Role of Incretin Therapies in the Management of Type 2 Diabetes Mellitus: An Update

Despite the wide array of medications available for the treatment of type 2 diabetes mellitus, a significant number of patients remain uncontrolled. The traditional agents including metformin, sulfonylureas, and insulin have proven effective, however, adverse effects and precautions limit their use in certain patient populations. The incretin-based therapies, GLP-1 analogs and DPP-IV inhibitors, provide clinicians an additional tool in treating patients with type 2 diabetes. By replacing GLP-1 or inhibiting its breakdown, the beneficial effects of GLP-1 are able to persist. GLP-1 stimulates insulin secretion, slows gastric emptying, decreases glucagon, improves β-cell function, and reduces appetite. Several GLP-1 analogs and DPP-4 inhibitors have been approved by the FDA or are in various stages of development. Many of these agents have been previously reviewed by the authors, however, new data has become available. Although additional studies are necessary to determine the long-term safety and efficacy of these agents, these incretin-based therapies offer several advantages over existing therapy options.

Inhibition of Glucagon Secretion by GLP-1 Agonists and DPP4 Inhibitors

Incretin-based treatments have emerged as new modalities for the treatment of type 2 diabetes mellitus (T2DM). In contrast to current antidiabetic treatments, these agents target both insulin insufficiency and inappropriate hyperglucagonemia—two major components of type 2 diabetic pathophysiology—both known to contribute significantly to the hyperglycemic state of patients with T2DM. This article outlines the role of hyperglucagonemia in type 2 diabetic pathophysiology, summarizes the physiologic effects of glucagon-like peptide-1 (GLP-1), and gives an introduction to incretin-based treatments with emphasis on their glucagon-lowering effects. Finally, we review available glucagon data from current clinical studies on incretin-based treatment modalities (dipeptidyl peptidase 4 [DPP4] inhibitors and GLP-1 receptor agonists). Most of these studies suggest that both DPP4 inhibitors and GLP-1 receptor agonists lower fasting and postprandial plasma glucagon, and recent data suggest that these effects contribute importantly to the glucose-lowering effect of these treatments.

Incretin-Based Therapy

Despite availability of several oral hypoglycemic agents, safe and effective treatment still represents a challenge in type 2 diabetes (T2DM) and a large percentage of patients do not reach the therapeutic goal of a near normal HbA1c value. Incretin-based therapies represent a relatively new treatment approach that may address some of the shortfalls of the traditional treatments. “Incretins” are hormones secreted by the gastrointestinal tract upon food intake. Glucagone like peptide-1 (GLP-1), the first incretin to be described, potentiates glucose-dependent insulin secretion and appears capable, at least in vitro and in animal models, to preserve beta-cell mass and function. Due to its characteristics, GLP-1 is considered a very attractive molecule for treatment of type 2 diabetes. However, native GLP-1 is rapidly degraded by the enzyme dipeptidyl-peptidase IV (DPP-4) and, therefore, it is not suitable for clinical use. This has led to development of the two classes of incretin-based drugs that are presently approved for type 2 diabetes treatment: DPP-4 inhibitors (or incretin enhancers) that are small compounds readily absorbable when assumed orally, which will prolong endogenous GLP-1 half-life and GLP-1-receptor agonists (or GLP-1 mimetics), which are injectable molecule mimicking endogenous GLP-1 action but with a longer half-life. Efficacy, safety, and clinical use of the available compounds of these two classes are discussed in this review. It is concluded that, on the basis of the available evidence, incretin-based therapies do represent a very flexible tool to achieve optimal blood glucose control in type 2 diabetic patients.

