Diabetes and COVID-19: What 2 Years of the Pandemic Has Taught Us

The global community has been grappling with an unprecedented spread of a novel infectious organism, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of the so-called coronavirus disease 2019 (COVID-19). ¹ Repeated partial or total lockdowns have dramatically altered our lifestyles, and major restrictions are still present in our everyday lives. ^2,3 According to the World Health Organization, ¹ as of October 31, 2021, there have been 250 million COVID-19 reported cases and 5 million deaths worldwide. The global response has been robust, with fast-track development of effective vaccines, almost 7 billion vaccine doses of which have been already administered. ¹ Although these numbers give us hope, more contagious and resistant virus variants have emerged; as a results, thousands of people continue to die every day.

Data from China and other countries have shown that individuals most vulnerable to higher morbidity and mortality rates from COVID-19 are the elderly and those with hypertension, diabetes, cardiovascular disease, and obesity. ^{4 –8} The presence of diabetes is a negative prognostic factor for SARS-Cov-2 infection. Although subjects with diabetes do not contract the virus more readily than the general population, they manifest more severe disease, a higher risk of hospitalization and need for intensive care, and increased mortality. ^9,10 Data from China in the early days of the pandemic showed that up to 20% of COVID-19 patients had diabetes ⁴ ; this preliminary observation was confirmed in Italy, the first European nation that faced the onslaught of the disease, where about 20% of patients in intensive care units in March 2020 with COVID-19 had diabetes. ¹¹ Early data from Wuhan, China, the origin of the pandemic, revealed that patients with diabetes had about a threefold higher risk of dying from COVID-19. ¹²

It has been shown that inflammation, altered immune status, and activation of the renin–angiotensin–aldosterone system represents pathogenetic links between COVID-19 and diabetes. ^13,14 Cellular angiotensin-converting enzyme (ACE)-2 and dipeptidyl peptidase-4 (DPP-4) potentially act as receptors for the viral spike glycoproteins, and pharmacological agents targeting both these receptor pathways were conceptualized. ^15,16 However, the use of ACE inhibitors and DPP-4 inhibitors has not pointed to change COVID-19 course or mortality. ¹⁷

In addition, recent findings have suggested that other molecules may play important roles in SARS-CoV-2 infection; one example is the glucose-regulated protein 78 (GRP78), a molecular chaperon that plays a role in protein folding and assembly. ¹⁸ In conditions of increased stress, such as a viral illness, GRP78 is overexpressed and translocated to cell surfaces, acting as a receptor for several ligands, including viruses. The resultant cascade affects multiple steps in the viral cycle, from entry and replication to systemic spread. ¹⁹

Interestingly, the SARS-CoV-2 spike protein has been shown to interact with cell surface GRP78, which may be thus considered as a binding partner together with ACE-2. ²⁰ The expression of GRP78 is enhanced in the adipose tissue ²¹ and increased in subjects that are older and in those with obesity and diabetes ²⁰ ; on this basis, it has been postulated that the main mechanism for overexpression of GRP78 is adipose hyperinsulinemia. ²² In the aforementioned study, ²⁰ the limitation of adipose hyperinsulinemia by metformin, but not by thiazolidinediones, led to decreased expression of GRP78, whereas sodium-glucose cotransporter 2 inhibitors (SGLT-2i) abrogated the induction of the GRP78 gene and protein expression in the adipose tissue of an obese diabetic mouse model. ²⁰ This mechanism may help to explain why obesity and diabetes are associated with COVID-19 in its most severe forms, and why some antidiabetic drugs seem to have favorable effects in patients with diabetes and COVID-19.

Abnormalities in both the concentration and the function of lipids and lipoproteins may represent another pathogenetic link between COVID-19 and diabetes. It has been shown that reduced high-density lipoproteins (HDL) concentrations and high triglycerides (TG) levels predict COVID-19 severity ²³ and that the TG/HDL ratio, an indirect measure of atherogenic small dense low-density lipoproteins (LDL), is significantly elevated in COVID-19 patients. ²⁴ Elevated concentrations of TG-rich lipoproteins, ²⁵ the direct precursors of small dense LDL, the most atherogenic lipoprotein subclass, have been reported in severe COVID-19 infection. ²⁶

It has been, therefore, postulated that lipoprotein dysfunction may represent a pathogenetic mechanism in COVID-19, ²⁷ and it is known that the atherogenic lipoprotein phenotype, which is constituted by high TG, low HDL, and elevated small dense LDL, is strongly associated with cardiovascular risk, ^28,29 particularly in some ethnicities. ^30,31 An association between atherogenic lipoproteins and inflammatory cytokines has been also reported in COVID-19 patients, ³² similarly to the well-known relationship between cytokine biomarkers, endothelial inflammation, and atherosclerosis as observed in diabetes. ^33,34

There is broad international consensus that glucose control be optimized in patients with diabetes and COVID-19 to reduce disease severity and acute complications. In this respect, the relationship between the two disorders is bidirectional. ^{35 –37} Tight management of diabetes is also of importance to reduce the burden of indirect COVID-19 mortality; indeed, beyond those deaths that have been attributed solely to COVID-19, excess mortality was reported in 2020 in relation to previous years. ³⁸ A major component of this trend is reduced access to medical care, particularly for those with chronic diseases such as diabetes and obesity.

