A total of 80,348 patients had a diagnosis of diabetes and evidence of CKD. Of all patients with CKD and diabetes, 36,702 patients did not satisfy the 1-year follow-up period or the 6-month pre-index (baseline) period. Overall, 913 patients were excluded for baseline ESRD, and 300 patients were subsequently excluded for baseline PKD and IgA neuropathy. To analyze possible patients with CKD and diabetes, patients without any antiglycemic drugs during the baseline period were excluded. Finally, a total of 19,582 patients with CKD and diabetes were included in the analysis.
The mean age was 70.32 (standard deviation (SD): 10.59) years in the main cohort and 71.54 (SD: 11.05) years in the MRA subcohort (Table 1). Overall, there were more male patients (60.14%) than female patients in the main cohort, and most patients had type 2 diabetes (64.49% for the main cohort and 72.29% for the MRA subcohort). For the eGFR level at baseline, the majority (75.84%) of the main cohort had eGFR between 45 and 59 mL/min/1.73 m2, and the rest (24.16%) had an eGFR less than 45 mL/min/1.72 m2. However, since the MRA subcohort was indexed at the MRA date, 1.18% of patients were missing the eGFR at baseline, and 19.56% of patients had eGFR ≥ 60 mL/min/1.73 m2.
Table 1
Patients’ baseline characteristics
| CKD with diabetes cohort (N = 19,582) | MRA subcohort (N = 2,295) |
| Mean | SD | Mean | SD |
Age on index date (years) | 70.32 | 10.59 | 71.54 | 11.05 |
Modified Charlson Comorbidity Index | 3.00 | 2.39 | 3.68 | 2.38 |
| n | % | n | % |
Gender, n (%) | | | | |
Male | 11,776 | 60.14 | 1,364 | 59.43 |
Female | 7,806 | 39.86 | 931 | 40.57 |
Type of diabetes, n (%) | | | | |
T1DM (E10) | 436 | 2.23 | 30 | 1.31 |
T2DM (E11) | 12,629 | 64.49 | 1,659 | 72.29 |
Unknown (E12, E13, E14) | 11,546 | 58.96 | 1,229 | 53.55 |
HbA1c at baseline, n (%) | | | | |
≤ 7% | 8,946 | 45.68 | 976 | 42.53 |
> 7% | 8,607 | 43.95 | 1,074 | 46.80 |
None | 2,029 | 10.36 | 245 | 10.68 |
eGFR at baseline, n (%) | | | | |
≥ 60 ml/min/1.73 m2 | - | 0.00 | 449 | 19.56 |
45–59 ml/min/1.73 m2 | 14,851 | 75.84 | 1,134 | 49.41 |
30–44 ml/min/1.73 m2 | 2,822 | 14.41 | 441 | 19.22 |
15–29 ml/min/1.73 m2 | 1,062 | 5.42 | 179 | 7.80 |
< 15 ml/min/1.73 m2 | 847 | 4.33 | 65 | 2.83 |
None | - | 0.00 | 27 | 1.18 |
Additional Comorbidities | | | | |
Hypertension | 14,994 | 76.57 | 1,906 | 83.05 |
Congestive heart failure | 1,755 | 8.96 | 645 | 28.10 |
Primary hyperaldosteronism | 26 | 0.13 | 15 | 0.65 |
Other findings | | | | |
Hyperkaliemia | 668 | 3.41 | 55 | 2.40 |
Edema | 775 | 3.96 | 229 | 9.98 |
Renin-angiotensin-aldosterone system inhibitors (RAASis) were used at baseline by 52.3% of the main cohort with CKD and diabetes and 58.8% of the MRA subcohort (Fig. 2). At baseline, 33.91% of patients with CKD and diabetes did not have a treatment of interest. Even during follow-up, 28% of patients did not have any treatment (Figure S1). The most common treatment group at baseline was ARB + CCB (23.47%), followed by ARB alone (16.48%) and then CCB alone (10.37%). For the MRA subcohort, since the index date was defined based on the first MRA claim, all patients had MRA-based treatment at baseline. The most common treatment group was MRA alone (27.58%), followed by ARB + CCB + MRA (24.05%), then ARB + MRA (17.47%), and then CCB + MRA (13.59%).
Table 2 shows crude event rates for hyperkalemia and renal and CV-related events during follow-up. The event rate for hyperkalemia for all patients with CKD and diabetes was 5.42 per 100 person-years (PY), and 8.06 per 100 PY for the MRA subcohort. Cumulative incidences during the observation period were 5.19% for the main cohort and 7.63% for the MRA subcohort. When stratified by eGFR at baseline in the main cohort, the event rate for hyperkalemia was lowest in the 45–59 mL/min/1.73 m2 group (2.23 per 100 PY), and it jumped to 31.1 per 100 PY in the lower eGFR groups. For renal failure, the event rate for all patients was 13.39 per 100 PY. When stratified by eGFR at baseline, the event rate for renal failure was again lowest in the 45–59 mL/min/1.73 m2 group. The event rate for renal events increased as the eGFR level decreased, and this pattern was observed across all renal-related events.
