COVID-19 - Issues Related To Diabetes Mellitus in Adults - UpToDate

9/8/22, 13:42 COVID-19: Issues related to diabetes mellitus in adults - UpToDate
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COVID-19: Issues related to diabetes mellitus in adults

Author: Deborah J Wexler, MD, MSc
Section Editor: Irl B Hirsch, MD
Deputy Editor: Jean E Mulder, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2022. | This topic last updated: Feb 18, 2021.
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".)
● (See "COVID-19: Management in hospitalized adults".)
● (See "COVID-19: Questions and answers".)
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].
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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 [2-7].
● In China, the case fatality rate was 7.3 percent among patients with diabetes (most likely
type 2 diabetes) whereas the overall case fatality rate was 2.3 percent [8].
● In a retrospective study from the United States, the mortality rate was 14.8 percent among
patients with diabetes and 28.8 percent in patients with diabetes or uncontrolled
hyperglycemia, compared with 6.2 percent without either [3].
● In a report of a population cohort study from the United Kingdom, the crude mortality
rate for patients with type 2 diabetes was 260 per 100,000 persons compared with 27 per
100,000 persons in the overall population without diabetes (adjusted [for age, sex,
socioeconomic factors, other comorbidities] odds ratio [OR] 1.80, 95% CI 1.75-1.86) [7].
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 [9].
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 [10]. 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 [11-13].
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 few data evaluating the impact of glycemic
control prior to COVID-19 infection on the risk of severe infection. 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 [14]:
● 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]).
Elevated body mass index (BMI) was also associated with increased COVID-19 mortality (eg, for
BMI 35 to 39.9 kg/m2 compared with 25 to 29.9 kg/m2, HRs 1.72 [95% CI 1.21-2.46] and 1.17
[95% CI 1.08-1.26] for type 1 and type 2 diabetes, respectively).
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) [12].
Factors, other than obesity, older age, and associated comorbidities, such as differential
expression of angiotensin-converting enzyme (ACE) receptors or other molecular mechanisms,
may play a stronger role in COVID-19 outcomes among patients with diabetes [10].
CLINICAL PRESENTATIONS
COVID-19 infection appears to precipitate severe metabolic manifestations of diabetes,

including diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), and severe
insulin resistance [15], 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. Patients
may or may not have a history of diabetes [16]. In a systematic review of 19 reports (110
patients with DKA or HHS), 77 percent of patients had pre-existing diabetes [17]. (See "Diabetic
ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and
diagnosis", section on 'Clinical presentation'.)
Sodium-glucose co-transporter 2 (SGLT2) inhibitors can increase the risk of DKA and should be
discontinued in ill or hospitalized patients. Glucose levels may be only modestly elevated in

patients with SGLT2 inhibitor-associated DKA. (See "Sodium-glucose co-transporter 2 inhibitors

for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Diabetic
ketoacidosis'.)
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 [18]. (See 'Severe insulin
resistance' below.)
Less severe presentations of newly diagnosed diabetes have also 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 [19]. 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 [20].
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 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. 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 [21,22]. 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 [21-23]. Some observational studies suggest protective effects with the use of
DPP-4 inhibitors following COVID-19 infection [24,25]. 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
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 — 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.)
Glycemic targets — In general, the goals of treatment are the same as in other hospitalized
patients (eg, avoid severe hyperglycemia, volume depletion, and electrolyte abnormalities;
avoid hypoglycemia; ensure adequate nutrition). A blood glucose target of 140 to 180 mg/dL
(7.8 to 10 mmol/L) is reasonable for most hospitalized patients. Many patients have severe
insulin resistance and require high doses of insulin to achieve these goals. (See 'Severe insulin
resistance' below and "Management of diabetes mellitus in hospitalized patients", section on
'Glycemic targets'.)
There are no interventional studies to inform appropriate glycemic targets in patients with
COVID-19.
Managing diabetes medications for patients with type 2 diabetes — In the setting of
hospitalization for acute illness, oral and non-insulin injectable diabetes agents (ie, GLP-1
receptor agonists) are often either contraindicated or not well tolerated. Therefore, home
diabetes medications are usually discontinued. (See 'Hyperglycemia without DKA/HHS' below
and "Management of diabetes mellitus in hospitalized patients", section on 'Patients treated
with oral agents or injectable GLP-1 receptor agonists'.)
As examples:
● SGLT2 inhibitors should be discontinued due to increased risk of dehydration and volume
contraction.
● Metformin is contraindicated in situations in which renal function and/or hemodynamic

