COVID-19: Issues related to diabetes mellitus in adults

INTRODUCTION — The care of patients with endocrine disorders during the coronavirus disease 2019 (COVID-19) pandemic poses unique challenges. Patients with diabetes are at risk for more severe illness. COVID-19 appears to precipitate severe manifestations of diabetes, including diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), and severe insulin resistance.

This topic will review the care of patients with diabetes during the COVID-19 pandemic. Other important aspects of COVID-19 care are discussed separately.

●(See "COVID-19: Epidemiology, virology, and prevention".)

●(See "COVID-19: Clinical features" and "COVID-19: Diagnosis".)

●(See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection".)

●(See "COVID-19: Evaluation of adults with acute illness in the outpatient setting" and "COVID-19: Management of adults with acute illness in the outpatient setting".)

●(See "COVID-19: Management in hospitalized adults".)

RISK OF SEVERE COVID-19 — Severe illness, manifested as the need for hospitalization, intubation, and death, can occur in otherwise healthy individuals of any age, but the risk of severe illness is most pronounced in adults with advanced age or underlying medical comorbidities, including diabetes [1,2].

Patients with type 2 diabetes are more likely to have serious complications, more intensive care unit (ICU) admissions, longer length of stay, and death from COVID-19 [2-10].

In a systematic review evaluating COVID-19 and diabetes, people with diabetes had increased risk of [9]:

●Disease severity

●ICU admission (relative risks [RR] ranged from 1.47 to 1.96)

●Mortality (RRs 1.48 to 1.83)

While the risk of adverse outcomes in COVID-19 is clearly increased among people with compared with those without diabetes, the relative risk is fortunately lower than earlier in the pandemic. This risk reduction is likely related to improvement in overall management of COVID-19 and vaccination rates, as well as in the setting of different variants.

There are few data evaluating the risk of severe illness and death in patients with type 1 diabetes. In the population cohort study from the United Kingdom, patients with type 1 diabetes also had an increased risk of in-hospital mortality compared with the general population without known diabetes (crude rate 138 versus 27 per 100,000 persons, adjusted OR 2.86, 95% CI 2.58-3.18) [7]. The United Kingdom study did not report data on people with type 1 diabetes age 49 or younger due to privacy concerns related to small sample size. Therefore, there are limited data in this population, although, if infected, they are likely to have a more prolonged course than similarly healthy people without type 1 diabetes, as is seen in other infections [11].

Age, obesity, and additional comorbidities are strong correlates of severe disease in diabetes in observational analyses, but the relationship among these risk factors is complex [12]. Both diabetes and obesity appear to be independent risk factors for severe disease, but depending on the population studied and the outcome, one may appear to be stronger than the other. For example, diabetes is positively associated with age, which is a strong predictor of death from COVID-19. Obesity is inversely associated with age, which may reduce its strength as a risk factor for mortality. Nevertheless, obesity, with its proinflammatory state and altered respiratory mechanics, is a strong risk factor for hospital admission, ICU admission, and respiratory failure [13-16].

Role of hyperglycemia — The role of hyperglycemia in the risk of severe infection in patients with diabetes has not been well studied. Poorly controlled diabetes is a risk factor for infection in general (see "Susceptibility to infections in persons with diabetes mellitus", section on 'Risk of infection'). Since COVID-19 can trigger an intense inflammatory response, it has been challenging to disentangle whether hyperglycemia in COVID-19 is a cause or, as appears more likely, a consequence of severe disease.

There are some data evaluating the impact of glycemic control prior to COVID-19 infection on the risk of severe infection. Some studies suggest that poor glycemic control is associated with worse COVID-19 outcomes [9,16-18]. As an example, an analysis of national diabetes and mortality data from the United Kingdom before and during the pandemic (over 10,000 COVID-19-related deaths in people with diabetes [predominantly type 2]) showed an association between preceding hyperglycemia and mortality, as illustrated by the following [16]:

●Type 2 diabetes – Mortality risk was higher with glycated hemoglobin (A1C) 7.6 to 8.9 percent (59 to 74 mmol/mol) compared with 6.5 to 7 percent (48 to 53 mmol/mol; hazard ratio [HR] 1.22 [95% CI 1.15-1.30]) and increased as A1C levels rose.

