Medalists (n = 351) had a mean ± SD age of 67.5 ± 7.5 years and diabetes duration of 56.5 ± 5.7 years. Characteristics () were consistent with type 1 diabetes: mean age at diagnosis 11.0 ± 6.3 years, BMI 26.0 ± 5.1 kg/m2, and HLA DR3 or DR4 risk alleles present in 90.8% of subjects. HbA1c levels were 7.3 ± 1.0% with HDL levels of 1.62 ± 0.51 mmol/L and LDL levels of 2.22 ± 0.63 mmol/L. Six percent of subjects demonstrated random C-peptide >0.13 nmol/L.
Baseline characteristics of 50-year Medalist cohort
High proportions of Medalists remained free from PDR (49.4%), nephropathy (86.9%), neuropathy (39.4%), or cardiovascular disease (51.5%) (). Of 255 subjects for whom all three microvascular complications were characterized, 21.2% were free of PDR, nephropathy, and neuropathy. A bimodal diabetic retinopathy distribution was present with 40.2% having no-mild nonproliferative diabetic retinopathy and 48.5% having PDR (). In contrast, 86.9% of Medalists had no nephropathy (ACR <70 μg/mg creatinine) with only 4.7% exhibiting proteinuria (ACR ≥300 μg/mg creatinine).
Figure 1 A: Prevalence of micro- and macrovascular diabetes complications in the 50-year Medalist cohort. mod, moderate; microalb, microalbuminuria; NPDR, nonproliferative diabetic retinopathy. B: Bimodal distribution of diabetic retinopathy severity in the Medalist (more ...)
Factors associated with complications after 50 years of diabetes differ from those in shorter duration diabetes
Factors associated with individual complications were not necessarily consistent with those established for shorter duration diabetes (Supplementary Table 2
). No significant relationship was found between glycemic control and any complication in the Medalist cohort.
Longitudinal glycemic control (HbA1c from 1993 onward) was assessed for 73 Medalists (20.1%) followed at the Joslin clinic. The average number of HbA1c measurements was 20.4. Mean HbA1c was 7.7%. This subgroup did not differ from the overall cohort on age, age of diagnosis, duration of diabetes, blood pressure, lipid profile, or complication status. Current HbA1c was highly correlated with longitudinal HbA1c (r = 0.82, P < 0.001). Consistent with the lack of association between current HbA1c and complications, no significant relationship was found between longitudinal HbA1c and complications.
Systolic (sBP) and diastolic (dBP) blood pressure, also typically associated with complications in subjects with shorter duration disease, did not correlate with microvascular complications in the Medalists. Longer duration of diabetes was associated with increased nephropathy (P = 0.009), neuropathy (P = 0.009), and cardiovascular disease (P = 0.03), but not retinopathy. Cardiovascular disease was more prevalent in subjects with lower sBP (P = 0.01) and mean arterial pressure (P = 0.004), lower heart rate (P = 0.002), and lower total cholesterol (P < 0.001) or LDL (P < 0.001), likely because of high percentages of these subjects on hypertensive and/or lipid-lowering medications.
Subjects with nephropathy were more likely to report a history of smoking (P < 0.001). Neuropathy was related to older current age (P < 0.001), increased height (P = 0.003), and heavier weight (P = 0.03). Macrovascular complications were related to older current age (P = 0.02).
Lipoprotein subpopulations were assessed (Supplementary Table 2
). Higher rates of cardiovascular disease were related to elevations in lipoprotein(a) (P
= 0.04) and decreases in HDL (P
< 0.001). Higher levels of pre-β2 HDL were associated with each complication, but these elevations were statistically significant only for nephropathy (P
= 0.02) and cardiovascular disease (P
Inflammatory marker evaluation revealed that higher levels of C-reactive protein were observed for cardiovascular disease (P < 0.001), and significant elevations of soluble vascular cell adhesion molecule-1 were present in those with neuropathy (P = 0.02) and nephropathy (P = 0.05) but not retinopathy. Other inflammatory markers did not differ between subjects with and without complications. Similarly, oxidative stress biomarkers including urinary 8-isoprostane and mRNA levels of superoxide dismutase, heme oxygenase 1, catalase, and glutamate-cysteine ligase catalytic subunit were not associated with complication status.
