U-shaped association between serum calcium and in-hospital mortality in diabetes patients with congestive heart failure: a cohort study

Numerous studies have identified prevalent disturbances in serum calcium homeostasis among critically ill patients, wherein both elevated and diminished levels correlate with heightened susceptibility to adverse clinical outcomes^24,25. This phenomenon has been independently corroborated in cohorts of patients with diabetes and heart failure^16,17,19. To the best of our knowledge, we are the first to demonstrate such an association between blood calcium concentrations and in-hospital mortality in the context of concomitant diabetes mellitus and heart failure. Our findings distinctly unveil a substantial nexus between in-hospital mortality and aberrant serum calcium levels, encompassing both hypercalcemia and hypocalcemia, within individuals afflicted with diabetes mellitus and heart failure. Importantly, this correlation perseveres even subsequent to meticulous adjustment for plausible confounding variables.

In alignment with our investigation, prior research has consistently indicated a robust correlation between serum calcium levels and the onset, prognosis, and outcomes of individuals afflicted with diabetes or heart failure. A recent cross-sectional study, employing a constrained cubic spline curve, unveiled a J-shaped association between serum calcium levels and type 2 diabetes (T2D). Logistic regression analysis further disclosed a statistically significant elevation in the risk of T2D among individuals in the high serum calcium group in comparison to the moderate group²⁶. Concurrently, three distinct cohort analyses conducted in China (n = 6096)²⁷, the United States (n = 12,800)²⁸, and Norway (n = 27,158)²⁹, consistently affirmed a positive correlation between serum calcium levels and diabetes risk. Moreover, serum calcium exhibits an indirect influence on in-hospital mortality among diabetic patients. Kwak et al., by introducing serum calcium as a continuous variable in a multivariate model, demonstrated that each 1 SD mg increase in serum calcium resulted in a 30% rise in coronary artery calcification scores¹⁶. A significant interaction between the average coronary calcium score (CCS) and diabetes mellitus (DM) also emerged (p < 0.00001). Notably, mortality rates exhibited a substantial elevation in diabetic subjects relative to non-diabetic subjects as CCS levels escalated¹⁷. These findings collectively suggest a connection between hypercalcemia and unfavorable outcomes among diabetic individuals, partially aligning with our own observations. However, existing conclusions primarily emphasize high serum calcium as a diabetes risk factor, with insufficient consideration for the impact of low serum calcium on mortality. This discordance underscores the intricate nature of the relationship between calcium levels and diabetes, likely influenced by factors such as sample size, ethnicity, confounding adjustments, and study design. While studies pertaining to heart failure patients are comparatively smaller than those concentrating on diabetes, a cross-sectional echocardiographic investigation identified an independent association between elevated albumin-adjusted serum calcium levels and heart failure with preserved ejection fraction in individuals with type 2 diabetes mellitus³⁰. Notably congruent with our findings, a Danish cohort study involving chronic heart failure patients revealed a parallel observation. Both hypocalcemia and hypercalcemia conferred increased mortality risks in the short term (within 30 days) and the long term (beyond 30 days)¹⁹.

In our study, we observed a U-shaped dose–response relationship between serum calcium levels and the odds ratio for intrahospital mortality. This curve exhibited an initial decrease followed by an increase. The inflection point of the curve, corresponding to the nadir, occurred around 9.05 mg/dL. At this point, the odds ratio for in-hospital mortality reached 1. Deviations from the 9.05 mg/dL threshold, whether higher or lower, were associated with an escalating risk of in-hospital mortality. Previous research has predominantly focused on heart failure or diabetes as individual ailments. However, given the frequent coexistence of these conditions, our study design better reflects real-world clinical scenarios. Moreover, our investigation underscores the importance of hypocalcemia as a critical indicator warranting meticulous attention. Within a clinical context, low serum calcium levels hold as much significance as elevated levels. The findings of this study hold the potential to facilitate earlier and more efficacious medical interventions and strategies for individuals dealing with both diabetes mellitus and heart failure, ultimately culminating in a reduction of their mortality rate.