●Type 1 diabetes – Mortality risk was significantly higher with A1C >10 percent (86 mmol/mol) compared with 6.5 to 7 percent (48 to 53 mmol/mol, HR 2.23 [95% CI 1.50-3.30]).

In a small observational study from France, 1317 patients with diabetes hospitalized with COVID-19, pre-admission A1C was not significantly associated with poor prognosis (mechanical ventilation and/or death within seven days of admission) [14].

Role of diabetes medications — There have been many observational studies evaluating diabetes medication use in relation to COVID-19 outcomes. Medications that are more frequently used in less advanced stages of diabetes such as metformin, glucagon-like peptide 1 (GLP-1) receptor agonists, and sodium-glucose co-transporter 2 (SGLT2) inhibitors, have been associated with less severe outcomes [19-21], However, it is not clear whether this is related to the properties of the medications themselves or allocation bias (eg, healthier people are more likely to be prescribed these medications).

CLINICAL PRESENTATIONS — Initial variants of COVID-19 precipitated severe metabolic manifestations of diabetes, including diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), and severe insulin resistance [22], usually in the setting of a severe inflammatory response to the virus in which other inflammatory markers such as interleukin 6 (IL-6) are markedly elevated (see "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Clinical presentation'). Patients may or may not have had a history of diabetes [23,24]. In a systematic review of 19 reports (110 patients with DKA or HHS), 77 percent of patients had preexisting diabetes [25]. The insulin requirements in patients with COVID-19 and severe insulin resistance are much higher than those generally reported in studies of critically ill patients [26] (see 'Severe insulin resistance' below).

This presentation may become less common as COVID presentations overall have become less severe.

Less severe presentations of newly diagnosed diabetes have been reported. In a systematic review of eight retrospective cohort studies (3700 patients with severe COVID-19), diabetes was newly diagnosed in 0.6 to 62 percent [27]. Newly diagnosed hyperglycemia may be due to critical illness per se, or there may be direct beta cell injury from SARS-CoV-2 or from the inflammatory response to the virus [28]. In one study, pancreatic expression of angiotensin-converting enzyme 2 (ACE2, the key entry factor for SARS-CoV-2 infection) was high in exocrine ductal tissues but not in islet cells, suggesting that direct infection and destruction of beta cells by the virus is less likely [29]. In other studies, the incidence of insulin-requiring diabetes in patients with COVID-19 was not greater than that reported in the pre-pandemic period (although there was an increase in the frequency of severe DKA at presentation when pandemic restrictions were in place) [30], nor was the incidence of type 1 diabetes over a 15-month period in individuals up to 18 years greater in those with than without COVID-19 [31].

APPROACH TO MANAGEMENT

Outpatient management — In the presence of COVID-19 infection, sick-day management is directed towards preventing hypoglycemia, significant hyperglycemia, and diabetic ketoacidosis (DKA). (See "Management of blood glucose in adults with type 1 diabetes mellitus", section on 'Follow-up'.)

●Type 2 diabetes – In the ambulatory setting, patients with type 2 diabetes and COVID-19 may be able to continue their usual diabetes treatment, based on symptoms and, particularly, if they are able to eat (close to their usual diet) and maintain hydration. Blood glucose should be monitored frequently, at least twice daily, and more frequently if needed, particularly for those requiring insulin therapy. Oral and injectable medications may require adjustment based on glucose trends, diet, and symptoms. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus".)

