Amylin Analog Research Articles

Opportunities and challenges for the development of pharmacological therapies for obesity treatment

In the 1970s, the drugs available for the treatment of obe-sity were either bulking agents, such as methylcellulose, orsympathomimetic agents. These are chemically related toamphetamine, although one of them, fenfluramine, hadquite different pharmacological properties, being a seroto-nin (5HT) uptake inhibitor, whereas the other compoundsacted on the noradrenergic system (1,2). None of the sym-pathomimetic agents are available in the UK now as a resulteither of potential for abuse or, in the case of fenfluramine,the finding that one isomer, dexfenfluramine, induced heartvalve defects (3). Phentermine is still available in the USA.These drugs were prescribed for short-term use only andanalysis of many trials of such drugs by the US Food andDrug Administration (FDA) showed that they give a weightloss of approximately 0.5 lb (0.22 kg) more each week thanplacebo (4). It was thought that they produced their anti-obesity effect through a reduction in food intake, althoughthere is little direct evidence that this was their only effectand an increase in metabolic rate also seems likely. Dura-tion of use was restricted, based on the belief that once anew plateau body weight was reached, it showed that thedrugs were no longer working. In fact, removal of thetherapy usually resulted in the return to the original over-weight body mass, indicating that the drugs were success-fully maintaining a lower body mass.In the 1970s and 1980s, there was little drug researchfor new anti-obesity drugs, largely because most companiesdid not perceive obesity as a major therapeutic opportunityand because of registration difficulties and a small numberof patients. It was also thought that obesity was simply theresult of gluttony and sloth. Exceptions were the BeechamGroup (now GlaxoSmithKline) and ICI (now AstraZen-eca), both of which had active research programmes aimedat producing exercise-mimetic drugs that would increaseenergy expenditure (5,6).Between the 1970s and today, few drugs have been mar-keted. As already indicated, dexfenfluramine was with-drawn as a result of heart valve defects (3) and some casesof pulmonary hypertension. Topiramate, originally mar-keted as an anti-epileptic agent, was suspended while inphase III clinical trials because of its many side effects.Currently marketed agents are sibutramine (Reductil), a5HT and noradrenaline re-uptake inhibitor, which acts cen-trally to reduce appetite but may have some thermogenicactivity (7), and orlistat (Xenical), which is an inhibitor ofpancreatic lipase and reduces fat absorption from the gut(8). Both these agents have some problems causing, respec-tively, slightly raised blood pressure and fatty stools withthe possibility of anal leakage. Rimonabant, a cannabinoidCB-1 receptor antagonist (9), has recently (July 2006) beenapproved in Europe and is under review by the FDA.Several drugs have entered phase III trials. Pramlintide –a peptide hormone amylin analogue marketed for treat-ment of type 1 and type 2 diabetes – has some weight losseffects (10), as does exendin – a hormone originally foundin lizards and used in type 2 diabetes (11). Sertraline is

Pramlintide acetate in the treatment of Type 2 and Type 1 diabetes mellitus

Maintenance of glucose homeostasis involves the interplay of multiple glucoregulatory factors, including the pancreatic β-cell hormones insulin and amylin. Amylin, a neuroendocrine hormone, is secreted in response to nutrient intake and suppresses postprandial glucagon secretion, helps regulate gastric emptying, and reduces food intake. Patients with diabetes are deficient in both insulin and amylin – contributing to postprandial hyperglycemia. Pramlintide, an analogue of amylin, is the active ingredient in the SYMLIN® (pramlintide acetate) injection. SYMLIN is indicated as an adjunctive treatment for insulin-using patients with diabetes and works through mechanisms similar to those of amylin. Clinical trials have demonstrated that pramlintide therapy improves postprandial glucose control, lowers A1C, and is accompanied by a reduction in body weight. Mild-to-moderate nausea and an increased risk of insulin-induced severe hypoglycemia have been the most common side effects. These side effects can be mitigated by gradual pramlintide dose escalation during treatment initiation and proactive mealtime insulin dose reduction upon initiation of pramlintide therapy.

