Thiazolidinediones: the Forgotten Diabetes Medications.

PURPOSE OF REVIEW: Thiazolidinediones (TZDs) are the only pharmacologic agents that specifically treat insulin resistance. The beneficial effects of TZDs on the cardiovascular risk factors associated with insulin resistance have been well documented. TZD use has been limited because of concern about safety issues and side effects. RECENT FINDINGS: Recent studies indicate that cardiovascular toxicity with rosiglitazone and increase in bladder cancer with pioglitazone are no longer significant issues. There are new data which show that pioglitazone treatment reduces myocardial infarctions and ischemic strokes. New data concerning TZD-mediated edema, congestive heart failure, and bone fractures improves the clinician's ability to select patients that will have minimal significant side effects. Thiazolidinediones are now generic and less costly than pharmaceutical company-promoted therapies. Better understanding of the side effects coupled with clear benefits on the components of the insulin resistance syndrome should promote TZD use in treating patients with type 2 diabetes.

Gastric Contractility Modulation - a novel method for the treatment of type 2 diabetes mellitus and obesity.

Because the majority of antidiabetic medications are of limited efficacy and patient compliance with treatment is usually poor, new therapies are still being searched for. In the review a newly developed system for treatment of subjects with type 2 diabetes and concomitant overweight/obesity is described. The system consists of an implantable pulse generator that delivers electrical stimuli through leads implanted in the sero-muscular layer of the stomach. The device recognises and automatically modulates natural electrical activity of the stomach during meals, strengthening gastric contractility. This increase in the force of contractions enhances vagal afferent activity. Modulated signals are transmitted to the regulatory centres in the brain in order to provoke an early response of the gut typical of a full meal. Clinical trials performed to date show that the system improves glycaemic control with minimal patient compliance needed and with added benefits of body weight loss, a decrease in blood pressure, and favourable changes in the lipid profile. The system is safe, well-tolerated, with a low risk of hypoglycaemia, and will probably become an alternative to the use of incretins or to bariatric surgery in obese patients who are unwilling to undergo a major and anatomically irreversible operation.

A pilot study to compare meal-triggered gastric electrical stimulation and insulin treatment in Chinese obese type 2 diabetes.

BACKGROUND: Gastrointestinal electromodulation therapy is a novel alternative for achieving diabetes control without traditional bariatric surgery. We compared the efficacy of a meal-initiated implantable gastric contractility modulation (GCM) device with that of insulin therapy in obese Chinese type 2 diabetes (T2D) patients, for whom oral antidiabetes drugs (OADs) had failed. PATIENTS AND METHODS: Sixteen obese (body mass index, 27.5-40.0 kg/m(2)) T2D patients with a glycated hemoglobin (HbA1c) level of >7.5% on maximal doses of two or more OADs were offered either insulin therapy (n=8) or laparoscopic implantation of a GCM (n=8). We compared changes in body weight, waist circumference (WC), and HbA1c level 1 year after surgery. RESULTS: The GCM and insulin groups had similar baseline body weight and HbA1c. At 12 months, body weight (-3.2±5.2 kg, P=0.043) and WC (-3.8±4.5 cm, P=0.021) fell in the GCM group but not in the insulin group (P<0.05 for between-group difference). At 6 and 12 months, the HbA1c level fell by 1.6±1.1% and 0.9±1.6% (P=0.011), compared with 0.6±0.3% and 0.6±0.3% (P=0.08) for the insulin group (P=0.15 for between-group difference). The mean 24-h systolic blood pressure (BP) fell by 4.5±1.0 mm Hg in the GCM group (P=0.017) but not in the insulin group. The GCM group required fewer antidiabetes medications (P<0.05) and BP-lowering drugs (P<0.05) than the insulin group. A subgroup analysis showed that patients with a triglyceride level of <1.7 mmol/L had a tendency toward a lower HbA1c level (P=0.090) compared with the controls. CONCLUSIONS: In obese T2D patients for whom OADs had failed, GCM implantation was a well-tolerated alternative to insulin therapy, with a low triglyceride level as a possible predictor for glycemic response.

Metabolic surgery for type 2 diabetes: appraisal of clinical evidence and review of randomized controlled clinical trials comparing surgery with medical therapy.

Bariatric surgical procedures were originally developed to treat morbid obesity where their benefits certainly outweigh their potential side effects. Although they are very beneficial in improving metabolic control in type 2 diabetes, there are many medical treatments that are also effective. The role of bariatric surgery as primary therapy for type 2 diabetes depends on whether the benefit exceeds the surgical and nutritional complications, which are significant. The ultimate role for bariatric surgery in treating type 2 diabetes can only be determined by large, long-term randomized clinical trials which compare clinical outcomes of bariatric surgery with those of current intensive medical treatment. The four reported small, mostly 1-year trials have shown superior glycemic control by surgery as compared with medical treatment, but at the expense of significant surgical complications and unknown nutritional liability. They show that future trials will have to be much larger and last for at least 5-10 years.

