The Incretin Axis in Cardiovascular Disease

Diabetes mellitus, defined as a fasting plasma glucose of ≥126 mg/dL or a glycosylated hemoglobin A1c level (HbA1c) of ≥6.5%, afflicts ≈12.9% of adults in the United States and nearly 285 million adults worldwide.1,2 Diabetes mellitus is a major risk factor for the development of cardiovascular disease, independently conferring a 2-fold excess risk of coronary heart disease and stroke.3 Macrovascular events in diabetes mellitus remain the leading cause of mortality, and the burden of cardiovascular disease attributable to diabetes mellitus has increased over the past decade.4 An increase in the prevalence of obesity has contributed to the rise in diabetes mellitus. Additionally, obesity independently increases the risk of cardiovascular disease in patients with diabetes mellitus.5 Although strict glycemic control unequivocally reduces the microvascular complications of diabetes mellitus, the macrovascular benefits of intensive therapy have been difficult to establish, with conflicting results from large clinical trials.6–9 Multifactorial strategies are recommended to reduce cardiovascular risk in diabetes mellitus through enhanced glycemic control, blood pressure reduction, lipid management, weight loss, and physical activity.10 Unfortunately, despite aggressive interventions for hyperglycemia, <50% of patients achieve standard HbA1c targets with conventional therapy.11 Polypharmacy is required to achieve glycemic control in the majority of patients within 3 years of diagnosis.12 Although combinations of drug classes can synergistically target multiple pathophysiological defects, novel therapies are required to manage diabetes mellitus and mitigate cardiovascular risks. Dipeptidyl-peptidase IV (DPP-IV) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist incretin therapies were developed to complement conventional treatment options for diabetes mellitus. Despite promising initial reports of cardioprotective effects, DPP-IV inhibitors have failed to demonstrate improved cardiovascular outcomes in large clinical trials.13–15 Randomized studies to evaluate cardiovascular outcomes associated with GLP-1 receptor agonists are currently underway. This review presents …

The global epidemic of type 2 diabetes mellitus (T2DM) has substantial implications for cardiovascular disease–related morbidity and mortality.1 The prevalence of T2DM in patients with heart failure (HF) is high, with strong and independent association between T2DM and incident HF observed in multiple prospective studies and in randomized-controlled clinical trials. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which enrolled subject’s ≥55 years of age with hypertension and ≥1 risk factor, patients with T2DM had a 2-fold risk for HF hospitalization or death after adjustment for other risk factors (RR, 1.95). The association with T2DM was independent of coronary artery disease and at least equivalent in magnitude and greater than that for electrocardiographic left ventricular (LV) hypertrophy.2 All measures of glycemia including fasting, postprandial, measures of insulin resistance, and hemoglobin A1c (HbA1c) have been associated with risk of developing HF, with the association extending to both HF with preserved ejection fraction and to HF with reduced ejection fraction.3,4 A substantial body of evidence from preclinical studies, endomyocardial biopsies in humans and more recently with cardiac MRI, support increased myocardial stiffness in T2DM related to alteration in extracellular matrix. There are multiple proximate mediators that have been hypothesized to play a role including advanced glycation end product deposition and reactive oxygen species that may increase myocardial stiffness during diastole, by cross-linking collagen or by enhancing collagen formation.5,6 Another pernicious proximal mediator is the elevation in postprandial lipids, such as remnant lipoproteins, characteristic of atherogenic dyslipidemia, a highly prevalent abnormality in T2DM, that may result in direct myocellular deposition of lipid, leading to microcirculatory dysfunction, alteration in substrate use and mitochondrial dysfunction.7,8 Indeed, positron emission tomography studies show reduced myocardial glucose uptake in favor of fatty acid …

New Glucose-Lowering Agents for Diabetic Kidney Disease.

