Recent US guidelines expand the indications for high-intensity statin therapy, yet data on the safety of attaining very low-density lipoprotein cholesterol (LDL-C) levels are scarce. Among 16,304 participants in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) with on-treatment LDL-C levels, we identified 767 who did and 7,387 who did not achieve LDL-C <30 mg/dl on rosuvastatin 20 mg daily and 718 participants who did and 7,436 who did not achieve LDL-C reductions of ≥70% on rosuvastatin, and 8,150 allocated to placebo. In participants with an LDL-C <30 mg/dl, we observed an increase in the risk of physician-reported type 2 diabetes with an adjusted hazard ratio (95% confidence interval) of 1.56 (1.09 to 2.23, p = 0.01) and physician-reported hematuria (hazard ratio 2.10 [1.39 to 3.19], p <0.001) compared with rosuvastatin-treated participants with LDL-C ≥30 mg/dl. There was also an increased risk of certain musculoskeletal, hepatobiliary, and psychiatric disorders. No difference in renal failure, cancer, memory impairment, or hemorrhagic stroke was observed, although there were few events in these categories. In rosuvastatin-treated participants, achieving LDL-C reduction ≥70% versus <70% did not appear to be associated with increased risk of hepatobiliary, renal, or urinary disorders. In conclusion, in this post hoc analysis in the JUPITER, achieving LDL-C levels <30 mg/dl with high-intensity statin therapy appeared to be generally well tolerated but associated with certain adverse events, including more physician-reported diabetes, hematuria, hepatobiliary disorders, and insomnia. These data may guide the monitoring of patients on intensive statin therapy and adverse events in trials of therapies that lead to very low LDL-C levels.
Highlights
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Approximately 10% of participants in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin achieved low-density lipoprotein cholesterol (LDL-C) <30 mg/dl on rosuvastatin.
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The rate of adverse events in those with LDL-C <30 mg/dl on a statin was low.
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However, there was a modest increase in diabetes and hematuria in patients with LDL-C <30 mg/dl.
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No increased risk of diabetes or hematuria was seen for patients with large (≥70) percent reductions in LDL-C.
We used data from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER; clinicaltrials.gov NCT00239681 ) to evaluate the safety and adverse event profile of achieving 1 of 2 benchmarks for very low LDL-C levels while on rosuvastatin 20 mg daily: either an LDL-C <30 mg/dl or an LDL-C reduction of ≥70% from baseline.
Methods
JUPITER was a randomized, double-blind, placebo-controlled trial in men ≥50 years and women ≥60 years without a history of diabetes or cardiovascular disease and with an LDL-C <130 mg/dl and a high-sensitivity C-reactive protein ≥2.0 mg/L. Fasting lipids and apolipoprotein levels were measured according to trial protocol at baseline, annually, and at the final visit. Institutional review boards approved the protocol at each site and subjects provided written informed consent.
Of 16,304 eligible participants with on-treatment LDL-C levels, we identified placebo-allocated subjects (n = 8150) and 2 subgroups of rosuvastatin-allocated subjects based on achieving either on-treatment LDL-C <30 mg/dl (n = 767) or ≥70% LDL-C reduction (n = 718). Four hundred sixty-nine patients achieved both LDL-C goals. In a supplementary analysis, we also identified participants achieving the lowest apolipoprotein B (apoB) decile (<0.45 g/L) or top decile apoB percent reduction (≥56%) on rosuvastatin. Details on LDL-C and apoB measurements are in the Supplementary Methods online .
Adverse events were reported by local physicians and coded to Medical Dictionary for Drug Regulatory Activities preferred terms. Subjects with preexisting type 2 diabetes were excluded from the trial. The occurrence of type 2 diabetes during JUPITER was a prespecified secondary trial end point. Aside from hemorrhagic stroke, which was a component of the primary trial end point, adverse events were not adjudicated. As per the trial protocol, blood for alanine aminotransferase and creatinine and urine for urinalysis were collected at baseline, every 6 months, and at the final visit. Creatinine kinase was measured at baseline, at the final visit, and at physician discretion.
