Reviews

The Continuing Need for Drug Development and Clinical Trials in Type 2 Diabetes and its Complications: Introduction to The RDS Special Issue

Itamar Raz¹, Baptist Gallwitz²

Abstract

The increased burden of type 2 diabetes (T2D) necessitates the need for effective and safe novel drugs to treat this epidemic disease and its complications. By compiling this RDS Special Issue, our aim was to provide a comprehensive and critical overview on recent, ongoing, and future developments in this field. In collaboration with distinguished and renowned experts, we analyzed and discussed the most important advances in the field of incretin-based therapies, their extraglycemic effects, cardiovascular actions, and specific properties of the central nervous system. Another important drug class currently in development, the SGLT-2 inhibitors, and the role of the kidney in T2D are topics also covered by this issue. In addition to drug developments, new physiological insights into the understanding of the organ pathophysiology in T2D are presented that may eventually lead to additional therapeutic targets for obesity, T2D, and chronic inflammation acting on the brain, cardiovascular system, and pancreatic islets. The outcome of this Special Issue is a comprehensive reference work including bundled knowledge and expert opinions on the various aspects of the disease and its possible therapy strategies available now and in the near future. However, despite the advances delivered by modern incretin-based therapies today, there are still many limitations associated with efficacy data, application routes, and safety issues, which prevent the decline in diabetes complication rates. We conclude that further drug development and clinical trials are required to overcome these limitations, and to counteract the movement towards higher incidence rates of T2D and its complications.

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Physiology of Incretins in Health and Disease

Carolyn F. Deacon¹, Bo Ahrén²

Abstract

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are gut peptides which are secreted by endocrine cells in the intestinal mucosa. Their plasma concentrations increase quickly following food ingestion, and carbohydrate, fat, and protein have all been shown to stimulate GLP-1 and GIP secretion. Although neural and hormonal mechanisms have also been proposed to regulate incretin hormone secretion, direct stimulation of the enteroendocrine cells by the presence of nutrients in the intestinal lumen is probably the most important factor in humans. The actions of the incretin hormones are crucial for maintaining normal islet function and glucose homeostasis. Furthermore, it is also now being recognized that incretin hormones may have other actions in addition to their glucoregulatory effects. Studies have shown that GLP-1 and GIP levels and actions may be perturbed in disease states, but interpretation of the precise relationship between disease and incretins is difficult. The balance of evidence seems to suggest that alterations in secretion and/or action of incretin hormones arise secondarily to the development of insulin resistance, glucose intolerance, and/or increases in body weight rather than being causative factors. However, these impairments may contribute to the deterioration of glycemic control in diabetic patients.

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Incretin Therapy - Present and Future

Alan J. Garber

Abstract

Although newer treatments for type 2 diabetes (T2D) patients have produced continual improvements in outcome, a large and growing population with prediabetes remains under-treated. In the last few years, incretin-based therapies have become an important treatment option for patients with T2D. There are two classes of incretin agents: the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon like peptide 1 (GLP-1) receptor agonists. The ultimate goal of agents within both of these classes is to increase GLP-1 signaling, which results in augmented glucose-induced insulin secretion, inhibition of glucagon secretion, and decreased appetite. This should result in improved regulation of glucose homeostasis. GLP-1 receptor agonists enable patients to achieve significant weight loss. In contrast, DPP-4 inhibitors result in a less dramatic increase in GLP-1 levels; therefore, they are weight neutral. Incretin therapies are currently recommended for use early in the treatment algorithm for T2D patients whose disease is not manageable by diet and exercise alone, but the potential for these agents may be farther reaching. Current studies are evaluating the potential benefits of combining incretin therapies with basal insulin to provide continuous glucose control before and after meals. In addition, these agents may be promising for patients with prediabetes since they effectively reduce glycosylated hemoglobin levels and fasting plasma glucose levels, enable weight control, and have the potential to preserve β-cell function. Clearly, all of these properties are desirable for patients with prediabetes.

