Leah Lawrence

A newly published meta-analysis using data from 78 trials showed that most glucagon-like peptide (GLP)-1 receptor agonists effectively lowered glycemic levels in patients with type 2 diabetes, and also decreased the rate of hypoglycemia compared with treatment with insulin.

“The network meta-analysis based on Bayesian model makes indirect comparison among multiple treatments available, especially when there are few trials for direct comparison between different anti-diabetic drugs, such as comparisons between dulaglutide and insulin in our study,” wrote researchers led by Zhixia Li, Peking University Health Science Center, Beijing, China. “Network meta-analysis has been proved to be the most appropriate method for multiple treatments comparison to date.”

For the study, the researchers conducted a systematic review of literature comparing GLP-1 receptor agonists with placebo or other traditional anti-diabetes treatments in patients with type 2 diabetes. They used data from 78 trials including 13 treatments (seven GLP-1 receptor agonists) to calculate odds ratios [ORs] for incidence of hypoglycemia, treatment discontinuation, and achievement of HbA1c goals. The studies were published between 2004 and 2014. The results were published in 

All of the GLP-1 receptor agonists in the studies were found to increase the risk for hypoglycemia compared with placebo except for albiglutide. However, compared with insulin and sulphonylureas, all of the GLP-1 receptor agonists decreased the risk for hypoglycemia with the exception of dulaglutide.

A higher proportion of patients were found to discontinue treatment when treated with exenatide (OR=3.11), liraglutide (OR=3.48), lixisenatide (OR=1.78) and taspoglutide (OR=5.43) compared with placebo, insulin, or sitagliptin.

The researchers listed two reasons why this increase may occur.

“Firstly, all GLP-1 receptor agonists are injected subcutaneously, and cannot be administered orally. The incidence of treatment discontinuation among patients who had injection site adverse events was high,” the researchers wrote. “Secondly, the adverse events of GLP-1 receptor agonists like nausea, diarrhea, and vomiting, also account for the incidence of treatment discontinuation. Especially for the most commonly occurred nausea, which usually lasts a long time, is a tough experience for type 2 diabetics to bear.”

Looking at glycemic levels, the researchers found that compared with placebo, patients assigned to any of the GLP-1 receptor agonists in the studies had decreases in levels. Additionally, compared with sitagliptin and insulin, dulaglutide, exenatide long-acting release, liraglutide, and taspoglutide significantly lowered HbA1c.

Efficacy and acceptability of glycemic control of glucagon-like peptide-1 receptor agonists among type 2 diabetes: a systematic review and network meta-analysis

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A network meta-analysis compared GLP-1 receptor agonists to traditional anti-diabetes drugs based on hypoglycemia incidence, HbA1c goals, and more.

GLP-1 Receptor Agonists vs Other Anti-Diabetics

Use of the glucagon-like peptide (GLP)-1 receptor agonist dulaglutide in patients aged 65 years or older resulted in similar efficacy and safety as it did in patients younger than 65, according to the results of a pooled analysis published in 

“Given the increasing prevalence of type 2 diabetes in older adults, continued evaluation of diabetes medications for efficacy and safety in this population are necessary,” wrote researcher Malaz A. Boustani, MD, MPH, of Indiana University, and colleagues. “The results of this analysis show that treatment with both dulaglutide doses improves glycemic control, decreases body weight (or results in less weight gain), has a low risk of hypoglycemia, and similar incidence of gastrointestinal adverse events in patients ≥65 years of age and those <65 years of age and can be considered a safe and effective treatment option for use in older adults.”

According to the study, patients with diabetes aged older than 65 present a more challenging patient population because of the presence of comorbidities such as renal impairment, neuropathy, and cognitive dysfunction, and challenges using insulin therapy related to poor vision, arthritis, or cognitive dysfunction. In contrast, dulaglutide is administered in a single use pen.

In this study, Boustani and colleagues pooled data from six phase III AWARD studies of dulaglutide 1.5 mg and 0.75 mg and compared outcomes among patients aged 65 and older and those aged younger than 65. Among the study populations, 958 (15.7%) patients were 65 or older.