Details on the methods used to compare the baseline characteristics by achieved LDL-C and apoB, and the development of the propensity score used for risk adjustment, are in the Supplementary Methods online . The risk of adverse events for rosuvastatin-treated participants with LDL-C <30 versus ≥30 mg/dl was calculated using Cox proportional hazards models adjusted for deciles of the propensity to achieve LDL-C <30 mg/dl. Both rosuvastatin-treated groups were compared with those assigned to placebo after propensity score adjustment. We repeated this propensity-adjusted analysis for each group of rosuvastatin-treated participants achieving LDL-C ≥70% reduction, apoB <0.45 g/L, and apoB ≥56% reduction and compared them with rosuvastatin-treated participants not achieving the specific goal and to placebo-treated participants. Because this study focused on the safety of very low LDL-C, we used a p value threshold <0.05 for evidence of statistical significance. However, p values for significance should be interpreted in the context of the multiple end points that were analyzed.
Results
Baseline characteristics of participants who achieved an LDL-C <30 mg/dl on rosuvastatin, participants who achieved LDL-C reductions ≥70% on rosuvastatin, and those who did not achieve those goals on rosuvastatin or were allocated to placebo are presented in Table 1 and Supplementary Table 1 . Compared with those allocated to rosuvastatin not achieving LDL-C <30 mg/dl, participants who did had lower LDL-C levels at baseline were more likely to be men, black, and have metabolic syndrome or its components (impaired fasting glucose, higher triglycerides and BMI, lower high-density lipoprotein cholesterol). Compared with participants achieving LDL-C reductions <70%, those who achieved an LDL-C reductions ≥70% were more likely to have the metabolic syndrome or its components, more likely to be white, and had lower estimated glomerular filtration rate.
| Characteristic ∗ | LDL-cholesterol (mg/dL) < 30 (N=767) | LDL-cholesterol (mg/dL) ≥ 30 (N=7387) | P value † | Placebo (N=8150) | P-value ‡ | P-value § |
|---|---|---|---|---|---|---|
| Age (years) | 66.0 (61.0-72.0) | 66.0 (60.0-71.0) | 0.62 | 66.0 (60.0-71.0) | 0.48 | 0.63 |
| Women | 32.2% | 38.9% | <0.001 | 37.8% | 0.002 | 0.14 |
| Race/ethnicity | ||||||
| White | 69.6% | 72.6% | 0.001 | 71.8% | 0.004 | 0.50 |
| Black | 16.7% | 11.7% | 12.4% | |||
| Hispanic | 9.9% | 12.1% | 12.4% | |||
| Asian | 1.3% | 1.7% | 1.5% | |||
| Other/unknown | 2.5% | 1.9% | 1.9% | |||
| Body mass index (kg/m 2 ) | 29.3 (26.2-33.2) | 28.2 (25.2-31.9) | <0.0001 | 28.4 (25.3-32.0) | <0.0001 | 0.06 |
| Systolic blood pressure (mm Hg) | 136 (125-148) | 134 (124-145) | 0.047 | 134 (124-145) | 0.030 | 0.70 |
| Diastolic blood pressure (mm Hg) | 80 (76-87) | 80 (75-87) | 0.33 | 80 (75-87) | 0.24 | 0.64 |
| Current Smoking | 16.8% | 15.4% | 0.31 | 15.7% | 0.44 | 0.60 |
| Family History of CHD | 9.8% | 11.6% | 0.13 | 11.9% | 0.081 | 0.55 |
| Metabolic syndrome | 51.6% | 40.3% | <0.001 | 42.1% | <0.001 | 0.02 |
| Impaired fasting glucose | 36.3% | 30.6% | 0.001 | 31.8% | 0.009 | 0.13 |
| Adherence to study medication | 97.8% | 89.0% | <0.0001 | 89.3% | <0.0001 | 0.45 |
| Baseline Biomarkers | ||||||
| Total cholesterol (mg/dL) | 166 (146-186) | 187 (171-201) | <0.0001 | 185 (169-199) | <0.0001 | <0.0001 |
| LDL cholesterol (mg/dL) | 86 (70-100) | 109 (97-120) | <0.0001 | 109 (94-119) | <0.0001 | <0.0001 |
| HDL cholesterol (mg/dL) | 46 (38-56) | 49 (41-60) | <0.0001 | 49 (40-60) | <0.0001 | 0.11 |
| Triglycerides (mg/dL) | 134 (93-206) | 118 (84-166) | <0.0001 | 118 (86-170) | <0.0001 | 0.10 |
| Hemoglobin A1c (%) | 5.7 (5.4-5.9) | 5.7 (5.4-5.9) | 0.29 | 5.7 (5.5-5.9) | 0.91 | 0.006 |
| hsCRP (mg/L) | 4.4 (3.0-7.3) | 4.2 (2.8-7.0) | 0.048 | 4.3 (2.9-7.1) | 0.17 | 0.18 |
| eGFR (ml/min/1.73m 2 ) | 72.6 (64.8-86.9) | 73.6 (64.6-83.7) | 0.74 | 73.6 (64.6-83.7) | 0.87 | 0.65 |
∗ Values are medians (IQR) for continuous measures and proportion (%) for categorical measures.