Incretin-based Therapies: An Update from Literature

Type 2 diabetes represents a chronic metabolic disease characterised by insulin-resistance and a progressive decline of pancreatic β-cell glucose-mediated insulin secretion. Beyond traditional therapeutic approaches, which are directed either to improve β-cell dysfunction, or to enhance insulin sensitivity, a relatively new concept of treatment for type 2 diabetes is based on the effects of several intestinal hormones, called incretins, which are normally secreted after a meal and contribute to glucose homeostasis by enhancing insulin secretion and inhibiting glucagon release in pancreatic islets in a glucose-dependent manner. Glucagon-like peptide-1 (GLP-1) is the incretin hormone that mainly enhances glucose-dependent insulin secretion and inhibits glucagon release. The resulting “incretin-based therapies”, based either on the development of mimetics of the GLP-1, or on the inhibition of the incretins degrading enzyme dipeptidyl peptidase 4 (DPP-4), have been reported to improve glycemic control with minimal risk of hypoglycemia in type 2 diabetic patients. Incretin-based therapy can exert several beneficial effects on blood pressure, myocardial function, dyslipidemia and, limited to GLP-1 analogues, body weight. Furthermore, in rodent models of diabetes, but not yet in humans, both GLP-1 receptor agonists and DPP-4 inhibitors have been demonstrated to improve pancreatic islets mass and preserve β-cell function. Along with a safety profile similar to other anti-diabetic agents, these glycemic and extraglycemic effects of incretin-based therapies make them promising therapeutic options in order to reduce the burden of cardiovascular risk, which still represents the major cause of mortality in type 2 diabetic patients.

Best Practice to Manage Patients with Type 2 Diabetes with an HbA1c Between 6.5 and 7.5

The majority of patients with type 2 diabetes do not reach the treatment goals with metformin therapy during the progress of the disease. Therefore, an escalation of therapeutic efforts is required as metabolic control deteriorates. Metformin is the first-line drug due to its efficacy, its effect on insulin resistance, ist weight neutrality, its pharmacological profile, and the lack of risk for causing hypoglycemia. Following this initial pharmacological monotherapy step, the escalation of antidiabetic treatment has many options for second-line combinations. These options are discussed in this manuscript. As a basis for this manuscript besides stating national and international evidence-based guidelines a literature search in PubMed, Scopus, and Embase was performed to retrieve preclinical and prospective randomized controlled clinical trial data of the antidiabetic agents. On the basis of these data, a comparison of the antidiabetic treatment combinations is made.

A Population Kinetic Analysis of Prehepatic Insulin Secretion

Regulation of Bone Mineral Density in Morbidly Obese Women

Vagal Nerve Transection During Pouch Formation in Laparoscopic Roux-Y-Gastric Bypass for Technical Simplification

Laparoscopic Roux-Y gastric bypass is one of the most often performed procedures to treat morbid obesity. During the procedure, the vagal nerve is tempted to be preserved by most surgeons due to the fear of postoperative side effects such as dumping, diarrhea, and abdominal pain. To keep postoperative morbidity and mortality low it is mandatory to simplify the operative procedure and to avoid leakage at the anastomosis. Division of the minor omentum including the anterior branch of the vagal nerve allows a better view to create the small gastric pouch in primary bypass procedures. In revisional surgery, an anastomosis close to the esophagus including total vagotomy may be necessary to allow an uncomplicated postoperative course. So far the available data does not report significant differences after gastric bypass with and without vagotomy, respectively.

Telomere Length Regulation and Reproduction: Current Concepts and Putative Threats To Ovarian Reserve

Micro- and Macrovascular Risk and Complications In T2DM Males With Obstructive Sleep Apnea

BACKGROUND

Obstructive sleep apnea syndrome (OSAS) is a comorbidity of obesity. OSAS is also an independent risk factor for type 2 diabetes (T2DM). OSAS promotes incident major adverse cardiovascular events (MACE). The prevalence of OSAS and its association with MACE are poorly documented in T2DM, a high-risk population.

METHODS

We analyzed 580 consecutive male T2DM outpatients in whom OSAS was diagnosed through combined evaluation, including (hetero)anamnesis, Epworth's Sleepiness Scale (ESS), overnight oximetry, and confirmed by polysomnography. OSAS (+) (n=66) were compared to OSAS (–) (n=514) regarding cardiovascular (CV) risk factors, microvascular complications, MACE, and UKPDS 10-year absolute CVD risk.