Metabolic surgery for type 2 diabetes with BMI <35 kg/m(2) : an endocrinologist's perspective.

Is bariatric surgery as primary therapy for type 2 diabetes mellitus (T2DM) with body mass index (BMI) <35 kg/m(2) justified? Open-label studies have shown that bariatric surgery causes remission of diabetes in some patients with BMI <35 kg/m(2). All such patients treated had substantial weight loss. Diabetes remission was less likely in patients with lower BMI than those with higher BMI, in patients with longer than shorter duration and in patients with lesser than greater insulin reserve. Relapse of diabetes increases with time after surgery and weight regain. Deficiencies of data are lack of randomized long-term studies comparing risk/benefit of bariatric surgery to contemporary intensive medical therapy. Current data do not justify bariatric surgery as primary therapy for T2DM with BMI <35 kg/m(2).

Science, clinical outcomes and the popularization of diabetes surgery.

PURPOSE OF REVIEW: Bariatric surgery is an important option for the treatment of severe (type III) obesity. Its role in the management of type 2 diabetes in overweight and obese patients needs to be defined. RECENT FINDINGS: Intensified medical therapy can achieve target metabolic goals in many but not all patients with type 2 diabetes. Bariatric surgery can normalize or improve glycemia in severely obese patients with type 2 diabetes. The complications of bariatric surgery are significant and include operative mortality, early and late surgical complications and late nutritional deficiencies. Comparative studies of bariatric surgery versus intensive medical therapy in the management and clinical outcomes of patients with type 2 diabetes are needed to evaluate relative risk/benefit of each. Bariatric surgery studies in type 2 diabetes are lacking long-term follow-up metabolic and clinical outcomes data. SUMMARY: Current data are insufficient to recommend bariatric surgery as a primary treatment for type 2 diabetes. However, it can be recommended for patients whose target metabolic control cannot be achieved by intensive glycemic control because of intolerance or inadequate responses to nutritional and pharmacologic treatments.

Non-insulin injectable treatments (glucagon-like peptide-1 and its analogs) and cardiovascular disease.

Glucagon-like peptide-1 (GLP-1) [GLP-1 (7-36)-amide] plays a fundamental role in regulating postprandial nutrient metabolism. GLP-1 acts through a G-protein-coupled receptor present on the membranes of many tissues, including myocardium and endothelium. GLP-1 is cleaved by the dipeptidyl peptidase-4 enzyme to its metabolite GLP-1 (9-36)-amide within 1-2 min of its release into the circulation. Investigations have been done in humans and in animal models to determine whether GLP-1 has effects on the myocardium. Infusions of GLP-1 increase cardiac function in ischemic and non-ischemic cardiovascular disease. In humans and animal models, constant infusions of GLP-1 decrease the size of infarction and improve myocardial function in ischemic/reperfusion injury. In cardiomyopathy and heart failure, infusions of GLP-1 improve myocardial function. These beneficial effects of GLP-1 on cardiac function are mediated by both GLP-1 receptor activation and GLP-1 receptor independent actions. Infusions of the metabolite GLP-1 (9-36)-amide improve cardiac function in experimental animals with cardiovascular disease even though the metabolite does not bind to the GLP-1 receptor. The beneficial effects of GLP-1 on the heart occur in the presence of a GLP-1 receptor antagonist and in animals devoid of GLP-1 receptors. Preliminary data in animals with available GLP-1 receptor agonists and cardiac disease suggest that exenatide has beneficial effects in porcine models of ischemic heart disease. The animal data with liraglutide are inconclusive. Clinical trials with exenatide and liraglutide show significant improvements in weight, systolic blood pressure, lipid profiles, and other cardiovascular risk factors. Whether these will decrease cardiovascular events is currently under investigation.

Type 2 diabetes mellitus--current therapies and the emergence of surgical options.

