survival were observed across diagnosis cohorts, with the exception of LEAD incidence, which was highest in the 1975–1980 yet lowest in the 1970–1974 diagnosis cohort, and a marginal improvement in PR in the more recent diagnosis cohorts. Similar results were obtained when risk factor trajectories were accounted for, with nonsignificant improvements observed in the 1975–1980 diagnosis cohort for DSP, PR, and macroalbuminuria.
The clinical course of cumulative complication incidence by 30 years’ duration was previously compared among the intensive arm of the DCCT/EDIC, its conventional therapy arm, and a subset of the EDC cohort selected to match DCCT entry criteria 15. Lower cumulative incidences for cardiovascular disease, nephropathy, and PR were observed in the intensive therapy group, with similar complication rates observed between the conventional therapy group of DCCT/EDIC and the EDC subcohort. In addition to their support of intensive therapy as a means to curb complication development, these findings suggest that rates observed within the EDC cohort are not unusual, but rather represent those of the general T1D population in the USA.
The fact that only marginal improvements in complication-free survival with a more recent diabetes onset arose for most of the vascular complications studied after adjusting for risk factor trajectories, suggests that important risk factors may not have improved as expected over time among those diagnosed with the disease more recently. Indeed, no deviations in risk factor levels were observed across cohorts at the same diabetes duration. Thus, diabetes management improved during the study follow-up, with dramatic increases in the adoption of intensive insulin therapy after 1996–1998 and sharp declines in the concentration of HbA1c, a trend similar across diagnosis cohorts. Trends for nondiabetes specific risk factors were also similar by diabetes duration among diagnosis cohorts, and although the proportion of current smokers fell, as did the concentrations of non-HDL cholesterol, both BMI and the proportion with hypertension increased. These findings, therefore, challenge the notion that a more recent T1D diagnosis necessarily denotes improved risk factor management, leading to improved health outcomes. These results may also help explain the lack of a difference across diagnosis cohorts in the incidence of the majority of complications assessed in unadjusted models, despite a more recent onset coinciding with younger chronological age.
There exist few prospective studies, which could offer comparable data, having a similar length of follow-up on a well-phenotyped T1D cohort, and objective assessments for an extensive list of complications. The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) has previously shown that the prevalence of PR by 35 years duration declined among those diagnosed in 1975–1980 compared with individuals with a diabetes diagnosis occurring between 1922 and 1974 16. These findings, both in terms of the cumulative incidence rate and the observed trends, are similar to our data of a declining incidence of PR, which was also more pronounced in the most recent, 1975–1980, diagnosis cohort. More recently, a comparison of retinopathy severity between the WESDR cohort and another cohort from the same geographic area but diagnosed 8–34 years later showed threefold higher odds of more severe retinopathy in WESDR by 20 years of duration, a relationship which was somewhat attenuated, though still significant, after adjusting for HbA1c 17. A Danish study of individuals diagnosed with T1D between 1965 and 1984 also suggested a declining cumulative incidence of PR with a more recent diabetes onset by 20 years of duration 18; once again, these cumulative incidence rates were similar to those we observed in the EDC study by 20 years. Declines in retinopathy incidence were further reported in adolescents with T1D 19,20 and, as the previously mentioned studies in adults, these studies in youth also suggested that improvements in risk factors, including glycemic control, may be responsible for the reductions in retinopathy in more recently diagnosed cohorts. In the EDC study, taking into account repeated covariate measurements over time reduced the marginally lower risk associated with the 1975–1980 and eliminated the lower risk associated with the 1970–1974 diagnosis cohort.
