Glucagon-like peptide-1 receptor agonist therapeutics for total diabetes management: assessment of composite end-points

Abstract

Assessment of the benefits of anti-diabetic drugs for type 2 diabetes requires analysis of composite end-points, taking HbA1c, bodyweight, hypoglycemia and other metabolic parameters into consideration; continuous, optimal glycemic control as well as bodyweight, blood pressure and lipid levels are critical to prevent micro- and macro-vascular complications. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are now established as an important total treatment strategy for type 2 diabetes, exerting glucose-lowering effects with little hypoglycemia risk and also ameliorating bodyweight, blood pressure and lipid levels, which are therapeutic targets for prevention of complications of the disease. The available data strongly suggest only beneficial effects of GLP-1RAs; however, long-term evaluation of the relevant composite end-points including health-related quality of life and cost-effectiveness remain to be investigated in adequately powered, prospective, controlled clinical trials. In the meantime, healthcare professionals need to be scrupulously attentive for potential, rare adverse events in patients using GLP-1RAs.

Keywords: :

• GLP-1 receptor agonists
• type 2 diabetes
• composite end-points
• health-related quality of life
• cost effectiveness

The drastic increase of type 2 diabetes (T2DM) is one of the most serious health-related problems today. The number of patients with diabetes, estimated to be 385 million in 2014, is expected to be 592 million by 2035; the global health expenditure for diabetes is now at least US$612 billion, approximately 11% of total medical spending on adults worldwide1. T2DM is a progressive metabolic disorder characterized by deterioration of pancreatic β-cell function and insulin resistance in the liver and peripheral tissues. These factors combine to result in overproduction of hepatic blood glucose, elevation of fasting plasma glucose levels and insufficient glucose uptake by muscle cells that elevate postprandial plasma glucose following meals2. In addition to that of β-cells, liver and muscle, dysfunction of pancreatic α-cells (hyperglucagonemia), fat cells (accelerated lipolysis) and kidney (increased glucose reabsorption) all can play a role in the development and progression of T2DM1. Because chronic elevation of plasma glucose levels eventually results in microvascular complications (neuropathy, retinopathy, nephropathy, etc.) and macrovascular complications (ischemic heart disease, cerebrovascular disease, peripheral arterial disease etc.)3, therapies to achieve optimal glycemic control together with optimal management of bodyweight, blood pressure and lipid levels have been sought for decades. Evaluation of the benefits of each of the new anti-diabetic drugs on the complications of the disease requires long-term analysis of composite end-points, taking HbA1c, bodyweight, hypoglycemia and other metabolic parameters into consideration4.

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are established as an important total treatment strategy for T2DM, with an efficacy and safety profile distinct from that of other anti-diabetic drugs5. Many studies have shown that GLP-1 RAs exert glucose-lowering effects in Asian T2DM characterized by impaired insulin secretion6–8, but GLP-1 RAs can also ameliorate glycemic control in obese as well as non-obese T2DM5. GLP-1 RAs exert glucose-lowering effects through multiple mechanisms, including enhancement of glucose-induced insulin secretion, suppression of glucagon secretion and delayed gastric emptying9^,10. Since GLP-1 stimulates insulin secretion glucose-dependently, GLP-1 RAs administered alone are thought to have little hypoglycemia risk11. GLP-1 RAs also promote bodyweight reduction, possibly by suppression of appetite through activation of GLP-1 receptors in the brain12^,13. GLP-1 RAs reduce blood pressure by enhancing urinary sodium excretion and inducing vasodilation, thereby lowering blood pressure. GLP-1 RAs ameliorate postprandial hyperlipidemia by suppressing production of apolipoprotein B-48 and triglyceride absorption9^,10. GLP-1 RAs also can suppress chronic inflammation by reducing production of inflammatory cytokines and macrophage infiltration9^,10. Thus, GLP-1 RAs exert beneficial effects not only on glycemia but also on bodyweight, blood pressure, lipid levels and chronic inflammation, all of which are therapeutic targets for prevention of complications of the disease, and for these reasons the drugs are often considered an attractive alternative to other treatment regimens.

Ross recently reported a summary of original articles and meta-analyses assessing the efficacy of liraglutide and exenatide, the only available GLP-1 RAs in Canada at the time, using composite end-points including HbA1c <7%, no weight gain and no hypoglycemic episodes14. He found that liraglutide and exenatide showed better achievement of these end-points compared to placebo and oral anti-diabetic drugs, which was expected in accord with the therapeutic characteristics of GLP-1 RAs described above. Ross also noted that the benefits of GLP-1 RA were more prominent in patients with shorter duration T2DM in one report on liraglutide. This is consistent with several reports demonstrating that the HbA1c-lowering effects of liraglutide depend on residual β-cell function such as may be found in patients with shorter duration of the disease15–17. Despite the possible amelioration of diabetic complications independently of glycemic control, there are important issues to be considered, including patient health-related quality of life (HRQOL) and cost-effectiveness; GLP-1 RAs involve injections, which often lower HRQOL, and there are considerably higher medical costs in comparison with oral anti-diabetic drugs. Analysis of HRQOL and the medical costs associated with GLP-1 RAs is currently limited18^,19, and delineation of the effects of the various GLP-1 RAs on diabetic complications requires clinical trials with adequately powered, prospective, controlled and relevant diabetic complication end-points.