† P-value for comparison of LDL-cholesterol < 30 mg/dL with LDL cholesterol ≥ 30 mg/dL among those receiving rosuvastatin.
‡ P-value for comparison LDL-cholesterol < 30 mg/dL on rosuvastatin compared to those receiving placebo.
§ P-value for comparison LDL-cholesterol ≥ 30 mg/dL on rosuvastatin compared to those receiving placebo.
Independent predictors of achieving LDL-C <30 mg/dl or an LDL-C reduction ≥70% in those randomized to rosuvastatin are displayed in Table 2 . Baseline LDL-C was a significant predictor of achieving LDL-C <30 mg/dl but not a ≥70% reduction in LDL-C. Compliance with randomized rosuvastatin therapy, age, BMI, and triglycerides were associated with increased odds of achieving each of the LDL-C goals. Hispanic subjects (vs whites) had reduced odds of achieving very low LDL-C.
| On-treatment LDL-cholesterol threshold | Adjusted Odds Ratio (95% CI) ∗ | P-value |
|---|---|---|
| LDL-cholesterol < 30 mg/dL | ||
| Age (per 5 year increment) | 1.11 (1.05-.18) | 0.0008 |
| Race/ethnicity (vs. white) | ||
| Black | 0.81(0.62-1.07) | 0.13 |
| Hispanic | 0.50 (0.37-0.67) | <0.0001 |
| Asian | 0.86 (0.42-1.77) | 0.68 |
| Other | 1.22 (0.70-2.15) | 0.48 |
| Male sex | 1.27 (1.05-1.54) | 0.02 |
| BMI (per 1 kg/m 2 increment) | 1.03 (1.02-1.05) | <0.0001 |
| Metabolic syndrome | 1.20 (0.98-1.48) | 0.08 |
| Baseline LDL-C (per 10 mg/dL increment) | 0.58 (0.55-0.60) | <0.0001 |
| Baseline triglycerides (per 10 mg/dL increment) | 1.03 (1.02-1.04) | <0.0001 |
| Systolic blood pressure (per 10 mm Hg increment) | 1.04 (0.99-1.10) | 0.11 |
| hsCRP (per 1 mg/L increment) | 0.99 (0.98-1.00) | 0.05 |
| eGFR (per 10 ml/min/1.73 m 2 increment) | 0.96 (0.91-1.02) | 0.15 |
| Adherence to study medication | 6.97 (4.12-11.80) | <0.0001 |
| LDL-cholesterol ≥ 70% reduction | ||
| Age (per 5 year increment) | 1.13 (1.07-1.20) | <0.0001 |
| Race/ethnicity (vs. white) | ||
| Black | 0.74 (0.56-0.99) | 0.04 |
| Hispanic | 0.46 (0.34-0.62) | <0.0001 |
| Asian | 1.11 (0.61-2.02) | 0.73 |
| Other | 1.03 (0.58-1.81) | 0.93 |
| Body mass index (per 1 kg/m 2 increment) | 1.03 (1.01-1.04) | 0.0001 |
| Impaired fasting glucose | 1.28 (1.09-1.52) | 0.003 |
| Baseline LDL-C (per 10 mg/dL increment) | 0.96 (0.92-1.00) | 0.05 |
| Baseline triglycerides (per 10 mg/dL increment) | 1.05 (1.04-1.06) | <0.0001 |
| Systolic blood pressure (per 10 mm Hg increment) | 1.05 (1.00-1.11) | 0.03 |
| eGFR (per 10 ml/min/1.73 m 2 increment) | 0.95 (0.90-1.01) | 0.08 |
| Adherence to study medication | 9.51 (5.06-17.87) | <0.0001 |
| Current cigarette smoker | 1.21 (0.97-1.52) | 0.10 |
∗ Odds ratios (OR), 95% confidence intervals, and P-values are adjusted for all listed variables. Variables were identified for inclusion with stepwise logistic regression using P <0.15 in univariable analyses for inclusion. Once a variable was in the model, multivariate P <0.15 was required for it to remain in the model. Terms for race/ethnicity were included in the model as a group if any one category of race/ethnicity met the P-value threshold for remaining in the multivariate model. Adherence to study medication was defined as taking at least 80% of the assigned medication at the 1-year visit. The variables listed were used to develop two propensity scores: one for achieving an LDL-C < 30 mg/dL and another for achieves a ≥ 70% reduction in LDL-C.