Table 2
Crude event rates for hyperkalemia and renal and cardiovascular events
| CKD with diabetes cohort | MRA subcohort |
| All | eGFR 45–59* | eGFR 30–44* | eGFR 15–29* | eGFR < 15* | All |
At risk | 19,582 | 14,851 | 2,822 | 1,062 | 847 | 2,295 |
Hyperkalemia | | | | | | |
N events | 1,016 | 326 | 221 | 262 | 207 | 175 |
Event Rate (95% CI) | 5.42 (5.09, 5.76) | 2.23 (2, 2.49) | 8.34 (7.31, 9.52) | 31.1 (27.56, 35.11) | 31.13 (27.16, 35.67) | 8.06 (6.95, 9.35) |
Renal failure | | | | | | |
N events | 2,358 | 654 | 576 | 640 | 488 | 409 |
Event Rate (95% CI) | 13.39 (12.86, 13.94) | 4.56 (4.22, 4.92) | 24.38 (22.47, 26.46) | 127.25 (117.77, 137.5) | 123.05 (112.6, 134.47) | 20.64 (18.73, 22.74) |
Reduction of eGFR ≥ 40% | | | | | | |
N events | 1,643 | 882 | 326 | 224 | 211 | 466 |
Event Rate (95% CI) | 8.86 (8.44, 9.3) | 6.16 (5.77, 6.59) | 12.44 (11.16, 13.86) | 24.05 (21.1, 27.41) | 31.06 (27.14, 35.54) | 23.48 (21.44, 25.71) |
Composite CV events | | | | | | |
N events | 4,536 | 3128 | 808 | 353 | 247 | 840 |
Event Rate (95% CI) | 28.77 (27.95, 29.62) | 25.67 (24.79, 26.59) | 37.57 (35.07, 40.25) | 45.14 (40.67, 50.1) | 38.09 (33.63, 43.15) | 50.74 (47.43, 54.29) |
Myocardial infarction | | | | | | |
N events | 513 | 371 | 81 | 32 | 29 | 107 |
Event Rate (95% CI) | 2.68 (2.46, 2.92) | 2.55 (2.31, 2.83) | 2.94 (2.36, 3.65) | 3.08 (2.18, 4.36) | 3.52 (2.45, 5.07) | 4.85 (4.01, 5.86) |
Stroke | | | | | | |
N events | 2,963 | 2,140 | 500 | 178 | 145 | 343 |
Event Rate (95% CI) | 17.48 (16.86, 18.12) | 16.54 (15.85, 17.25) | 21.03 (19.26, 22.95) | 19.61 (16.93, 22.71) | 20.09 (17.07, 23.64) | 17.12 (15.4, 19.03) |
Hospitalization for HF | | | | | | |
N events | 1,515 | 886 | 327 | 195 | 107 | 537 |
Event Rate (95% CI) | 8.17 (7.77, 8.59) | 6.22 (5.82, 6.64) | 12.58 (11.28, 14.02) | 20.99 (18.24, 24.16) | 13.8 (11.42, 16.68) | 27.59 (25.35, 30.03) |
* Unit: mL/min/1.73 m2; CI: Confidence Interval; CV: Cardiovascular; HF: Heart Failure. |
Composite CV event: the first event among myocardial infarction, Stroke, or hospitalization for heart failure |
In contrast, for CV-related events, the event rate did not show an evident pattern among the different eGFR groups in the main cohort. In general, the CV-related event rate was lowest for the 45–59 mL/min/1.73 m2 group, but it varied across the other stratifications. In particular, there were higher risks for hospitalization for heart failure and composite CV-related events in the 15–29 mL/min/1.73 m2 group. All event rates for renal and CV-related events were relatively higher in the MRA subcohort.
Table 3 shows the hazard ratios (HRs) of the eGFR level at baseline for renal and CV-related events in the entire cohort with CKD and diabetes. Cox regression models showed that the adjusted HRs of renal events were much higher as the baseline eGFR decreased. For MI and stroke, the risk of eGFR at baseline was not significant after adjusting for potential confounders across all stratified groups. However, the hazard of hospitalization for heart failure was the highest in the 15–29 mL/min/1.73 m2 group (HR, 3.13; 95% confidence interval (CI), 2.68–3.66), even after adjusting for covariates. For the composite CV-related outcome, the 30–44 mL/min/1.73 m2 eGFR group had a higher hazard of the composite CV-related outcome compared to the 45–59 mL/min/1.73 m2 eGFR group (HR, 1.22; 95% CI, 1.09–1.36), although significant differences in HRs were not observed in the other strata.