•Sulfonylureas or meglitinides – Oral agents that can cause hypoglycemia (eg, sulfonylureas, meglitinides) are not typically administered to patients who are not eating. However, if a patient is experiencing marked hyperglycemia (eg, >200 mg/dL [11.1 mmol/L]), sulfonylureas and meglitinides may be continued, highlighting the important role of self-monitoring of blood glucose.

•SGLT2 inhibitors – Sodium-glucose co-transporter 2 (SGLT2) inhibitors (eg, dapagliflozin, canagliflozin, empagliflozin, ertugliflozin) should have a low threshold to be discontinued in patients with COVID-19 who are unable to eat and maintain hydration. SGLT2 inhibitors promote the renal excretion of glucose. They increase calorie losses, risk of dehydration and volume contraction, and genitourinary tract infections. In addition, euglycemic DKA has been reported in patients with both type 1 (during off-label use) and type 2 diabetes who were taking SGLT2 inhibitors. Glucose levels may be only modestly elevated in patients with SGLT2 inhibitor-associated DKA (see "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Diabetic ketoacidosis'). In patients with very mild illness who are maintaining normal diet and fluid intake, SGLT2 inhibitors may be continued.

•DPP-4 inhibitors – Dipeptidyl peptidase 4 (DPP-4) inhibitors should not be used as protection against COVID-19 complications, nor should they be discontinued, excluding known reasons for discontinuation, in those recently contracting COVID-19 infection.

DPP-4 has been implicated in the pathogenesis of coronavirus infections, including SARS-CoV-2. The relationship between use of DPP-4 inhibitors and risk of SARS-CoV-2 infection as well as COVID-19 outcomes has been described in population-based observational studies [32,33]. The use of DPP-4 inhibitors was not associated with increased risk of COVID-19 infection or complications in a number of large population trials [32-34]. Some observational studies suggest protective effects with the use of DPP-4 inhibitors following COVID-19 infection [35,36]. No randomized controlled trials comparing the use of DPP-4 inhibitors with other diabetes drugs on the impact of COVID-19 infection have been conducted. One major challenge for all such studies is risk of allocation bias, in which older patients or patients with chronic kidney disease (CKD) may be more likely to be prescribed a DPP-4 inhibitor than other glucose-lowering medications. Since these factors may also be associated with COVID-19 outcomes, it can be difficult to eliminate this bias, even with advanced propensity score matching methods.

•GLP-1 receptor agonists – Patients experiencing nausea and diarrhea should withhold glucagon-like peptide 1 (GLP-1) receptor agonists (and possibly metformin).

•For patients who are unable to take their usual diabetes treatment, or if glucose levels remain elevated (>180 to 200 mg/dL [>10 to 11.1 mmol/L]) with usual treatment, once-daily intermediate or long-acting insulin can be initiated. (See "Insulin therapy in type 2 diabetes mellitus", section on 'Insulin initiation'.)

•All patients should maintain hydration by drinking 8 ounces (approximately 250 mL) of carbohydrate-free fluids (eg, water, broth) every one to two hours, as needed, to match urinary and insensible losses.

●Type 1 diabetes – Patients should always continue basal insulin, even if they are not eating regularly, and perform frequent blood glucose and ketone (urinary/blood) monitoring, particularly with fever and erratic oral intake. (See "Management of blood glucose in adults with type 1 diabetes mellitus", section on 'Follow-up'.)

•Continuous glucose monitoring (CGM) or fingerstick capillary glucoses can be checked every two to four hours depending on severity of illness. Of note, medications containing acetaminophen or high-dose vitamin C may cause falsely elevated CGM results with some older CGM devices. This is a dose-dependent effect that results from oxidation of acetaminophen at the CGM electrode. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'CGM systems'.)

•If hyperglycemia develops (blood glucose >240 mg/dL [13.4 mmol/L]), advise patients to check urinary or capillary ketones (home testing of blood for beta-hydroxybutyrate is available, but it is used infrequently in adults, at least in the United States).