Participants of black, Hispanic, and Asian race were all less likely than whites to achieve either apoB <0.45 g/L or apoB reductions ≥56% ( Supplementary Table 2 ). Higher concentrations of apoB reduced the odds of achieving apoB <0.45 g/L but increased the odds of achieving apoB reductions ≥56%. Compliance with rosuvastatin and higher concentrations of total cholesterol, high-density lipoprotein cholesterol, triglycerides, and HbA1c increased the odds, whereas smoking and high-sensitivity C-reactive protein reduced the odds of achieving very low apoB.
In the participants who achieved LDL-C <30 mg/dl, the adjusted risk of the composite outcome of any adverse event was higher than in those assigned to active therapy with LDL-C ≥30 mg/dl ( Table 3 ). No difference was seen by LDL-C reduction ≥70% or <70% ( Table 4 ). The rate of musculoskeletal disorders was similar for rosuvastatin-treated patients, regardless of achieved LDL-C <30 or ≥30 mg/dl. However, compared with the placebo-treated group, musculoskeletal disorders were more common in each of the rosuvastatin-treated groups. Rates of musculoskeletal disorders in those with LDL-C reductions ≥70% versus <70% on rosuvastatin were similar. Although the incidence of hepatobiliary disorders was low in each of the achieved LDL-C groups, we observed a statistically significant increase in the risk for those with LDL-C <30 mg/dl compared with rosuvastatin-treated patients with LDL-C ≥30 mg/dl and compared with those allocated to placebo ( Table 3 ). No differences by LDL-C reduction ≥70% or <70% were observed.
| Adverse Event | LDL-cholesterol (mg/dL) <30 (N=767) | LDL-cholesterol (mg/dL) ≥30 (N=7387) | Adjusted † Relative Risk (LDL-cholesterol (mg/dL) < vs. ≥ 30) | Placebo (N=8150) | Adjusted † Relative Risk (LDL-cholesterol (mg/dL) <30 vs. Placebo) | Adjusted † Relative Risk (LDL-cholesterol (mg/dL) ≥30 vs. Placebo) |
|---|---|---|---|---|---|---|
| N (Incidence rate ∗ ) | N (Incidence rate ∗ ) | N (Incidence rate ∗ ) | ||||
| Any | 620 (103.0) | 5930 (106.5) | 1.10 (1.01-1.21) ‡ | 6509 (103.1) | 1.06 (0.98-1.16) | 1.02 (0.98-1.05) |
| Musculoskeletal Disorders | 306 (23.6) | 2874 (24.4) | 1.08 (0.95-1.23) | 2930 (21.7) | 1.14 (1.00-1.29) ‡ | 1.11 (1.06-1.17) § |
| Myalgia | 49 (2.8) | 594 (3.8) | 0.88 (0.64-1.20) | 559 (3.2) | 1.00 (0.74-1.36) | 1.16 (1.03-1.31) ‡ |
| Rhabdomyolysis/myopathy/myositis | 2 (0.1) | 8 (0.05) | 1.83 (0.34-9.87) | 9 (0.05) | 2.33 (0.44-12.33) | 1.04 (0.40-2.71) |
| Muscular weakness | 4 (0.2) | 69 (0.4) | 0.87 (0.30-2.58) | 61 (0.3) | 0.76 (0.27-2.19) | 1.26 (0.88-1.77) |
| CK >2x ULN | 1 (0.05) | 1 (0.006) | – | 1 (0.005) | – | – |
| Hepatobiliary Disorders | 30 (1.7) | 149 (0.9) | 1.77 (1.15-2.73) ¶ | 177 (1.0) | 2.01 (1.33-3.05) ¶ | 0.92 (0.74-1.14) |