Bodyweight Changes Associated with Antihyperglycaemic Agents in Type 2 Diabetes Mellitus

The majority of patients with type 2 diabetes mellitus are overweight or obese at the time of diagnosis, and obesity is a recognised risk factor for type 2 diabetes and coronary heart disease (CHD). Conversely, weight loss has been shown to improve glycaemic control in patients with type 2 diabetes, as well as to lower the risk of CHD. The traditional pharmacotherapies for type 2 diabetes can further increase weight and this may undermine the benefits of improved glycaemic control. Furthermore, patients' desire to avoid weight gain may jeopardise compliance with treatment, thereby limiting treatment success and indirectly increasing the risk of long-term complications. This review evaluates the influences of established and emerging therapies on bodyweight in type 2 diabetes. Improvement in glycaemic control with insulin secretagogues has been associated with weight gain. On the other hand, biguanides such as metformin have been consistently shown to have a beneficial effect on weight; metformin appears to modestly reduce weight when used as a monotherapy. alpha-Glucosidase inhibitors are considered weight neutral; in fact, the results of some studies show that they cause reductions in weight. Thiazolidinediones (TZDs) are typically associated with weight gain and increased risk of oedema, while the impact of some TZDs, such as pioglitazone, on lipid homeostasis could be beneficial. Insulin, the most effective therapy when oral agents are ineffective, has always been linked to significant weight gain. Newly developed insulin analogues can lower the risk of hypoglycaemia compared with human insulin, but most have no advantage in terms of weight gain. The basal analogue insulin detemir, however, has been demonstrated to cause weight gain to a lesser extent than human insulin. The emerging treatments, such as glucagon-like peptide-1 agonists and the amylin analogue, pramlintide, seem able to decrease weight in patients with type 2 diabetes, whereas dipeptidyl peptidase-4 inhibitors seem to be weight neutral. In summary, while reduction of hyperglycaemia remains the foremost goal in the treatment of patients with type 2 diabetes, the avoidance of weight gain may be a clinically important secondary goal. This is already possible with careful selection of available therapies, while several emerging therapies promise to further extend the options available.

Pramlintide in the treatment of diabetes

Diabetes treatment has traditionally focused on correcting insulin deficiency with exogenous insulin and oral agents designed to enhance insulin secretion or insulin sensitivity in peripheral tissues. The more recent view of diabetes as a disease that affects multiple hormones in addition to insulin has led to the development of new therapies more broadly aimed at restoring glucose homeostasis by correcting abnormalities in additional glucoregulatory hormones. Pramlintide, a synthetic analogue of the beta-cell hormone amylin, regulates the appearance of glucose in the circulation following meals through several mechanisms of action: slowing gastric emptying, preventing inappropriate postprandial secretion of glucagon and increasing satiety. Long-term studies have demonstrated that pramlintide improves postprandial glucose fluctuations and A1C while reducing insulin dose and body weight. This combination of benefits associated with pramlintide makes it an attractive new treatment option for patients with diabetes. Clinical Trial Registry Numbers: 137-155 open-label clinical trial: NCT00108004 (Pramlintide long-term, placebo-controlled clinical trials were completed prior to the requirement for NCT registry).

Adjunctive Therapy with Pramlintide in Patients with Type 1 or Type 2 Diabetes Mellitus

Uncontrolled diabetes mellitus is associated with both microvascular and macrovascular complications. Despite an array of treatment options available, achievement of euglycemia in most patients with diabetes is still lacking. Pramlintide acetate, a synthetic analog of the human hormone amylin and belonging to a new class of agents, was approved in March 2005 as adjunctive treatment in patients with type 1 or 2 diabetes mellitus. To evaluate the data available on the efficacy and safety of pramlintide, we conducted a search of MEDLINE (January 1966-May 2006) and International Pharmaceutical Abstracts (January 1970-May 2006). Bibliographies of clinical trials were reviewed for additional references. The literature reviewed demonstrated that pramlintide is effective in reducing levels of glycosylated hemoglobin and potentially preventing weight gain. The most commonly reported adverse effects associated with pramlintide were nausea, anorexia, and hypoglycemia. These adverse effects occurred more often during the initiation of therapy and were usually mild to moderate in nature. Whether this therapy is a cost-effective option for patients with type 1 or type 2 diabetes mellitus is yet to be determined.

New therapies available for the treatment of type 2 diabetes

In type 2 diabetes multiple lesions have been identified; new drugs are being developed that target these lesions. This review considers the most recent pharmaceutical options to reduce hyperglycaemia. Two new classes of agents were introduced in the USA in 2005, both of which are administered by injection. The first agent, pramlintide, is a soluble analogue of the islet peptide amylin which is used as an adjunct to insulin therapy. Exenatide is an analogue of the incretin hormone GLP-1 and has similar actions to native GLP-1. Both agents reduce hyperglycaemia without causing weight gain and can aid weight loss. A cannabinoid receptor antagonist (rimonabant) which aids weight loss and improves glycaemic control in type 2 diabetes has recently received marketing approval as an antiobesity agent in Europe. The gliptins and glitazars are at advanced stages of development and fixed-dose combination ‘2.4.1’ tablets containing established agents are being introduced.

