Relationships between obesity, glycemic control, and cardiovascular risk factors: a pooled analysis of cross-sectional data from Spanish patients with type 2 diabetes in the preinsulin stage

Intricate, heterogeneous sociosanitary, and cultural circumstances are behind the past and projected steady increase in the prevalence of type 2 diabetes mellitus (T2D) [1]. The critical public health priority of diabetes prevention does not imply control of this phenomenon is straightforward. In the absence of effective pharmacotherapy for primary prevention of dysglycemia [2], interventions should be based on weight control, physical activity, and improved quality of diet. However, such interventions are difficult to implement at the population level [3, 4]. Consequently, health systems are increasingly confronted with the task of improving diabetes surveillance and management to reduce the long-term complications of T2D [5]. Robust evidence supports the effectiveness of appropriate glycemic control to prevent microvascular complications in patients with T2D [6–8]. Conversely, there is much less clarity regarding the potential of intensive glycemic control to reduce macrovascular complications of T2D [9–11], although epidemiologic data and meta-analyses have shown a direct relationship between glycemic control and cardiovascular disease [12, 13]. In addition, macrovascular complications have considerable medical relevance because cardiovascular disease is the leading cause of death in people with T2D [8, 14]. Microvascular complications, such as persistent albuminuria, are also important contributors to cardiovascular risk and may be driven by non-traditional risk factors.

Obesity plays a central role in the pathophysiology of both T2D and its macrovascular complications [1, 15]. Nevertheless, some normal-weight individuals have considerable risk of developing T2D and cardiovascular disease because they have a metabolically adverse profile, including hyperinsulinemia, insulin resistance, and hypertriglyceridemia [1, 16]. Thus, a high body mass index (BMI) is not necessary for the occurrence of these conditions, suggesting that the underlying mechanisms of cardiovascular complications of T2D are not straightforward.

Epidemiologic research of cardiovascular risk factors among patients with T2D and different BMI ranges may provide clues as to the relative contribution of obesity to the cardiovascular risk of patients who already have a higher risk of cardiovascular complications because of T2D.

This article reports the results of an analysis of pooled Spanish data from 5 observational studies of patients with T2D during the last decade. The objectives were to investigate the distribution of cardiovascular risk factors among patients across a range of BMI strata, glycated hemoglobin (HbA1c; glycemic control) strata, and age groups.

In this population of patients with T2D at the preinsulin stage, most of the modifiable cardiovascular risk factors we investigated showed deviations from recommended goals (see Figure 1 for goals). As BMI strata increased, we found that impairment of most cardiovascular risk factors increased as well, and this was confirmed using generalized logit analysis. Indeed, cardiovascular risk factors were most prominent in patients in the higher BMI strata. This finding is in agreement with that of Gomis et al. [22], who reported an increased frequency of dyslipidemia and hypertension with increasing BMI among 7371 Spanish patients with T2D (P < .0001). By contrast, although glycemic control (HbA1c strata) also appeared to be associated with most of the cardiovascular risk factors we considered, the association was significant only for duration of T2D and dyslipidemia.

Noteworthy, BMI strata were also inversely related to age and duration of T2D. This relationship between BMI strata and age is consistent with previously published data [23, 24]. Previous epidemiological studies in Spain, performed over the entire age spectrum of the general adult population, had found a direct association between BMI and age up to the fifth or sixth decade [25, 26]. Our patients, all of whom had T2D, had higher BMI values on average than their Spanish population peers [25, 27, 28]. The inverse association between BMI strata and age in the current study may relate to the recognized role that obesity at early ages has in the current T2D epidemic [29–31]. This role would entail a reduction in the age of onset of T2D [29].

In addition, the most recent estimates of T2D prevalence in Spain were considerably high and included a large proportion of undiagnosed cases, which were younger and more obese than previously diagnosed patients [32]. In consequence, in Spain, as in other countries [3], effective prevention and therapeutic strategies, and T2D surveillance specific for overweight or obese youth, are required. It has been shown that obesity in early ages may not permanently increase cardiovascular risk if it is treated successfully [33]. On the other hand, if left unchecked, sustained increases in obesity and T2D prevalence might, in the mid-term, offset the declines in cardiovascular mortality [34] and the positive influences in longevity [35] achieved over recent decades in Western countries.

Although the HbA1c target of below 7.0% was not met by more than one-half the patients in this analysis, 70% of our sample had HbA1c below 8%. Notably, in patients older than 75 years of age, mean HbA1c was close to 7.0%, whereas in all groups of younger patients it was somewhat higher (Figure 1 stars: chart 5). Similarly, Vinagre et al. [36] found that, in Catalonia, patients with T2D aged ≥65 years were more likely to achieve HbA1c ≤7.0% than younger patients. It is likely that the older patients from the studies included in the current analysis were those with a more easily managed hyperglycemia. Glycemic control was related to T2D duration in the current analysis, but this duration was similar in patients aged >75 years and in those aged 65–75 years. A more recent analysis of the Catalan data similarly revealed deterioration in glycemic control with increasing duration of T2D [24]. The major randomized clinical trials that provided evidence supporting intensive glycemic control (ACCORD [37], ADVANCE [38], and VADT [39]) also confirmed the importance of adequate, comprehensive treatment of cardiovascular risk factors to prevent macrovascular complications [10], and this aspect of patient management was insufficiently addressed in the patients of this pooled analysis. When compared with results of a pooled analysis of population-based studies of cardiovascular risk factors performed within the last decade in Spain [40], our patients had similar cholesterol levels, but mean BMI, SBP, and triglyceride levels were higher. Of note, control of cardiovascular risk factors seemed to be slightly better in the systematic evaluation of patients with T2D recently performed in Catalonia, even though about a quarter of those evaluated were receiving insulin therapy and the Catalan population was slightly older than patients in this analysis [36]. We should highlight that the control of glycemia and cardiovascular risk factors might have improved in recent years, because Vinagre et al. [36] gathered information as of 2009, while the present series spanned the last decade.

Our analyses did not show that BMI and waist circumference were associated with HbA1c. This finding is not unexpected, as some individuals with BMI in the obesity range are otherwise metabolically healthy [41]. Indeed, obesity does not seem to always be harmful, and there are some phenotypes in which chronic metabolic inflammation, probably a pivotal condition in obesity and diabetes, is not present. Investigations are therefore underway to identify predictors or biomarkers of healthy versus unhealthy obesity, such as heme oxygenase-1 [42], to allow clinicians to better personalize treatment.

Patients included in our analyses were taking a variety of medications for control of blood pressure and lipid levels, and the blood pressure and lipid levels presented in this manuscript are unadjusted for such medication usage. Although this is consistent with the context of summarizing cardiovascular risk factors in real life, it limits our ability to assess 'underlying' blood pressure or dyslipidemia in isolation.

Strengths of this research include a large sample size and a variety of clinics. In addition, we only included patients naïve to insulin therapy in our analyses to reduce the confounding effect of insulin therapy on weight [43] and cardiovascular risk factors such as hypertension [44, 45]. The limitations include the nature of this post-hoc analysis, performed with heterogeneous observational studies, which were designed with different objectives. As this was not a longitudinal analysis, cardiovascular event rates could not be provided, we instead report a description of cardiovascular risk factors across BMI and HbA1c strata. Moreover, clinical data with known therapeutic or prognostic implications, such as the presence and extent of retinopathy, persistent albuminuria, or non-traditional cardiovascular risk factors/markers were not captured. Regarding body composition, waist circumference data were not available for about 40% of the sample, and data were incomplete to evaluate the ‘healthy’ or ‘unhealthy’ metabolic condition of the obesity seen in patients [46]. Finally, a significant percentage of the patients in this analysis needed a progression in their treatment for hyperglycemia, and this might have introduced a bias towards the inclusion of those patients with worse glycemic control.

In summary, the results of this pooled analysis in insulin-naïve patients with T2D show that glycemic control is independent of BMI, but this is not the case for other cardiovascular risk factors, such as hypertension and hypertriglyceridemia. Greater effort should be undertaken to reduce cardiovascular risk in patients with T2D, particularly in young, obese individuals, by controlling hypertension and dyslipidemia, as well as blood glucose. Increased emphasis should also be given to treatment strategies for weight control, especially in younger individuals and women.