| Hepatic steatosis | 3 (0.2) | 13 (0.08) | 2.00 (0.54-7.48) | 22 (0.1) | 2.16 (0.60-7.73) | 0.64 (0.32-1.28) |
| ALT > 3x ULN | 13 (0.7) | 109 (0.7) | 1.14 (0.61-2.13) | 84 (0.5) | 1.43 (0.76-2.69) | 1.44 (1.08-1.92) ‡ |
| Biliary disease NOS | 3 (0.2) | 9 (0.05) | 2.01 (0.45-8.97) | 9 (0.05) | 4.48 (1.08-18.52) ‡ | 1.14 (0.45-2.87) |
| Cholecystitis | 5 (0.3) | 22 (0.1) | 1.74 (0.61-4.94) | 32 (0.2) | 2.02 (0.74-5.51) | 0.73 (0.42-1.26) |
| Cholelithiasis/choledocholithiasis | 15 (0.8) | 78 (0.5) | 1.67 (0.91-3.06) | 92 (0.5) | 1.90 (1.06-3.41) ‡ | 0.91 (0.67-1.23) |
| Hepatic disease NOS | 5 (0.3) | 30 (0.2) | 1.83 (0.62-5.40) | 29 (0.2) | 1.51 (0.54-4.23) | 1.15 (0.68-1.94) |
| Nervous system disorders | 136 (8.3) | 1212 (8.3) | 1.13 (0.93-1.38) | 1431 (8.8) | 1.02 (0.85-1.23) | 0.92 (0.86-1.00) |
| Fatigue | 27 (1.5) | 282 (1.8) | 1.76 (0.55-1.32) | 297 (1.7) | 1.04 (0.68-1.59) | 1.05 (0.90-1.25) |
| Memory Impairment | 4 (0.2) | 29 (0.2) | 1.26 (0.34-4.59) | 33 (0.2) | 0.63 (0.18-2.21) | 1.05 (0.63-1.74) |
| Hemorrhagic stroke | 0 | 5 (0.03) | – | 8 (0.04) | – | 0.58 (0.18-1.95) |
| Psychiatric Disorders | 69 (4.0) | 534 (3.4) | 1.40 (1.06-1.85) ¶ | 619 (3.6) | 1.20 (0.92-1.57) | 0.95 (0.84-1.07) |
| Insomnia | 27 (1.5) | 195 (1.2) | 1.59 (1.03-2.48) ‡ | 205 (1.1) | 1.55 (1.01-2.38) ‡ | 1.05 (0.86-1.28) |
| Depression | 19 (1.0) | 167 (1.0) | 1.14 (0.68-1.92) | 217 (1.2) | 0.86 (0.52-1.41) | 0.86 (0.70-1.05) |
| Anxiety | 17 (0.9) | 114 (0.7) | 1.42 (0.80-2.50) | 158 (0.9) | 1.21 (0.71-2.06) | 0.77 (0.60-0.99) ‡ |
| Diabetes | 47 (2.6) | 209 (1.3) | 1.56 (1.09-2.23) ‡ | 209 (1.2) | 1.90 (1.34-2.68) § | 1.15 (0.96-1.41) |
| Cancer | 19 (1.0) | 240 (1.5) | 0.76 (0.46-1.25) | 269 (1.5) | 0.65 (0.40-1.06) | 1.02 (0.85-1.21) |
| Renal and Urinary Disorders | 107 (6.4) | 676 (4.3) | 1.51 (1.21-1.90) § | 782 (4.5) | 1.37 (1.10-1.70) ¶ | 0.95 (0.86-1.05) |
| Physician-reported hematuria | 34 (1.9) | 175 (1.1) | 2.10 (1.39-3.19) § | 175 (1.0) | 1.85 (1.24-2.77) ¶ | 1.10 (0.89-1.36) |
| Physician-reported Proteinuria | 15 (0.8) | 113 (0.7) | 1.33 (0.74-2.41) | 111(0.6) | 1.46 (0.82-2.59) | 1.13 (0.87-1.47) |
| Renal failure | 13 (0.7) | 58 (0.4) | 1.90 (0.95-3.79) | 70 (0.4) | 1.43 (0.76-2.74) | 0.91 (0.64-1.29) |
| Drop in eGFR by 30+% | 68 (3.7) | 643 (3.9) | 0.87 (0.66-1.15) | 774 (4.2) | 0.84 (0.64-1.09) | 0.92 (0.83-1.03) |
| Fall in eGFR to < 60 mL/min/1.73 m 2 | 292 (17.3) | 2704 (17.7) | 0.95 (0.83-1.09) | 3067 (18.2) | 0.92 (0.81-1.05) | 0.97 (0.92-1.02) |
| Hematuria ≥2+ ‖ | 71 (4.1) | 570 (3.6) | 1.18 (0.90-1.55) | 531 (3.0) | 1.29 (0.99-1.69) | 1.20 (1.07-1.36) ¶ |
| Proteinuria ≥2+ || | 57 (3.2) | 404 (2.5) | 1.02 (0.74-1.37) | 387 (2.2) | 1.24 (0.92-1.69) | 1.17 (1.01-1.35) ‡ |
∗ Incidence rates are the number of events per 100 person-years of observation.