GLP-1–Based Therapies: The Dilemma of Uncertainty

Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes by preventing degradation of two incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP are secreted from the intestine on ingestion of various nutrients, and enhance insulin secretion from pancreatic β-cells glucose-dependently1. Both incretin hormones show various biological functions in addition to their glucose-dependent insulinotropic action. Thus, DPP-4 inhibitors are expected to exert extra effects on various tissues and cell types. Among them, their effects on bones are of particular interest. A recent meta-analysis of randomized clinical trials comparing DPP-4 inhibitors with placebo or active comparator drugs in patients with type 2 diabetes suggested that treatment with DPP-4 inhibitors could be associated with a reduced risk of bone fractures2. Type 2 diabetes is associated with higher bone mineral density and, paradoxically, with increased fracture risk, presumably because of impaired bone quality that causes fragility fractures even when bone mass remains normal3. Duration of more than 10 years, presence of diabetic nephropathy, presence of diabetic neuropathy and high serum levels of pentosidine are shown to be risk factors for bone fractures3. One plausible mechanism of increased risk of bone fractures in patients with type 2 diabetes relates to chronic hyperglycemia, raising concentrations of advanced glycation end-products, such as pentosidine, that increases non-enzymatic collagen cross-linking and impairs bone quality. Furthermore, accumulating evidence shows negative impacts of antidiabetic drugs, thiazolidinediones, on bone turnover and bone fractures in patients with type 2 diabetes. However, so far, no oral antidiabetic drugs have been associated clinically with a reduction of bone fractures. Thus, the current finding on DPP-4 inhibitors by Monami et al. is highly promising despite some limitations, including short duration of the trials included, bone fractures being not principal end-points, and no discrimination between sexes and between pre- and postmenopausal women; and the Monami study provides a premise to initiate randomized, prospective, long-term clinical trials evaluating the effects of DPP-4 inhibitors on bone metabolism and bone fractures in patients with type 2 diabetes. The effects of GIP and GLP-1 on bone metabolism have been well characterized mainly in rodents (Figure 1)1. Investigations on GIP receptor-deficient mice and GIP transgenic mice showed that GIP increases bone mass by acting on osteoblasts to promote bone formation after meal ingestion, and inhibiting parathyroid hormone-induced bone resorption. Furthermore, GIP administration has been shown to attenuate ovariectomy-induced bone loss in rats. In contrast, studies on GLP-1 receptor-deficient mice showed that GLP-1 controls bone resorption, likely through a calcitonin-dependent pathway. Administration of GLP-1 receptor agonist exenatide has been shown to promote bone formation in normal and streptozotocin-induced diabetic rats, suggesting its insulin-independent action. Although these lines of evidence suggest an association of GIP and GLP-1 with bone turnover, the effects of GIP and GLP-1 on human bone turnover are largely unknown. A recent study showed that 44-week exenatide treatment did not affect bone mineral density in patients with type 2 diabetes4. As aforementioned, GLP-1 action on the bone is presumably mediated through calcitonin. A series of clinical trials on liraglutide, another GLP-1 receptor agonist, showed few changes in serum calcitonin levels in patients with type 2 diabetes, suggesting that GLP-1 might not play a role in human bone metabolism. Regarding GIP, Henriksen et al.5 previously reported that postprandial reduction of bone resorption was not mediated by GIP, but GLP-2 – another intestinal hormone cosecreted with GLP-1. However, caution should be taken when interpreting their results, as they investigated the effects of subcutaneous single injections of native GIP that should be rapidly inactivated by DPP-4 before it reaches the bones. Therefore, further investigations are definitely required to understand GIP and GLP-1 actions on bone metabolism in humans. The effects of two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like polypeptide-1 (GLP-1), on bone metabolism. GIP binds to GIP receptors expressed on osteoblasts, thereby activating new bone formation. GIP also acts on osteocrasts, presumably through osteoblasts, to suppress bone resorption. In contrast, GLP-1 stimulates calcitonin secretion from the thyroid gland, which then suppresses bone resorption by osteocrasts. Prevention of bone fractures could be the tip of the iceberg among potentially beneficial effects of DPP-4 inhibitors in patients with type 2 diabetes. It has been shown that DPP-4 inhibitors target not only two incretin hormones, GIP and GLP-1, but also other DPP-4 substrates, such as pituitary adenylate cyclase-activating peptide and stromal cell-derived factor-1α in patients with type 2 diabetes. Enhancement of these bioactive polypeptides could prevent progression of diabetic micro- and macrovascular complications independently of improvement in glycemic control. In the future, clinical trials with adequately powered, prospective, controlled relevant end-points will clarify the effects of DPP-4 inhibitors beyond glycemic control. The authors have no competing financial interests to disclose.