Mechanisms by which the amylin analog pramlintide reduces postprandial glucose (PPG) excursions in humans: Important role for splanchnic glucose sequestration

Mechanisms by which the amylin analog pramlintide reduces postprandial glucose (PPG) excursions in humans: Important role for splanchnic glucose sequestration

Update in the Pharmacologic Treatment of Diabetes Mellitus

There are now more than 20 million people in America with diabetes mellitus (DM), and the prevalence of this illness continues to increase especially in those with type 2 DM. Over the past decade, research in the area of DM treatment has focused on pharmacologic approaches to modifying glucose metabolism as well as on lifestyle interventions to prevent and manage DM. Pharmacologic research has been guided by an improved understanding of the human physiology of glucose metabolism, allowing for development of new hormonal drug therapies and improved insulin formulations. As a result, there are several new pharmacologic treatments now available or on the horizon for DM. In this article, the authors review the first of the new hormonal therapies for DM, with a focus on information that will be useful for diabetes educators including the medication actions, side effects, patient counseling points, monitoring, and place in therapy in comparison to existing DM treatments. This series on new therapies has been divided into 3 parts, with this first part devoted to an update on the new incretin mimetic and amylin analog agents recently approved for use in DM. Subsequent parts in this series will focus on the new insulin products and oral therapies available or soon to be available. Cases will be used to assist with understanding the type of patient who will benefit from each of these new therapies.

Pramlintide: A new tool in diabetes management

The amylin analogue pramlintide acts in concert with insulin to regulate glucose metabolism. It reduces postprandial hyperglycemia by suppressing postprandial glucagon secretion, regulating gastric emptying, and reducing food intake. In clinical use, pramlintide reduces postprandial glycemic excursions and improves A(1c) without the weight gain and increased risk of hypoglycemia typically seen with intensification of diabetes therapy.

Pramlintide in the management of insulin-using patients with type 2 and type 1 diabetes

In patients with diabetes, dysregulation of multiple glucoregulatory hormones results in chronic hyperglycemia and an array of associated microvascular and macrovascular complications. Optimization of glycemic control, both overall (glycosylated hemoglobin [A1C]) and in the postprandial period, may reduce the risk of long-term vascular complications. However, despite significant recent therapeutic advances, most patients with diabetes are unable to attain and/or maintain normal or near-normal glycemia with insulin therapy alone. Pramlintide, an analog of amylin, is the first in a new class of pharmaceutical agents and is indicated as an adjunct to mealtime insulin for the treatment of patients with type 1 and type 2 diabetes. By mimicking the actions of the naturally occurring hormone amylin, pramlintide complements insulin by regulating the appearance of glucose into the circulation after meals via three primary mechanisms of action: slowing gastric emptying, suppressing inappropriate post-meal glucagon secretion, and increasing satiety. In long-term clinical trials, adjunctive pramlintide treatment resulted in improved postprandial glucose control and significantly reduced A1C and body weight compared with insulin alone. The combination of insulin and pramlintide may provide a more physiologically balanced approach to managing diabetes.

