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. 2019 Aug 28;14(8):e0221044.
doi: 10.1371/journal.pone.0221044. eCollection 2019.

Major adverse cardiovascular events in people with chronic kidney disease in relation to disease severity and diabetes status

Craig J Currie  1   2 , Ellen R Berni  1 , Thomas R Berni  1 , Sara Jenkins-Jones  1 , Marvin Sinsakul  3 , Lutz Jermutus  4 , Philip Ambery  4 , Meena Jain  4
Affiliations

Major adverse cardiovascular events in people with chronic kidney disease in relation to disease severity and diabetes status

Craig J Currie et al. PLoS One. .

Abstract

Diabetes plays an important role in the complex relationship between chronic kidney disease (CKD) and cardiovascular disease. This retrospective observational study compared the influence of estimated glomerular filtration rate (eGFR) and proteinuria on the risk of major adverse cardiovascular event (MACE; myocardial infarction or stroke) in CKD patients with and without diabetes. Data were from a linked database of UK electronic health records. Individuals with CKD and no prior MACE were classified as type 1 diabetes (T1DM; n = 164), type 2 diabetes (T2DM; n = 9,711), and non-diabetes (non-DM; n = 75,789). Monthly updated time-dependent Cox proportional hazard models were constructed to calculate adjusted hazard ratios (aHRs) for progression to MACE from first record of abnormal eGFR or proteinuria (index date). In non-DM, aHRs (95% CIs) by baseline eGFR category (referent G2) were G1: 0.70 (0.55-0.90), G3a: 1.28 (1.20-1.35), G3b: 1.64 (1.52-1.76), G4: 2.19 (1.98-2.43), and G5: 3.12 (2.44-3.99), and by proteinuria category (referent A1) were A2: 1.13 (1.00-1.28), A2/3 (severity indeterminable): 1.58 (1.28-1.95), and A3: 1.64 (1.38-1.95). In T2DM, aHRs were G1: 0.98 (0.72-1.32), G3a: 1.18 (1.03-1.34), G3b: 1.31 (1.12-1.54), G4: 1.87 (1.53-2.29), G5: 2.87 (1.82-4.52), A2: 1.22 (1.04-1.42), A2/3: 1.45 (1.17-1.79), and A3: 1.82 (1.53-2.16). Low numbers in T1DM precluded analysis. Modelling T2DM and non-DM together, aHRs were, respectively, G1: 3.23 (2.38-4.40) and 0.70 (0.55-0.89); G2: 3.18 (2.73-3.70) and 1.00 (referent); G3a: 3.65 (3.13-4.25) and 1.28 (1.21-1.36); G3b: 4.01 (3.40-4.74) and 1.65 (1.54-1.77); G4: 5.78 (4.70-7.10) and 2.21 (2.00-2.45); G5: 9.00 (5.71-14.18) and 3.14 (2.46-4.00). In conclusion, reduced eGFR and proteinuria were independently associated with increased risk of MACE regardless of diabetes status. However, the risk of MACE in the same eGFR state was 4.6-2.4 times higher in T2DM than in non-DM.

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Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: CJC is a director of and EB, TRB, and SJJ are employees of Pharmatelligence, a research consultancy that received funding from MedImmune (now AztraZeneca PLC) for this study. MS, LJ, PA, and MJ are employees of AstraZeneca PLC. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Kaplan–Meier plots, with 95% confidence intervals, for time to first major adverse cardiovascular event by diabetes cohort and baseline eGFR category.
a. Type 1 diabetes, b. Type 2 diabetes, c. Non-diabetes, d. Overall MACE, major adverse cardiovascular event. eGFR, estimated glomerular filtration rate. * Index date defined as the earlier of the patient’s first abnormal eGFR or, if available, first abnormal proteinuria record.
Fig 2
Fig 2. Kaplan–Meier plots, with 95% confidence intervals, for time to first major adverse cardiovascular event by diabetes cohort and nearest proteinuria category prior to event.
a. Type 1 diabetes, b. Type 2 diabetes, c. Non-diabetes, d. Overall MACE, major adverse cardiovascular event. * Index date defined as the earlier of the patient’s first abnormal eGFR or, if available, first abnormal proteinuria record.
Fig 3
Fig 3. Adjusted hazard ratios for first major adverse cardiovascular event in type 2 diabetes, non-diabetes, and overall (combined types 1 and 2 diabetes and non-diabetes) cohorts.
* Non-hypertension = systolic < 140, or diastolic < 90; stage 1 = 140 ≤ systolic blood pressure < 160, or 90 ≤ diastolic < 100; stage 2 = 160 ≤ systolic < 180, or 100 ≤ diastolic < 110; severe = systolic ≥ 180, or diastolic ≥ 110 (units = mmHg). ** Patient has a prior record of immunosuppressive disease or was prescribed an immunosuppressive therapy in the year prior to baseline. aHR, adjusted hazard ratio. CI, confidence interval. DM, diabetes. Non-DM, non-diabetes. T2DM, type 2 diabetes. ACE, angiotensin-converting enzyme inhibitor. ARB, angiotensin II receptor antagonist. HbA1c, glycosylated haemoglobin.
Fig 4
Fig 4. Adjusted hazard ratios for first major adverse cardiovascular event by eGFR category and diabetes status in Cox models combining type 2 and non-diabetes cohorts.
eGFR, estimated glomerular filtration rate. aHR, adjusted hazard ratio. CI, confidence interval. Non-DM, non-diabetes. T2DM, type 2 diabetes. aHR, adjusted hazard ratio.
Fig 5
Fig 5. Adjusted hazard ratios for first major adverse cardiovascular event by time-dependent eGFR category in Cox models for type 2 and non-diabetes cohorts split by gender.
a. Non-diabetes–female, b. Non-diabetes–male, c. Type 2 diabetes–female, d. Type 2 diabetes–male eGFR, estimated glomerular filtration rate. aHR, adjusted hazard ratio. CI, confidence interval. Non-DM, non-diabetes. T2DM, type 2 diabetes.
Fig 6
Fig 6. Adjusted hazard ratios for first major adverse cardiovascular event by combined eGFR and proteinuria categories in Cox models combining type 1, type 2, and non-diabetes cohorts.
Low risk: adjusted hazard ratio (aHR) 1–1.5, moderately increased risk: aHR 1.5–2.5, high risk: aHR 2.51–3.5, very high risk: aHR >3.5; 95% confidence intervals are shown in parentheses. N, number of patient months.
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