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The Role of Incretin Therapy at Different Stages of Diabetes

Simona Cernea

Abstract

The pathogenetic mechanisms causing type 2 diabetes are complex, and include a significant reduction of the incretin effect. In patients with type 2 diabetes, GLP-1 secretion may be impaired, while GIP secretion seems unaffected. In contrast, the insulinotropic activity of GIP is severely altered, whereas that of GLP-1 is maintained to a great extent. Better understanding of the role of incretin hormones in glucose homeostasis has led to the development of incretin-based therapies that complement and offer important advantages over previously used agents. Incretin-based agents have significant glucose-lowering effects, promote weight loss (or are weight-neutral), inhibit glucagon secretion while maintaining counter-regulatory mechanisms, exhibit cardiovascular benefits, and protect β-cells while possessing a low risk profile. At present, incretin-based therapies are most widely used as add on to metformin to provide sufficient glycemic control after metformin failure. However, they are also recommended as monotherapy early in the disease course, and later in triple combination. These agents may also be a promising therapeutic tool in prediabetic subjects. Therefore, a therapeutic algorithm is needed for their optimal application at different stages of diabetes, as suggested in this article.

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Therapy for Obesity Based on Gastrointestinal Hormones

Jonatan I. Bagger, Mikkel Christensen, Filip K. Knop, Tina Vilsboll

Abstract

It has long been known that peptide hormones from the gastrointestinal tract have significant impact on the regulation of nutrient metabolism. Among these hormones, incretins have been found to increase insulin secretion, and thus incretin-based therapies have emerged as new modalities for the treatment of type 2 diabetes. In contrast to other antidiabetic treatments, these agents have a positive outcome profile on body weight. Worldwide there are 500 million obese people, and 3 million are dying every year from obesity-related diseases. Recently, incretin-based therapy was proposed for the treatment of obesity. Currently two different incretin therapies are widely used in the treatment of type 2 diabetes: 1) the GLP-1 receptor agonists which cause significant and sustained weight loss in overweight patients, and 2) dipeptidyl peptidase 4 (DPP-4) inhibitors being weight neutral. These findings have led to a greater interest in the physiology of intestinal peptides with potential weight-reducing properties. This review discusses the effects of the incretin-based therapies in obesity, and provides an overview of intestinal peptides with promising effects as potential new treatments for obesity.

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SGLT-2 Inhibitors in Development for Type 2 Diabetes Treatment

Mithun Bhartia¹, Abd A. Tahrani^2,3, Anthony H. Barnett^3,4

Abstract

The prevalence of type 2 diabetes is increasing worldwide. The majority of currently available glucose-lowering agents work via insulin-dependent mechanisms and have significant limitations. Hence, there is a need for newer treatments utilizing novel therapeutic targets. Drugs which inhibit the sodium glucose cotransporter in the renal tubules (SGLT-2 inhibitors), represent a novel class of drugs under development. By inhibiting SGLT-2, they promote increased renal glucose excretion and thereby calorie loss with improved glycemic control and weight loss. Dapagliflozin is most advanced in development of this new drug class and currently undergoing phase 3 trials. In addition to its glucose lowering effect, dapagliflozin appears to have favorable impacts on weight and blood pressure, with low risk of hypoglycemia. However, as with all new treatments, long-term safety is an issue. Clinical trials showed increased risk of genital and possibly urinary infections with dapgliflozin. Furthermore, concerns have arisen regarding a possible increased incidence of breast and bladder cancer in patients on dapagliflozin. However, it needs further investigation to confirm or refute whether these concerns are concrete.

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Peptides and Their Potential Role in the Treatment of Diabetes and Obesity

Hannah C. Greenwood, Stephen R. Bloom, Kevin G. Murphy

Abstract

It is estimated that 347 million people worldwide have diabetes and that over 1.5 billion adults worldwide are overweight. Predictions suggest these rates are increasing. Diabetes is a common complication in overweight and obese subjects, and in 2004, an estimated 3.4 million people died from consequences of high blood sugar. Thus, there is great interest in revealing the physiological systems that regulate body weight and blood sugar. Several peptidergic systems within the central nervous system and the periphery regulate energy homeostasis. A number of these systems have been investigated as potential treatments for obesity and the metabolic syndrome. However, manipulation of peptidergic systems poses many problems. This review discusses the peptidergic systems currently attracting research interest for their clinical potential to treat obesity. We consider first neuropeptides in the brain, including the orexigenic neuropeptide Y and melanin-concentrating hormone, and anorectic factors such as the melanocortins, ciliary neurotrophic factor, and neuromedin U. We subsequently discuss the utility of targeting peripheral gut peptides, including pancreatic polypeptide, peptide YY, amylin, and the gastric hormone ghrelin. Also, we analyze the evidence that these factors or drugs based on them may be therapeutically useful, while considering the disadvantages of using such peptides in a clinical context.