‘Gastric’ hypoglycaemia – an important concept in diabetes management

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) and UK Prospective Diabetes Studies (UKPDS) have established that both the development and progression of the microvascular (i.e. neuropathy, nephropathy and retinopathy), and probably macrovascular (i.e. cardiovascular disease), complications of type 1 (insulin-dependent) and type 2 (non-insulin dependent) diabetes mellitus are related to average glycaemic control, as assessed by measurement of glycated haemoglobin. This evidence provides a persuasive rationale for the widespread use of intensive therapy for diabetes directed at the normalization of glycaemia. For example, in the recently reported DCCT/EDIC study which involved type 1 patients, a period of intensive , as opposed to conventional , therapy for a mean period of 6.5 years during the DCCT study (i.e. between 1983 and 1993) was associated with a reduction in the risk of a subsequent (i.e. between 1994 and 2005) cardiovascular event of 42%. Hence, a major goal in treating diabetes is to achieve blood glucose levels as close as possible to the normal, fasting, range. This is compatible with the American Diabetes Association recommendation of a target glycated haemoglobin of <7.0%, which may in fact be conservative given that a specific healthy glycaemic threshold has hitherto not been demonstrated. To achieve current targets, the majority of type 2 patients will require treatment with insulin within 10 years of the diagnosis of diabetes. In practice, however, glycaemic targets are not often met in either type 1 or type 2 patients. There is a natural reluctance to initiate insulin therapy in type 2 patients because of the potentially deleterious consequences of insulininduced hypoglycaemia, especially in those patients whose ability to recognize impending hypoglycaemia is impaired. In the DCCT study, the reduction in microvascular complications seen in the intensive care group was accompanied by a threefold increase in the rate of severe hypoglycaemia. Effective management of recurrent hypoglycaemia is, of course, dependent on the correction of the underlying cause(s), which include excessive insulin dosage, inadequate carbohydrate intake, psychiatric disorders, various endocrinopathies, coeliac disease and vomiting (whether self-induced or associated with gastroparesis). However, in a substantial minority of patients a cause is not clearly identifiable. The interesting study by Lysy et al. reported in this issue of the Journal indicates that delayed gastric emptying represents a significant risk factor for hypoglycaemia in insulin-treated type 1 and type 2 diabetes. The authors evaluated gastric emptying in 31 insulin-treated patients who had recurrent episodes of hypoglycaemia early in the postprandial period. Gastric emptying of a scrambled egg meal was significantly slower when compared to a control group of patients with diabetes who did not have recurrent hypoglycaemia; in about 30% of patients, the magnitude of the delay in emptying was marked, even though none of them reported upper gastrointestinal symptoms such as nausea or bloating. Strengths of the study include the relatively large number of patients and the prospective design, although demographic differences (e.g. in age Address for correspondence Prof Michael Horowitz, Discipline of Medicine, University of Adelaide, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000, Australia. Tel: 61 8 8222 4327; fax: 61 8 8223 3870; e-mail: michael.horowitz@adelaide.edu.au Received: 11 April 2006 Accepted for publication: 11 April 2006 Neurogastroenterol Motil (2006) 18, 405–407 doi: 10.1111/j.1365-2982.2006.00804.x

The Physiology of Amylin and Insulin: Maintaining the Balance Between Glucose Secretion and Glucose Uptake

Glucose homeostasis is accomplished through intricate, and arguably, elegant interactions among several organs and hormones. Historically, glucose homeostasis has been viewed somewhat narrowly--insulin from pancreatic beta cells regulated glucose disposal, while glucagon from pancreatic alpha [corrected] cells regulated glucose appearance during fasting states. But more recent characterization and understanding of the role of incretin hormones from the gut--notably, glucagon-like peptide 1 and gastric inhibitory polypeptide--and amylin from pancreatic beta cells has led to a more complete model of glucose homeostasis. Furthermore, availability of pharmacologic agents to replace, mimic, or enhance the actions of these hormones allows application of this more complete model of glucose homeostasis to the treatment of type 1 and type 2 diabetes. This article provides an overview of the role of the pancreatic hormone amylin in glucose homeostasis and of Pramlintide, a analogue of native amylin, recently approved as adjunct therapy to insulin in people with type 1 and type 2 diabetes.

The Physiology of Amylin and Insulin

Glucose homeostasis is accomplished through intricate, and arguably, elegant interactions among several organs and hormones. Historically, glucose homeostasis has been viewed somewhat narrowly-insulin from pancreatic β cells regulated glucose disposal, while glucagon from pancreatic β cells regulated glucose appearance during fasting states. But more recent characterization and understanding of the role of incretin hormones from the gut-notably, glucagon-like peptide 1 and gastric inhibitory polypeptide-and amylin from pancreatic β cells has led to a more complete model of glucose homeostasis. Furthermore, availability of pharmacologic agents to replace, mimic, or enhance the actions of these hormones allows application of this more complete model of glucose homeostasis to the treatment of type 1 and type 2 diabetes. This article provides an overview of the role of the pancreatic hormone amylin in glucose homeostasis and of Pramlintide, a analogue of native amylin, recently approved as adjunct therapy to insulin in people with type 1 and type 2 diabetes.