Patients with type 2 diabetes mellitus (T2DM) are usually treated with pharmacologic agents in combination with lifestyle modification. The development of new antidiabetic agents, such as insulin analogs and incretin-based therapies, has led to treatment strategies that enable many patients with T2DM to achieve target HbA(1c) levels (≤7.0%). However, many factors-including those related to the patient or the health-care provider, drug inadequacies and adverse effects-can interfere with the ability of some patients to reach metabolic targets. Clinical data from the USA indicate that HbA(1c) concentration, blood pressure and serum levels of lipids in patients with T2DM are progressively decreasing toward the target goals set by the American Diabetes Association. These improvements in metabolic regulation have led to a 30-40% decrease in reported microvascular and macrovascular complications of diabetes mellitus in the USA. Gastric bypass surgery in morbidly obese individuals with T2DM leads to remission of the diabetes mellitus in the majority of patients and improvement in the rest. A major contributor to this improvement is an alteration in gastrointestinal hormone secretions. Interventional surgery might, therefore, be considered a reasonable therapeutic alternative for overweight and obese (BMI <35 kg/m²) patients with T2DM who do not respond to medical therapy.

Adjunct therapy for type 1 diabetes mellitus.

Insulin replacement therapy in type 1 diabetes mellitus (T1DM) is nonphysiologic. Hyperinsulinemia is generated in the periphery to achieve normal insulin concentrations in the liver. This mismatch results in increased hypoglycemia, increased food intake with weight gain, and insufficient regulation of postprandial glucose excursions. Islet amyloid polypeptide is a hormone synthesized in pancreatic beta cells and cosecreted with insulin. Circulating islet amyloid polypeptide binds to receptors located in the hindbrain and increases satiety, delays gastric emptying and suppresses glucagon secretion. Thus, islet amyloid polypeptide complements the effects of insulin. T1DM is a state of both islet amyloid polypeptide and insulin deficiency. Pramlintide, a synthetic analog of islet amyloid polypeptide, can replace this hormone in patients with T1DM. When administered as adjunctive therapy to such patients treated with insulin, pramlintide decreases food intake and causes weight loss. Pramlintide therapy is also associated with suppression of glucagon secretion and delayed gastric emptying, both of which decrease postprandial plasma glucose excursions. Pramlintide therapy improves glycemic control and lessens weight gain. Agents that decrease intestinal carbohydrate digestion (alpha-glucosidase inhibitors) or decrease insulin resistance (metformin) might be alternative adjunctive therapies in T1DM, though its benefits are marginally supported by clinical data.

Therapeutic options in development for management of diabetes: pharmacologic agents and new technologies.

OBJECTIVE: To review new pharmacologic therapies and technologies relevant to the management of diabetes and its complications. METHODS: New treatment options for diabetes, made available through research efforts during the past 2 decades, are discussed. RESULTS: Several new drugs and drug classes for the management of diabetes are under development, including the incretin mimetic agents (exenatide, dipeptidyl peptidase 4 inhibitors, and glucagon-like peptide 1 analogues), the amylin analogue pramlintide, the cannabinoid-1 receptor antagonist rimonabant, the mixed peroxisome proliferator-activated receptor agonists muraglitazar and tesaglitazar, the inhaled insulin preparation Exubera, and the insulin analogues (insulin glulisine and insulin detemir). CONCLUSION: New drugs and technologic advances being made available will help achieve the goals of treating patients with diabetes to all the appropriate metabolic targets. Many other agents that act on fundamental abnormalities such as energy imbalance, inflammation, and vascular biologic conditions are in very early stages of development but are likely to become available during the next 5 to 10 years.

The relationship of obesity to the metabolic syndrome.

Obese patients with the metabolic syndrome generally have a visceral (apple-shaped) fat distribution and are at an increased risk of macrovascular disease, while those with peripheral (pear-shaped) obesity tend not to have metabolic abnormalities and are at less risk. This difference appears to be related to the differing metabolic functions (and secretory products) of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), as well as the fact that VAT drains directly into the liver. Thus, it appears that increased VAT, but not SAT, is associated with both hepatic and peripheral biochemical abnormalities leading to insulin resistance and the associated metabolic syndrome. Insulin resistance is associated with VAT products, such as free fatty acids and their metabolites, as well as cytokines, such as tumour necrosis factor alpha (TNF-alpha). These factors may activate components of the inflammatory pathway such as nuclear factor kappa-B (NFkappaB), and inhibit insulin signalling. Insulin resistance is further associated with decreased levels of another tissue product, adiponectin. The incidence and prevalence of obesity is increasing at an unprecedented rate. The classic treatment of obesity is weight loss via lifestyle modification. However, prevention of obesity comorbidity can also be achieved by modifying the mechanisms by which obesity causes these comorbid conditions. For instance, it is now known that the peroxisome proliferator-activated receptor (PPAR) family of transcriptional regulators are crucial in regulating adipose tissue development and metabolism; this helps explain why compounds with PPARgamma agonist activity, e.g. thiazolidinediones, increase insulin action through their effects in regulating adipose tissue metabolism.