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The Alpha-Cell as Target for Type 2 Diabetes Therapy

Mikkel Christensen, Jonatan I. Bagger, Tina Vilsboll, Filip K. Knop

Abstract

Glucagon is the main secretory product of the pancreatic alpha-cells. The main function of this peptide hormone is to provide sustained glucose supply to the brain and other vital organs during fasting conditions. This is exerted by stimulation of hepatic glucose production via specific G protein-coupled receptors in the hepatocytes. Type 2 diabetic patients are characterized by elevated glucagon levels contributing decisively to hyperglycemia in these patients. Accumulating evidence demonstrates that targeting the pancreatic alpha-cell and its main secretory product glucagon is a possible treatment for type 2 diabetes. Several lines of preclinical evidence have paved the way for the development of drugs, which suppress glucagon secretion or antagonize the glucagon receptor. In this review, the physiological actions of glucagon and the role of glucagon in type 2 diabetic pathophysiology are outlined. Furthermore, potential advantages and limitations of antagonizing the glucagon receptor or suppressing glucagon secretion in the treatment of type 2 diabetes are discussed with a focus on already marketed drugs and drugs in clinical development. It is concluded that the development of novel glucagon receptor antagonists are confronted with several safety issues. At present, available pharmacological agents based on the glucose-dependent glucagonostatic effects of GLP-1 represent the most favorable way to apply constraints to the alpha-cell in type 2 diabetes.

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Cardiovascular Effects of Incretin-Based Therapies

Michael Lehrke, Nikolaus Marx

Abstract

GLP-1-modulating therapies are a class of anti-diabetic drugs that improve glycemic control by stimulating glucose-dependent insulin secretion from pancreatic beta-cells. In addition, GLP-1-based therapies have a variety of extrapancreatic effects, including satiety induction and gastric mobility reduction, which extend to distinct cardiovascular actions. GLP-1 was found to reduce infarct size in the context of acute myocardial ischemia which depends on the activation of prosurvival pathways including PI3-kinase, Akt, and ERK1/2. Also, GLP-1 augments the left ventricular function in dilative and metabolic cardiomyopathy, possibly by increasing insulin independent cardiomyocyte glucose uptake. Furthermore, experimental and preliminary clinical evidence suggest vasoprotective efficacy of GLP-1 mediated by improved endothelial function and anti-inflammatory capacities leading to atheroprotection. Mechanistically, the GLP-1 receptor is relevant for glucose lowering efficacy of GLP-1. However, many of its vasoprotective actions have also been described for the GLP-1 metabolite (9-37), which does not activate the GLP-1 receptor, suggesting the presence of an additional, yet unknown, signaling pathway. Ongoing research investigates the relevance of these observations in human disease and underlying mechanisms, which are reviewed in the present article.

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The Kidney in Type 2 Diabetes Therapy

Hiddo J. Lambers Heerspink¹, Dick de Zeeuw²

Abstract

Renal and cardiovascular complications make type 2 diabetes one of the most morbid conditions in medicine. The kidney frequently gets involved in this "multi-organ disease". Of the large proportion of patients who progress with further loss of renal function, most prematurely die or end up in dialysis. Many interventions have targeted a decelerated progression of renal function loss, including metabolic control, blood pressure, and lipid management. Recently, modulation of the renin-angiotensin-aldosterone-system (RAAS) have been combined with the existing therapeutic armamentarium. RAAS inhibitors lower blood pressure and decrease albuminuria which leads to additionally protective renal and cardiovascular effects. Although this has been the success story of the last two decades, it has still made a relatively small contribution to patient welfare, since the residual risk in patients that received this optimal care remains extremely high. New treatment strategies are required that further slow the progression of renal and cardiovascular functions. Recently, several pathways have been investigated, targeting traditional risk factors such as blood pressure- and lipid-lowering strategies with unexpected results. Furthermore, novel targets and drugs have been identified. Preliminary studies on surrogate markers for renal outcome show a great potential for additive renal protection, such that in many cases hard endpoint trials are initiated. Novel interventions, which are reviewed here, include vitamin D receptor activators, RAASi with direct renin inhibitors or aldosterone antagonists, endothelin-antagonist, inflammation suppression with pentoxyfillin, MCP-1 synthesis inhibitors, or with Nrf2 agonists. Despite the current depressing situation of type 2 diabetic patients with nephropathy, new treatment options are under development to reduce the high morbidity and mortality associated with this universal ever-increasing disease threat.

