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Glucocorticoids (GC) represent therapeutic agents of great importance in the treatment and prophylaxis of multiple inflammatory and non-inflammatory conditions. Despite their efficacy, the use of GCs is associated with a variety of side effects, one of the immediate ones being the development of glucocorticoids induced hyperglycemia.
GCs decrease peripheral insulin sensitivity, increase hepatic gluconeogenesis, trigger insulin resistance, as well as inhibit pancreatic insulin production.([1] It has been shown that acute and chronic hyperglycemia that are present in many cases in the hospital setting are important risk factors for prolonged hospital stays, infectious complications, poorer surgical outcomes, and increased mortality.
In-hospital glucocorticoid induced hyperglycemia is usually managed with optimization of oral anti-diabetic drugs and basal bolus insulin, which has been well established over sliding scale insulin as the preferred regimen for GIH. Through this study we aim to compare to different basal insulins, glargine and degludec in terms of their efficacy and safety (hypoglycemic events) in this setting.
This study protocol describes a randomized controlled trial conducted at Max Super Specialty Hospital to compare the safety and efficacy of insulin glargine and insulin degludec in the management of glucocorticoid-induced hyperglycemia (GIH) among hospitalized patients. The study is being undertaken as a DNB thesis in the Department of Endocrinology under the guidance of Dr. Ambrish Mithal and colleagues.
Glucocorticoids are widely used in hospitalized patients for inflammatory, autoimmune, respiratory, infectious, and malignant conditions. However, they commonly cause hyperglycemia by increasing insulin resistance, enhancing hepatic gluconeogenesis, promoting lipolysis and proteolysis, and impairing pancreatic beta-cell insulin secretion. Approximately 40-50% of hospitalized patients receiving steroids develop GIH, which is associated with poor clinical outcomes such as prolonged hospitalization, infections, delayed wound healing, intensive care admission, and increased mortality.
The study aims to compare insulin glargine, a long-acting basal insulin with approximately 24-hour duration, and insulin degludec, an ultra-long-acting basal insulin with about 42-hour duration. Degludec is hypothesized to provide similar glycemic control with fewer hypoglycemic episodes because of its flatter and more stable pharmacokinetic profile.
The primary objective is to compare the efficacy of glargine and degludec in reducing mean glucose levels in patients with GIH. Secondary objectives include comparing the incidence of hypoglycemia and identifying predictors of glycemic control.
The study population includes non-pregnant adults above 18 years with type 2 diabetes or without diabetes who are admitted under Respiratory Medicine and are receiving glucocorticoids equivalent to more than 20 mg and less than 160 mg prednisolone daily. Patients already on basal insulin, those receiving steroids for less than 48 hours, pregnant patients, or patients with diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), or requiring insulin infusion are excluded.
A total of 112 patients (56 per group) will be enrolled and randomized using the SNOSE (Sequentially Numbered Opaque Sealed Envelope) method into either the insulin glargine or insulin degludec group. Both groups will receive the same rapid-acting bolus insulin (insulin aspart).
Insulin Protocol
The insulin regimen is based on body weight and baseline blood glucose levels:
0.5 units/kg/day for blood glucose <140 mg/dL 0.8 units/kg/day for blood glucose 141-200 mg/dL
1 unit/kg/day for blood glucose >200 mg/dL
Patients already on basal-bolus insulin at home receive 130% of their prior total daily dose.
The total insulin dose is divided into:
Basal insulin (40%) using either insulin glargine or insulin degludec administered at 10 AM, 10 PM, or both depending on glycemic profile.
Bolus insulin (60%) using insulin aspart distributed as:
15% before breakfast 20% before lunch 10% before evening snack 15% before dinner
Correctional insulin doses are added or reduced according to pre-meal glucose levels. For glucose above 200 mg/dL, additional insulin is administered incrementally, while doses are reduced for glucose below 100 mg/dL. Separate lower correction scales are used for patients with chronic liver disease (CLD) or chronic kidney disease (CKD) to minimize hypoglycemia risk.
Blood glucose monitoring is performed using both capillary blood glucose (CBG) testing and continuous glucose monitoring (CGM) before meals, at 10 AM and/or 10 PM, and occasionally at 2 AM. Insulin doses are adjusted daily according to hospital protocol.
Hypoglycemia is defined as blood glucose below 70 mg/dL. Mild hypoglycemia is greater than or equal to 54 mg/dl and below 70 mg/dl; and severe hypoglycemia will be defined as <54 mg/dl or hypoglycemia with severe symptoms and requiring third party assistance. It will be managed according to standardized hospital treatment protocols with repeat glucose monitoring every 15 minutes until recovery.
