Obesity Predicts Response to Treatment Intensification with Biphasic Insulin 50/50


A recent study identifies a sweet spot for use of premixed biphasic insulin 50/50 in routine clinical practice.

Premixed biphasic insulin 50/50 effectively controls hyperglycemia in patients whose T2DM is inadequately controlled with other lower mix insulin formulations, according to a UK study published online on May 2014 in BMJ Open Diabetes Research and Care. Obesity and A1c were found to be independent predictors of response.

“The management of hyperglycaemia among patients who are on insulin treatment is challenging. There has been recent interest in the use of Humalog mix50 premixed insulin, but evidence for this [formulation] is limited,” commented lead author Iskandar Idris, clinical associate professor in the Faculty of Medicine & Health Sciences at the University of Nottingham in the UK. “This study examined the predictor for response to [premixed biphasic insulin 50/50] and showed, interestingly, that obese patients with diabetes seem to respond well to this premixed insulin.”

People with T2DM who need intensive insulin therapy using multiple daily injections or pumps require 50% of basal and 50% of rapid-acting insulin. Physiologic requirements, it was determined, could be more closely approximated with a premixed biphasic insulin formulation that contains 50% rapid-acting and 50% basal insulin. Past studies have suggested that insulin intensification with premixed biphasic insulin 50/50 (HM50) is effective because it provides better prandial coverage than biphasic human insulin 30/70, biphasic insulin aspart 30/70, or biphasic insulin lispro 25/75. Insuman Comb 50 (IC50) is also available as biphasic insulin 50/50, and contains 50% soluble insulin and 50% crystalline protamine insulin.

The authors used a retrospective cohort design to look at 2183 primary care patients aged 18 years and older who had begun treatment with biphasic insulin 50/50 in the UK between January 2000 and May 2012. The researchers compared baseline data to 12-month outcomes for patients whose information was available in the Health Improvement Network database. The final analysis included 1267 participants with inadequately controlled baseline A1c (>7.5%), who had been treated for a minimum of 6 months with other forms of insulin before starting a biphasic insulin 50/50 regimen (HM50 or IC50). Participants were considered responders if their A1c was below 7.5% and/or if their HbA1c decreased by 1% or more at 12 months, compared to baseline. Comparative analyses were also performed on a subgroup of patients (n=237) who had not been on any insulin before the start point of the study, and compared those on HM50 to those taking IC50.

Overall, 36% of patients responded to insulin intensification with biphasic insulin 50/50, and responders had significantly higher baseline A1c, compared to nonresponders (10.2% vs. 9.3%, p<.001).  Responders also had significantly higher mean weight increase (1.6 kg vs. 0.5 kg, p<.001), and mean HbA1c decrease (1.9% vs. 0.3%, p<.001).  

At 12 months, patients had an overall mean A1c decrease of 0.5% with intensification and 1.6% with initiation of biphasic insulin 50/50.  Adjusted odds ratios indicated that obesity (BMI ≥ 30 kg/m2), 9 or more months of intensified treatment, and baseline A1c were independent predictors of response (OR 1.50, 95% CI 1.08-2.09; OR 1.98, 95% CI 1.23-3.20; and OR 1.55, 95% CI 1.42-1.69, respectively). 

When stratified for baseline A1c values, HM50 was linked to greater reduction in A1c compared with IC50 (mean reduction in HbA1c: 0.6% vs 0.4%, respectively, p<.001). Mean weight change at 12 months was similar for both agents, with an increase of about 0.9 kg.

“We could not speculate the mechanism [by which HM50 could provide better improvement of glycemic control, as compared to IC50] because the study was not designed for this,” Idris concluded. “We would speculate that the use of Humalog Mix50 allows patients to reduce the dose of insulin per day. This would facilitate a more efficient use of insulin and allow some weight loss.”

Data analyzed in the study did not include ethnic information, which could call into question the ability to generalize the results.  Other limitations include inability to control for potential confounders:  medication compliance, diabetes duration, indications for insulin therapy, differences in insulin regimens or titration protocols across institutions, and comorbid illnesses.


This study was funded by an unrestricted education grant from Eli Lilly Pharmaceutical.


Obesity independently predicts responders to biphasic insulin 50/50 (Humalog Mix50 and Insuman Comb 50) following conversion from other insulin regimens:  a retrospective cohort study. BMJ Open Diabetes Research and Care. 2014 2: e000021. Doi:10.1136/bmjdrc-2014-000021

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