GLP-1 RAs are generally grouped into short- and long-acting agents depending on their half-lives, which alters the mechanism by which they exert their glucose lowering effects5^,20. While long-acting agents such as liraglutide mainly affect insulin and glucagon secretions to improve both pre- and post-prandial glucose excursions, short-acting agents primarily affect gastric emptying to strongly suppress elevation of post-prandial glucose levels immediately after injection. These very different modes of action suggest that short- and long-acting GLP-1 RAs are distinct anti-diabetic drug categories. Previous studies comparing the achievement of composite end-points found the long-acting liraglutide to be somewhat superior to the short-acting exenatide21^,22, although thorough comparison of long- and short-acting awaits more detailed investigation. Accumulating results on short-acting (exenatide23^,24 and lixisenatide25–27) and long-acting (liraglutide18^,19^,28^,29, exenatide long-acting release30^,31, albiglutide, dulaglutide and semaglutide) are becoming available, allowing comparison of achievement of composite end-points by these agents in future. Moreover, long-acting GLP-1 RAs seem to differ in bodyweight reduction according to their molecular weight and permeability across the brain–blood barrier, possibly by affecting their accessibility to GLP-1 receptors in the brain32^,33. Although liraglutide therapy involves once daily injection, the other long-acting GLP-1 RAs require injection only once weekly, which might both improve adherence and minimize the reduction in HRQOL. Most importantly, the differences in achievement of composite end-points by the various GLP-1 RAs available need to be considered carefully when selecting which GLP-1 RAs to use for each patient.

Combination of GLP-1 RAs and basal insulin have been recently gaining much attention due to their complementary action34^,35. Add-on of GLP-1 RAs to insulin generally reduces bodyweight gain without increasing hypoglycemic risk, when compared to an increase of insulin dosage. Recent meta-analysis reveals that GLP-1 RA and basal insulin combinations have HbA1c-lowering effects similar to that of basal–bolus insulin therapies, but suppress bodyweight gain and do not increase hypoglycemia35, and could improve HRQOL by reducing injection frequency. Insulin co-administration could also benefit patients with severely reduced β-cell function who are generally unable to achieve optimal glycemic control by GLP-1 RAs alone15^,36. It remains to be determined how much remaining β-cell function is actually required for GLP-1 RAs in combination with insulin injection to exert optimal glycemic control.

It is now recognized that GLP-1 RAs can ameliorate several pathophysiological deficits of T2DM and can also reduce metabolic risk factors such as bodyweight, blood pressure and dyslipidemia, all of which are associated with the disease. This has established GLP-1 RA as an important treatment strategy for T2DM. However, long-term safety issues need to be carefully monitored. Scrutiny of the data related to acute pancreatitis and pancreatic cancers has not resulted in any recommendation to stop use of incretin therapies in management of T2DM37. Pancreatic cancers take years before becoming metastatic38, but recent investigation of GLP-1 receptor expression profiles in human tissues does not support a causal relationship of GLP-1 receptor activation with the pathogenesis of any of these cancers39. However, careful observation for possible onset of malignancies remains essential. Recently, Koehler et al. reported that GLP-1 receptor activation in a mouse model of colorectal cancer facilitated onset of tumorigenesis40, suggesting possible colorectal cancer risks with use of GLP-1 RAs in special populations, such as those with familial adenomatous polyposis. While there are many expectations of possible beneficial pleiotropic effects of GLP-1 RA therapy such as prevention of dementia41^,42, healthcare professionals need to be scrupulously careful of potential adverse events until results of ongoing large-scale randomized clinical trials clarify these dire possibilities.

Transparency

Declaration of funding

This editorial was written independently and received no professional help. D.Y. has received Grant-in-Aid for Young Scientists (B) from the Japan Society for Science Promotion and Grants for Young Researchers from the Japan Association for Diabetes Education and Care; Y.S. has received grants from the Japan Vascular Disease Research Foundation.

Declaration of financial/other relationships

D.Y. has disclosed that he has received consulting and/or speaker fees from Eli Lilly, MSD, Sanofi, Novo Nordisk, Boehringer Ingelheim, Takeda and Taisho pharmaceutical; he has also received clinical commissioned/joint research grants from Nippon Boehringer Ingelheim, Eli Lilly, and MSD. T.K. has disclosed that he has received consulting and/or speaker fees from Astellas, Boehringer Ingelheim, Sanofi, Novo Nordisk, MSD, Takeda, Kowa, Tanabe Mitsubishi, Kaken Pharm, AstraZeneca, Daiichi-Sankyo, and Kyowa Kirin; he has also received clinical commissioned/joint research grants from Boehringer Ingelheim, Novo Nordisk, Merck, Sharp and Dohme, Takeda, Ono Pharm, Eli Lilly, Teijin, and Sanofi. Y.S. has disclosed that he has received consulting and/or speaker fees from Eli Lilly, Sanofi, Novo Nordisk, Glaxo-Smith-Kline, Taisho Pharmaceutical, Astellas Pharma, BD, Boehringer Ingelheim, Johnson & Johnson and Takeda; he has also received clinical commissioned/joint research grants from Boehringer Ingelheim, Eli Lilly and MSD. H.K. and R.U. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

Acknowledgments

The authors thank Michiko Yamane of Kansai Electric Power Hospital for secretarial assistance.