status is either impaired or threatened, due to the small but increased risk of lactic
acidosis, and therefore should be discontinued at least temporarily until the clinical course
is more certain.
● GLP-1 receptor agonists often cause nausea and are avoided in the acute care setting. Of
note, patients who use long-acting GLP-1 receptor agonists (eg, dulaglutide, semaglutide)
may have this medication in their system for the week following the last dose
administration [26].
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 [26]. 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 self-monitoring of
blood glucose, 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 [27,28].
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 — 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
[29]. (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
[30], 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 [31]. While patients with COVID-19 and diabetes
can be quite insulin resistant, meriting high starting doses, individual insulin resistance
cannot be predicted at presentation.
● Montefiore DKA protocol

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• 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 [30].
• 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 [30]. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in
adults: Treatment", section on 'Resolution of DKA/HHS'.)
● Mount Sinai COVID-19 DKA protocol
• Intermediate or long-acting insulin – Initiate basal insulin (0.2 units/kg/day).

Continue every 24 hours [30].
• 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 [30]. 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 [32].
• 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 [32]. 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
manage DKA, along with intravenous fluids and electrolyte replacement in a monitored
inpatient or observational setting. In most cases, the pump should be removed, and the DKA
should be managed with intravenous or subcutaneous regiments per hospital protocol [32]. For
patients using a hybrid closed-loop system, we advise using "open loop" until resolution of the
DKA. Although there is increasing use of CGM in the hospital with COVID-19 [33], 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 [18]. 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 [34]. 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 pre-existing diabetes mellitus

and may precipitate steroid-induced hyperglycemia in patients without pre-existing
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, 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'.)
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
● 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 coronavirus disease 2019
(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.)
● COVID-19 infection appears to precipitate severe manifestations of diabetes, including

diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), and severe insulin
resistance. Patients may or may not have a history of diabetes. (See 'Clinical presentations'
above.)
● Sick-day management is directed towards preventing hypoglycemia, significant

hyperglycemia, and DKA. (See 'Outpatient management' above.)
● 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.)
● There are no data to inform precise glycemic targets for patients with COVID-19. In
general, the goals are the same as in other hospitalized patients (eg, avoid severe
hyperglycemia, volume depletion, and electrolyte abnormalities; avoid hypoglycemia;
ensure adequate nutrition). A blood glucose target of 140 to 180 mg/dL (7.8 to 10 mmol/L)
is reasonable for most hospitalized patients. (See 'Glycemic targets' above.)

● Many oral agents have specific contraindications that may occur in acutely ill or
hospitalized patients. Therefore, home diabetes medications are usually discontinued. In
particular, sodium-glucose co-transporter 2 (SGLT2) inhibitors should be discontinued due
to increased risk of dehydration and volume contraction. Metformin is contraindicated in
situations in which renal function and/or hemodynamic status is either impaired or
threatened, due to the increased risk of lactic acidosis, and therefore should be
discontinued at least temporarily until the clinical course is more certain. Other diabetes
medications may not be appropriate due to adverse side-effect profile. (See 'Managing
diabetes medications for patients with type 2 diabetes' above.)
● 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.)
● 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.)
● 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.)
Use of UpToDate is subject to the Terms of Use.
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with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395:1054.
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Diabetes (autoimmune) may be spared by the infection of Covid-19? Med Hypotheses 2020;
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with COVID-19 and diabetes: the CORONADO study. Diabetologia 2020; 63:1500.
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Reports. Diabetes Metab J 2020; 44:349.
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Topic 128127 Version 7.0