The precise mechanism underlying the association between serum calcium and the concurrent diagnosis of diabetes mellitus (DM) and congestive heart failure (CHF) remains unclear, though several potential hypotheses have been proposed. Firstly, calcium influx is implicated in the stimulation of insulin secretion, and its aberration is linked to β-cell dysfunction and the onset of type 2 diabetes³¹. Additionally, calcium ions (Ca2 +) modulate insulin signaling pathways, thereby influencing cellular insulin sensitivity³². Research suggests that heightened serum calcium levels inhibit the production of parathyroid hormone (PTH), leading to a reduction in the biologically active form of vitamin D³³. Deficiency in vitamin D augments systemic inflammatory mediators, exacerbates cellular oxidative stress, suppresses the immune system’s release of anti-inflammatory factors, and heightens susceptibility to diabetes and cardiovascular disease^34,35,36. Furthermore, a complex interplay exists between cardiovascular well-being and mineral homeostasis. Calcium functions as a pivotal secondary messenger, exerting a critical role in governing mitochondrial activity and upholding excitation–contraction coupling mechanisms³⁷. Perturbation of calcium homeostasis detrimentally impacts the contractile proficiency of the heart, culminating in compromised cardiac performance³⁸. Anomalies in calcium signaling may lead to cardiac arrhythmias, thereby exacerbating heart failure conditions³⁹. The deleterious effects of calcium imbalance extend to myocardial and vascular structures. For instance, the deposition of calcium along the coronary artery walls gives rise to coronary calcification, a well-recognized risk factor contributing to the progression of heart failure^40,41.

Our research possesses notable design and statistical advantages. Initially, we focused on assessing serum calcium levels, a clinically feasible metric. Calcium’s role as a straightforward and dependable clinical marker enhances the translational prospects of our theoretical discoveries in the realm of medical application. Secondly, our investigation represents a pioneering effort in examining a sizable cohort of patients with diabetes and heart failure, distinguished by a substantial sample size and data quality. Furthermore, our study substantiates a significant non-linear correlation between serum calcium levels and in-hospital mortality, demonstrated via refined curve fitting techniques. Additionally, we mitigated bias arising from confounding variables by employing subgroup analyses and multivariate logistic regression.

However, there exist several limitations within this study. First, it is a retrospective cohort study, which by design cannot establish causal relationships, but is intended to assess associations. Secondly, our methodology used ICD9 codes to identify patients. But the method relies on the accuracy of ICD9 coding. Coding inconsistencies vary significantly by diagnosis, and rates of coding issues have been reported as high as 80%⁴². Thirdly, different types of heart failure, such as Heart failure with preserved ejection fraction (HFpEF), Heart failure with reduced ejection fraction (HFrEF), and Heart failure with mildly reduced ejection fraction (HFmrEF), may have different impacts on the results. However, due to the lack of relevant subtype heart failure data, we will verify it in our own database in the future. In addition, our study population primarily consisted of participants in the United States, which may limit the generalization of the findings to other populations. Finally, due to the limitations of the institutional database, we were unable to collect detailed information on different drugs in patients, which plays an important role in heart failure (HF). For example, different types and doses of diuretics, patient enuresis status, and patient resistance to diuretics have a certain impact on the treatment and management of heart failure in patients. And the role of parathyroid hormone is related to calcium serum levels and prognosis of patients with HF⁴³. Similarly, we used total serum calcium level rather than corrected values of calcium because it is readily available. In the future, based on the present research, we will further supplement the data and conduct detailed and conduct prospective controlled trials with large sample sizes to provide more powerful evidence to support our findings.

In summary, our study expands upon prior research concerning the links between serum calcium and diabetes as well as heart failure. Deviations in serum calcium levels, whether elevated or diminished, significantly impact the likelihood of in-hospital mortality among diabetes patients with congestive heart failure. Optimal in-hospital survival rates were observed when serum calcium levels reached 9.05 mg/dL. The serum calcium level holds promise as a straightforward and dependable prognostic marker.