At the end of the 26-week study periods there was a similar decrease in HbA1c among both ages groups for both the 1.5-mg dose (≥65: -1.24 vs. <65: -1.29) and the 0.75-mg dose (≥65: -1.16 vs. <65: -1.10). 

“The current standards for treating type 2 diabetes recommend an HbA1c of <7% for healthy adults, but less stringent goals, such as <8-9%, are recommended for those with limited life expectancy and/or comorbid illness,” the researchers wrote. In this analysis, a similar percentage of patients in both age groups were able to achieve goal HbA1c targets:

“From a safety perspective, the incidences of documented symptomatic, asymptomatic, and nocturnal hypoglycemic (PG ≤3.9 mmol/L) events were similar across age groups, and were low when patients were not on concomitant sulfonylurea or insulin therapy,” the researchers wrote.

Similar rates of gastrointestinal adverse events were seen among patients in both age groups and severe hypoglycemia was infrequent.

This study was funded by Eli Lilly and Company.

Comparable efficacy and safety of once weekly dulaglutide in patients with type 2 diabetes ≥65 and <65 years of age

Researchers compared the safety and efficacy of a GLP-1 receptor agonist in patients aged 65 years or older to those under 65 years.

Dulaglutide Safety in Older Diabetic Patients

A patient’s baseline body mass index (BMI) did not seem to have an effect on the efficacy of the glucagon-like peptide (GLP)-1 receptor agonist exenatide twice daily added to insulin glargine among a group of patients with type 2 diabetes, according to the results of a post hoc analysis published in 

“In this secondary analysis of two clinical trials in which patients with type 2 diabetes were randomized to add-on exenatide twice daily versus add-on insulin lispro or placebo, while taking background insulin glargine with or without metformin and/or pioglitazone, baseline BMI was not correlated with changes from baseline in the efficacy parameters evaluated,” wrote Bruce H.R. Wolffenbuttel, MD, PhD, of University of Groningen, the Netherlands, and colleagues. “In both studies, exenatide twice daily was associated with significant reductions in HbA1c and body weight.”

According to the background of the study, certain countries restrict reimbursement for the use of GLP-1 receptor agonists to only those patients with a BMI of 35 kg/m

 or greater. Therefore, in this study, Wolffenbuttel and colleagues wanted to evaluate the validity of that restriction by examining the relationship between BMI and the effects of exenatide twice daily.

In this study, the researchers conducted a post hoc analysis of two randomized, non-inferiority studies. In the first study, exenatide was compared with insulin lispro added to background insulin glargine and metformin (n=627). In the second study, exenatide was compared with placebo added to insulin glargine with or without metformin and/or pioglitazone (n=259). The researchers assessed the relationship between BMI ranges (<30, 30-35, and >35 kg/m

) and treatment effects of exenatide twice daily.

All patients across all BMI ranges experienced significant reductions in HbA1c. The patients assigned to exenatide in both studies had numerically greater reductions in fasting plasma glucose than those who were assigned the comparators across all BMI groups except those with a BMI less than 30 assigned placebo.

In addition, a greater number of patients achieved an HbA1c of less than 7% when assigned exenatide versus the comparators in all of the BMI groups except for those with a BMI of 30-35 in the lispro-comparator study. An HbA1c less than 7% plus no weight gain was higher among patients assigned exenatide twice daily versus insulin-lispro and placebo.

Based on these results, the researchers wrote that “the decision by some European national authorities or health insurance companies to restrict GLP-1RA reimbursement to patients with BMI >35 kg/m

 is not consistent with medical evidence.”

The analysis also showed that all patients assigned to exenatide had significant reductions in body weight except those with a BMI less than 30 in the placebo study (P<0.05). In contrast, patients assigned to the comparators had increases in body weight.

Finally, there were significant decreases in systolic blood pressure across all of the BMI groups when assigned exenatide compared with insulin lispro (P<0.0001).

