Jennifer M. Trujillo

GLP-1 receptor agonists: a review of head-to-head clinical studies.

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are attractive options for the treatment of type 2 diabetes (T2D) because they effectively lower A1C and weight while having a low risk of hypoglycemia. The GLP-1 RA class has grown in the last decade with several agents available for use in the US and Europe and several more in development. Since the efficacy and tolerability, dosing frequency, administration requirements, and cost may vary between agents within the class, each agent may offer unique advantages and disadvantages. Through a review of phase III clinical programs for exenatide twice daily, exenatide once weekly, liraglutide, albiglutide, lixisenatide, and dulaglutide, eight head-to-head trials have evaluated the safety and efficacy of GLP-1 RA active comparators. The purpose of this review is to provide an analysis of these trials. The GLP-1 RA head-to-head clinical studies have demonstrated that all GLP-1 RA agents are effective therapeutic options at reducing A1C. However, differences exist in terms of magnitude of effect on A1C and weight as well as frequency and severity of adverse effects.

Association of Pancreatitis with Glucagon-Like Peptide-1 Agonist Use

OBJECTIVE: To review the possible association between glucagon-like peptide-1 (GLP-1) agonist use and pancreatitis in patients with type 2 diabetes mellitus. DATA SOURCES: A MEDLINE search (1950-January 2010) identified key clinical trials delineating adverse effects associated with GLP-1 agonist use. Key search terms included type 2 diabetes mellitus, pancreatitis, incretins, exenatide, liraglutide, albiglutide, and taspoglutide. Review of references listed in the articles identified was also performed. The Food and Drug Administration (FDA) Web site and Amylin Pharmaceuticals file data were utilized to extract case report information and unpublished clinical development data related to GLP-1 agonist use and pancreatitis. STUDY SELECTION AND DATA EXTRACTION: Phase 2 and 3 clinical trials evaluating exenatide, liraglutide, albiglutide, and taspoglutide that discussed treatment-related adverse effects as well as FDA-reviewed case reports of pancreatitis in patients taking these same therapies were included. One study evaluating type 2 diabetes as a risk factor for development of acute pancreatitis was also included. Exenatide case reports and clinical development data were also included. DATA SYNTHESIS: Currently there have been 8 cases during clinical development and 36 postmarketing reports of acute pancreatitis in exenatide-treated patients. Four patients have developed acute (n = 3) or chronic (1) pancreatitis during liraglutide clinical trials. There have been no reports to date of development of acute pancreatitis in patients taking albiglutide or taspoglutide. CONCLUSIONS: Observational reports and clinical trial data suggest an association between GLP-1 agonist use and acute pancreatitis; however, additional clinical trial data and in-depth case report analysis are needed to further evaluate and verify this finding.

GLP-1 receptor agonists for type 2 diabetes mellitus: recent developments and emerging agents.

More than 26 million people in the United States have type 2 diabetes mellitus (T2D). Many treatment options exist, but achieving long‐term glycemic control in patients with T2D remains challenging. The glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) offer a treatment option that improves glycemic control and reduces weight, with a low risk of hypoglycemia. They have emerged as attractive options for the treatment of T2D, and significant advances and developments continue to be published regarding these agents. To identify relevant literature on emerging issues related to GLP‐1 RAs, a search of the MEDLINE database was performed. Studies published in English evaluating the safety and efficacy of GLP‐1 RAs were analyzed. Because of their advantages and unique mechanism of action, GLP‐1 RAs are currently being studied in new clinical areas, including in combination with basal insulin, as adjunctive therapy in type 1 diabetes, and for weight loss. In addition, there are several emerging agents in development. Lixisenatide is a once‐daily GLP‐1 RA that targets postprandial glucose and may be most useful when added to basal insulin as an alternative to rapid‐acting insulin. Albiglutide and dulaglutide are once‐weekly GLP‐1 RAs that may offer more convenient dosing. The most common adverse effects of all GLP‐1 RA agents are gastrointestinal (e.g., nausea, diarrhea, and vomiting), but the rates of occurrence vary among agents. Due to the differences in pharmacokinetics, efficacy, rates of adverse effects, and administration requirements within the GLP‐1 RA class, each agent should be evaluated independently. The future of GLP‐1 RAs offers broader treatment options for T2D as well as potential in other treatment areas.