•The insulin dose is adjusted as needed, based on the measurements of blood glucose and blood or urinary ketones. Insulin requirements may be either increased or decreased during an illness.

•If moderate or large ketones, vomiting, or other symptoms of DKA develop, give supplemental doses of rapid-acting (lispro, aspart, or glulisine) insulin (see 'DKA/HHS' below). For insulin pump users, it is usually wise to change the infusion set and site because failure of pump or infusion set is a very common cause of hyperglycemia and ketosis/ketoacidosis in pump users.

•Advise patients to hydrate by drinking 8 ounces (approximately 250 mL) of carbohydrate-free fluids (eg, water, broth) every hour. For patients with nausea/vomiting or otherwise unable to eat, advise drinking something with carbohydrates (eg, sports drinks, diluted apple juice, clear soda) every four hours.

•If blood ketones remain elevated (>1.5 mmol/L) or urine ketones remain "large" despite extra insulin and hydration, or the patient has ongoing nausea or vomiting and is unable to maintain hydration, the patient should seek urgent medical attention.

Hospitalized patients — In general, the management of diabetes in patients hospitalized for COVID-19 is similar to all inpatient diabetes management (see "Management of diabetes mellitus in hospitalized patients"). In the setting of hospitalization for acute illness, some oral and non-insulin injectable diabetes agents used to treat type 2 diabetes (eg, SGLT2 inhibitors, GLP-1 receptor agonists, metformin) are either contraindicated or not well tolerated and should be discontinued. (See "Management of diabetes mellitus in hospitalized patients", section on 'Patients treated with oral agents or injectable GLP-1-based therapies'.)

The main nuances for patients hospitalized with COVID-19 are the potentially higher risk of DKA or HHS, and potentially higher-than-anticipated insulin resistance in the setting of severe infection [37]. (See "Management of diabetes mellitus in hospitalized patients" and 'DKA/HHS' below and 'Severe insulin resistance' below.)

For patients with COVID-19 who have laboratory results suggestive of metabolic acidosis on initial laboratory evaluation (see "COVID-19: Management in hospitalized adults", section on 'Evaluation'), we check serum ketones to assess for DKA. The diagnostic criteria proposed by the American Diabetes Association (ADA) for mild, moderate, and severe DKA and hyperosmolar hyperglycemic state (HHS) are shown in the table (table 1). (See 'DKA/HHS' below.)

Hyperglycemia without DKA/HHS — Insulin is the preferred treatment for hyperglycemia in patients hospitalized with moderate to severe COVID-19, even if they do not have diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic state (HHS). For patients with type 2 diabetes, the need for insulin therapy may be temporary. Patients with type 1 diabetes have an absolute requirement for insulin at all times, whether or not they are eating, to prevent ketosis. (See "Management of diabetes mellitus in hospitalized patients", section on 'Insulin delivery'.)

The management of diabetes in hospitalized patients with COVID-19 is similar to the management of other hospitalized patients with diabetes, except for the presence of often extreme, labile insulin resistance that resolves with improvement in COVID-19, and the potential need to minimize injection frequency to maximize safety for health care staff. (See 'Severe insulin resistance' below.)

●Type 2 diabetes (not eating regularly) – Insulin may be given subcutaneously with an intermediate-acting insulin, such as neutral protamine hagedorn (human NPH), or a long-acting (basal) insulin analog, such as glargine or detemir combined with correction insulin (rapid-acting insulin analog [lispro, aspart, glulisine] or regular insulin) every six hours. (See "Management of diabetes mellitus in hospitalized patients", section on 'Insulin delivery'.)

•Previously treated with insulin – For patients previously treated with intermediate or long-acting insulin who will not be eating regularly during the hospitalization, reduce the dose by 0 to 50 percent initially, depending on the amount of prandial intake typically covered by the intermediate or long-acting insulin, with correction insulin (rapid-acting or short-acting) administered for blood glucose >150 mg/dL (8.3 mmol/L) (algorithm 1). The basal insulin dose may be adjusted based on response.