“There is evidence of clinically meaningful glycaemic and weight benefits from the addition of exenatide twice daily to insulin glargine in both patients of normal weight and patients with mild to severe obesity, and there does not appear to be a threshold below which exenatide twice daily is not effective,” the researchers wrote. “Limiting reimbursement to patients with obesity (BMI >35 kg/m

) may result in the undertreatment of patients with lower BMI and may increase their risk of hypoglycaemia and unwanted weight gain.”

The studies included in the analysis were supported by the Alliance of Eli Lilly and Company and Amylin Pharmaceuticals and the alliance of Bristol-Myers Squibb and AstraZeneca.

Relationship of body mass index with efficacy of exenatide twice daily added to insulin glargine in patients with type 2 diabetes

Does the body mass index of a diabetic patient have any effect on the efficacy of GLP-1 receptor agonists?

GLP-1 RA Efficacy with BMI

Treatment with the glucagon-like peptide (GLP)-1 receptor agonist liraglutide 3.0 mg combined with improvements in diet and exercise resulted in significant improvements in obstructive sleep apnea and several measures of cardiovascular risk, according to the results of a study published in the

“This study suggests that liraglutide 3.0 mg in conjunction with a diet and exercise regimen may be useful as a weight management component of a comprehensive therapeutic approach for obstructive sleep apnea management,” wrote Adam Blackman, MD, of Toronto Sleep Institute, MedSleep and University of Toronto, and colleagues. “Given its range of beneficial pharmacodynamic effects, liraglutide 3.0 mg may also be a useful tool in individuals already on CPAP treatment.”

Liraglutide currently has marketing approval in several countries for weight management. Because weight loss has been associated with improvements in obstructive sleep apnea, Blackman and colleagues conducted this study to investigate if liraglutide plus lifestyle changes could improve sleep apnea better than lifestyle changes alone.

Participants in the study had moderate (apnea-hypopnea index [AHI] 15.0-29.9 events per hour) or severe (AHI 30 events per hour or more) obstructive sleep apnea, and were either unable or unwilling to use CPAP therapy. All patients received counseling on diet and physical activity every 4 weeks with (n=180) or without (n=179) liraglutide.

After completing treatment with liraglutide, patients had a mean reduction in AHI of -12.2 events per hour compared with -6.1 events per hour for patients assigned to placebo (P=0.0150). In addition, treatment with liraglutide resulted in a greater percentage weight loss compared with placebo (-5.7% vs. -1.6%; P<0.0001).

“Accompanying the AHI reduction, consistent trends for improvement were also seen with liraglutide versus placebo across oxygen saturation, sleep architecture and sleep/health-related quality of life endpoints,” the researchers wrote. “Improvements in obstructive sleep apnea endpoints were related to the degree of weight loss at the end of the study, with greater improvement seen with greater weight loss.”

In addition, the researchers noted that the largest improvement in AHI were seen in those patients with the most serve sleep apnea at baseline.

The researchers also observed significant improvement in several cardiovascular measures for patients assigned liraglutide. Patients on liraglutide had significant reductions in systolic blood pressure (-3.4 mmHg vs. 0.0 mmHg; P<0.0003), HbA1c (-0.4% vs. -0.2%; P<0.0001), and fasting plasma glucose (-0.2 mmol/L vs. 0.2 mmol/L; P<0.0001).

The trial was limited by its duration, which may not have allowed for maximum weight loss and observation, the researchers noted.

“Although power was maintained, approximately 23% of participants across both groups withdrew before trial completion,” the researchers wrote. “This attrition rate is reasonable given the difficulty of retaining patients in sleep apnea trials (due to the discomfort/burden associated with overnight PSG assessments), and corresponds to that seen in another obstructive sleep apnea trial with a large sample size.”

Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: The SCALE Sleep Apnea randomized clinical trial

Can adding a GLP-1 receptor agonist to lifestyle changes improve obstructive sleep apnea management in your patients?