Use of Pramlintide: The Patient's Perspective

Pramlintide is the first new antihyperglycemic agent approved for both type 2 and type 1 diabetes since insulin was developed in the 1920s. It is a synthetic analogue of human amylin, a naturally occurring neuroendocrine hormone synthesized by pancreatic beta cells. Pramlintide helps regulate the rate of glucose appearance and improves glucose control postprandially. This action is accomplished through suppressing inappropriate postprandial glucagon secretion and regulating gastric emptying, and is associated with a feeling of satiety. It is given at mealtimes and is indicated for use in type 2 and type 1 diabetes as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy. Pramlintide therapy should only be considered for patients who are receiving ongoing care under the guidance of a health care professional skilled in the use of insulin and supported by services of diabetes educators. Pramlintide is used with insulin and has been associated with an increased risk of insulin-induced severe hypoglycemia, particularly in type 1 diabetes. Appropriate patient selection, careful patient instruction, and insulin dose adjustments help reduce this risk. In type 2 diabetes, pramlintide is initiated at 60 microg and may be increased to 120 microg two to three times daily with meals. In type 1 diabetes, pramlintide is initiated at 15 microg and may be increased to 30 or 60 microg with meals. Mealtime insulin should be reduced by 50% at pramlintide initiation and adjusted as the pramlintide dose is increased. It should be given subcutaneously with an insulin syringe and should not be mixed with insulin. The most commonly reported side effect is mild to moderate nausea with initiation, which is usually transient and short term in nature. Frequent self-monitoring of blood glucose is important during initiation to assist in insulin adjustments. Insulin type, dose, and timing as well as basal/bolus balance may require adjustment during pramlintide initiation. Despite requiring additional injections, patients report satisfaction with pramlintide therapy.

Use of Pramlintide

Pramlintide is the first new antihyperglycemic agent approved for both type 2 and type 1 diabetes since insulin was developed in the 1920s. It is a synthetic analogue of human amylin, a naturally occurring neuroendocrine hormone synthesized by pancreatic β cells. Pramlintide helps regulate the rate of glucose appearance and improves glucose control postprandially. This action is accomplished through suppressing inappropriate postprandial glucagon secretion and regulating gastric emptying, and is associated with a feeling of satiety. It is given at mealtimes and is indicated for use in type 2 and type 1 diabetes as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy. Pramlintide therapy should only be considered for patients who are receiving ongoing care under the guidance of a health care professional skilled in the use of insulin and supported by services of diabetes educators. Pramlintide is used with insulin and has been associated with an increased risk of insulin-induced severe hypoglycemia, particularly in type 1 diabetes. Appropriate patient selection, careful patient instruction, and insulin dose adjustments help reduce this risk. In type 2 diabetes, pramlintide is initiated at 60 μg and may be increased to 120 μg two to three times daily with meals. In type 1 diabetes, pramlintide is initiated at 15 μg and may be increased to 30 or 60 μg with meals. Mealtime insulin should be reduced by 50% at pramlintide initiation and adjusted as the pramlintide dose is increased. It should be given subcutaneously with an insulin syringe and should not be mixed with insulin. The most commonly reported side effect is mild to moderate nausea with initiation, which is usually transient and short term in nature. Frequent self-monitoring of blood glucose is important during initiation to assist in insulin adjustments. Insulin type, dose, and timing as well as basal/bolus balance may require adjustment during pramlintide initiation. Despite requiring additional injections, patients report satisfaction with pramlintide therapy

Amylin Replacement Therapy in Patients With Type 1 Diabetes

Amylin is a pancreatic β-cell hormone that is cosecreted with insulin and plays an important physiologic role in glucose homeostasis. Pramlintide is an analogue of amylin recently approved by the Food and Drug Administration and represents the first new treatment for people with type 1 diabetes since the discovery of insulin more than 80 years ago. Pramlintide has been shown to reduce the day-to-day fluctuations in glucose values that are commonly seen despite maximized insulin therapy alone. Additional proven clinical benefits include flattening of the postprandial glucose values, reducing the A1C, and concomitant weight loss. This combination of benefits makes pramlintide an important therapeutic tool for improving the metabolic control and quality of life of people with type 1 diabetes.

Amylin Replacement Therapy in Patients With Type 1 Diabetes

Amylin is a pancreatic beta-cell hormone that is cosecreted with insulin and plays an important physiologic role in glucose homeostasis. Pramlintide is an analogue of amylin recently approved by the Food and Drug Administration and represents the first new treatment for people with type 1 diabetes since the discovery of insulin more than 80 years ago. Pramlintide has been shown to reduce the day-to-day fluctuations in glucose values that are commonly seen despite maximized insulin therapy alone. Additional proven clinical benefits include flattening of the postprandial glucose values, reducing the A1C, and concomitant weight loss. This combination of benefits makes pramlintide an important therapeutic tool for improving the metabolic control and quality of life of people with type 1 diabetes.

