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When Should Basal Insulin Therapy Be Intensified In Patients With Unmanaged Type 2 Diabetes?

Apr 2, 2019
 
Editor: Steve Freed, R.PH., CDE

Author: Ghazal Blair, Pharm.D. Candidate 2019, LECOM School of Pharmacy

Addition of bolus insulin to avoid overbasalization is key.

Management of type 2 diabetes has been following a stepwise process. Oral antidiabetic agents, such as metformin and GLP-1 agonists, are considered the preferred first-line options early in the disease because they deliver adequate glycemic management. Initiation of insulin therapy as a glucose-lowering intervention for patients with type 2 diabetes is considered a later treatment option, necessary for those with advanced disease. The guidelines recommend initiation of insulin in any patient with type 2 diabetes who has an A1C level greater than 9%.

There are many different insulin therapy regimens that could be used for treating type 2 diabetes. One of the common insulin regimens is to initiate or add a once-a-day dose of a long-acting insulin, also known as basal insulin, to the patient’s treatment. Initially, the addition of basal insulin appears to help functioning β cells and provides an efficient control on fasting glucose levels with limited effect on postprandial glucose levels. However, as diabetes progresses, degeneration of β cell function occurs causing a greater level of post-prandial glucose and eventually higher HbA1C levels.

Therefore, to prevent “overbasalization,” defined as excessively high fasting glucose despite increased basal insulin dose, the addition of mealtime insulin (bolus insulin) may be necessary. Bolus insulin therapy is either rapid-acting or short-acting insulin that is taken before meals and for corrections. Often guidelines recommend the use of basal-bolus insulin regimen for patients who inject over 0.5 units per kilogram of basal insulin. There are limited studies on the threshold dose of basal insulin and this recommendation is mostly based on professional opinions. Additionally, the maximum insulin dose that should be used before initiation of bolus insulin treatment has not been evaluated via prospective data analysis.

A post hoc analysis of three insulin trials was recently published, to evaluate the benefits and risks associated with increasing basal insulin. Data in this meta-analysis, were gathered for 458 individuals from previous eligible studies. All studies included in this meta-analysis had a minimum duration of 24 weeks, and were designed as prospective, randomized, controlled, treat-to-target trials. Furthermore, all individuals included in this data analysis were patients who have type 2 diabetes taking insulin glargine 100 units in addition to metformin and a sulfonylurea with a minimum of 6 fasting glucose measurements. The outcomes for this study were defined as the effect of basal insulin dose on body weight, HbA1c level, fasting glucose level, and lastly occurrence of hypoglycemia.

In order to assess the outcomes, changes in fasting glucose and HbA1C were calculated with all insulin doses. Overall rate of hypoglycemia and changes in body weight for any patients who were on an insulin dose ≤0.5 unit per kilogram were assessed through the duration of  study. Moreover, for patients who were on a dose greater than 0.5 unit/kg/day, changes in body weight were evaluated for the time periods when patients received that insulin dose.

The results from data analysis appeared to show that there is a non-linear relationship between increased basal insulin dose and glycemic management. Data suggested that as basal insulin dose increased, decrease in fasting glucose and HbA1C was smaller. This non-linear relation was noticeable for basal insulin doses over 0.3 unit/kg/day and there was a ceiling effect noted at dose of 0.5 unit/kg/day. and over. Additionally, it was noted that doses greater than 0.5 lead to more adverse effects such as weight gain and higher rate of hypoglycemia.

This meta-analysis concluded that the greatest decrease (approximately 40 mg/dL per 0.1 unit/kg/day increase in insulin dose) in fasting glucose was seen with insulin doses 0.3 unit/kg/day. Moreover, comparable to the effect on fasting glucose, the greatest HbA1C reductions were observed with doses below 0.3 unit/kg/day. Investigators of this data analysis recommended that therapy intensification with additional agents to cover postprandial glucose levels may be necessary when basal insulin dose is close to 0.5 unit/kg/day and A1C remains above target.

Practice Pearls:

  • Increasing basal insulin beyond dose of 0.5 units/kg/day in patients with type 2 diabetes may lead to “overbasalization” and higher risk of adverse events.
  • There is a non-linear relationship between increased basal insulin dose and glycemic management.
  • Clinicians should consider other antidiabetic treatment adjuncts to reduce hyperglycemia, once basal insulin dose of 0.5 units/kg/day is reached.

References:

LaSalle, James R., and Rachele Berria. “Insulin Therapy in Type 2 Diabetes Mellitus: A Practical Approach for Primary Care Physicians and Other Health Care Professionals.” The Journal of the American Osteopathic Association, American  steopathic Association, 1 Feb. 2013, jaoa.org/article.aspx?articleid=2094449#73005461.

Umpierrez, Guillermo E., et al. “When Basal Insulin Is Not Enough: A Dose Response Relationship Between Insulin Glargine 100 Units/ML (U100) and Glycemic Control.” The Canadian Journal of Chemical Engineering, Wiley-Blackwell, 5 Feb. 2019, onlinelibrary.wiley.com/doi/abs/10.1111/dom.1365

Ghazal Blair, Pharm.D. Candidate 2019, LECOM School of Pharmacy