The study duration is 18 months, and outcomes assessed include mean glucose levels, time in range, glycemic variability, and hypoglycemic events over the first five days of steroid therapy.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Degludec | Experimental | Degludec was used as a basal insulin against active comparator glargine. |
|
| Glargine | Active Comparator | Glargine is an established treatment for glucocorticoid induced hyperglycemia, hence was used as active comparator in this study. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Degludec insulin | Drug | Degludec was used as part of basal bolus insulin regimen in the experimental arm of this study. Glargine was used as active comparator. |
|
| Measure | Description | Time Frame |
|---|---|---|
| basal insulin dose - on Day 1 and Day 5 of basal bolus treatment | Basal insulin dose measured in units on Day 1 and Day 5 of basal bolus treatment - expressed in IU | for 5 days while admitted to the hospital, from Day 1 of initiation of basal bolus insulin in hospital, to Day 5 of treatment |
| Bolus insulin dose on Day 1 and Day 5 of treatment | Insulin dose of bolus insulin - on Day 1 and Day 5 of treatment , expressed in IU. | for 5 days while admitted in hospital, from Day 1 of initiation of basal bolus insulin to Day 5 of basal bolus insulin |
| Estimated average glucose on Day 1 and Day 5 of basal bolus insulin treatment - in mg/dl | Estimated average glucose on Day 1 and Day 5 of basal bolus insulin treatment - in mg/dl | for 5 days while admitted in hospital, from Day 1 of initiation of basal bolus insulin to Day 5 of basal bolus insulin |
| Time in range | Time in range - as measured on continuous glucose monitor - in percentage | for 5 days while admitted in hospital, from Day 1 of initiation of basal bolus insulin to Day 5 of basal bolus insulin |
| Time above range | Time above range - as measured on continuous glucose monitor - expressed in percentage | for 5 days while admitted in hospital, from Day 1 of initiation of basal bolus insulin to Day 5 of basal bolus insulin |
| Percent change in coefficient of variation - as measured by continuous glucose monitor - expressed in percentage | Percent change in coefficient of variation - as measured by continuous glucose monitor - expressed in percentage |
| Measure | Description | Time Frame |
|---|---|---|
| Incidences of fasting hypoglycemia on any Day, between Day 1 and day 5 of basal bolus treatment, occuring fasting state (early morning, between 5-6 am) - expressed in mg/dl | Fasting Hypoglycemia as measured by glucometer (capillary blood glucose) will be defined as - mild - less than 70 mg/dl but more than or equal to 54 mg/dl; severe -- less than 54 mg/dl, or requirement of third person assistance in correcting hypoglycemia and hypoglycemic symptoms, in the fasting state. Expressed in mg/dl. |
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Inclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Max Institute of Medical Education | New Delhi | Saket | 110017 | India |
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Hospitalized, non pregnant adult patients (above 18 years of age) with or without diabetes, receiving glucocortcoids (prednisolone dose equivalent of 20-160 mg per day) and having glucocorticoid induced hyperglycemia and requiring basal bolus insulin for the management of the same, were randomized to two groups. One group received glargine, and the other degludec insulin as the basal insulin. Both groups received insulin aspart as the bolus. Weight based insulin dosing was done as per study protocol. Patients from both groups were followed for five days, and blood glucose monitoring was done using capillary blood glucose as well as continuous glucose monitoring
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| Glargine insulin | Drug | Glargine was used as part of basal bolus insulin regimen in the active comparator arm of this study. |
|
| for 5 days while admitted in hospital, from Day 1 of initiation of basal bolus insulin to Day 5 of basal bolus insulin |
| Change in Mean amplitude of glycemic excursions (MAGE) - expressed in mg/dl | MAGE the amplitude of glucose variations over time, calculated using Continuous glucose monitoring data in open source software known as EasyGV - expressed in mg/dl | for 5 days while admitted in hospital, from Day 1 of initiation of basal bolus insulin to Day 5 of basal bolus insulin |
| Change in basal insulin, bolus insulin, and total insulin doses from Day 1 to Day 5 in both groups | The change in basal insulin, bolus insulin and total insulin dose from Day 1 to Day 5 will be calculated for both glargine and degludec group, | for 5 days while admitted in hospital, from Day 1 of initiation of basal bolus insulin to Day 5 of basal bolus insulin |
| for 5 days while admitted in hospital during the clinical trial , from Day 1 of initiation of basal bolus insulin to Day 5 of basal bolus insulin |
| Incidences of non -fasting (random) hypoglycemia on any Day, between Day 1 and day 5 of basal bolus treatment, occuring in non-fasting states | Non fasting hypoglycemia (random hypoglycemia, in mg/dl) as measured by glucometer (capillary blood glucose) will be defined as - mild - less than 70 mg/dl but more than or equal to 54; severe - less than 54 mg/dl, or requirement of third person assistance in correcting hypoglycemia and hypoglycemic symptoms . It will be expressed as mg/dl. | for 5 days while admitted in hospital, from Day 1 of initiation of basal bolus insulin to Day 5 of basal bolus insulin |
| Time below range | Time below range, expressed in percentage, as measured by continuous glucose monitor, on Day 1 and Day 5 of basal bolus treatment | for 5 days while admitted in hospital, from Day 1 of initiation of basal bolus insulin to Day 5 |
| ID | Term |
|---|---|
| C571886 | insulin degludec |
| D000069036 | Insulin Glargine |
| ID | Term |
|---|---|
| D049528 | Insulin, Long-Acting |
| D061385 | Insulins |
| D010187 | Pancreatic Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
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