Albiglutide A New GLP-1 Receptor Agonist for the Treatment of Type 2 Diabetes

Objective: To review the pharmacology, pharmacokinetics, safety, and efficacy of albiglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in type 2 diabetes (T2D). Data Sources: A MEDLINE search (1950-June 2014) was conducted using the keyword albiglutide. References were reviewed to identify additional sources. Study Selection and Data Extraction: Articles evaluating pharmacokinetics, pharmacodynamics, safety, or efficacy of albiglutide were included. Data Synthesis: Albiglutide is a long-acting GLP-1 RA that lowers glycosylated hemoglobin (A1C) and reduces weight by stimulating glucose-dependent insulin secretion, suppressing glucagon secretion, delaying gastric emptying, and promoting satiety. Albiglutide has a long half-life as a result of resistance to degradation by dipeptidyl peptidase-4 and fusion to albumin, thus allowing once-weekly dosing. Albiglutide has been studied as monotherapy and add-on therapy to metformin, sulfonylureas, thiazolidinediones, insulin glargine, and varying combinations of these agents. Clinical studies have shown albiglutide to be superior to placebo, sitagliptin, and glimepiride and noninferior to insulin glargine and insulin lispro at reducing A1C in T2D patients, with A1C changes from baseline ranging from −0.55% to −0.9%. Noninferiority was not achieved when compared to liraglutide and pioglitazone. Weight changes ranged from +0.28 to −1.21 kg. The most common side effects are upper-respiratory-tract infections, diarrhea, nausea, and injection-site reactions. Conclusion: Albiglutide is the fourth GLP-1 RA approved in the United States. Advantages include once-weekly dosing and fewer gastrointestinal side effects compared with liraglutide, but it is less effective at reducing A1C and weight compared to liraglutide. It has not been compared head to head with other GLP-1 RAs.OBJECTIVE To review the pharmacology, pharmacokinetics, safety, and efficacy of albiglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in type 2 diabetes (T2D). DATA SOURCES A MEDLINE search (1950-June 2014) was conducted using the keyword albiglutide. References were reviewed to identify additional sources. STUDY SELECTION AND DATA EXTRACTION Articles evaluating pharmacokinetics, pharmacodynamics, safety, or efficacy of albiglutide were included. DATA SYNTHESIS Albiglutide is a long-acting GLP-1 RA that lowers glycosylated hemoglobin (A1C) and reduces weight by stimulating glucose-dependent insulin secretion, suppressing glucagon secretion, delaying gastric emptying, and promoting satiety. Albiglutide has a long half-life as a result of resistance to degradation by dipeptidyl peptidase-4 and fusion to albumin, thus allowing once-weekly dosing. Albiglutide has been studied as monotherapy and add-on therapy to metformin, sulfonylureas, thiazolidinediones, insulin glargine, and varying combinations of these agents. Clinical studies have shown albiglutide to be superior to placebo, sitagliptin, and glimepiride and noninferior to insulin glargine and insulin lispro at reducing A1C in T2D patients, with A1C changes from baseline ranging from -0.55% to -0.9%. Noninferiority was not achieved when compared to liraglutide and pioglitazone. Weight changes ranged from +0.28 to -1.21 kg. The most common side effects are upper-respiratory-tract infections, diarrhea, nausea, and injection-site reactions. CONCLUSION Albiglutide is the fourth GLP-1 RA approved in the United States. Advantages include once-weekly dosing and fewer gastrointestinal side effects compared with liraglutide, but it is less effective at reducing A1C and weight compared to liraglutide. It has not been compared head to head with other GLP-1 RAs.

