Diabetes and SARS-COV-2
Type 2 diabetes mellitus (T2DM), as well as other cardiovascular (CV) risk factors, predisposes to the Severe Acute Respiratory Syndrome (SARS)-COV-2, also referred to as Coronavirus Disease-19 (COVID-19).(1) This may reflect the known increased susceptibility of T2DM for infections(2). Approximately 1 in 10 (8 to 14% depending on the cohorts) symptomatic patients requiring hospitalization for COVID-19 have T2DM.(1, 2) T2DM is associated with a 2-fold increase of developing severe disease requiring intensive care unit (ICU) or ventilation,(1, 3) and with 2-3 times higher mortality as compared to non-DM COVID-19 hospitalized subjects. (2, 3) Moreover, severe obesity, frequently associated with T2DM, is reported in up to 47% of ICU COVID-19 patients,(2) and worsens the prognosis.(4) Therefore, prevention, precautions and treatment, when necessary, are crucial in T2DM, since additional risk factors (hypertension, obesity, kidney disease) frequently co-exist in these patients. Unlike T2DM, type 1 DM does not seem a COVID-19 risk factor.(2)
Preventing the infection, reaching and maintaining a good metabolic control, possibly through telemedicine, are all essential. There are no clearly contraindicated drugs for glucose management through telemedicine in patients with stable both clinical and metabolic conditions. Self-Monitoring Blood Glucose (SBMG) should be implemented to detect and prevent hypo- and/or hyperglycemia, thus avoiding hospitalization. Moreover, a healthy lifestyle (balanced eating, physical activity), optimal hydration and full compliance with the medication plan (including drugs other than glucose-lowering ones) should be particularly implemented to avoid complications and access to hospitals. Limiting outpatient or hospital access, social distancing (5) and personal hygiene are key precautions as for non-DM subjects.
For infected, both symptomatic and asymptomatic, patients, glucose management depends on the severity of the illness and some adjustments may be needed according to drugs targeting the viral infection. Metformin and Sodium-Glucose Cotransporter-2 (SGLT-2) inhibitors may be continued in infected asymptomatic patients on stable conditions including normal kidney function. In symptomatic (hospitalised or non-hospitalised) non-critical patients, metformin should be discontinued to prevent lactic acidosis, in case of high risk of respiratory illness, dehydration, and/or acute kidney disease.(6) In symptomatic subjects, SGLT-2i may worsen dehydration secondary to fever or gastrointestinal symptoms, through increased diuresis, and may increase the risk of euglycemic ketoacidosis, supporting their discontinuation also in case of mild symptoms and/or unstable clinical condition.(7)
In non-critical patients, either at home or hospitalized, Glucagon Like Peptide-1 receptor agonists (GLP-1RAs) must be stopped in case of nausea and vomiting, while their safety and efficacy in the critical setting are currently unknown.(2) In non-critical patients, dipeptidyl peptidase 4 (DPP-4) inhibitors do not seem contraindicated, but the dose should be adapted to renal function or volume depletion.
Sulfonylureas (preferably gliclazide) may be continued in outpatients without history of CV events who have regular meals, good metabolic control without hypoglycemia, performing regular SBMG,(8) but should stop in hospitalised subjects due to an increased risk of hypoglycemia.(9)
Importantly, chloroquine and hydroxychloroquine are known to enhance the effect of all glucose-lowering treatments, thus close monitoring and glucose-lowering drug dose reduction may be required. Clinically relevant drug-drug interactions (DDIs) with some drugs currently used or tested in COVID-19 patients may occur with canaglifozin, saxagliptin and sulfonylureas (Table).
Insulin remains first-line treatment if no adequate metabolic control can be achieved in critically ill patients.(2) Its dosage and way of administration (i.v. or s.c.) depend on the type of feeding (oral, enteral or parenteral). In case of oral feeding, insulin should be adjusted to carbohydrate intake. Sliding scale s.c. insulin must be avoided. Insulin therapy needs regular blood glucose monitoring and/or continuous glucose monitoring to optimize dosing and decrease hypoglycemic risk.
