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Insulin, GLP-1 receptor agonist combinations increase glycemic control without hypoglycemia, weight gain
In two separate studies evaluating fixed-ratio combinations of a glucagon-like peptide-1 receptor agonist and a basal insulin, adults assigned the combinations were more likely to reach a target HbA1c without hypoglycemia or weight gain vs. those assigned insulin alone or insulin plus metformin.
In May, an FDA advisory panel voted in favor of recommending approval of each of the combination drugs: iGlarLixi, a combination of insulin glargine (Lantus) and lixisenatide (Lyxumia) developed by Sanofi Aventis, and IDegLira, a combination of insulin degludec (Tresiba) and liraglutide (Victoza) developed by Novo Nordisk.
Insulin glargine plus lixisenatide
In a randomized, open-label, parallel-group trial, researchers comparing the efficacy and safety of iGlarLixi vs. insulin glargine alone found the drug was well tolerated over 30 weeks, with a low rate of nausea and vomiting reported in patients.
Vanita R. Aroda, MD, director of the MedStar Community Clinical Research Center at the MedStar Health Research Institute, and colleagues analyzed data from 736 patients with poorly controlled type 2 diabetes on either basal insulin alone or with up to two oral antidiabetes drugs (mean age, 60 years; 53% women; 92% white; mean diabetes duration, 12 years; average basal insulin therapy use, 3 years; mean BMI, 31 kg/m²). Within the cohort, the mean insulin dose prior to randomization was 35 units; 52% were taking metformin; 32% were taking metformin and sulfonylureas. Included patients remained in poor control (HbA1c greater than 7% despite a morning fasting plasma glucose of 140 mg/dL or less) following a 6-week run-in phase where insulin glargine was either introduced or optimized; any oral antidiabetes agents with the exception of metformin were discontinued prior to the start of the trial.
Researchers randomly assigned patients to iGlarLixi (self-injected once daily in the hour before breakfast) or insulin glargine alone for 30 weeks. Researchers assigned patients taking an insulin dose of less than 30 units daily prior to randomization to “pen A,” delivering insulin glargine and lixisenatide at a 2:1 ratio (20 units; 10 mg lixisenatide). Patients on a daily insulin dose of at least 30 units daily prior to randomization were assigned “pen B,” with a 3:1 ratio of insulin glargine and lixisenatide (30 units; 10 mg lixisenatide), Aroda said while presenting study findings.
Primary outcome was change in HbA1c from baseline to week 30.
From screening to baseline (after run-in), mean HbA1c for the cohort fell from 8.5% to 8.1% in both groups. Over the treatment period, patients assigned iGlarLixi saw a further decrease in HbA1c to 6.9% vs. 7.5% for those assigned insulin glargine alone (mean treatment difference, .52%; P < .0001); 55% of iGlarLixi patients achieved an HbA1c of 7% or less vs. 30% of insulin glargine patients.
Patients in the iGlarLixi group also experienced a decrease in body weight (–0.7 kg), whereas the insulin glargine group saw a mean increase of 0.7 kg. (mean difference, 1.4 kg; P < .0001). Both groups experienced similar rates of documented hypoglycemia (40% vs. 42%). Treatment was well tolerated; however, patients in the iGlarLixi group reported more adverse gastrointestinal events (10%) vs. those assigned insulin glargine alone (0.5%).
“This improvement in glycemic control likely reflected the combined effect of insulin glargine on fasting glucose and lixisenatide on postprandial glucose control,” Aroda. “This paradigm of basal insulin with GLP-1 receptor agonist therapy appears to be efficacious, well tolerated with complementary physiologic effects.”
Insulin degludec plus liraglutide
In a post-hoc analysis of the DUAL V study, Ildiko Lingvay, MD, MPH, MSCS, associate professor of internal medicine at University of Texas Southwestern Medical Center, evaluated whether patients achieving an HbA1c of 7% or less or a fasting plasma glucose of 130 mg/dL or less also achieved composite endpoints relevant to diabetes management. DUAL V included patients with poorly controlled type 2 diabetes (HbA1c between 7% and 10%) on insulin glargine and metformin therapy (n = 557; mean age, 58 years, mean BMI, 31 kg/m²; mean diabetes duration, 11 years; mean insulin use, 30 units daily). Researchers randomly assigned patients to IDegLira plus metformin (mean baseline HbA1c, 8.4%; 16 dose steps initially) or to continue with insulin glargine plus metformin up-titrated as needed (mean baseline HbA1c, 8.2%).
