What is the cause of hyperglycemia (elevated glucose) despite administration of insulin (insulin therapy)?

From the Guidelines

Hyperglycemia despite insulin therapy is often caused by insulin resistance, and the most effective approach to manage this condition is to combine medication adjustments with lifestyle changes, as recommended by the 2021 study in The Lancet Diabetes and Endocrinology 1. To address hyperglycemia despite insulin use, it's essential to consult a healthcare provider for a thorough evaluation and potential treatment adjustments. The first step may be to increase the insulin dosage or change to a different insulin regimen, such as adding long-acting insulin or switching to an insulin pump.

Key Considerations

• The 2021 study in The Lancet Diabetes and Endocrinology 1 suggests that for patients with mild-to-moderate hyperglycemia, a basal-plus approach with or without non-insulin agents might simplify treatment regimens and reduce the risk of hypoglycemia.
• For patients with severe hyperglycemia or those using high doses of insulin at home, a more complex regimen (e.g., basal-bolus) is indicated, as recommended by the 2021 study in The Lancet Diabetes and Endocrinology 1.
• The use of GLP-1 receptor agonists, such as semaglutide, may be a safe and effective option to decrease the need for insulin without increasing the risk of hypoglycemia, as suggested by the 2021 study in The Lancet Diabetes and Endocrinology 1.

Lifestyle Modifications

In addition to medication changes, lifestyle modifications are crucial to manage hyperglycemia despite insulin use.

• Aim for 150 minutes of moderate-intensity exercise per week, spread over at least three days, as recommended by the American Diabetes Association 1.
• Adopt a balanced diet rich in vegetables, lean proteins, and whole grains, while limiting processed foods and simple carbohydrates.
• Monitor carbohydrate intake and consider working with a registered dietitian to develop a personalized meal plan.

Blood Glucose Monitoring

Regular blood glucose monitoring is essential to identify patterns and adjust treatment accordingly.

• Check glucose levels more frequently, including before meals and at bedtime.
• Track food intake, physical activity, and stress levels alongside glucose readings to identify factors affecting blood sugar. By combining medication adjustments with lifestyle changes and regular blood glucose monitoring, individuals with hyperglycemia despite insulin use can improve their body's insulin sensitivity and glucose management, ultimately reducing the risk of morbidity, mortality, and improving quality of life.

From the FDA Drug Label

1. 2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen 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 unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions (6)]

The cause of hyperglycemia (elevated glucose) despite administration of insulin (insulin therapy) may be due to:

• Changes in insulin regimen, such as insulin strength, manufacturer, type, injection site, or method of administration
• Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis These factors can affect glycemic control and predispose to hyperglycemia 2

From the Research

Causes of Hyperglycemia Despite Insulin Therapy

• Inadequate insulin dosing or regimen, as insulin therapy may need to be intensified or adjusted over time to improve glycemic control and prevent diabetes-related complications 3
• Inability of basal insulin alone to achieve optimal glucose control due to its inability to cover postprandial glucose excursions, highlighting the need for intensifying therapy with addition of bolus insulin or switching to premixed insulin 4
• Failure to reach glycemic targets with initially prescribed regimen, requiring intensification of insulin therapy, which increases the risks of weight gain and hypoglycemia 5
• Fear of hypoglycaemia, regimen complexity, and increased burden of multiple daily injections, leading to a delay in intensifying insulin therapy in patients with sub-optimal glycaemic control 4
• Extremes of blood glucose, as blood glucose levels >180 mg/dL may increase the risk of hospital complications, and blood glucose levels <110 mg/dL have been associated with an increased risk of hypoglycemia 6

Factors Contributing to Hyperglycemia

• Weight gain, which is more common with bolus insulin 3
• Hypoglycemia, which is more common with premixed and bolus insulin 3
• Increased risk of hypoglycemia with intensification of insulin therapy 5, 6
• Individual patient considerations, such as age, life expectancy, comorbid conditions, duration of diabetes, risk of hypoglycemia, cost, patient motivation, and quality of life, which should be taken into account when adjusting insulin regimens 7

Insulin Regimen Adjustments

• Adjusting insulin regimens every three or four days until targets of self-monitored blood glucose levels are reached 7
• Using a basal-bolus insulin strategy, which resulted in better glycemic control than sliding scale insulin and lower risk of hypoglycemia than premixed insulin regimen 6
• Considering the use of insulin analogues, which are as effective as human insulin at lowering A1C levels with lower risk of hypoglycemia, but have significantly higher cost 7