Liraglutide: A New Option for the Treatment of Obesity

Obesity continues to pose a major public health risk to the United States and across the world, with an estimated one‐third of adult Americans being defined as obese. Obesity treatment guidelines recommend the use of pharmacologic therapy in adults who have a body mass index (BMI) of 30 kg/m2 or higher or in patients with a BMI of 27 kg/m2 or higher who have at least one weight‐related comorbid condition (e.g., hypertension, dyslipidemia, insulin resistance, type 2 diabetes mellitus). Liraglutide is a glucagon‐like peptide‐1 receptor agonist that has been successfully used in the treatment of type 2 diabetes for several years. Weight loss has been well described as an additional benefit with liraglutide therapy, which prompted the manufacturer to evaluate and develop a higher dose formulation specifically for the treatment of obesity. Liraglutide 3 mg/day was approved by the U.S. Food and Drug Administration for this indication in December 2014. We performed a search of the Medline database to identify relevant literature focused on liraglutides role specifically in treating obesity. Five clinical trials with this primary end point were identified. Data demonstrated that liraglutide can successfully achieve weight‐loss benchmarks of 5% or more and 10% or more loss from baseline. The most common adverse effects were gastrointestinal and mild to moderate in intensity. The cost of therapy is high, averaging over

Dulaglutide The Newest GLP-1 Receptor Agonist for the Management of Type 2 Diabetes

1000/month for out‐of‐pocket expenses if insurance coverage is not available. Liraglutide is also available for delivery only by subcutaneous injection, which may represent a barrier for patients. Liraglutide 3 mg/day represents another pharmacologic option for the treatment of obesity.

Follow-up assessment of a faculty peer observation and evaluation program.

Objective: To review the pharmacology, pharmacokinetics, safety, and efficacy of the glucagon-like peptide-1 receptor agonist (GLP-1 RA), dulaglutide, in the treatment of type 2 diabetes mellitus (T2D). Data Sources: A PubMed search was completed to identify publications from 1947 to October 2014 using the search terms dulaglutide and LY2189265. References were reviewed to identify additional resources. Study Selection and Data Extraction: Articles were included if they evaluated the pharmacology, pharmacokinetics, safety, or efficacy of dulaglutide. Data Synthesis: Dulaglutide reduces both glycosylated hemoglobin (A1C) and weight by stimulating insulin secretion and suppressing glucagon in a glucose-dependent manner, delaying gastric emptying, and promoting satiety. Dulaglutide consists of 2 GLP-1 analogues that have been modified to make it a long-acting, once-weekly agent. Dulaglutide has been studied as monotherapy and in combination with metformin, glimepiride, pioglitazone, and insulin lispro. It has demonstrated superior A1C reduction compared with placebo, metformin, insulin glargine, sitagliptin, and twice-daily exenatide. It demonstrated noninferiority in A1C reduction to liraglutide. Dulaglutide changed A1C by −0.78% to −1.51%, and it changed weight by −0.35 kg to −3.03 kg. The most common adverse effects in clinical studies were nausea, vomiting, and diarrhea. Conclusions: Dulaglutide is the fifth GLP-1 RA approved for T2D in the United States. It is an attractive option because it is dosed once-weekly, provides A1C lowering similar to liraglutide, weight reduction similar to exenatide, and has an adverse effect profile similar to exenatide and liraglutide.OBJECTIVE To review the pharmacology, pharmacokinetics, safety, and efficacy of the glucagon-like peptide-1 receptor agonist (GLP-1 RA), dulaglutide, in the treatment of type 2 diabetes mellitus (T2D). DATA SOURCES A PubMed search was completed to identify publications from 1947 to October 2014 using the search terms dulaglutide and LY2189265. References were reviewed to identify additional resources. STUDY SELECTION AND DATA EXTRACTION Articles were included if they evaluated the pharmacology, pharmacokinetics, safety, or efficacy of dulaglutide. DATA SYNTHESIS Dulaglutide reduces both glycosylated hemoglobin (A1C) and weight by stimulating insulin secretion and suppressing glucagon in a glucose-dependent manner, delaying gastric emptying, and promoting satiety. Dulaglutide consists of 2 GLP-1 analogues that have been modified to make it a long-acting, once-weekly agent. Dulaglutide has been studied as monotherapy and in combination with metformin, glimepiride, pioglitazone, and insulin lispro. It has demonstrated superior A1C reduction compared with placebo, metformin, insulin glargine, sitagliptin, and twice-daily exenatide. It demonstrated noninferiority in A1C reduction to liraglutide. Dulaglutide changed A1C by -0.78% to -1.51%, and it changed weight by -0.35 kg to -3.03 kg. The most common adverse effects in clinical studies were nausea, vomiting, and diarrhea. CONCLUSIONS Dulaglutide is the fifth GLP-1 RA approved for T2D in the United States. It is an attractive option because it is dosed once-weekly, provides A1C lowering similar to liraglutide, weight reduction similar to exenatide, and has an adverse effect profile similar to exenatide and liraglutide.