GRAPHICS
Typical laboratory characteristics of diabetic ketoacidosis and

hyperosmolar hyperglycemic state*
DKA
HHS
Mild Moderate Severe
Plasma glucose (mg/dL) >250 >250 >250 >600
Plasma glucose (mmol/L) >13.9 >13.9 >13.9 >33.3
Arterial pH 7.25 to 7.30 7.00 to 7.24 <7.00 >7.30
Serum bicarbonate (mEq/L) 15 to 18 10 to <15 <10 >18
Urine ketones¶ Positive Positive Positive Small
Serum ketones – Nitroprusside Positive Positive Positive ≤ Small

reaction
Serum ketones – Enzymatic assay of 3 to 4 4 to 8 >8 mmol/L <0.6 mmol/L

beta hydroxybutyrate (normal mmol/L mmol/L
range <0.6 mmol/L)Δ
Effective serum osmolality Variable Variable Variable >320

(mOsm/kg)◊
Anion gap§ >10 >12 >12 Variable
Alteration in sensoria or mental Alert Alert/drowsy Stupor/coma Stupor/coma

obtundation
DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state.
* There may be considerable diagnostic overlap between DKA and HHS.
¶ Nitroprusside reaction method.
Δ Many assays for beta hydroxybutyrate can only report markedly elevated values as >6.0 mmol/L.
◊ Calculation: 2[measured Na (mEq/L)] + glucose (mg/dL)/18.
§ Calculation: (Na+) – (Cl– + HCO3–) (mEq/L).
Copyright © 2006 American Diabetes Association. From Diabetes Care Vol 29, Issue 12, 2006. Information updated from
Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009;
32:1335. Reprinted with permission from the American Diabetes Association.
Graphic 72111 Version 9.0

Hyperglycemia treatment for hospitalized patients

receiving nothing by mouth
Proposed algorithm for management of diabetes and hyperglycemia

in the noncritical care setting.
NPO: nil per os (nothing by mouth); DM: diabetes mellitus: GLP-1:

glucagon-like peptide-1; BG: blood glucose; IV: intravenous.
* Adjusted based on current degree of hyperglycemia; consider

modest (20-25%) dose reduction if tightly controlled on admission, to
be conservative.
Reproduced with permission from: Inzucchi SE. Diabetes facts and guidelines. Yale
Diabetes Center, 2011. Copyright © 2011.
Graphic 59822 Version 4.0

Contributor Disclosures
Deborah J Wexler, MD, MSc Consultant/Advisory Boards: Novo Nordisk – Data Monitoring Committee
[Cardiovascular and renal outcome trials]. All of the relevant financial relationships listed have been
mitigated. Irl B Hirsch, MD Grant/Research/Clinical Trial Support: Beta Bionics [Diabetes]; Insulet
Corporation [Diabetes]. Consultant/Advisory Boards: Abbott [Diabetes]; GWave [Diabetes]; Lifescan
[Diabetes]; Roche [Diabetes]. All of the relevant financial relationships listed have been mitigated. Jean E
Mulder, MD No relevant financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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9/8/22, 13:42 COVID-19: Issues related to diabetes mellitus in adults - UpToDate

Official reprint from UpToDate®

COVID-19: Issues related to diabetes mellitus in adults

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

RISK OF SEVERE COVID-19

https://www.uptodate.com/contents/covid-19-issues-related-to-diabetes-mellitus-in-adults/print?search=diabetes y covid&source=search_result&sele… 1/20

