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Type 2 diabetes mellitus and comorbidities related to overweight/obesity are risk factors for the development of cardiovascular disease (CVD). In addition to insulin resistance and progressive beta-cell failure as key factors in the pathogenesis of type 2 diabetes mellitus, defects in the incretin system are now known to contribute as well. Lifestyle modifications including diet and exercise are often insufficient for reducing glucose and weight, and most patients with type 2 diabetes will require pharmacotherapy to treat their hyperglycemia. Goals of therapy should be to reduce blood glucose to as low as possible, for as long as possible, without weight gain and hypoglycemia, and correcting cardiovascular risk factors. Numerous antidiabetes medications lower blood glucose; however, many are associated with weight gain and do not address risk factors present for CVD. Newer pharmacotherapies include the glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and amylinomimetics. The GLP-1 receptor agonists and amylinomimetics reduce glucose while promoting weight loss and improving other cardiovascular risk factors with a low incidence of hypoglycemia. The DPP-4 inhibitors effectively lower glucose and are weight neutral.
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PMID:Therapeutic options that provide glycemic control and weight loss for patients with type 2 diabetes. 2010 1

Type 2 diabetes (T2DM) is a heterogeneous syndrome, characterized by beta-cell failure in the setting of obesity-related insulin resistance. T2DM has a progressive course and is associated with a high cardiovascular disease (CVD) risk, regardless of the treatment used. The incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are secreted in the gut upon meal ingestion and lower blood glucose by glucose-dependent stimulation of insulin secretion and production. Exogenously administered GLP-1 lowers postprandial glucose excursions by inhibiting glucagon secretion and delaying gastric emptying, improves beta-cell function, and promotes satiety and weight loss. Native GLP-1 is degraded rapidly by the ubiquitous enzyme dipeptidyl-peptidase (DPP)-4. Thus, injectable DPP-4-resistant GLP-1 receptor agonists (GLP-1RA) and oral DPP-4 inhibitors have been developed. Exenatide is the first GLP-1RA that became available for the treatment of T2DM patients. Exenatide has unique characteristics, as to date it is the only agent that addresses the multiple defects of the T2DM phenotype, including hyperglycaemia, islet-cell dysfunction, alimentary obesity, insulin resistance, hypertension and dyslipidaemia. In animals, exenatide also increased beta-cell mass. Long-term prospective studies in high-risk populations should address the potentially disease modifying effect of exenatide and its effect on CVD risk, in addition to its safety and tolerability.
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PMID:Does glucagon-like peptide-1 receptor agonist therapy add value in the treatment of type 2 diabetes? Focus on exenatide. 2011 29

Dipeptidyl-peptidase (DPP)-4, which catalizes the degradation of the insulinotropic incretin glucagon-like-peptide (GLP)-1, and the DPP-4 like enzyme attractin are involved in activation of T-lymphocytes and monocytes. Recently, it has been demonstrated, that the risk for certain infections is increased in type 2 diabetic patients under DPP-4 inhibitor treatment. The aim of the present study was to examine the expression of DPP-4 and attractin in circulating blood monocytes of obese and type 2 diabetic subjects. Monocytes were isolated by CD14-antibody based magnetic cell sorting from blood samples of 17 lean controls, 20 obese, non-diabetic subjects and 19 obese patients with type 2 diabetes. FACS analysis was performed to test purity of the cell preparations. Expression was measured by multiplex RT-PCR on RNA-level. DPP-4 and attractin were detectable in human circulating monocytes with attractin being expressed at higher levels compared to DPP-4. Both enzymes were significantly higher expressed in circulating blood monocytes of obese subjects compared to lean controls. In contrast, type 2 diabetes did not significantly affect expression levels. Finally, neither DPP-4 nor attractin expression was altered by sitagliptin or insulin treatment. In conclusion, our data demonstrate, that expressions of DPP-4 and attractin in circulating blood monocytes of human subjects are influenced by metabolic abnormalities with obesity being an important factor.
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PMID:Dipeptidyl-peptidase 4 and attractin expression is increased in circulating blood monocytes of obese human subjects. 2019 59

