Real-world insulin titration support needed for patients, providers
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An analysis of two real-world studies comparing standard of care basal insulin therapy with insulin glargine 300 U/mL suggests that more patient and provider support are needed regarding insulin dosing and titration, according to findings published in Current Medical Research and Opinion.
“Even after initiation, those using basal insulin frequently experience poor glycemic control, which may be related to insulin dose up-titration that is often suboptimal in real-world practice,” Nicholas Freemantle, PhD, professor and director of the Comprehensive Clinical Trials Unit at University College London, and colleagues wrote in the study background. “Such therapeutic inertia (a phenomenon that includes delayed therapy initiation, lack of dose adjustment and delayed therapy intensification), which probably contributes to the low level of HbA1c target achievement in routine clinical practice, may be related to perceived barriers, such as hypoglycemia and weight gain.”
Real-world analysis
Freemantle and colleagues analyzed data from adults with type 2 diabetes treated with insulin glargine 300 U/mL (Toujeo, Sanofi) who were insulin naive at baseline (REACH CONTROL trial; n = 703) or treated with another basal insulin (REGAIN CONTROL trial; n = 609). Both trials, conducted between 2015 and 2017, were randomized, open-label, parallel-group studies. Participants had an HbA1c of at least 7% and were randomly assigned to insulin glargine 300 U/mL or a standard of care basal insulin (insulin glargine 100 U/mL [Lantus, Sanofi], insulin detemir [Levemir, Novo Nordisk], NPH insulin or insulin degludec [Tresiba, Novo Nordisk]) for 6 months, followed by a 6-month extension period continuing with the assigned treatment. Insulin titration and other medication changes were at investigator or participant discretion after randomization. Primary outcome was noninferiority of insulin glargine 300 U/mL vs. standard of care for HbA1c change from baseline to month 6.
“REACH and REGAIN are the first randomized, real-life studies (often known as pragmatic studies as they aim to assess the outcomes of treatment in routine clinical practice, rather than in the controlled explanatory setting of a regulatory randomized controlled trial) using basal insulin treatments in Europe and Brazil, and the first such studies in the field of basal insulin therapy,” the researchers wrote. “The studies were intended to allow for direct treatment comparisons in a real-life setting, and also provide an opportunity to determine whether this pragmatic study design is a valid approach to investigate the impact of novel therapies on therapeutic inertia.”
Researchers found that the primary outcome of noninferiority was met in REACH (least squares mean difference, 0.12%; 95% CI, –0.046 to 0.281) but not in REGAIN (least squares mean difference, 0.17%; 95% CI, 0.015-0.329). There was no between-treatment difference in HbA1c change at 12 months for either study.
During REACH and REGAIN, the mean basal insulin dose increased minimally from baseline to 12 months. For REACH, mean daily insulin dose increased from 0.18 U/kg at baseline to 0.35 U/kg at 12 months for insulin glargine 300 U/mL and from 0.17 U/kg at baseline to 0.33 U/kg at 12 months for standard of care basal insulin. For REGAIN, mean daily insulin dose increased from 0.41 U/kg at baseline to 0.52 U/kg at 12 months for insulin glargine 300 U/mL and from 0.41 U/kg at baseline to 0.48 U/kg at 12 months for standard of care basal insulin. Incidence of hypoglycemia was low and similar between treatment arms for both studies.
“The failure to achieve noninferiority for the difference in HbA1c change in REGAIN compared to standard of care was unexpected,” the researchers wrote. “It is possible that this simply reflects no benefit, or even a lack of parity, with insulin glargine 300 U/mL vs. other standard of care basal insulins in a real-world scenario. However, given the results from previous randomized controlled trials, we feel that this is unlikely.”
‘Therapeutic inertia’
The researchers noted that dose titration in REACH and REGAIN was performed at the discretion of the investigators, without a predefined titration algorithm or a titration committee, and that “overall therapeutic inertia” may be related to the failure to achieve noninferiority at month 6 during REGAIN.
“Results from REACH and REGAIN show that, in addition to appropriate insulin therapy, more dedicated basal insulin titration support using evidence-based algorithms may be required for patients and health care providers in order to help patients with uncontrolled type 2 diabetes to achieve glycemic targets,” the researchers wrote. “These studies also highlight the importance of appropriate patient selection and treatment. Appropriate titration of insulin glargine 300 U/mL and other second-generation basal insulin analogues may be required to realize their potential clinical benefits of decreasing the risk of hypoglycemia vs. older basal insulins.” – by Regina Schaffer
Disclosures: Sanofi sponsored the REACH and REGAIN trials, was involved in data analysis and provided editorial support. Freemantle reports he has received research support from Accelovance, Akcea, AstraZeneca, Biopharma, Ipsen, Sanofi, Takeda and Tesareo, and has served as a speaker for Sanofi. Please see the study for all other authors’ relevant financial disclosures.
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