RESULTS

Mean (1 SD) age was 63 (11) years, diabetes duration 13 (9) years. Metabolic syndrome (MetS) prevalence was 77%, and HbA 7.5 (1.5)%. OSAS prevalence was 11.4%. There were no differences in age, diabetes duration, smoking, blood pressure (BP), and lipids (except for triglycerides) between OSAS (+) and (–). There were significant differences in the ESS score, BMI, waist, relative/absolute fat, skeletal muscle, conicity index, and visceral fat, all significantly higher in OSAS (+). Micro- and macrovascular complication prevalences were high, though not significantly different, in both groups, except for stroke prevalence, which was doubled in OSAS (+): 15 vs 7%; P=.05). Fasting triglycerides and cystatin-C levels were significantly higher in OSAS (+), the increase in the latter being unrelated to differences in eGFR between groups. UKPDS Risk Engine input variables and predicted risk were all similar in both groups, with a 10-year risk for CAD 20% and 22%, respectively in OSAS (–) and OSAS (+) patients (NS).

CONCLUSIONS

OSAS is frequent in male T2DM patients who exhibit a high-risk cardiometabolic phenotype characterized by severe MetS score and prevalence, central fat accretion, insulin resistance, hypertriglyceridemia, and raised cystatin-C. The data indicate an association between OSAS and stroke prevalence. Using the T2DM-specific UKPDS Risk Engine, absolute 10-year CVD risk estimates were elevated, though not significantly different, between OSAS subgroups in primary CV prevention.

Can We Delay or Even Reverse Diabetic Complications By Islet Transplantation?

Treatment of diabetes is of crucial importance not only for glycemic control but also for the prevention of complications that causes irreversible damage to peripheral nerves, heart, kidney, and eyes. Despite a major effort to obtain prolonged metabolic control, diabetes complication can only be delayed in time. In a recent publication we investigated the effect of islet transplantation on diabetic complications in a rat model of streptozotocin-induced diabetes (1). We reported that islet transplantation induced an amelioration of impaired nociceptive threshold and normalization of nerve conduction velocity in diabetic rats. Cardiomyocyte loss was also reduced by islet transplantation and the observed mild kidney damage of diabetic rats was prevented. We concluded that transplantation of pancreatic islets, besides controlling glycemia, induced regression of neuropathy and prevented cardiovascular alterations, which was always there supporting the potential of islet transplantation. In this review we compare our recently published data with previous reports on prevention and regression of diabetic neuropathy, cardiovascular disease, nephropathy, and retinopathy with a particular attention to those on animal models of diabetes. In details, the potential of islet transplantation in inducing the regression of diabetic complications is discussed.

Sagittal Abdominal Diameter and Waist Circumference as Markers of Early Organ Damage in Patients With Type 2 Diabetes

INTRODUCTION AND OBJECTIVES

In a cohort of 465 patients with type 2 diabetes aged 55–66 years, the association between the anthropometric measures, waist circumference (WC) and sagittal abdominal diameter (SAD) versus subclinical cardiovascular organ damage by measuring pulse wave velocity (PWV) and left ventricular mass index (LVMI), was studied.

METHODS

Blood pressure, weight, height, and WC were measured within primary care. The SAD was measured by using standardized caliper equipment. Blood samples were taken for analysis of HbA1c and serum lipids. The LVMI was measured by M-mode echocardiography. Aortic PWV was measured by applanation tonometry (Sphygmocor) over the carotid and femoral arteries. The baseline characteristics were compared with data from a control group with nondiabetic patients that were randomly recruited from the general population.

RESULTS

The diabetic cohort was more obese than the age-matched controls and there were significant correlations between aortic PWV and WC (r=0.23; p<.01) and SAD (r=0.25; p<.01) in the diabetic group. The LVMI was also correlated to WC (r=0.26; p<.01) and SAD (r=0.25; p<.01). When analyzed in a multiple regression model, SAD and WC were both associated with PWV and LVMI, independently of age, sex, systolic blood pressure, serum lipids, and HbA1c.

CONCLUSION

Patients with type 2 diabetes were more obese than the nondiabetic controls and both measurements of abdominal obesity, WC or SAD, were associated with markers of early cardiovascular organ damage.