Metabolic Disease Drug Discovery— “Hitting the Target” Is Easier Said Than Done

<scp>LEADER</scp> and the new ‘cardiovascular’ glucose‐lowering agents

An Albumin-Exendin-4 Conjugate Engages Central and Peripheral Circuits Regulating Murine Energy and Glucose Homeostasis

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells in response to the presence of nutrients in the small intestines. These homones facilitate glucose regulation by stimulating insulin secretion in a glucose dependent manner while suppressing glucagon secretion. In patients with type 2 diabetes (T2DM), an impaired insulin response to GLP-1 and GIP contributes to hyperglycemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors block the breakdown of GLP-1 and GIP to increase levels of the active hormones. In clinical trials, DPP-4 inhibitors have a modest impact on glycemic control. They are generally well-tolerated, weight neutral and do not increase the risk of hypoglycemia. GLP-1 receptor agonists (GLP-1 RA) are peptide derivatives of either exendin-4 or human GLP-1 designed to resist the activity of DPP-4 and therefore, have a prolonged half-life. In clinical trials, they have demonstrated superior efficacy to many oral antihyperglycemic drugs, improved weight loss and a low risk of hypoglycemia. However, GI adverse events, particularly nausea, vomiting, and diarrhea are seen. Both DPP-4 inhibitors and GLP-1 RAs have demonstrated safety in robust cardiovascular outcome trials, while several GLP-1 RAs have been shown to significantly reduce the risk of major adverse cardiovascular events in persons with T2DM with pre-existing cardiovascular disease (CVD). Several clinical trials have directly compared the efficacy and safety of DPP-4 inhibitors and GLP-1 RAs. These studies have generally demonstrated that the GLP-1 RA provided superior glycemic control and weight loss relative to the DPP-4 inhibitor. Both treatments were associated with a low and comparable incidence of hypoglycemia, but treatment with GLP-1 RAs were invariably associated with a higher incidence of GI adverse events. A few studies have evaluated switching patients from DPP-4 inhibitors to a GLP-1RA and, as expected, improved glycemic control and weight loss are seen following the switch. According to current clinical guidelines, GLP-1RA and DPP-4 inhibitors are both indicated for the glycemic management of patients with T2DM across the spectrum of disease. GLP-1RA may be preferred over DPP- 4 inhibitors for many patients because of the greater reductions in hemoglobin A1c and weight loss observed in the clinical trials. Among patients with preexisting CVD, GLP-1 receptor agonists with a proven cardiovascular benefit are indicated as add-on to metformin therapy.

BackgroundSodium-Glucose Cotransporter-2 (SGLT-2) inhibitors, Glucagon-Like Peptide-1 (GLP-1) agonists and Dipeptidyl Peptidase-4 (DPP-4) inhibitors are the three latest drug classes to receive regulatory approval for the treatment of type 2 diabetes....

To examine the mechanisms of action, therapeutic potential, and challenges inherent in the use of incretin peptides and dipeptidyl peptidase-IV (DPP-IV) inhibitors for the treatment of type 2 diabetes. The scientific literature describing the biological importance of incretin peptides and DPP-IV inhibitors in the control of glucose homeostasis has been reviewed, with an emphasis on mechanisms of action, experimental diabetes, human physiological experiments, and short-term clinical studies in normal and diabetic human subjects. Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) exert important effects on beta-cells to stimulate glucose-dependent insulin secretion. Both peptides also regulate beta-cell proliferation and cytoprotection. GLP-1, but not GIP, inhibits gastric emptying, glucagon secretion, and food intake. The glucose-lowering actions of GLP-1, but not GIP, are preserved in subjects with type 2 diabetes. However, native GLP-1 is rapidly degraded by DPP-IV after parenteral administration; hence, degradation-resistant, long-acting GLP-1 receptor (GLP-1R) agonists are preferable agents for the chronic treatment of human diabetes. Alternatively, inhibition of DPP-IV-mediated incretin degradation represents a complementary therapeutic approach, as orally available DPP-IV inhibitors have been shown to lower glucose in experimental diabetic models and human subjects with type 2 diabetes. GLP-1R agonists and DPP-IV inhibitors have shown promising results in clinical trials for the treatment of type 2 diabetes. The need for daily injections of potentially immunogenic GLP-1-derived peptides and the potential for unanticipated side effects with chronic use of DPP-IV inhibitors will require ongoing scrutiny of the risk-benefit ratio for these new therapies as they are evaluated in the clinic.