Determining predictors of response to exenatide in type 2 diabetes

Objective. To assess a previously described peer observation and evaluation program 2 years after implementation. Methods. An pre-implementation survey assessed faculty needs and attitudes related to peer evaluation. Two years after implementation, the survey was repeated and additional questions asked regarding adherence to peer observation and evaluation policies and procedures, feedback received, and impact on teaching. Results. Faculty attitudes towards peer evaluation stayed the same or improved post-implementation. Adherence to the initial 3 steps of the process was high (100%, 100%, and 94%, respectively); however, step 4, which required a final discussion after student assessments were finished, was completed by only 47% of the respondents. All faculty members reported receiving a balance of positive and constructive feedback; 78% agreed that peer observation and evaluation gave them concrete suggestions for improving their teaching; and 89% felt that the benefits of peer observation and evaluation outweighed the effort of participating. Conclusions. Faculty members adhered to the policies and procedures of peer observation and evaluation and found peer feedback was beneficial.

A Comparison of New Pharmacological Agents for the Treatment of Obesity

OBJECTIVES To determine predictors of glycemic response to exenatide and to assess change in glycosylated hemoglobin (A1C) and whether a correlation exists between weight loss and glycemic response. DESIGN Retrospective observational cohort study. SETTING United States in 2009. PATIENTS 100 adult patients with type 2 diabetes prescribed exenatide. INTERVENTION Retrospective chart review of patients to collect demographic data, weight, serum creatinine, diabetes education, and concurrent diabetes medications. MAIN OUTCOME MEASURES Patients were categorized as responders or nonresponders based on change in A1C. Responders had an A1C decrease of 0.5% or more and nonresponders had an A1C decrease of less than 0.5% from baseline to post-exenatide initiation. Demographic data for each cohort were analyzed. RESULTS 100 patients met inclusion criteria (61 responders and 39 nonresponders). Responders had a mean A1C decrease of 1.57%, whereas nonresponders had a mean A1C increase of 0.23% (P < 0.001). Post hoc linear regression analysis revealed that baseline A1C was a predictor of response to exenatide (P < 0.001). Binary logistic regression analysis demonstrated that no other variables were predictors of response to exenatide (P > 0.05 for all). No correlation was found between weight loss and exenatide and glycemic response (P = 0.99). CONCLUSION Our data indicate that patients with a higher baseline A1C are more likely to have a glycemic response to exenatide than patients with a lower baseline A1C.

Impact of Sodium-Glucose Cotransporter 2 Inhibitors on Nonglycemic Outcomes in Patients with Type 2 Diabetes

Objective: To review and compare the phase 3 clinical trial evidence on the 4 new pharmacological agents approved for the management of overweight and obesity. Data Sources: Searches were performed (from 1966 through January 2016) in PubMed/MEDLINE, Scientific Citation Index, and product package inserts to identify key phase 3 clinical trials that were used in the approval of each agent. Study Selection and Data Extraction: Phase 3 clinical trials that listed end points of ≥5% and ≥10% weight loss benchmarks from baseline as well as total percentage of weight loss by participants were selected for the review. Data Synthesis: No head-to-head trials have been identified between these agents at this point, which limits comparisons across agents. Phentermine/topiramate ER appeared to have the best overall average weight loss from baseline as well as highest percentages of patients achieving both ≥5% and ≥10% weight loss benchmarks, followed second by naltrexone/bupropion, and then liraglutide, with lorcaserin showing the lowest rates. Phentermine/topiramate ER completion rates were highest for both treatment and placebo groups, followed by liraglutide, with lorcaserin and naltrexone/bupropion showing similar completion rates, below that of the other 2 agents. Common side effects reported differed between agents, although the most common adverse events reported were gastrointestinal in nature, with liraglutide demonstrating the highest reported rates and lorcaserin demonstrating the lowest. Conclusion: These 4 new pharmacological agents represent new options for the clinician to utilize when trying to manage the problem of obesity. No clear first-line agent has emerged, so treatment decisions should be based on patient-specific factors.