This excess indirect mortality from COVID-19 was first described in Italy in March 2020 ³⁹ where a 50% reduction in hospitalizations for acute myocardial infarction was observed, with a concomitant three to five times higher in-hospital mortality compared with the same time in the previous year ⁴⁰ ; presumably, acute ill patients simply faced difficult access to timely medical attention. Some authors have interestingly proposed the use of simple scores upon hospital admission to predict COVID-19 fatality in patients with diabetes. ⁴¹ In an interesting observation from Wuhan, China, newly diagnosed diabetes with inpatient hyperglycemia was associated with higher mortality risk than known diabetes in hospitalized COVID-19 patients. ⁴²

Although optimal glycemic control is imperative to improve clinical outcomes, emerging evidence indicates that the pharmacological therapy for the effective management of hyperglycemia in patients with COVID-19 is more complicated than it might seem. Insulin is obviously the preferred drug, particularly in severely ill and hospitalized individuals who are prone to co-morbidities and require rapid control. ¹⁷ However, some concerns have been raised due to results of studies reporting that patients with type 2 diabetes (T2DM) and COVID-19 had a worse prognosis and increased mortality with insulin treatment. ⁴³

As a possible modulating factor, Crouse et al. reported that the mortality rates in patients treated with metformin before acquiring SARS-CoV-2 infection was only one-third compared with those not taking metformin, an effect independent from its antihyperglycemic actions. ⁴⁴ This has significant clinical relevance, since metformin is commonly used as a first-line agent in patients with T2DM; however, an increase in lactic acidosis in patients on metformin and hospitalized for COVID-19 has been reported, ⁴⁵ leading to the recommendation that its use be avoided in patients with severe COVID-19 infection. ¹⁷

Alternatively, the role of incretin-based therapies in such scenarios has been highlighted: the DPP-4-inhibitors and the glucagon-like peptide 1 receptor agonists (GLP1-RAs) have the ability to achieve acceptable glucose control without increasing the risk of hypoglycemia. ^{13 –34} The GLP1-RAs also have significant cardiorenal metabolic benefits that could help the prevention of such complications. ^17,34 Of interest, GLP1-RAs reduce inflammation and improve cardiovascular outcomes by reducing atherogenic lipoproteins, ⁴⁶ in contrast to what shown by certain traditional antidiabetic drugs. ⁴⁷

Restrictions and lockdowns as a societal response to COVID-19 have been reported to worsen glycemic control and diabetes-related complications and co-morbidities ⁴⁸ ; in this context, the importance of GLP-1RAs use extends to the mitigation of obesity, a co-morbid condition closely associated with a worse prognosis in COVID-19. ⁴⁹ Retrospective analyses of large databases have shown some benefit with the use of GLP-1RAs in patients with T2DM and COVID-19. ⁵⁰

Beneficial effects in COVID-19 patients have been also observed with another class of novel antidiabetic agents, the SGLT-2i. These drugs may prevent complications from SARS-COV-2 infection in patients with diabetes, reducing all-cause mortality and improving the clinical course. ⁵¹ The suggested mechanism of action of SGLT-2i benefit in COVID-19 is the inhibition of glycolysis and stimulation of lipolysis, which may limit viral spread and also protect cell damage. ⁵²

Concurrently, an important action of SGLT-2i is to improve endothelial dysfunction, reducing insulin resistance and inflammatory status by limiting the effects of oxidative stress. ⁵³ Prior concern regarding the use of SGLT-2i for patients with diabetes and COVID-19 was the potential high incidence of ketoacidosis, in the setting of hypovolemia, dehydration, and limited food intake. ⁵⁴ Importantly, the use of SGLT-2i like dapagliflozin in patients with diabetes and COVID-19 was associated with less organ dysfunction and a generally safer more favorable clinical course. ⁵⁵

In conclusion, it is imperative to manage the most fragile patients in the best possible way during the COVID-19 era, and clinicians should be proactive in addressing the needs of patients using telemedicine technologies, including phone calls and video visits. The consequences of this pandemic would be particularly deleterious for patients with chronic cardiometabolic illnesses, such as diabetes; therefore, adequate care of such patients must be provided.