Cardio-Renal-Metabolic Syndrome?
The association between type 2 diabetes (DM2) and atherosclerotic cardiovascular disease (ASCVD) is often referred to as cardiometabolic syndrome, while the relationship between chronic kidney disease (CKD) and heart failure (HF) is known as cardiorenal syndrome. Additionally, an increased prevalence of ASCVD, CKD, and HF is known among patients with type 2 diabetes. A recent study investigated the hypothesis that both syndromes constitute a single entity − the so-called cardio-renal-metabolic syndrome.
Study Methodology and Data Analyzed
The authors of this study analyzed the impact of the presence of DM2, ASCVD, and HF on the incidence and progression of CKD over 15 years of follow-up.1 They used the electronic health records of Kaiser Permanente Northwest, a healthcare provider in Washington, and identified 387,985 adults who had serum creatinine levels determined between 2005 and 2017. If their estimated glomerular filtration rate (eGFR) was < 60 ml/min/1.73 m2, further measurement was necessary within 3-12 months to confirm renal dysfunction.
Patients were followed until 2019. The incidence and progression of CKD adjusted for age and gender were then calculated per 1,000 patient-years of follow-up. CKD incidence was estimated in individuals without CKD at study entry, and CKD progression in those with CKD at study entry. Progression was defined as a worsening of eGFR according to The Kidney Disease Improving Global Outcomes criteria (stage 3a defined as eGFR 45-59 ml/min/1.73 m2; stage 3b as eGFR 30-44 ml/min/1.73 m2; stage 4 as eGFR 15-29 ml/min/1.73 m2; and stage 5 as eGFR < 15 ml/min/1.73 m2 or dialysis or kidney transplantation). The time-dependent effect of individual diseases (CKD, ASCVD, HF, and DM2) on the incidence of the remaining three diseases was further estimated using a Cox model. The incidence of ASCVD, HF, and DM2 was determined using ICD-9 codes.
Key Findings
Association of CKD at Study Entry with Cardiovascular Diseases and DM
At study entry, 17,240 (4.5%) patients had CKD. They were significantly older (average 72.8 vs. 49.6 years; p < 0.001) and more likely to suffer from DM2, ASCVD, or HF, either individually or in various combinations, compared to individuals without CKD at study entry. Only 46.5% of patients with CKD had none of these three diseases at study entry compared to 85.4% of patients without CKD (p < 0.001).
Higher CKD Incidence with the Presence of Cardiovascular Disease and DM
The observed CKD incidence was highest in patients with DM2, ASCVD, and HF (27 per 1,000 patient-years) compared to a CKD incidence of 5.9 per 1,000 patient-years in individuals without all three mentioned diseases. The second most risky combination of diseases for CKD onset was the presence of DM2 and HF. After adjusting for risk factors, the risk of developing CKD was 77% higher in individuals with DM2 at study entry, 76% higher in individuals with HF, and 21% higher in individuals with ASCVD. In a time-dependent model, the most significantly increased CKD risk was among individuals who developed HF during follow-up (2.14-fold increased risk).
More Frequent CKD Progression with Cardiovascular Disease and DM
Similar results were obtained regarding CKD progression risk: the progression incidence reached 309 per 1,000 patient-years in patients with DM2, ASCVD, and HF at study entry, and 280 per 1,000 patient-years in those with DM2 and HF, compared to 147.8 per 1,000 patient-years in individuals without any of these three diseases at the study’s start. The risk of CKD progression was 37% higher in individuals with DM2 and 35% higher in those with HF at study entry.
Bidirectional Association
All associations between the occurrence/progression of CKD, DM2, HF, and ASCVD were statistically significant and bidirectional. It was confirmed that each of these diseases represents an independent risk factor for the others.
Need for a Holistic Approach to Type 2 Diabetes Treatment
The interrelationship of DM2, CKD, HF, and ASCVD and the possible existence of cardio-renal-metabolic syndrome necessitates a holistic view of patient care. The consensus recommendations of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) for the treatment of DM2 strongly emphasize this therapeutic approach and describe the importance of multifactorial treatment and the use of a comprehensive approach even when selecting antidiabetic medication.2
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Sources:
1. Nichols G. A., Amitay E. L., Chatterjee S., Steubl D. The bidirectional association of chronic kidney disease, type 2 diabetes, atherosclerotic cardiovascular disease, and heart failure: the cardio-renal-metabolic syndrome. Metab Syndr Relat Disord 2023 Jun; 21 (5): 261−266, doi: 10.1089/met.2023.0006.
2. Davies M. J., Aroda V. R., Collins B. S. et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2022 Nov 1; 45 (11): 2753−2786, doi: 10.2337/dci22-0034.
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