Lingvay noted that, across stratified baseline HbA1c groups, patients switched to IDegLira were more likely to reach the target HbA1c goal of 7% or less vs. patients who continued with insulin glargine.
Across three baseline HbA1c groups (7.5% or less, between 7.5% and 8.5%, and 8.5% or greater) more patients in the IDegLira group achieved an HbA1c of 7% or less vs. those assigned insulin glargine (87% vs. 66%; 76% vs. 50%; 59% vs. 31%, respectively). Across the same baseline HbA1c groups, more patients also achieved the target HbA1c without hypoglycemia (67% vs. 45%; 55% vs. 30%; 47% vs. 19%, respectively) and without hypoglycemia or weight gain (51% vs. 25%; 39% vs. 11%; 32% vs. 5%, respectively; P < .005 for all).
For patients switched to IDegLira, there was a faster drop in fasting plasma glucose levels vs. those continuing with insulin glargine therapy, despite patients in the IDegLira group decreasing their insulin glargine dose at randomization, Lingvay said.
“They were dropping much more rapidly with IDegLira vs. insulin glargine,” Lingvay said while presenting her findings, and added that, ultimately, the two groups’ fasting plasma glucose numbers merged because of the intent-to-treat design of the trial. Results were similar for a drop in HbA1c, Lingvay said.
“This is important from two sides,” Lingvay said. “For the patients, unless they see quick results when we change therapies, compliance with the therapy decreases, and we’re not able to get them to goal. From my standpoint, I was a worried in the beginning, if we cut back on the insulin dose on randomization, will they lose control or will they take longer to get to the same goal?” — by Regina Schaffer
- Reference:
- Aroda VR. 238-OR.
- Lingvay I. 239-OR.
Disclosure: Aroda reports receiving research support from Amylin, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eisai, GI Dynamics, GlaxoSmithKline, Halozyme, Hanmi, Intarcia, Janssen, Novo Nordisk, Sanofi and Takeda, and receiving consulting honoraria from Janssen, Novo Nordisk, and Sanofi. Lingvay reports receiving research support or serving on advisory boards for GI Dynamics, Jannsen, Merck and Novo Nordisk and Sanofi.
Perspective
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Type 2 diabetes is characterized by a progressive decline in beta-cell function, with most patients ultimately requiring insulin therapy to achieve glycemic control. Clinical guidelines and randomized controlled trials have reported significant glycemic benefits of adding a daily dose of basal insulin in patients with poor glycemic control on oral antidiabetic drugs. Unfortunately, about half of patients on the combination of oral antidiabetic drugs and basal insulin do not achieve or maintain glycemic control. In such patients, the addition of either a single dose of rapid-acting insulin before the largest meal or the addition of multiple doses of prandial insulin is recommended. Although basal bolus insulin regimen is associated with improved glycemic control, hypoglycemia and weight gain remain significant challenges to care. The addition of a GLP-1 receptor agonist has been shown to be an effective and safe alternative to basal bolus therapy in patients with type 2 diabetes. Nevertheless, this approach requires multiple daily injections and is subject to the gastrointestinal-related side effects associated with the initiation and up-titration of GLP-1 receptor agonists.
Fixed-ratio combinations of GLP-1 receptor agonists and basal insulin analogues are currently under review by the FDA for the treatment of patients with type 2 diabetes. These combinations have the potential to address both fasting and postprandial glucose control without incurring the tolerability issues associated with prandial insulin and the gastrointestinal-related side effects of GLP-1 receptor agonists. Early studies on the use of fixed-ratio combination reported that iGlarLixi and iDegLira result in greater improvement in glycemic control compared with the use of basal insulin or a GLP-1 receptor agonist alone.
The studies by Aroda and colleagues and Lingvay and colleagues confirmed the beneficial effects of the fixed-ratio combination therapy and, together with reports from previous clinical trials, indicate significant advantages of fixed-ratio combination of GLP-1 receptor agonists and basal insulin analogues over the use of either agent alone, allowing patients to experience improvements in glycemic control without the detrimental effects of hypoglycemia or weight gain. The slow titration results in a reduction in GI side effects observed with the use of standard doses of GLP-1 receptor agonists. The evidence to date is solid and indicates that the fixed-ratio combination drugs can be used for the management of most adult patients with poorly controlled type 2 diabetes.