•Previously treated with diet, oral agent, or GLP-1 receptor agonist – For patients with type 2 diabetes previously treated at home with diet, an oral agent, or an injectable GLP-1 receptor agonist who will not be eating regularly during the hospitalization, correction insulin alone may also be used as initial insulin therapy or as a dose-finding strategy (algorithm 1).

●Type 2 diabetes (eating a normal diet) – Some patients with type 2 diabetes and mild to moderate COVID-19 may be able to continue part of their outpatient regimen if glucose is well-controlled and no contraindications are present. However, SGLT2 inhibitors and medications that cause nausea or vomiting (eg, GLP-1 receptor agonists) and, in some cases, metformin, should be discontinued. If glucose levels are poorly controlled (eg, persistently >200 mg/dL [11.1 mmol/L]), discontinue oral agents and begin basal and prandial insulin. A typical starting dose for basal insulin is 0.2 to 0.3 units/kg/day, divided in two doses if NPH or detemir, or administered once daily if glargine; in patients with severe insulin resistance, a higher starting dose may be warranted, or the dose may be rapidly escalated. A typical starting dose for prandial insulin is 0.05 to 0.1 units/kg/meal. (See "Management of diabetes mellitus in hospitalized patients", section on 'Insulin delivery'.)

●Type 1 diabetes – Most patients should continue their outpatient regimen, if glucose was well controlled. A modest dose reduction may be necessary if nutritional intake is limited. Never stop basal insulin, even if the patient is not eating. For patients in whom nutritional intake is uncertain, correction insulin every six hours can be administered, as needed, in addition to basal insulin until the patient is eating regularly (algorithm 1).

Most hospitals have protocols for patient self-management of insulin pump therapy. Ideally, patients using an insulin pump may continue, as long as they are clinically stable and assessed to be competent to continue diabetes self-management [37]. If there is a deterioration in their condition, the patient should be transitioned to subcutaneous or intravenous insulin. Similarly, alert, knowledgeable patients may continue use of CGM devices and hybrid closed-loop insulin delivery systems, but given the lack of training of hospital personnel on these devices, endocrinology team consultation is advisable.

The frequency of glucose monitoring depends upon the patient's status, the results of earlier measurements, and the steps taken as a result of those measurements. CGM is particularly attractive in patients with COVID-19 as it may decrease the need for frequent hospital staff monitoring of blood glucose [38,39], but CGM is not used in most hospitals. For insulin dosing decisions, CGM results require confirmation with standard point-of-care glucose monitoring. Moreover, barriers including lack of reimbursement and familiarity with the technology limit its use in patients who are not already using personal CGM [40,41].

In general, in patients with diabetes (or hyperglycemia) who are eating, blood glucose monitoring should occur just before the meal. In those who are receiving nothing by mouth, the blood glucose monitoring should occur at regular, fixed intervals, usually every six hours. (See "Management of diabetes mellitus in hospitalized patients", section on 'Blood glucose monitoring'.)

DKA/HHS — Insulin infusion, fluid resuscitation, and electrolyte repletion according to the standard approach remains the treatment of choice for diabetic ketoacidosis (DKA)/hyperosmolar hyperglycemic state (HHS). (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment", section on 'Overview and protocols'.)

Subcutaneous insulin protocols (rather than intravenous insulin infusions) were adopted early in the COVID-19 pandemic to treat mild to moderate diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic state (HHS) when intravenous insulin was less feasible owing to the need to limit frequency of contact of staff with patients. Subcutaneous insulin protocols for treatment of DKA/HHS require dosing and monitoring every two to four hours, rather than hourly, as is usual in intravenous insulin protocols. Treatment of DKA with subcutaneous insulin has not been evaluated in severely ill patients (with or without COVID-19). In mild DKA, direct comparison of intramuscular, subcutaneous, and intravenous insulin therapy for hemodynamically stable patients with DKA (without COVID-19) shows similar efficacy and safety with decreased intensive care unit (ICU) admission [42,43]. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment", section on 'Subcutaneous insulin regimens'.)