The pandemic explosion of type 2 diabetes incidence is well established, due to dramatic global changes in lifestyle over the past few decades and in the foreseeable future. To alter the course of this trend may take, at best, up to half a century. Until then, we need, in addition to lifestyle guidance, pharmacological solutions to reduce the markedly increasing incidence of macrovascular complications that, in its wake, confer a huge burden on patients and their families as well as an enormous economic burden to society. In the United States, for example, diabetes afflicts more than 21 million people, with an estimated cost of around $130 billion annually (http://diabetes.niddk.nih.gov/ dm/pubs/statistics/index.htm#7). The Steno 2 study has clearly demonstrated the efficacy of aggressive intervention against dyslipidemia, hypertension, and elevated glycemia brought on by diabetes (1). In daily life, however, it is also clear that less than half of the type 2 diabetic patients reach the recommended glycemic level employing so-called standard therapy, i.e. sulfonylureas, metformin, thiazolidinediones, and insulin. Hence, all new efficient blood glucose-lowering compounds without serious side effects are greeted with open arms. The glucagon like peptide-1 (GLP-1) concept holds promise. GLP-1 is mainly secreted by the intestinal L cells, although neural signals probably also contribute. The active peptides [GLP-1(7-37) and GLP-1(7-36) amide] increase insulin secretion in a glucose-dependent manner, i.e. lowering risk of hypoglycemia, decreasing basal as well as postprandial glucagon secretion, delaying gastric emptying, and increasing satiety by actions in the hypothalamus. Animal and in vitro models have shown that GLP-1 also increases -cell proliferation and neogenesis and decreases apoptosis (2). In these models, GLP-1 has other extrapancreatic effects beyond those described above, but whether these effects are also reflected in humans remains to be seen. In the circulation, GLP-1 undergoes enzymatic deactivation to GLP-1(9-37) and GLP-1(9-36) amide within minutes, primarily by dipeptidyl peptidase-4 (DPP-4), an enzyme present on the surface of lymphocytes, macrophages, and endothelial cells, and in tissues, such as the pancreas, liver, intestine, kidneys, and lungs. Localization of DDP-4 in endothelial cells indicates that degradation already takes place upon GLP-1 entry into the capillaries; endothelial DPP-4 in the liver degrades 50% of the protein. From this it can be deduced that only approximately 15% of the secreted GLP-1 reaches the pancreas in its intact form (3). DPP-4 also metabolizes other biologically active peptides of relevance in the regulation of carbohydrate metabolism such as glucose-dependent insulinotropic polypeptide, vasoactive intestinal polypeptide, and gastrin-releasing polypeptide. Active GLP-1 operates through the GLP-1 receptor (GLP-1R) belonging to the class B family of seven-transmembrane-spanning, heterotrimeric G protein-coupled receptors. Apart from the cells of the islet of Langerhans, several tissues express GLP-1R, including the heart, central nervous system, kidneys, lungs, stomach, intestine, and pituitary gland, as well as the nodose ganglion of abdominal vagal afferent nerve fibers, the central branches of which terminate in the brain stem. The presence of GLP-1Rs in skeletal muscle, liver, and adipose tissue is debatable. Due to the short half-life of native GLP-1, it is not feasible for long-term use, but its parenteral use may be of interest during acute medical and/or surgical conditions (4). For long-term therapy, two classes of pharmaceutical agents are involved and are still in development: 1) long-acting analogs, or so-called GLP-1 mimetics; and 2) DPP-4 inhibitors, or so-called incretin enhancers.