Long-term data on retinopathy progression and stabilization
Factors associated with prolonged protection from complications were evaluated in 97 Medalists with median ophthalmic follow-up of 23 years (Q1, Q3: 8, 31 years), number of visits 33 (4, 63 visits), and diabetes duration 56 years (53, 61 years). This group was not significantly different from the cross-sectional cohort in age, age at diagnosis, current or longitudinal HbA1c, sBP or dBP, or heart rate, but it did have higher total cholesterol levels (4.46 vs. 4.25 mmol/L, P = 0.03).
Over time, 46 patients (47.4%) without PDR at baseline progressed to PDR (median time to PDR: 38.4 years). Subjects who developed PDR had higher sBP than those who did not develop PDR (144 vs. 125 mmHg, P = 0.02), but there was no relationship between PDR development and current or longitudinal HbA1c, age, age at diagnosis, diabetes duration, sex, BMI, dBP, heart rate, or lipid parameters.
Of 25 subjects with no baseline diabetic retinopathy in either eye, 11 (44%) remained free of PDR in both eyes at the last visit. The retinopathy progression rate was slower in Medalists who did not progress to PDR in either eye as compared with those that did (P < 0.001) (). Of the 24 Medalists (52%) whose retinopathy did not worsen over the first 17 years of follow-up, 23 (96%) did not worsen thereafter with follow-up out to a minimum duration of diabetes of 50.4 years and median follow-up of 13 years (Q1, Q3: 6, 27 years).
Worsening retinopathy in Medalists who do and do not progress to PDR. DR, diabetic retinopathy; sig, significant. (A high-quality color representation of this figure is available in the online issue.)
Complication associations with AGEs
Given the lack of correlation between current HbA1c
and complications, we assessed markers of long-term glycemic control in the Medalists by evaluating the early glycation product fructose-lysine/fructosamine and AGE concentrations including CEL, an AGE derived from methylglyoxal; pentosidine, a glycoxidation product; and CML, a glycoxidation and advanced lipoxidation product. CEL and fructose-lysine CML were significantly elevated in the Medalists as compared with nondiabetic, age-matched control subjects (n
= 23, mean age 67.7 years) (Supplementary Table 3
A combined biomarker of CEL and pentosidine was highly associated with complication status. Subjects with both CEL and pentosidine ≥median levels (“high CEL and pentosidine”: CEL ≥5.3 μmol/mol lysine and pentosidine ≥1.0 pmol/mg protein) were the most likely to have any complication (P = 0.001) or suffer from nephropathy (P = 0.007), neuropathy (P = 0.005), or cardiovascular disease (P = 0.002). Subjects with either CEL or pentosidine (but not both) at or above the median had an intermediate risk of severe complications, and subjects with both CEL and pentosidine below the median had the lowest complication risk. The odds of complications in Medalists with high CEL and pentosidine as compared with those with low CEL and pentosidine were 7.2-fold for any complication, 1.3-fold for retinopathy, 3.1-fold for nephropathy, 2.5-fold for neuropathy, and 2.3-fold for cardiovascular disease ().
Figure 3 A: Relative odds of complications associated with high vs. low CEL and pentosidine levels. Cx, complication; Pent, pentosidine. B: Risk of PDR development by CEL and pentosidine levels. DM, diabetes; Pent, pentosidine. C: Progression to PDR in patients (more ...)
The relationship between current AGE concentrations and risk of progression to PDR was examined in Medalists with longitudinal follow-up. Increased risk of PDR was seen in subjects with high CEL and pentosidine as compared with the rest of the cohort (P = 0.05) (). A combination biomarker that also included CML and fructose-lysine segmented by median (“low CML and fructose-lysine”: CML <59.8 and fructose-lysine <1,004 μmol/mol lysine) was even more strongly associated with PDR outcome (P = 0.02) (). None of the four subjects with low CEL and pentosidine (CEL and pentosidine levels below the median) and high CML and fructose-lysine (CML and fructose-lysine levels above the median) progressed to PDR over the course of follow-up. Conversely, five of seven subjects with high CEL and pentosidine and low CML and fructose-lysine progressed to PDR.