The results of this population-based study show that two-thirds of T2DM patients were free of CVDK on the index date. During the follow up (2013–2019), HF and CKD were the most frequent first manifestations compared with MI, stroke, and PAD, and also had higher mortality rates. In addition, both were associated with a higher incidence of rehospitalization when compared with MI, stroke, and PAD, increasing the use of healthcare and indirect resources, and increasing Spanish National Health System expenditure. These two diseases also resulted in a worse prognosis because, as described in our study, both HF and CKD are accompanied by a higher incidence of subsequent diagnoses that worsen the evolution. It should be noted that the 6% prevalence that we found corresponds approximately to the 50% of known diabetes that is described in the usual prevalence studies .
Winell , in a 1996–2012 study in Finland, found that diabetic patients have a higher incidence rate of HF, with a worse prognosis, than non-diabetic patients. Sukkar  studied 9,313 diabetic patients and found that 22.6% developed CKD during a mean follow up of 5.7 years. Advanced age and cardiovascular comorbidity, among other factors, were associated with an increased incidence. Our results are in line with these studies, with HF and CKD being the two most common manifestations of T2DM, and these two complications presented earlier than other CVD analyzed .
Albuminuria increases the cardiovascular risk, and its association with reduced glomerular filtration increases mortality . Based on the results of the study, which show the importance of CKD and HF as serious and early complications in T2DM, strategies should be established to prevent and treat these patients early. Among them, the use of albuminuria and the albumin / creatinine ratio as early markers are of special importance. Koye  found an annual incidence rate of microalbuminuria of 7–8% in T2DM patients. Until recently, the treatments used for preventing kidney disease (renin angiotensin system inhibitors) were of very limited efficacy and there was no optimal tool to prevent HF development or its progression in any way. Our data are not surprising and show one of the therapeutic areas with unmet needs. Therefore, current data on SGLT-2 inhibitors are encouraging since they have demonstrated a capacity to both prevent and slow the progression of HF and CKD in diabetic patients and reduce hospitalization rate due to HF which is the most important cause of increase healthcare expenditure [23–31]. HF of ischemic etiology is associated with a higher risk of death compared with non-ischemic HF among patients with T2DM , however, this has not been confirmed in more recent data . We had no access to the etiology of HF in our sample and therefore cannot analyze this aspect, which is a limitation of the study.
The cumulative hospital costs per patient of HF (€ 50,942.8) and CKD (€ 48,979.2) were higher than those for MI (€ 47,343.2) and stroke (€ 47,070.3) and similar to those for PAD (€ 51,240.0), compared with € 13,098.9 in patients without CVKD. Rehospitalization is common in this type of patients (HF and CKD), and results in high health resource use and costs. The most striking cost components were hospital admissions (39%) and medication (19%). A review by Einarson  described high comorbidity in T2DM patients with a mean annual cost per patient according to the absence or presence of CVD of $3,418 and $9,705, respectively. Wan , in a large cohort of patients (1.6 million patient-years) and with an 8.5 year follow up, found that the effect of CVD, cerebrovascular accidents, CKD and the combination of these factors has an additive impact to health costs, with special emphasis on CKD on T2DM patients. A Spanish study also highlighted a higher cost in patients with CKD + HF (€ 14,868) compared with those with HF (€ 9,365). The comorbidity associated with HF was high . Goncalves  described the associated cost of HF and CKD attributable to diabetes in 2010–2016 in Brazil, which was $ 180 million per year for HF, with an upward trend. The presence of CKD increased the cost ($ 475 million). The authors emphasized that the economic burden of CKD will gradually increase in coming years, with serious implications for the financial sustainability of the Brazilian public health system. McQueen  found that costs increase as kidney function decreases in T2DM patients (phase 1: $1,732 vs. phase 5: $6,949). Other authors highlighted the effect of prevention and self-care in the early stages of HF, reviewing the medical record and symptoms with the aim of reducing the economic burden of HF + T2DM on hospital admissions . All these studies conclude that the cost of hospitalization and the presence of HF and/or CKD increases health costs in T2DM patients.
The study had some limitations: (a) the main limitation was the bias regarding the time of evolution of T2DM, as a single fixed index date was used for patient selection; (b) the inherent limitations of retrospective, observational studies using databases, such as disease underreporting or possible variations in the recording of information by health professionals; the database was constructed in 2012, and therefore, for some patients it was not possible to determine with certainty whether patients were CVKD-free on or before the index date, even though the obtention of records from both primary and hospital care may have minimized this bias; c) the possible inaccuracy of disease coding in the diagnosis of CVKD and other comorbidities; d) the absence of specific variables, such as socioeconomic level, adherence and variations in the dose of the medication administered, comorbidities, healthy lifestyle, variations in blood pressure or cholesterol, among other unmeasured factors which could have influenced the results; e) only hospitalizations due to CVKD were considered, so there could be an underestimate of less serious conditions; f) the lack of information from the private healthcare sector, which although much less relevant in Spain, could have had a certain influence on the results.