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Fatty Heart, Cardiac Damage, and Inflammation

Maria A. Guzzardi, Patricia Iozzo

Abstract

Type 2 diabetes and obesity are associated with systemic inflammation, generalized enlargement of fat depots, and uncontrolled release of fatty acids (FA) into the circulation. These features support the occurrence of cardiac adiposity, which is characterized by an increase in intramyocardial triglyceride content and an enlargement of the volume of fat surrounding the heart and vessels. Both events may initially serve as protective mechanisms to portion energy, but their excessive expansion can lead to myocardial damage and heart disease. FA overload promotes FA oxidation and the accumulation of triglycerides and metabolic intermediates, which can impair calcium signaling, β-oxidation, and glucose utilization. This leads to damaged mitochondrial function and increased production of reactive oxygen species, pro-apoptotic, and inflammatory molecules, and finally to myocardial inflammation and dysfunction. Triglyceride accumulation is associated with left ventricular hypertrophy and dysfunction. The enlargement of epicardial fat in patients with metabolic disorders, and coronary artery disease, is associated with the release of proinflammatory and proatherogenic cytokines to the subtending tissues. In this review, we examine the evidence supporting a causal relationship linking FA overload and cardiac dysfunction. Also, we disentangle the separate roles of FA oxidation and triglyceride accumulation in causing cardiac damage. Finally, we focus on the mechanisms of inflammation development in the fatty heart, before summarizing the available evidence in humans. Current literature confirms the dual (protective and detrimental) role of cardiac fat, and suggests prospective studies to establish the pathogenetic (when and how) and possible prognostic value of this potential biomarker in humans.

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GLP-1, the Gut-Brain, and Brain-Periphery Axes

Cendrine Cabou, Remy Burcelin

Abstract

Glucagon-like peptide 1 (GLP-1) is a gut hormone which directly binds to the GLP-1 receptor located at the surface of the pancreatic β-cells to enhance glucose-induced insulin secretion. In addition to its pancreatic effects, GLP-1 can induce metabolic actions by interacting with its receptors expressed on nerve cells in the gut and the brain. GLP-1 can also be considered as a neuropeptide synthesized by neuronal cells in the brain stem that release the peptide directly into the hypothalamus. In this environment, GLP-1 is assumed to control numerous metabolic and cardiovascular functions such as insulin secretion, glucose production and utilization, and arterial blood flow. However, the exact roles of these two locations in the regulation of glucose homeostasis are not well understood. In this review, we highlight the latest experimental data supporting the role of the gut-brain and brain-periphery axes in the control of glucose homeostasis. We also focus our attention on the relevance of β-cell and brain cell targeting by gut GLP-1 for the regulation of glucose homeostasis. In addition to its action on β-cells, we find that understanding the physiological role of GLP-1 will help to develop GLP-1-based therapies to control glycemia in type 2 diabetes by triggering the gut-brain axis or the brain directly. This pleiotropic action of GLP-1 is an important concept that may help to explain the observation that, during their treatment, type 2 diabetic patients can be identified as 'responders' and 'non-responders'.

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Metabolic Memory and Individual Treatment Aims in Type 2 Diabetes – Outcome-Lessons Learned from Large Clinical Trials

Cristina Bianchi, Stefano Del Prato

Abstract

Reducing the burden of long-term complications in type 2 diabetic patients remains a major task, and represents a huge challenge. Whilst tight glycemic control has been shown to reduce the risk of microvascular complications, controversy remains regarding the benefit of intensive treatment in relation to the prevention of cardiovascular events. Recent large trials (including ACCORD, ADVANCE, and VADT) were unable to show a significant impact of glycemic control on cardiovascular events. Also, it has been argued that these trials included patients with a long duration of the disease, and with previous unsatisfactory glycemic control. Chronic exposure to hyperglycemia may cause a kind of negative metabolic memory, and thereby reduce the potential impact of good glycemic control. This concept has been corroborated by the UKPDS which recruited only subjects with newly diagnosed diabetes and without prior cardiovascular events. In these patients, early achievement of glycemic control translated into a long-term reduction of the risk of micro- and macrovascular complications. This observation prompted the UKPDS investigators to propose a positive "glycemic legacy", supporting the need for early and appropriate treatment of hyperglycemia and associated metabolic disturbances. This should be feasible now through the selection of individual targets and personalized pharmacologic treatments. In doing so, the potential risks of intensive treatment might then be avoided.

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