† Risk estimates adjusted for deciles of propensity to achieve LDL-C < 30 mg/dl. The propensity score was calculated using the covariables associated with achieving this degree of LDL-C reduction, presented in Table 3 .
| Adverse Event | LDL-cholesterol reduction ≥70% (N=718) | LDL-cholesterol reduction < 70% (N=7436) | Adjusted † Relative Risk (reduction ≥ 70% vs. <70%) | Placebo (N=8150) | Adjusted † Relative Risk (reduction ≥ 70% vs. placebo) | Adjusted † Relative Risk (reduction < 70% vs. Placebo) |
|---|---|---|---|---|---|---|
| N (Incidence rate ∗ ) | N (Incidence rate ∗ ) | N (Incidence rate ∗ ) | ||||
| Any Adverse Event | 587 (103.9) | 5963 (106.3) | 1.00 (0.92-1.09) | 6509 (103.1) | 1.01 (0.93-1.10) | 1.03 (0.99-1.06) |
| Musculoskeletal Disorders | 303 (24.4) | 2877 (24.3) | 1.03 (0.91-1.16) | 2930 (21.7) | 1.12 (0.99-1.27) | 1.12 (1.06-1.18) ‡ |
| Myalgia | 51 (3.0) | 592 (3.8) | 0.99 (0.74-1.33) | 559 (3.2) | 1.11 (0.83-1.49) | 1.16 (1.03-1.30) § |
| Rhabdomyolysis/myopathy/myositis | 1 (0.06) | 9 (0.05) | 1.12 (0.97-1.29) | 9 (0.05) | 1.37 (0.17-10.99) | 1.11 (0.44-2.81) |
| Muscular weakness | 4 (0.2) | 69 (0.4) | 0.61 (0.22-1.71) | 61 (0.3) | 0.75 (0.75-2.10) | 1.27 (0.90-1.80) |
| CK >2x ULN | 0 | 2 (0.01) | – | 1 (0.01) | – | 2.55 (0.23-28.32) |
| Hepatobiliary Disorders | 26 (1.5) | 153 (0.9) | 1.44 (0.93-2.24) | 177 (1.0) | 1.51 (0.98-2.33) | 0.95 (0.76-1.18) |
| Hepatic steatosis | 3 (0.2) | 13 (0.1) | 1.85 (0.51-6.67) | 22 (0.1) | 1.77 (0.51-6.15) | 0.66 (0.33-1.31) |
| ALT > 3x ULN | 9 (0.5) | 113 (0.7) | 0.88 (0.44-1.76) | 84 (0.5) | 1.48 (0.73-3.01) | 1.45 (1.09-1.93) ¶ |
| Biliary disease NOS | 1 (0.06) | 11 (0.07) | 0.90 (0.11-7.39) | 9 (0.05) | 1.36 (0.56-3.29) | 1.10 (0.14-9.07) |
| Cholecystitis | 6 (0.3) | 21 (0.1) | 1.77 (0.65-4.85) | 32 (0.2) | 0.73 (0.42-1.26) | 1.59 (0.60-4.22) |
| Cholelithiasis/choledocholithiasis | 14 (0.8) | 79 (0.5) | 1.50 (0.83-2.71) | 92 (0.5) | 0.92 (0.68-1.25) | 1.52 (0.86-2.71) |
| Hepatic disease NOS | 5 (0.3) | 30 (0.2) | 1.92 (0.72-5.17) | 29 (0.2) | 1.15 (0.68-1.94) | 1.86 (0.52-6.66) |