Subcutaneous insulin protocols are best used in patients with mild to moderate DKA without other serious comorbidities. Mild to moderate DKA is generally defined as follows:

●pH ≥7

●Serum bicarbonate ≥10 mEq/L

●Serum potassium ≥3.3 mEq/L

●Awake/alert mental status

Insulin infusions should be used for patients with severe DKA, acute heart failure or coronary syndrome, CKD stage 4 or 5 or end-stage kidney disease (ESKD), acute liver failure or cirrhosis, anasarca, weight >120 kg, treatment with high-dose corticosteroids, or in women who are pregnant. Intravenous insulin infusions for the treatment of DKA and HHS are reviewed separately. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment", section on 'Insulin'.)

●General principles of subcutaneous insulin protocols – When mild to moderate DKA is treated with subcutaneous insulin, begin (or continue) basal insulin (glargine, detemir, or NPH) at the initiation of treatment (0.15 to 0.3 units/kg), along with rapid-acting insulin. Higher initial doses of basal insulin (eg, 0.3 units/kg/day) may be needed in the setting of severe insulin resistance (obesity, high-dose glucocorticoids). In patients previously treated with intermediate or long-acting insulin, the usual dose of basal insulin can be used to gauge usual insulin requirements and guide insulin dosing. Continue basal insulin every 12 to 24 hours, depending on the insulin formulation used.

When the serum glucose reaches 250 mg/dL (13.9 mmol/L), add dextrose to the intravenous saline solution and adjust the dose of rapid-acting insulin per DKA protocol being followed. Blood glucose in patients taking SGLT2 inhibitors may be normal or minimally elevated (<250 mg/dL [13.9 mmol/L]). In this setting, dextrose is added to intravenous fluids at the initiation of therapy. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment", section on 'Fluid replacement'.)

In patients with COVID-19, a variety of subcutaneous protocols have been used for DKA [44], none of which have been formally tested for safety and efficacy. Basal insulin is initiated early in each protocol. Note that doses can be wide-ranging based on starting recommendation and patient weight. It is important to use judgment and consult colleagues when using these protocols [45]. While patients with COVID-19 and diabetes can be quite insulin resistant, potentially meriting high starting doses, individual insulin resistance cannot be predicted at presentation.

●Montefiore DKA protocol

•Intermediate or long-acting insulin – Initiate basal insulin immediately (0.15 to 0.2 units/kg/day), unless the last dose was within 12 hours. Continue every 24 hours [44].

•Rapid-acting insulin – Initial rapid-acting insulin dose 0.2 units/kg, followed by 0.2 units/kg every four hours. When glucose is <250 mg/dL, decrease to 0.1 units/kg every four hours [44]. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment", section on 'Resolution of DKA/HHS'.)

●Mount Sanai COVID-19 DKA protocol

•Intermediate or long-acting insulin – Initiate basal insulin (0.2 units/kg/day). Continue every 24 hours [44].

•Rapid-acting insulin – Initial rapid-acting insulin dose 0.2 units/kg followed by 0.1 units/kg every three hours if the glucose has decreased by at least 75 mg/dL. If the change in glucose three hours after the initial dose is <75 mg/dL, continue 0.2 units/kg every three hours. When glucose is <250 mg/dL, decrease to 0.1 units/kg every three hours [44]. Continue until resolution of ketoacidosis. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment", section on 'Resolution of DKA/HHS'.)

●Diabetes UK protocol

•Intermediate or long-acting insulin – Initiate basal insulin (0.15 units/kg). Continue every 24 hours [46].

