Repurposing exercise training and pharmacological therapies to address the post-acute sequelae of COVID-19 (PASC) in diabetes mellitus

1. Introduction

There is growing evidence that a significant proportion of individuals infected with the SARS-CoV-2 virus may develop long-term complications. Termed the post-acute sequelae of COVID-19 (PASC) or the long COVID syndrome, these individuals may remain symptomatic months after the acute infection [1].

The long COVID syndrome may be associated with increased metabolic derangements. A study comparing more than 180,000 COVID-19-recovered individuals with matched controls reported a 1.4 higher hazard ratio and excess burden of 13.5 per 1000 individuals with incident diabetes mellitus (DM) at 12 months [2]. It is postulated that the SARS-CoV-2 virus may induce pancreatic beta-cell dysfunction and aggravate insulin resistance by enhancing inflammation in the peripheral tissues [2]. Moreover, a recent meta-analysis found that individuals with DM may be at increased risk of long COVID [3]. As the immune responses of individuals with poorly controlled DM are impaired, breakthrough COVID infections can occur despite vaccination [4]. Optimizing glycaemic control is key given the tripartite relationship between DM, acute and long COVID.

The deleterious effects of DM and long COVID on the cardiovascular system are additive [5]. Firstly, long COVID may impair cardiorespiratory fitness. A meta-analysis comprising 2160 individuals with long COVID reported a significant reduction in exercise capacity by 4.9 ml/kg, [6] potentially eradicating years of exercise abilities accrued. Several mechanisms may contribute to exercise intolerance. These include reduced peak oxygen consumption, [7] impaired oxygen extraction in the microcirculation, [8] altered mitochondria function, and dysfunctional fatty acid beta-oxidation with increased lactate release during exercise [8], which may be aggravated in the presence of DM.

Secondly, individuals with concurrent type 2 DM (T2DM) and long COVID may be more susceptible to orthostatic hypotension and chronotropic incompetence because of autonomic dysfunction, which could further aggravate exercise intolerance [9]. The direct difficulty in increasing cardiac output, coupled with persistent endothelial dysfunction, could compromise oxygen delivery to the muscles, limit cardiac response and propagate the sensation of ‘unsatisfied respiration’ and easy fatigue [10].

Finally, the proinflammatory state and oxidative stress associated with long COVID may rapidly worsen sarcopenia and aggravate glycaemic control due to reduced muscle glucose disposal, [11] creating a vicious cycle impairing the physical function of these individuals.

The change in the COVID-19 disease pattern has also spurred countries to adopt an approach toward endemicity, shifting the focus toward managing the long-term sequelae of COVID-19 infections. Individuals with long COVID and DM may be more susceptible to adverse health consequences. Moreover, these individuals present unique challenges, including reduced aerobic capacity than individuals without T2DM [12] and increased susceptibility to musculoskeletal problems (e.g., frozen shoulder, osteoarthritis) [13]. It is, therefore, appropriate to reappraise nonpharmacological approaches and repurpose existing pharmacological agents as potential strategies. Given the multiple challenges, individuals with T2DM and long COVID may face, we propose a multimodal approach to manage these individuals (Fig 1 ).

Fig. 1.

(A) Combined detrimental effects of T2DM and long COVID on exercise tolerance. (B) A proposed multimodal approach combining nonpharmacological and pharmacological management strategies in the patient with concomitant T2DM and long COVID.

Exercise remains a cornerstone in DM management. However, given the physical limitations faced by individuals with concomitant DM and long COVID, practitioners should assess the patient’s capacity to exercise using a standardized questionnaire, such as the Physical Activity Readiness Questionnaire. As cardiopulmonary exercise testing is not readily available, cardiorespiratory status may be assessed using surrogate tests such as the 6-minute walk or 3-minute step test. The Borg scale for fatigue and dyspnoea can be simultaneously implemented to determine participants’ exercise tolerance. Muscle strength can be assessed using hand-held dynamometers. Functional mobility can be evaluated using the short physical performance battery, which combines balance, walking and chair standing. While these tests are easy to conduct in clinics, some individuals with long COVID may suffer from dizziness and postural instability, and may require submaximal, seated cycle-ergometer tests.

A comprehensive training regime with multiple exercise elements can be implemented in a graded manner to allow acclimatization and minimize exercise-related injuries in patients with T2DM and long COVID. Comprehensive training should incorporate aerobics training, resistance training, stretching, pulmonary rehabilitation, including cough, breathing exercises, and diaphragmatic muscle training. Aerobic training should start at a low intensity and then step up gradually, aiming for an individualized peak heart rate as tolerated [14]. Resistance training should be started concurrently at low intensity and increased as tolerated. Patients with significant exercise intolerance may benefit from pulmonary rehabilitation [15]. Participants could opt for remote delivery via digital technologies to facilitate flexible delivery of the exercise program. Improvement in cardiorespiratory fitness may be monitored using a combination of a self-implemented 6-minute walk test and Borg’s scale.

Regarding the role of pharmacological therapies, it is worth considering repurposing antihyperglycaemic medications, such as metformin, SGLT2-inhibitors, and GLP1 receptor agonists, as potential treatment strategies for long COVID. In a recent preprint, metformin has been shown to reduce the risk of long COVID by 63% if started within four days of symptom onset [16]. The postulated benefits of metformin include alleviation of inflammation [17] and inhibition of SARS-CoV-2 viral replication in vitro [18]. The SGLT2 inhibitors potentially target the underlying mechanisms of long COVID, given the anti-inflammatory properties [19]. In addition, SGLT2-inhibition optimizes myocardial substrate utilization, improves cardiac function, promotes skeletal muscle remodelling and exercise capacity in heart failure [19]. Regarding GLP1 receptor agonists, studies have shown benefits in attenuating endothelial dysfunction by reducing the release of adhesion molecules and endothelin I, a potent vasoconstrictor [20]. Despite the above postulated benefits, the role of these medications in treating long COVID is currently uncertain. Further mechanistic studies and clinical trials are required to evaluate the effectiveness of these agents in managing long COVID.

The long COVID syndrome may be a double-edged sword in our efforts to optimize the management of individuals with DM. While nonpharmacological measures such as exercise training may be more challenging, increased public awareness of the long-term sequelae could, in turn, promote the adoption of healthier lifestyle habits. Reappraisal of pharmacological therapies that target the pathophysiology of the long COVID syndrome and assessing their efficacies through rigorous clinical trials will pave the way toward improving outcomes in individuals with DM and long COVID.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.