The incretin system plays an important role in glucose homeostasis, largely through the actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Unlike GIP, the actions of GLP-1 are preserved in patients with type 2 diabetes mellitus, which has led to the development of injectable GLP-1 receptor (GLP-1R) agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1R agonists—which can be dosed to pharmacologic levels—act directly upon the GLP-1R. In contrast, DPP-4 inhibitors work indirectly by inhibiting the enzymatic inactivation of native GLP-1, resulting in a modest increase in endogenous GLP-1 levels. GLP-1R agonists generally lower the fasting and postprandial glucose levels more than DPP-4 inhibitors, resulting in a greater mean reduction in glycated hemoglobin level with GLP-1R agonists (0.4%–1.7%) compared with DPP-4 inhibitors (0.4%–1.0%). GLP-1R agonists also promote satiety and reduce total caloric intake, generally resulting in a mean weight loss of 1 to 4 kg over several months in most patients, whereas DPP-4 inhbitors are weight-neutral overall. GLP-1R agonists and DPP-4 inhibitors are generally safe and well tolerated. The glucose-dependent manner of stimulation of insulin release and inhibition of glucagon secretion by both GLP-1R agonists and DPP-4 inhibitors contribute to the low incidence of hypoglycemia. Although transient nausea occurs in 26% to 28% of patients treated with GLP-1R agonists but not DPP-4 inhibitors, this can be reduced by using a dose-escalation strategy. Other adverse events (AEs) associated with GLP-1R agonists include diarrhea, headache, and dizziness. The main AEs associated with DPP-4 inhibitors include upper respiratory tract infection, nasopharyngitis, and headache. Overall, compared with other therapies for type 2 diabetes mellitus with similar efficacy, incretin-based agents have low risk of hypoglycemia and weight gain. However, GLP-1R agonists demonstrate greater comparative efficacy and weight benefit than DPP-4 inhibitors.

BackgroundIncretin-based therapies including dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon like peptide-1 (GLP-1) receptor agonists are novel medications for type 2 diabetes management. Several studies have found cardioprotective effects of incretin-based therapies; however, it remains unclear whether there is any difference in heart failure (HF) risk between the two incretin-based therapies (DPP-4 inhibitors and GLP-1 receptor agonists). We aimed to assess the risk of hospitalization due to HF with the use of DPP-4 inhibitors compared to GLP-1 receptor agonists.MethodsUsing Truven Health Marketscan data, we conducted a retrospective cohort study of patients with type 2 diabetes, who were newly initiated on DPP-4 inhibitors or GLP-1 agonists. Follow-up continued from drug initiation until the first occurrence of: HF hospitalization (primary outcome), discontinuation of therapy (i.e. no fill for 7 days), switch to the comparator, end of enrollment, or end of study (December 2013). Cox proportional hazards models with propensity-score-matching were used to compare the risk of HF hospitalization between DPP-4 inhibitors and GLP-1 agonists.ResultsA total of 321,606 propensity score-matched patients were included in the analysis (n = 160,803 for DPP-4 inhibitors; n = 160,803 for GLP-1 agonists). After adjusting for baseline characteristics and disease risk factors, the use of DPP-4 inhibitors was associated with a 14% decreased risk of HF hospitalization compared to GLP-1 agonists use [hazard ratio (HR), 0.86; 95% confidence interval (CI) 0.83, 0.90]. The results were consistent in patients without baseline HF (HR, 0.85; 95% CI 0.82, 0.89), but the association was not statistically significant for patients with baseline HF (HR, 0.90; 95% CI 0.74, 1.07).ConclusionIn this retrospective matched cohort of patients with type 2 diabetes, the use of DPP-4 inhibitors was associated with a reduced risk of HF hospitalization compared to GLP-1 agonists. However, the association was not statistically significant in patients who had HF prior to the use of DPP-4 inhibitors.

Mechanism of Action of DPP-4 Inhibitors—New Insights