What causes hyperglycemia despite insulin therapy?

From the Guidelines

Hyperglycemia despite insulin therapy is most commonly caused by inadequate insulin dosing or regimen, insulin resistance, or other underlying factors such as medication side effects, stress, or infection. According to the 2016 American Diabetes Association standards of medical care in diabetes 1, insulin therapy should be initiated when blood glucose levels are 16.7 to 19.4 mmol/L (300 to 350 mg/dL) or greater and/or HbA1c levels are 10% to 12%, especially if symptomatic or catabolic features are present.

Some key factors that contribute to hyperglycemia despite insulin therapy include:

• Inadequate basal insulin dosing, which can be initiated at 10 units or 0.1 to 0.2 units/kg of body weight 1
• Inadequate prandial insulin coverage, which can be addressed with rapid-acting insulin analogues such as lispro, aspart, or glulisine 1
• Insulin resistance, which can be improved with lifestyle modifications such as regular exercise and a balanced diet low in refined carbohydrates
• Medication side effects, such as corticosteroids, which can increase blood glucose levels
• Stress, illness, and infections, which can temporarily raise blood sugar due to the release of stress hormones

To address hyperglycemia despite insulin therapy, it is essential to:

• Monitor blood glucose levels regularly and adjust insulin dosing accordingly
• Work closely with a healthcare provider to optimize insulin regimens and address underlying factors contributing to hyperglycemia
• Consider combination injectable therapy, such as a GLP-1 receptor agonist or prandial insulin, to reduce postprandial glucose excursions 1
• Prioritize lifestyle modifications, such as regular exercise and a balanced diet, to improve insulin sensitivity and overall glucose control.

From the FDA Drug Label

Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions (5. 3)] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions (6.1,6. 3)]. Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings and Precautions (5.2,5.3) and Use in Specific Populations (8.6,8.7)].

Causes of hyperglycemia despite insulin therapy include:

• Changes in insulin regimen, such as strength, manufacturer, type, injection site, or method of administration
• Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis
• Changes in physical activity
• Changes in meal patterns, including macronutrient content or timing of food intake
• Changes in renal or hepatic function
• Acute illness 2
• Certain medications, such as corticosteroids, danazol, diuretics, sympathomimetic agents, isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, and progestogens 3

From the Research

Causes of Hyperglycemia Despite Insulin Therapy

• Hyperglycemia can occur despite insulin therapy due to various factors, including the natural progression of diabetes, which is characterized by increasing glucose levels requiring increasing therapy 4
• Infection is a common factor that can lead to hyperglycemic crisis, and intravenous insulin dosing may be necessary to control blood glucose levels 5
• The dosage of insulin may vary greatly, and the reduction in blood glucose levels can also vary significantly, making it challenging to achieve optimal glycemic control 5
• Glucose toxicity, which is the aggravation of defects in insulin secretion and insulin action by hyperglycemia, can also contribute to hyperglycemia despite insulin therapy 6

Factors Affecting Glycemic Control

• The patient's condition, including the presence of intercurrent illness, can affect the choice of insulin regimen and the achievement of glycemic goals 7, 5
• The type of insulin therapy, such as continuous intravenous insulin infusion or scheduled basal-bolus-correction insulin, can also impact glycemic control 7
• The use of oral glucose-lowering drugs, such as DPP-4 inhibitors or SGLT-2 inhibitors, in combination with insulin therapy can also influence glycemic control 8

Individualized Approach to Insulin Therapy

• An individualized approach to insulin therapy is necessary, taking into account the patient's characteristics, such as age, body mass index, and presence of comorbidities 7, 8
• The ease with which normoglycemia is achieved on insulin may predict those patients who can later succeed in controlling glucose levels with attention to diet alone 6