The incidence of DSP, a highly prevalent and severe complication of diabetes, nonsignificantly declined in the most recent diagnosis cohort, being 63% lower in the 1975–1980 compared with the 1965–1969 diagnosis cohort. This nonsignificant decline in the development of DSP with a more recent diabetes onset emerged only after taking into account risk factor trajectories, suggesting that both strict diabetes control, as well as management of other vascular disease risk factors, such as lipids, blood pressure, body fatness, and smoking are important for the progression of this complication, as previously shown 21. Currently, no other studies have published data on trends in DSP incidence in adults with T1D. Nevertheless, among T1D youth, peripheral nerve abnormalities were shown to increase over time, regardless of whether intensification of diabetes management resulted in reductions 22, or not 23, in the concentration of HbA1c. Notably, rates reported among youth at a median duration of 7.5 years 23 seem comparable to rates observed among EDC participants diagnosed after 1970 at a duration of ~18 years. Taken together, these data suggest that peripheral nerve abnormalities are highly prevalent even among young patients with T1D and that optimal control of nonglycemic risk factors may be essential in these complications in this population. Interestingly, similar to our findings of no improvement, among T1D youth, cardiac autonomic abnormalities appeared to remain unchanged over time 23, while their prevalence was reported to be comparable to that of adults with diabetes 24, suggesting that autonomic neuropathy develops early in the natural history of T1D and remains prevalent throughout a patient’s life.
Unlike other diabetes complications, where existing data may be limited, numerous studies have focused on diabetic nephropathy, although trend data are available mostly for more advanced forms of the disease, that is, ESRD. Within the EDC study, we recently showed that the crude cumulative incidence of macroalbuminuria was essentially identical between participants diagnosed in 1950–1964 and those diagnosed in 1965–1980 by 30 and 40 years of diabetes duration, whereas rates of ESRD dramatically declined across diagnosis cohorts 25. Our current analyses focusing on the post-1965 diagnosis EDC cohort provide further support for declining renal disease mortality by 35 years of diabetes duration and a stagnant crude cumulative incidence of macroalbuminuria over time. This picture for macroalbuminuria, only slightly changed when differences in risk factor trajectories across diagnosis cohorts were accounted for, revealing a marginally significant 28% reduction in disease incidence with a more recent diabetes diagnosis year in analyses with onset year used as a continuous variable. Declines in the incidence of increased albuminuria over time were previously reported in youth with T1D 20,23, although trend analyses in adults are only available for renal replacement therapy, mostly from European countries, where ESRD incidence was reported to be much lower compared with that in the USA 25–28. Despite this, European investigators observed that ESRD has declined further over time 27,28.
In multivariable analyses, survival free from LEAD appeared to have improved nonsignificantly only in the 1970–1974 compared with the 1965–1969 diagnosis cohort, while a nonsignificant increase in incidence was observed in the 1975–1980 cohort. This lack of a significant decline in the incidence of LEAD, especially in the most recent onset cohort, likely relates to unfavorable trajectories for nondiabetes related risk factors, as they have been previously shown to contribute to the development of LEAD in this population 29.
The incidence of CAD remained unchanged across diagnosis cohorts, although significant reductions were observed in cardiovascular disease mortality in the overall cohort. Substantial reductions in the incidence of mortality, but less marked declines in hospitalization for CAD, were previously reported from the Swedish National Diabetes Register, during a shorter timeframe (1998–2014) 30, but are consistent with our data suggesting greater improvements with CAD mortality than morbidity. Data from Australia also noted declines in all-cause and cardiovascular disease mortality between 2000 and 2011, with the exception of those 0–40 years 31; in the latter group, there were significant increases in all-cause mortality and no change in cardiovascular disease mortality. As risk factor data were not available, however, the increased risk among younger individuals is difficult to explain.
There are many inherent strengths of the present study, including a well-characterized, representative cohort of childhood-onset T1D, objective assessments for an extensive list of complications, and follow-up extending beyond 25 years. However, as with any research study, the present is not free of limitations. In particular, although restricting analyses to a diabetes duration of 35 years assured estimates obtained were comparable across diagnosis cohorts, it reduced the available sample size, likely reducing our power to detect significant results. It is further likely that survival bias would have differentially affected results for individuals diagnosed earlier than would those with a more recent diabetes onset. We, however, sought to address this issue by including data for those who died prior to study baseline for analysis pertaining to mortality outcomes.
It is clear that our efforts to optimize diabetes management have been fruitful, producing dramatic declines in glycemic levels across all diagnosis cohorts. It is also evident, however, that although glycemic control is certainly an important risk factor for vascular diabetes complications and all-cause mortality, it is not sufficient, unaided, to eliminate the excess complication risk associated with T1D. Other risk factors of great consequence for the development and progression of vascular complications, such as BMI, smoking, hypertension, and dyslipidemia continue to afflict the T1D population. Alarmingly, this continues to be the case also for the most recent onset subgroup of the EDC study, although data such as those presented from Australia 31 and the similar complication rates in youth as in adults with T1D 24, suggest this observation may not be restricted to the EDC cohort. Thus, the adverse risk factor patterns, present also in the most recent cohort, are counteracting the successes in curbing complication development, which would be expected from overall improved management of dysglycemia and dyslipidemia. It is therefore of utmost importance that efforts are expanded to address other modifiable risk factors whose intense control should occur early in the natural history of this disorder in order to assure not only an increased life expectancy but also a better quality of life for patients with T1D.
Conflicts of interest
There are no conflicts of interest.
2. The Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977–986.
3. Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes
. N Engl J Med 2005; 353:2643–2653.
4. Wagener DK, Sacks JM, LaPorte RE, MacGregor JM. The Pittsburgh Study of insulin-dependent diabetes mellitus: risk for diabetes among relatives of IDDM. Diabetes 1982; 31:136–144.
5. Orchard TJ, Dorman JS, Maser RE, Becker DJ, Drash AL, Ellis D, et al. Prevalence of complications in IDDM by sex and duration. Pittsburgh Epidemiology of Diabetes Complications Study II. Diabetes 1990; 39:1116–1124.
6. [No authors listed]. International Evaluation of Cause-Specific Mortality
and IDDM. Diabetes Epidemiology Research International Mortality
Study Group. Diabetes Care 1991; 14:55–60.
7. Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 1994; 17:1281–1289.
8. Ellis D, Buffone GJ. New approach to evaluation of proteinuric states. Clin Chem 1977; 23:666–770.
9. Ellis D, Coonrod BA, Dorman JS, Kelsey SF, Becker DJ, Avner ED, Orchard TJ. Choice of urine sample predictive of microalbuminuria in patients with insulin-dependent diabetes mellitus. Am J Kidney Dis 1989; 13:321–328.
10. University of Maryland School of Medicine. Early Treatment Diabetic Retinopathy Study Coordinating Center. Manual of Operations
. Baltimore Dept of Epidemiology and Preventive Medicine, University of Maryland School of Medicine 1980:1–15.
11. Borhani NO, Kass EH, Langford HG, Payne GH, Remington RD, Stamler J. The hypertension detection and follow-up program. Prev Med 1976; 5:207–215.
12. Warnick GR, Albers JJ. Heparin-Mn2+
quantitaion of high density lipoprotein cholesterol: an ultrafiltration procedure for lipemic samples. Clin Chem 1978; 24:900–904.
13. National Institutes of Health and Department of Health. Lipid Research Clinics Program. Washington, DC: US Government Printing Office; 1975.
14. Allain CC, Poon LS, Chan CSG, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem 1974; 20:470–475.
15. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group, Nathan DM, Zinman B, Cleary PA, Backlund JY, Genuth S, Miller R, Orchard TJ. Modern-day clinical course of type 1 diabetes
mellitus after 30 years’ duration: the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983–2005). Arch Intern Med 2009; 169:1307–1316.
16. Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BE. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XXII the twenty-five-year progression of retinopathy in persons with type 1 diabetes
. Ophthalmology 2008; 115:1859–1868.
17. LeCaire TJ, Palta M, Klein R, Klein BE, Cruickshanks KJ. Assessing progress in retinopathy outcomes in type 1 diabetes
: comparing findings from the Wisconsin Diabetes Registry Study and the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Diabetes Care 2013; 36:631–637.
18. Hovind P, Tarnow L, Rossing K, Rossing P, Eising S, Larsen N, et al. Decreasing incidence of severe diabetic microangiopathy in type 1 diabetes
. Diabetes Care 2003; 26:1258–1264.
19. Downie E, Craig ME, Hing S, Cusumano J, Chan AK, Donaghue KC. Continued reduction in the prevalence of retinopathy in adolescents with type 1 diabetes
: role of insulin therapy and glycemic control. Diabetes Care 2011; 34:2368–2373.
20. Tönnies T, Stahl-Pehe A, Baechle C, Castillo K, Kuss O, Yossa R, et al. Risk of microvascular complications and macrovascular risk factors in early-onset type 1 diabetes
after at least 10 years duration: an analysis of three population-based cross-sectional surveys in Germany between 2009 and 2016. Int J Endocrinol 2018; 2018:7806980.
21. Christen WG, Manson JE, Bubes V, Glynn RJ. Sorbinil Retinopathy Trial Research Group. Risk factors for progression of distal symmetric polyneuropathy in type 1 diabetes
mellitus. Am J Epidemiol 1999; 150:1142–1151.
22. Cho YH, Craig ME, Hing S, Gallego PH, Poon M, Chan A, Donaghue KC. Microvascular complications assessment in adolescents with 2- to 5-yr duration of type 1 diabetes
from 1990 to 2006. Pediatr Diabetes 2011; 12:682–689.
23. Mohsin F, Craig ME, Cusumano J, Chan AK, Hing S, Lee JW, et al. Discordant trends in microvascular complications in adolescents with type 1 diabetes
from 1990 to 2002. Diabetes Care 2005; 28:1974–1980.
24. Jaiswal M, Divers J, Urbina EM, Dabelea D, Bell RA, Pettitt DJ, et al. SEARCH for Diabetes in Youth Study Group. Cardiovascular autonomic neuropathy in adolescents and young adults with type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth Cohort Study. Pediatr Diabetes 2018; 19:680–689.
25. Costacou T, Orchard TJ. Cumulative renal complication risk by 50 years of type 1 diabetes
: the effects of gender, age and calendar year at onset. Diabetes Care 2018; 41:426–433.
26. 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.
27. Toppe C, Möllsten A, Schön S, Jönsson A, Dahlquist G. Renal replacement therapy due to type 1 diabetes
; time trends during 1995–2010: a Swedish population based register study. J Diabetes Complications 2014; 28:152–155.
28. Prischl FC, Auinger M, Säemann M, Mayer G, Rosenkranz AR, Wallner M, Kramar R. Austrian Dialysis and Transplant Registry. Diabetes-related end-stage renal disease in Austria 1965–2013. Nephrol Dial Transplant 2015; 30:1920–1927.
29. Forrest KY, Becker DJ, Kuller LH, Wolfson SK, Orchard TJ. Are predictors of coronary heart disease and lower-extremity arterial disease in type 1 diabetes
the same? A prospective study. Atherosclerosis 2000; 148:159–169.
30. Rawshani A, Rawshani A, Franzén S, Eliasson B, Svensson AM, Miftaraj M, et al. Mortality
and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med 2017; 376:1407–1418.
31. Harding JL, Shaw JE, Peeters A, Davidson S, Magliano DJ. Age-specific trends from 2000–2011 in all-cause and cause-specific mortality
in type 1 and type 2 diabetes: a cohort study of more than one million people. Diabetes Care 2016; 39:1018–1026.
microvascular and macrovascular complications; mortality; type 1 diabetes; vascular complications
Supplemental Digital Content
© 2019Wolters Kluwer Health Lippincott Williams Wilkins