Amylin Replacement Therapy in Patients With Insulin-Requiring Type 2 Diabetes

Normally, the release of glucagon is halted at the beginning of a meal by a direct mechanism: insulin secretion from the β cells within the pancreas inhibits the release of glucagon from the β cells. An “indirect” mechanismamylin (a neuroendocrine hormone also secreted from the β cells)-suppresses the release of glucagon through the central nervous system. In type 2 diabetes, the first phase insulin release is absent, and as amylin is released in direct proportion to insulin, both mechanisms to suppress glucagon are absent. The result is that glucagon secretion and, ultimately, the stimulation of hepatic glucose release continue, resulting in extreme postprandial hyper-glycemia. It has been shown that amylin supplementation with injections of the human amylin analogue pramlintide, in patients with insulin-requiring type 2 diabetes, helps limit postprandial hyperglycemia. Amylin supplementation not only suppresses glucagon secretion but also slows the absorption of glucose in the intestines and limits nutrient intake by providing a feeling of satiety, resulting in a moderate reduction in body weight for many patients. Recently approved by the FDA, pramlintide is now available for clinical use. However, it is important that pramlintide be prescribed only for selected patients and that these patients are thoroughly educated in the use of this agent, especially during initiation of treatment. Patients suited to pramlintide use are those who have not achieved adequate glycemic control despite optimal insulin use, are under the care of a professional health care provider skilled in the use of insulin and a diabetes educator, and are well-disciplined in diabetes self-management.

Amylin Replacement Therapy in Patients With Insulin-Requiring Type 2 Diabetes

Normally, the release of glucagon is halted at the beginning of a meal by a direct mechanism: insulin secretion from the beta cells within the pancreas inhibits the release of glucagon from the beta cells. An "indirect" mechanism--amylin (a neuroendocrine hormone also secreted from the beta cells)--suppresses the release of glucagon through the central nervous system. In type 2 diabetes, the first phase insulin release is absent, and as amylin is released in direct proportion to insulin, both mechanisms to suppress glucagon are absent. The result is that glucagon secretion and, ultimately, the stimulation of hepatic glucose release continue, resulting in extreme postprandial hyperglycemia. It has been shown that amylin supplementation with injections of the human amylin analogue pramlintide, in patients with insulin-requiring type 2 diabetes, helps limit postprandial hyperglycemia. Amylin supplementation not only suppresses glucagon secretion but also slows the absorption of glucose in the intestines and limits nutrient intake by providing a feeling of satiety, resulting in a moderate reduction in body weight for many patients. Recently approved by the FDA, pramlintide is now available for clinical use. However, it is important that pramlintide be prescribed only for selected patients and that these patients are thoroughly educated in the use of this agent, especially during initiation of treatment. Patients suited to pramlintide use are those who have not achieved adequate glycemic control despite optimal insulin use, are under the care of a professional health care provider skilled in the use of insulin and a diabetes educator, and are well-disciplined in diabetes self-management.

New and Emerging Strategies for Reducing Cardiometabolic Risk Factors

Several new drug therapies with beneficial effects on more than one of the cardiometabolic risk factors that contribute to the metabolic syndrome have been developed recently or are under investigation. Emerging risk factors for coronary heart disease (CHD), including low concentrations of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-1 (apoA-1), high levels of high-sensitivity C-reactive protein, and small dense low-density lipoprotein cholesterol particles, have been identified. We provide a detailed description of the mechanisms of action and findings from clinical trials of the new drug therapies and discuss established drug therapies with beneficial effects on emerging risk factors for CHD. The new and emerging drug therapies include an antiobesity agent that reduces atherogenic dyslipidemia and abnormal glucose metabolism; cholesteryl ester transfer protein inhibitors that increase HDL cholesterol and apoA-1 levels; glitazars that increase HDL cholesterol and decrease triglyceride concentrations, as well as improve abnormal glucose metabolism; and the amylin analog pramlintide and the incretin mimetic exenatide, both of which reduce body weight as well as improve abnormal glucose metabolism. The insulin-sensitizing effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs), which may help prevent new-onset diabetes mellitus, and the beneficial effects of the ARB telmisartan on the glucose and lipid profiles also are presented.