Table 3
Cox regression for hyperkalemia and renal and cardiovascular events in the entire cohort with CKD and diabetes
| eGFR 45–59* | eGFR 30–44* | eGFR 15–29* | eGFR < 15* |
At risk | 14,851 | 2,822 | 1,062 | 847 |
Hyperkalemia | | | | |
Hazard ratio (95% CI) | 1.00 (ref) | 3.50 (2.94, 4.15) | 11.81 (10.03, 13.91) | 12.17 (10.21, 14.51) |
Renal failure | | | | |
Hazard ratio (95% CI) | 1.00 (ref) | 4.92 (4.40, 5.51) | 18.90 (16.92, 21.10) | 18.28 (16.23, 20.59) |
Composite CV events | | | | |
Hazard ratio (95% CI) | 1.00 (ref) | 1.22 (1.09, 1.36) | 1.13 (0.95, 1.34) | 1.00 (0.81, 1.23) |
Myocardial infarction | | | | |
Hazard ratio (95% CI) | 1.00 (ref) | 1.09 (0.86, 1.39) | 1.12 (0.78, 1.60) | 1.31 (0.90, 1.91) |
Stroke | | | | |
Hazard ratio (95% CI) | 1.00 (ref) | 1.12 (0.98, 1.28) | 0.91 (0.73, 1.13) | 0.88 (0.68, 1.14) |
Hospitalization for HF | | | | |
Hazard ratio (95% CI) | 1.00 (ref) | 1.91 (1.68, 2.17) | 3.13 2.68, 3.66) | 2.25 (1.84, 2.76) |
* Unit: mL/min/1.73 m2; CI: Confidence Interval; CV: Cardiovascular; HF: Heart Failure; ref: reference; Composite CV event: the first event among myocardial infarction, Stroke, or hospitalization for heart failure. All models were adjusted for age group (< 50, 50–59, 60–69, and 70≥), gender, hypertension and hyperlipidemia at baseline. |
Table 4 shows the HRs of hyperkalemia and renal and CV-related events in the MRA subcohort. Adjusted HRs of hyperkalemia and renal events were higher as baseline eGFR decreased, as in the main cohort. For hospitalization for heart failure, the HRs were still high across the stratified groups, and the highest in the 15–29 mL/min/1.73 m2 group (HR, 2.55; 95% CI, 1.96–3.30). On the other hand, significant differences in HRs were not observed for composite CV, MI, and stroke events, except that the HR for MI was lower in the 30–44 mL/min/1.73 m2 group.
Table 4
Cox regression for hyperkalemia and renal and cardiovascular events in the MRA subcohort
| eGFR 60≥* or None | eGFR 45–59* | eGFR 30–44* | eGFR 15–29* | eGFR < 15* |
At risk | 476 | 1,134 | 441 | 179 | 65 |
Hyperkalemia | | | | | |
Hazard ratio (95% CI) | 0.73 (0.42, 1.25) | 1.00 (ref) | 1.84 (1.22, 2.77) | 5.75 (3.85, 8.57) | 6.37 (3.68, 11.00) |
Renal failure | | | | | |
Hazard ratio (95% CI) | 0.24 (0.08, 0.67) | 1.00 (ref) | 2.57 (1.52, 4.35) | 7.36 (4.42, 12.26) | 8.20 (4.24, 15.86) |
Composite CV events | | | | | |
Hazard ratio (95% CI) | 0.73 (0.51, 1.05) | 1.00 (ref) | 0.92 (0.66, 1.28) | 0.90 (0.56, 1.43) | 0.84 (0.38, 1.84) |
Myocardial infarction | | | | | |
Hazard ratio (95% CI) | 0.33 (0.11, 0.93) | 1.00 (ref) | 0.17 (0.04, 0.68) | 0.31 (0.06, 1.54) | 0.38 (0.03, 4.97) |
Stroke | | | | | |
Hazard ratio (95% CI) | 0.91 (0.68, 1.22) | 1.00 (ref) | 1.06 (0.80, 1.40) | 1.37 (0.96, 1.96) | 0.96 (0.49, 1.87) |
Hospitalization for HF | | | | | |
Hazard ratio (95% CI) | 0.96 (0.75, 1.22) | 1.00 (ref) | 1.36 (1.09, 1.71) | 2.55 (1.96, 3.30) | 1.96 (1.26, 3.04) |
* Unit: mL/min/1.73 m2; CI: Confidence Interval; CV: Cardiovascular; HF: Heart Failure; ref: reference; Composite CV event: the first event among myocardial infarction, Stroke, or hospitalization for heart failure. All models were adjusted for age group (< 50, 50–59, 60–69, and 70≥), gender, hypertension and hyperlipidemia at baseline. |