1. Dipeptidyl peptidase (DPP) IV inhibitors enhance renovascular responses to angiotensin (Ang) II in spontaneously hypertensive rats (SHR), but not Wistar-Kyoto rats. Because DPPIV inhibitors are often used in metabolic syndrome, it is important to determine whether DPPIV inhibition in this setting enhances renovascular responses to AngII. 2. Six-week-old Lean-ZSF1 rats (harbouring SHR genes, but without metabolic syndrome; n = 11) and Obese-ZSF1 rats (harbouring SHR genes and expressing metabolic syndrome; n = 10) were provided food and water ad libitum, and metabolic parameters and renovascular responses to AngII were assessed when the animals were 7 and 8 weeks of age, respectively. 3. At 7 weeks of age, compared with Lean-ZSF1, Obese-ZSF1 demonstrated significant (P < 0.05) increases in bodyweight (262 +/- 8 vs 310 +/- 13 g), plasma glucose (112 +/- 4 vs 153 +/- 9 mg/dL), haemoglobin A1c (4.7 +/- 0.1 vs 5.8 +/- 0.4%), urinary glucose excretion (0.021 +/- 0.003 vs 6.70 +/- 1.80 g/kg bodyweight per 24 h) and urinary protein excretion (100 +/- 7 vs 313 +/- 77 mg/kg bodyweight per 24 h). Mean blood pressure was high (133 +/- 7 mmHg) in both strains. 4. At 8 weeks of age, kidneys were isolated and perfused. In Lean-ZSF1 rats, renovascular responses (i.e. changes in perfusion pressure) to physiological levels of AngII (0.1 nmol/L) were 3.4 +/- 1.3 and 18.2 +/- 5.9 mmHg in untreated (n = 5) and 1 micromol/L sitagliptin-treated (n = 6) kidneys, respectively. In Obese-ZSF1 rats, renovascular responses to AngII were 5.5 +/- 1.3 and 17.8 +/- 8.2 mmHg in untreated (n = 4) and sitagliptin-treated (n = 6) kidneys, respectively. Analysis of variance revealed a significant (P = 0.0367) effect of sitagliptin on renovascular responses to AngII that was independent of strain. 5. In conclusion, sitagliptin enhances renovascular responses to AngII in rats harbouring SHR genes and this effect persists in rats with diabetic nephropathy and metabolic syndrome.
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PMID:Sitagliptin augments angiotensin II-induced renal vasoconstriction in kidneys from rats with metabolic syndrome. 2037 54

Obesity is a major risk factor for the development of diabetes and predisposes individuals to hypertension and dyslipidaemia. Together these pathologies increase the risk for cardiovascular disease (CVD), the major cause of morbidity and mortality in type 2 diabetes mellitus (T2DM). Worsening trends in obesity and T2DM raise a serious conundrum, namely, how to control blood glucose, blood pressure, and lipids when many antidiabetic agents cause weight gain and thereby exacerbate other cardiovascular risk factors associated with T2DM. Further, evidence suggests that some established antihypertensive agents may worsen glucose intolerance. Many patients who are obese, hypertensive, and/or hyperlipidaemic fail to achieve blood pressure, lipid and glycaemic goals, and this failure may in part be explained by physician reluctance to utilize complex combination regimens for fear of off-target effects. Thus, a clear need exists for clinicians to understand the risks and benefits of different pharmacologic, and indeed non-pharmacologic, options in order to maximize treatment outcomes. While intensive lifestyle modification remains an elusive gold standard, newer diabetes targets, including the incretin axis, may offer greater cardiovascular risk reduction than other antidiabetes therapies, although definitive clinical trial data are needed. The glucagon-like peptide-1 (GLP-1) receptor agonists exenatide and liraglutide and the dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin and vildagliptin effectively lower HbA1c; exenatide and liraglutide reduce weight and blood pressure and improve lipid profiles. Sitagliptin and vildagliptin are weight neutral but also appear to improve lipid profiles. Integration of incretin therapies into the therapeutic armamentarium is a promising approach to improving outcomes in T2DM, and perhaps even in reducing complications of T2DM, such as co-morbid hypertension and dyslipidaemia. Additional long-term studies, including CVD end-point studies, will be necessary to determine the appropriate places for incretin-based therapies in treatment algorithms.
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PMID:Diabetes and obesity: therapeutic targeting and risk reduction - a complex interplay. 2038 Jun 48

Management of severe insulin resistance (IR) is a major clinical challenge in many patients with obesity or lipodystrophy, and also in rarer patients with proven or suspected genetic defects in the insulin receptor or downstream signalling. The latter group can present at any time between birth and early adult life, with a variable clinical course broadly correlated with the severity of IR. Primary insulin signalling defects are usually associated with poor weight gain rather than obesity. Initially, extreme hyperinsulinaemia produces ovarian enlargement and hyperandrogenism in women, and often fasting or postprandial hypoglycaemia. However, any hypoglycaemia gradually evolves into insulin-resistant hyperglycaemia when beta cell function declines. Optimal management of these complex disorders depends on early diagnosis and appropriate targeting of both high and low glucose levels. In newborns, continuous nasogastric feeding may reduce harmful glycaemic fluctuations, and in older patients, acarbose may mitigate postprandial hypoglycaemia. Insulin sensitization, initially with metformin but later with trials of additional agents such as thiazolidinediones, is the mainstay of early therapy, but insulin replacement, eventually with very high doses, is required once diabetes has supervened. Preliminary data suggest that rhIGF-1 can improve survival in infants with the most severe insulin receptor defects and also improve beta cell function in older patients with milder receptoropathies. The utility of newer therapies such as glucagon-like peptide-1 agonists and dipeptidyl peptidase-IV inhibitors remains untested in this condition. Thus, management of these patients remains largely empirical, and there is a pressing need to collate data centrally to optimize treatment algorithms.
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PMID:What is the best management strategy for patients with severe insulin resistance? 2045 92