•Rapid-acting insulin – Initial dose 0.4 units/kg every four hours. When glucose is <250 mg/dL (13.9 mmol/L), decrease to 0.2 units/kg every four hours [46]. Continue until resolution of ketoacidosis. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment", section on 'Resolution of DKA/HHS'.)

Patients treated with an insulin pump should change the infusion set and connectors in case problems with the infusion set caused the DKA. If the pump is functioning correctly with a new infusion set and the DKA is mild, it may be possible in rare situations to use the insulin pump to deliver extra insulin to manage DKA, along with intravenous fluids and electrolyte replacement in a monitored inpatient or observational setting. For patients using a hybrid closed-loop system, we advise exiting the algorithmic mode of hybrid closed-loop pumps since many algorithms may not support the acute increase in insulin delivery required in the setting of DKA. In most cases, the pump should be removed and the DKA should be managed with intravenous or subcutaneous regiments per hospital protocol [46]. Although there is increasing use of CGM in the hospital with COVID-19 [47-49], there are no data about its use in DKA, and we typically do not use it in this setting.

Severe insulin resistance — Severe insulin resistance has been observed in severely ill patients with COVID-19 [26]. The degree of insulin resistance may improve quickly with resolution of COVID-19, resulting in a sudden decrease in insulin requirements (see 'Hypoglycemia' below). This has been presumed to be cytokine induced, and it appears to correlate with inflammatory markers such as IL-6. Although insulin resistance can be hard to quantify in clinical practice, in one report from China, an indicator of insulin resistance was associated with severity of illness and mortality [50]. In severely insulin-resistant patients, twice-daily dosing of long-acting insulin (eg, glargine) may be necessary.

Our approach in the most critically ill intensive care unit (ICU) patients, especially those who are intermittently taking nothing by mouth, is to use basal insulin (eg, daily glargine, twice-daily glargine, twice-daily NPH) to cover the basal requirement, with a superimposed insulin infusion to cover the variable insulin requirement. As patients recover, the insulin dose should be rapidly reduced to match requirements and reduce the risk of hypoglycemia.

●Enteral nutrition – The prolonged use of enteral nutrition in association with prolonged respiratory failure in COVID-19 can dramatically increase the insulin requirement in insulin-resistant patients. In patients receiving enteral nutrition, we use NPH twice daily along with regular insulin every six hours, adding the supplemental regular insulin requirement into the subsequent NPH dose. We have observed that insulin requirements can drop dramatically with resolution of illness, even when the patient continues the same formula and rate of enteral nutrition. Thus, insulin management should be re-evaluated daily, taking into account the course of the underlying illness and the nutritional plan. (See "Management of diabetes mellitus in hospitalized patients", section on 'Enteral feedings'.)

●Glucocorticoids – Glucocorticoids raise glucose levels in preexisting diabetes mellitus and may precipitate steroid-induced hyperglycemia in patients without preexisting diabetes. However, the magnitude of the hyperglycemic response and the duration of the effect depends on the dose and type of glucocorticoids. If dexamethasone is used for treatment of the inflammatory response to COVID-19, we often treat with NPH (0.2 to 0.3 units/kg/day, divided in two doses) at the time of glucocorticoid dosing, adjusting the NPH dose to match glucocorticoid dose and tapering as glucocorticoid dose is tapered.

Hypoglycemia — Although relatively brief and mild hypoglycemia does not usually have clinically significant sequelae, hospitalized patients are particularly vulnerable to severe, prolonged hypoglycemia since they may be unable to sense or respond to the early warning signs and symptoms of low blood glucose. In COVID-19, there is a risk of hypoglycemia when insulin requirements suddenly decrease with resolution of the underlying inflammatory state (and accompanying improvement in insulin resistance). (See 'Severe insulin resistance' above.)