COVID-19 infection appears to precipitate severe metabolic manifestations of diabetes,

https://www.uptodate.com/contents/covid-19-issues-related-to-diabetes-mellitus-in-adults/print?search=diabetes y covid&source=search_result&sele… 3/20

patients with SGLT2 inhibitor-associated DKA. (See "Sodium-glucose co-transporter 2 inhibitors

Outpatient management — In the presence of COVID-19 infection, sick-day management is

• Sulfonylureas or meglitinides – Oral agents that can cause hypoglycemia (eg,

• SGLT2 inhibitors – Sodium-glucose co-transporter 2 (SGLT2) inhibitors (eg,

• DPP-4 inhibitors – Dipeptidyl peptidase 4 (DPP-4) inhibitors should not be used as

DPP-4 has been implicated in the pathogenesis of coronavirus infections, including

https://www.uptodate.com/contents/covid-19-issues-related-to-diabetes-mellitus-in-adults/print?search=diabetes y covid&source=search_result&sele… 5/20

• Continuous glucose monitoring (CGM) or fingerstick capillary glucoses can be checked

• If moderate or large ketones, vomiting, or other symptoms of DKA develop, give

• Advise patients to hydrate by drinking 8 ounces (approximately 250 mL) of

● Metformin is contraindicated in situations in which renal function and/or hemodynamic

Hyperglycemia without DKA/HHS — Insulin is the preferred treatment for hyperglycemia in

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The management of diabetes in hospitalized patients with COVID-19 is similar to the

https://www.uptodate.com/contents/covid-19-issues-related-to-diabetes-mellitus-in-adults/print?search=diabetes y covid&source=search_result&sele… 8/20

● General principles of subcutaneous insulin protocols – When mild to moderate DKA is

● Montefiore DKA protocol

• Intermediate or long-acting insulin – Initiate basal insulin immediately (0.15 to 0.2

● Mount Sinai COVID-19 DKA protocol

• Intermediate or long-acting insulin – Initiate basal insulin (0.2 units/kg/day).

• Intermediate or long-acting insulin – Initiate basal insulin (0.15 units/kg). Continue

https://www.uptodate.com/contents/covid-19-issues-related-to-diabetes-mellitus-in-adults/print?search=diabetes y covid&source=search_result&sel… 11/20

● Glucocorticoids – Glucocorticoids raise glucose levels in pre-existing diabetes mellitus

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

● COVID-19 infection appears to precipitate severe manifestations of diabetes, including

● Sick-day management is directed towards preventing hypoglycemia, significant

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● Insulin is the preferred treatment for hyperglycemia in patients hospitalized with

Use of UpToDate is subject to the Terms of Use.

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Typical laboratory characteristics of diabetic ketoacidosis and

Plasma glucose (mg/dL) >250 >250 >250 >600

Plasma glucose (mmol/L) >13.9 >13.9 >13.9 >33.3

Arterial pH 7.25 to 7.30 7.00 to 7.24 <7.00 >7.30

Serum bicarbonate (mEq/L) 15 to 18 10 to <15 <10 >18

Urine ketones¶ Positive Positive Positive Small

Serum ketones – Nitroprusside Positive Positive Positive ≤ Small

Serum ketones – Enzymatic assay of 3 to 4 4 to 8 >8 mmol/L <0.6 mmol/L

Effective serum osmolality Variable Variable Variable >320

Anion gap§ >10 >12 >12 Variable

Alteration in sensoria or mental Alert Alert/drowsy Stupor/coma Stupor/coma

DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state.

* There may be considerable diagnostic overlap between DKA and HHS.

¶ Nitroprusside reaction method.

◊ Calculation: 2[measured Na (mEq/L)] + glucose (mg/dL)/18.

§ Calculation: (Na+) – (Cl– + HCO3–) (mEq/L).

Graphic 72111 Version 9.0

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Hyperglycemia treatment for hospitalized patients

Proposed algorithm for management of diabetes and hyperglycemia

NPO: nil per os (nothing by mouth); DM: diabetes mellitus: GLP-1: