How can we improve the management of individuals with attention deficit hyperactivity disorders and co-occurring cardiometabolic disease?

KEYWORDS:

• ADHD
• treatment
• prediction
• obesity
• type 2 diabetes
• cardiovascular disease

1. Introduction

Cardiometabolic diseases, including obesity, type-2 diabetes (T2D) and cardiovascular disease (CVD), are well-known chronic conditions that frequently co-occur [1,2]. Each of these conditions are associated with premature death [3], as well as high levels of health care costs [4]. Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental condition, characterized by hyperactivity, inattention, impulsivity, that often persist from childhood into adulthood [5]. ADHD is a costly disorder that often co-occurs with substance use disorders, bipolar disorder, and depression and individuals with ADHD presents with an increased risk for criminality, occupational problems, and premature death, including suicide [5]. A small but growing literature also suggest an increased risk of cardiometabolic diseases and risk factors in those with ADHD [6].

Research on psychiatric comorbidity in ADHD has informed clinical treatment guidelines to help mental health teams to build up an expertise in the diagnosis and treatment of individuals with ADHD and co-occurring psychiatric disorders [5]. In contrast, due to a lack of research, guidelines about the management of cardiometabolic disease in individuals with ADHD are scarce.

2. Why improve the management of cardiometabolic disease in ADHD?

Several studies have demonstrated that individuals with ADHD are presented with more cardiometabolic risks factors, such as lipid profiles and diastolic blood pressure, smoking and physical inactivity [6–9]. Findings from a comprehensive meta-analysis found that the pooled prevalence of obesity was increased with about 70% in adults with ADHD (28%) compared with those without ADHD (16%) [10]. The finding of an almost 2-fold increased prevalence of obesity in adult ADHD is consistent with the results from a large, register-based study in Sweden [11].

Compared to the substantial evidence base around ADHD and obesity, fewer studies have focused on the extent to which adult ADHD is associated with an increased risk for T2D and CVD. Findings from a systematic review and meta-analysis on ADHD and T2D identified four eligible epidemiological studies [12]. The meta-analysis demonstrated that individuals with ADHD have a more than doubled risk of T2D, which is consistent with results from a register-based data from Sweden showing a statistically significant two-fold increased risk of T2D in ADHD [12]. A recent meta-analysis of five studies [13], including a recent large register-based study [14], showed that adults with ADHD are nearly twice as likely to develop CVD than adults without ADHD. In addition to the above mentioned epidemiological studies, an increasing number of family studies [8,15,16] and molecular-genetic studies [17–19] suggest that the overlap between ADHD and cardiometabolic disease, including obesity, T2D and CVD, is influenced by genetic factors. Recent mendelian randomization results support a causal hypothesis for associations between ADHD and cardiometabolic disease [20]. Taken together, a better understanding of the management of cardiometabolic disease in ADHD is important because emerging evidence suggest increased risk of cardiometabolic disease (including not only obesity but also T2D and CVD) among adults with ADHD.

3. Which knowledge gaps needs to be addressed?

A first important knowledge gap relates to the role of adult ADHD in worsening the prognosis and hampering the management of cardiometabolic disease. As indicated by the studies presented above, cardiometabolic risks and poor health behaviors are established potential outcomes of ADHD and these factors are associated with a poor cardiometabolic prognosis. Furthermore, poor organization, planning, monitoring skills, and impulsivity are core features of ADHD [5] and these characteristics may increase the risk for influence poor adherence to treatments and management for cardiometabolic disease. We are not aware of any study exploring how comorbid ADHD may negatively impact the treatment for T2D and CVD, but there is a small but growing literature suggesting that comorbid ADHD may negatively impact the treatment of obesity [21] and more specifically that ADHD affect outcomes following bariatric surgery [22]. A systematic review examining the impact of ADHD on bariatric surgery outcomes reported a non-significant mean BMI difference following bariatric surgery between patients with and without ADHD, but individuals with ADHD had less frequent follow-up visits compared to non-ADHD patients [22]. Furthermore, a large study (N = 68 000 patents) based on the Scandinavian Obesity Surgery found that individuals with ADHD experienced higher risk of postoperative complications, self-harm and substance abuse after surgery, compared to individuals without ADHD [23]. Clearly, more research is needed to establish conclusive findings regarding the extent to which ADHD worsen the prognosis and management of other cardiometabolic diseases, in particular for T2D and CVD.

A second critical knowledge gap concern the real-world effectiveness and safety of ADHD medication in relation to cardiometabolic outcomes [24]. Concerns about the safety of ADHD medications for serious cardiometabolic outcomes have been raised due to case reports of CVD events (e.g. myocardial infarction, and stroke) in individuals using ADHD medications [25]. Findings from clinical trials indicate that ADHD medications elevate heart rate and blood pressure [26], whereas results from a recent meta-analysis of the available pharmaco-epidemiology studies suggest no statistically significant association between ADHD medications and the risk of CVD across age groups, although a modest risk increase cannot be ruled out, especially for the risk of cardiac arrest or tachyarrhythmias [27].

Individuals with ADHD and co-occurring cardiometabolic diseases typically need continuous treatment for ADHD but also for several other indications, which indicate that a detailed understanding of long-term effects and polypharmacy is highly warranted. ADHD medication may have beneficial effects on long-term cardiometabolic outcomes via improved adherence to pharmacological and non-pharmacological treatments for cardiometabolic disease. This is a plausible hypothesis as clinical trails have shown short-term beneficial effects of ADHD medication on the core symptoms of ADHD (impulsivity, attention and monitoring skills) [28] and a reduction of these symptoms may in turn improve adherence to complex treatment programs. Another plausible hypothesis is that the combined use of several pharmacological treatments (i.e. polypharmacy) may increase the risk adverse side effects via drug-drug interactions. Clearly, more research is needed not only on the long-term effects of ADHD medications for the prognosis of cardiometabolic disease, but also on potential risks associated with polypharmacy. Several reviews have highlighted that pharmaco-epidemiological analyses of real-world data (e.g. electronic health records, prescription databases) can fill the knowledge gap between clinical trials results and clinical practice needs [24], but such studies needs to address confounding carefully to avoid biased findings that could have serious negative implications for research, clinics, patients and society (e.g. miss-directed treatment recommendations) [29]. It is now possible to acquire more detailed real-world data using remote measurement technology, including both active (smartphone active app) and passive (smartphone passive app or wearable devices) monitoring [30]. Such data collections capture real-time disease processes that cannot be captured in the large pharmaco-epidemiological studies, such as detailed measurements of physical activity, sleep, heart rate and electrodermal activity. With such data, it is possible to, not only validate findings from large pharmaco-epidemiological studies, but also to obtain a more mechanistic understanding about the inter-relationships between ADHD medication and cardiometabolic risks and protective factors.

A third significant knowledge gap concerns the lack of risk stratification tools for cardiometabolic outcomes in adults with ADHD, which constrains possibilities to identify adults at high risk for these outcomes. Some areas of medicine, in particular cardiovascular medicine, have developed useful risk prediction scores (e.g. Framingham Risk Score and QRISK prediction algorithm) [31]. Personalized medicine, in the form of risk stratification estimators, has only recently entered the field of psychiatry and studies have now demonstrated the feasibility of developing risk prediction models, but the literature is still limited, and most studies are based on small samples [32]. As far as we know, there has only been one risk prediction study with a focus on cardiometabolic outcomes in ADHD [33]. This study used data from Swedish national registers to build a CVD prediction model optimized to individuals with ADHD to identify individuals with ADHD at high risk for cardiovascular outcomes. The study indicated that adding novel CVD risk factors which are associated with ADHD (i.e. comorbid psychiatric disorders, socio-demographic factors, and psychotropic medication) improve the prediction of CVDs in adults with ADHD compared to a model with traditional CVD predictors only (e.g. the Framingham risk score). More research is needed to develop and validate risk stratification tools that identify adult ADHD patients at risk for poor cardiometabolic prognosis. The combined use of ‘big-data’ sources (e.g. large-scale electronic health record databases) combined with novel statistical approaches (i.e. machine learning algorithms, such as deep learning neural networks) may arrive at clinically useful prediction models.

4. Conclusions

Emerging evidence points to substantial comorbidity between adult ADHD and cardiometabolic disease, but guidelines about the management of cardiometabolic disease in individuals with ADHD is still scarce. More research is therefore needed to improve the clinical outcomes and quality of life for adult with ADHD and co-occurring cardiometabolic disease. First, research is needed to advance the understanding about how ADHD associates with outcomes in people with obesity, T2DM and CVD diagnosis. Second, research is needed to explore real-world effectiveness and safety of ADHD medication in relation to cardiometabolic outcomes and treatments. Third, research is needed to develop prediction tool that allow identification of individuals with ADHD at high-risk for poor cardiometabolic outcomes and treatment adherence.

Declaration of interest

H Larsson reports receiving grants from Shire Pharmaceuticals; personal fees from and serving as a speaker for Shire Pharmaceuticals and Evolan Pharma AB outside the submitted work; and sponsorship for a conference on attention-deficit/hyperactivity disorder from Shire Pharmaceuticals outside the submitted work.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

The project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no [965381], and from Vetenskapsrådet [no. 2022-01119].