Thrombotic complications occur in approximately 30-40% of critical COVID-19 patients.(10, 11) Moreover, T2DM per se is a pro-thrombotic disease due to low-degree inflammation and endothelial dysfunction,(12) both being worsened by the COVID-19.(2) Thus starting or continuing an optimal antiplatelet treatment in DM patients at high/very high risk or with CV diseases, respectively, seems crucial,(2) and guidelines (13) should be maximally implemented under the current circumstances.
In infected, asymptomatic patients already on aspirin, alone or combined with other P2Y12 inhibitors (dual antiplatelet therapy-DAPT), for primary and/or secondary CV prevention, there is no rationale for stopping or changing ongoing therapy. In critical hospitalized patients, remdesivir is currently in a compassionate use programme in the EU,(14) and clinically-relevant DDIs with antiplatelet drugs have not been reported so far.(15) Lopinavir/ritonavir are currently been tested, alone or combined with other antiretroviral drugs for severe COVID-19 infection and may generate clinically-relevant DDI with both ticagrelor and clopidogrel, and therefore prasugrel may be preferred in patients needing DAPT (Table).(15) Notably, dyspnea can affect between 5 and 10% of ticagrelor-treated patients in ‘real world’ observational studies, as a drug-specific adverse event.(16) Chloroquine and hydroxychloroquine may generate DDI with clopidogrel.(15) Aspirin does not appear to generate DDIs with any of the drugs used or under development for COVID-19 treatment (Table).
Ongoing trials are testing the benefit of different regimens of low-molecular-weight heparin (LMWH) in hospitalized patients. LMWH treatment does not require stopping single antiplatelet drug treatment (usually aspirin). In particular, this is not advisable in T2DM patients. Patients on DAPT may have an excess of bleeding if LMWH is co-administered for a prolonged time, especially on top of DAPT with prasugrel or ticagrelor. DAPT is currently an exclusion criterion from trials testing LMWH, however, switching from prasugrel or ticagrelor to clopidogrel may be considered if prophylactic LMWH doses are used in critically ill patients. It remains unknown whether ongoing DAPT significantly protects against COVID-19-associated thrombotic complications. Azithromycin that is being used off label in COVID-19 patients, is associated with an increase in early CV mortality in patients with high CV risk profile including diabetes (HR 1.71; 95% CI, 1.06-2.76), independently of DDI.(17)
For DM patients already on oral anticoagulation (OAC), OAC should not be stopped either in asymptomatic or symptomatic COVID-19 patients. Dabigatran and edoxaban may generate relevant DDI with hydroxychloroquine, while lopinavir/ritonavir may potentially interact with all OACs, both direct oral anticoagulants (DOACs) and warfarin (Table), especially with apixaban, and rivaroxaban potentially increasing the risk of bleeding.(15) Thus, measuring anticoagulation levels (anti-Xa activity, thrombin time, closer INR monitoring, depending on the type of OAC) may be advisable. If a switch to full dose LMWH is decided, the short half-life of DOACs does not require bridging while the INR will guide switching from warfarin and LMWH should be used at doses consistent with the underlying patient’s disease (atrial fibrillation or recent thromboembolism). LMWH dosing may need measuring anti-Xa activity in moderate to severe obese patients in whom standard fixed or body weight-adjusted dosing may cause under or over drug exposure, respectively.(18) In a recent study of hospitalized, COVID-19 patients, none of the patients who continued their ongoing OAC developed thromboembolic complications,(11) but data are still limited.
A correct primary or secondary prevention of CV or thromboembolic disorders remains of utmost importance in T2DM patients, even more in the COVID-19 era. In patients treated with new or experimental drugs targeting COVID-19, DDI should be considered in the selection of antiplatelet or OAC drugs. Glucose monitoring is pivotal to avoid complications and access to hospital in patients followed through telemedicine. Glucose-lowering drugs should be adjusted in relation to the severity of the disease, its clinical manifestations and co-medications for COVID-19.
Table. Antithrombotic or glucose-lowering drugs that may generate clinically relevant drug-drug interactions (DDI) with drugs currently used or tested for COVID-19. Possible pharmacokinetic mechanisms are also specified.
Abbreviations: CY: cytochrome; IL: interleukin; UGT: UDP-glucuronosyltransferase; P-gp: P-glycoprotein. Data are from (15)