| Nervous system disorders | 134 (8.6) | 1214 (8.2) | 1.04 (0.86-1.25) | 1431 (8.8) | 0.98 (0.81-1.17) | 0.93 (0.86-1.01) |
| Fatigue | 29 (1.7) | 280 (1.7) | 1.01 (0.68-1.51) | 297 (1.7) | 1.03 (0.69-1.53) | 1.06 (0.90-1.25) |
| Memory Impairment | 3 (0.2) | 30 (0.2) | 0.72 (0.17-3.09) | 33 (0.2) | 0.59 (0.14-2.51) | 1.08 (0.66-1.79) |
| Hemorrhagic stroke | 0 | 5 (0.03) | – | 8 (0.04) | – | 0.55 (0.17-1.82) |
| Psychiatric Disorders | 63 (3.8) | 540 (3.4) | 1.15 (0.88-1.50) | 619 (3.6) | 1.02 (0.78-1.33) | 0.96 (0.86-1.08) |
| Insomnia | 27 (1.6) | 195 (1.2) | 1.32 (0.87-1.99) | 205 (1.1) | 1.29 (0.85-1.94) | 1.05 (0.87-1.29) |
| Depression | 20 (1.1) | 166 (1.0) | 1.16 (0.72-1.88) | 217 (1.2) | 0.91 (0.57-1.45) | 0.85 (0.69-1.04) |
| Anxiety | 14 (0.8) | 117 (0.7) | 1.12 (0.64-1.98) | 158 (0.9) | 0.90 (0.52-1.57) | 0.80 (0.63-1.02) |
| Diabetes | 42 (2.4) | 214 (1.3) | 1.33 (0.95-1.87) | 209 (1.2) | 1.55 (1.11-2.19) § | 1.18 (0.98-1.43) |
| Cancer | 22 (1.3) | 237 (1.5) | 0.83 (0.53-1.30) | 269 (1.5) | 0.84 (0.54-1.30) | 1.00 (0.84-1.20) |
| Renal and Urinary Disorders | 89 (5.4) | 694 (4.5) | 1.15 (0.92-1.45) | 782 (4.5) | 1.12 (0.90-1.41) | 0.98 (0.89-1.09) |
| Physician-reported hematuria | 27 (1.5) | 182 (1.1) | 1.34 (0.88-2.04) | 175 (1.0) | 1.52 (1.00-2.32) § | 1.15 (0.94-1.42) |
| Physician-reported proteinuria | 16 (0.9) | 112 (0.7) | 1.31 (0.77-2.04) | 111 (0.6) | 1.46 (0.86-2.50) | 1.13 (0.87-1.48) |
| Renal failure | 8 (0.5) | 63 (0.4) | 0.98 (0.46-2.09) | 70 (0.4) | 0.90 (0.43-1.90) | 0.98 (0.69-1.39) |
| Drop in eGFR by 30+% | 52 (2.9) | 659 (4.0) | 0.79 (0.59-1.06) | 774 (4.2) | 0.75 (0.56-1.00) | 0.93 (0.84-1.03) |
| Fall in eGFR to < 60 mL/min/1.73 m 2 | 310 (19.1) | 2686 (17.5) | 0.93 (0.82-1.05) | 3067 (18.2) | 0.91 (0.81-1.03) | 0.97 (0.92-1.02) |
| Hematuria ≥2+ ‖ | 65 (3.9) | 576 (3.6) | 1.03 (0.79-1.34) | 531 (3.0) | 1.33 (1.02-1.73) § | 1.21 (1.07-1.36) ¶ |
| Proteinuria ≥2+ ‖ | 52 (3.0) | 409 (2.5) | 1.02 (0.75-1.38) | 387 (2.2) | 1.16 (0.86-1.58) | 1.16 (1.01-1.34) § |
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