The management of type 2 diabetes is designed to reduce disease-related complications and improve long-term outcomes. Achieving glycemic control is a critical component of this process. The selection of drug therapy for reducing blood glucose is made more challenging when patients already have complications or comorbid conditions (eg, high risk for hypoglycemia, obesity, renal impairment). Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antihyperglycemic drugs that block degradation of incretin hormones. By enhancing and prolonging incretin effects, DPP-4 inhibitors stimulate glucose-dependent insulin secretion and also reduce glucagon secretion. This results in improved glycemic control, as reflected by decreases in glycated hemoglobin (HbA1c), fasting plasma glucose, and postprandial plasma glucose. Dipeptidyl peptidase-4 inhibitors also have the potential to improve beta-cell function. In randomized clinical trials, the DPP-4 inhibitors saxagliptin and sitagliptin reduced HbA1c by 0.5% to 0.8%, compared with placebo, whether used as monotherapy or in combination with another agent. As initial combination therapy with metformin, saxagliptin and sitagliptin have demonstrated reductions in HbA1c of 2.5% and 1.9%, respectively. The efficacy of the DPP-4 inhibitors was maintained during treatment for up to 2 years, and did not differ in the elderly compared with younger adults. Dipeptidyl peptidase-4 inhibitors offer efficacy similar to other drug classes, and are well tolerated with a lower risk of hypoglycemia, weight-neutral effects, and a low propensity for drug-drug interactions. On the basis of their clinical profiles, the DPP-4 inhibitors are emerging as an attractive option for improving glycemic control in patients with type 2 diabetes. Saxagliptin and sitagliptin are approved for use as initial therapy in combination with metformin, as monotherapy, as well as in combination with metformin, a sulfonylurea, or a thiazolidinedione in patients not adequately controlled by these agents alone.
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PMID:Type 2 diabetes comorbidities and treatment challenges: rationale for DPP-4 inhibitors. 2046 16

Most patients with type 2 diabetes present with comorbid overweight or obesity. Reaching and maintaining acceptable glycemic control is more difficult in overweight and obese patients, and these conditions are associated with increased risk for cardiovascular and other diseases. Glycemic management for these patients is complicated by the fact that insulin and many of the oral medications available to treat type 2 diabetes produce additional weight gain. However, an increasing number of therapeutic options are available that are weight neutral or lead to weight loss in addition to their glycemic benefits. This article evaluates the evidence from clinical trials regarding the relative glycemic benefits, measured in terms of glycated hemoglobin change, versus the impact on body weight of each medication currently approved for type 2 diabetes. In general, the sulfonylureas, thiazolidinediones, and D-phenylalanine derivatives have been shown to promote weight gain. The dipeptidyl peptidase-4 inhibitors are weight neutral, while the biguanides, incretin mimetics, and amylin mimetics promote weight loss. Trials examining the glycemic benefits of the weight loss agents orlistat and sibutramine are also examined. Awareness of this evidence base can be used to inform medication selection in support of weight management goals for patients with type 2 diabetes.
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PMID:Managing type 2 diabetes: balancing HbA1c and body weight. 2046 20

Successful management of type 2 diabetes mellitus (T2DM) requires attention to additional conditions often associated with hyperglycemia including overweight or obesity, dyslipidemia and hypertension, as each has some relationship with microvascular or macrovascular complications. Because control of cardiovascular risk factors is as important as glucose control in T2DM, these risk factors need to be addressed, and it is critical that antidiabetes medications do not exacerbate these risk factors. A patient-centered approach to treatment in which clinicians maximize patient involvement in the selection of antidiabetes therapy may lead to increased adherence and improved clinical outcomes. The incretin hormones, which include glucagon-like peptide-1 (GLP-1), are involved in glucoregulation and have become an important focus of T2DM research and treatment. Incretin-based therapies, such as the glucagon-like peptide-1 receptor agonists and the dipeptidyl peptidase-IV inhibitors, have shown beneficial effects on hyperglycemia, weight, blood pressure and lipids with a low incidence of hypoglycemia.
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PMID:Managing type 2 diabetes in the primary care setting: beyond glucocentricity. 2057 52

Glucagon-like peptide-1 (GLP-1) receptor is an ideal target in the development of incretin-based therapies for diabetes and obesity. Two approaches have been adopted: GLP-1 receptor agonists that mimic the effects of native GLP-1 and dipeptidyl peptidase-4 inhibitors that increase endogenous GLP-1 levels. During the past two decades, search for orally active, non-peptidic GLP-1 receptor agonists has been the focal point of research and development activities in many multinational pharmaceutical companies. Such efforts have not resulted in any success thus far. Serendipitous discovery of substituted cyclobutanes represented by Boc5 as a new class of GLP-1 receptor agonists led us to believe that a small molecule approach to class B G-protein coupled receptor agonism is no longer a fantasy but a reality. However, major obstacles still pose great challenges, and the reasons of which are discussed in this perspectives.
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PMID:Non-peptidic glucose-like peptide-1 receptor agonists: aftermath of a serendipitous discovery. 2067 18


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