The risk of hypoglycemia is also increased when caloric intake (including enteral feedings or total parenteral nutrition) is diminished or stopped completely in a patient treated with insulin. In this setting, an intravenous 10 percent dextrose solution, providing a similar number of carbohydrate calories as was being administered via the enteral feeds, should be infused in order to prevent hypoglycemia. (See "Management of diabetes mellitus in hospitalized patients", section on 'Avoidance of hypoglycemia' and "Management of diabetes mellitus in hospitalized patients", section on 'Patients receiving enteral or parenteral feedings'.)

Long-term risk of diabetes — Some studies suggest an increased incidence of diabetes after COVID-19 [51-55]. As an example, in an analysis using a United States Veterans Affairs database of a very large cohort of people who survived the first 30 days of COVID-19, there was an excess burden of diabetes mellitus at six months (hazard ratio [HR] 8.23, 95% CI 6.36-9.95), and obesity (HR 9.53, 95% CI 7.55-11.37) among COVID-19 patients [51]. Some of the newly diagnosed diabetes may be related to previously unrecognized diabetes, and approximately 50 percent of new-onset diabetes cases in the setting of COVID-19 regressed to normoglycemia after recovery in one series [56]. An increase in the incidence of diabetes after COVID-19 also has been reported in some, but not all, studies in children and adolescents <18 years of age [52,57-59]. (See "COVID-19: Management in children".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: COVID-19 – Index of guideline topics".)

SUMMARY AND RECOMMENDATIONS

●Increased risk of severe COVID-19 – Patients with type 2 diabetes are more likely to have serious complications, more intensive care unit (ICU) admissions, longer length of stay, and die from COVID-19. There are limited data evaluating the risk of severe illness and death in patients with type 1 diabetes. (See 'Risk of severe COVID-19' above.)

●Clinical presentations – Initial variants of COVID-19 precipitated severe manifestations of diabetes, including diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), and severe insulin resistance. Patients may or may not have had a history of diabetes. This presentation may become less common as COVID presentations overall have become less severe. (See 'Clinical presentations' above.)

●Outpatient management of diabetes – Sick-day management is directed toward preventing hypoglycemia, significant hyperglycemia, and DKA. SGLT2 inhibitors should be stopped, and other medications should be held or adjusted as needed. (See 'Outpatient management' above.)

●Inpatient management of diabetes – In general, the management of diabetes in patients hospitalized for COVID-19 is similar to all inpatient diabetes management (see "Management of diabetes mellitus in hospitalized patients"). The main nuances for patients hospitalized with COVID-19 are the potentially higher risk of DKA or HHS and potentially higher-than-anticipated insulin resistance in the setting of severe infection. For patients with a known history of diabetes, or in patients with metabolic acidosis on initial admission laboratory evaluation, assess serum ketones. (See 'Hospitalized patients' above.)

•Treatment of hyperglycemia without DKA/HHS – Insulin is the preferred treatment for hyperglycemia in patients hospitalized with moderate to severe COVID-19. For patients with type 2 diabetes, the need for insulin therapy may be temporary. Patients with type 1 diabetes have an absolute requirement for insulin at all times, whether or not they are eating, to prevent ketosis. (See 'Hyperglycemia without DKA/HHS' above.)

Severe insulin resistance has been observed in severely ill patients with COVID-19. The degree of insulin resistance may improve quickly with resolution of COVID-19, resulting in a sudden decrease in insulin requirements. (See 'Severe insulin resistance' above and 'Hypoglycemia' above.)

•Treatment of DKA/HHS – Insulin infusion, fluid resuscitation, and electrolyte repletion according to the standard approach remains the treatment of choice for DKA/HHS. Subcutaneous insulin protocols have been used to treat mild to moderate DKA during the COVID-19 pandemic when intravenous insulin may not be practical owing to the need to limit frequency of contact of staff with patients. In this setting, dosing and monitoring are being performed every two to four hours. Subcutaneous insulin protocols are not used in patients with severe DKA; severe cardiac, renal, or hepatic comorbidities; or in women who are pregnant. (See 'DKA/HHS' above.)