Taking into consideration the intimate interrelationship between diabetes and heart disease, the American Heart Association has coined in 1999 the phrase 'diabetes is a cardiovascular disease' . Diabetic patients with CAD connote an enormous population which deserve a specific approach. Incretins, DPP-4 inhibitors, glitazars and the amylin mimetic drugs represent novel pharmacological approaches.
The progressive impairment of beta cell function and increased insulin demand as tissue becomes insulin resistant are core pathophysiologic defects in the development of hyperglycemia in T2DM [59, 60]. Anyway, the process is a complex one and other important factors are also involved, further exacerbating the clinical setting. Excess glucagon secretion, abnormally accelerated gastric emptying during hyperglycemia, obesity, and increased food intake all contribute to hyperglycemia. Impaired release or action of incretin hormones, particularly GLP-1, and to a lesser degree glucose-dependent insulinotropic polypeptide (GIP), also play a role in the development and/or progression of T2DM. More recently, the essentially glucocentric view of the genesis and progression of T2DM has been supplemented by a more lipocentric perspective. Here the major mechanism is progressive ectopic lipid deposition (e.g., in myocytes and hepatocytes, rather than in adipocytes). Build-up of ectopic fat in those tissues ultimately induces insulin resistance, cell lipotoxicity, and diminished cell function, leading to metabolically inadequate insulin secretion .
Thus, incretin mimetic drugs are nowadays extensively investigated. A key role for intestinal peptides in the regulation of postprandial insulin secretion and glucose levels was proposed, based on the observation that insulin responses to an oral glucose load exceeded those measured after intravenous administration of an equivalent amount of glucose . This phenomenon, termed the "incretin effect," postulated the existence of gut-derived signals promoting insulin secretion in response to nutrient intake . Subsequently, the incretin hormones GIP and GLP-1, were discovered . These two principal incretin hormones are small peptides – 42 and 30 amino acids, respectively, that rapidly stimulate the release of insulin only when blood glucose levels are elevated, thereby enhancing the glucose-sensing and insulin secretory capacity of the endocrine pancreas during postprandial hyperglycemia .
Physiological actions of incretins were extensively defined in animal studies with exogenous GLP-1 and GLP-1 receptor antagonists, highlighting its role as a meal-stimulated factor with potent glucose-lowering activity. Of significant clinical relevance is that exogenous GLP-1 has the potential to normalize fasting plasma glucose concentrations in patients with T2DM. In several studies in subjects with diabetes, GLP-1- whether administered by intravenous or subcutaneous infusion – normalized both fasting and postprandial glycemia by enhancing glucose-mediated insulin secretion, as well as by suppressing glucagon secretion [66–69].
Additional studies in animals and humans have demonstrated glucose-lowering effects of GLP-1. GLP-1 slows gastric emptying to decrease the rate of nutrient absorption, which results in more synchronous nutrient delivery with endogenous insulin action. Significant acute reductions in appetite and food intake after intravenous administration of GLP-1 in both healthy individuals and in patients with T2DM have also been demonstrated [70–72].
The mechanism through which the incretin hormones elicit their cytoprotective effects on the beta cell has attracted significant attention because preservation and restoration of beta-cell mass may contribute to the therapeutic potential of the incretins for the treatment of both type 1 and T2DM. Endoplasmic reticulum stress within the beta cell, possibly occurring as the result of the overproduction or misfolding of insulin, may be a contributing factor to the increased beta-cell apoptosis and loss of islet mass observed in diabetic patients .
Exenatide was first in the new class of incretin mimetics for the treatment of patients with T2DM. Several short-term phase 2 clinical trials have reported that subcutaneos exenatide acutely lowered both fasting and postprandial plasma glucose concentrations. The rate of gastric emptying was also slowed in patients treated with exenatide. Large-scale clinical trials designed to assess the safety and efficacy of twice daily subcutaneos exenatide over a six-month period were completed in subjects with T2DM who were unable to attain glycemic control with oral sulfonylureas, metformin, or both . A novel formulation of exenatide consisting of biodegradable polymeric microspheres that entrap exenatide and provide extended release enabling once-weekly administration was recently developed . It resulted in significantly greater improvements in glycemic control than exenatide given twice a day, with no increased risk of hypoglycemia and similar reductions in bodyweight .
Another incretin mimetic compound, liraglutide, is a once-daily GLP-1 derivative in development for the treatment of T2DM. GLP-1, in its natural form, is short-lived in the body (the half-life after subcutaneous injection is approximately 1 hour), so it is not very useful per se as a therapeutic agent. However, prolonged activity is achieved by chemical manipulation, reaching to 11–15 hours and making it suitable for once-daily dosing. This is attained by attaching a fatty acid molecule at one position of the GLP-1 molecule, enabling it to bind to albumin within the subcutaneous tissue and bloodstream. The active GLP-1 is then released from albumin at a slow, consistent rate. Binding with albumin also results in slower degradation and reduced elimination of liraglutide from the circulation by the kidneys compared to its natural form [77, 78]. A recent report demonstrated that liraglutide once a day provided significantly greater improvements in glycemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for T2DM, especially when weight loss and risk of hypoglycemia are major considerations .
Additional long-acting incretin mimetic drugs, like albiglutide and taspoglutide are currently under investigation, presenting encouraging results [80, 81].
Dipeptidyl peptidase-4 inhibitors
While discovered in 1967, serine protease DPP-4 was only subject of intensive research during recent years. DPP-IV is ubiquitously expressed and exhibits postproline or alanine peptidase activity, thereby generating biologically inactive peptides via cleavage at the N-terminal region after X-proline or X-alanine. It is a complex molecule that exists as a membrane-spanning cell-anchored protein that is expressed on many cell types, and as a soluble form in the circulation; both forms have proteolytic activity.
Because both GLP-1 and GIP have an alanine residue at position 2, they are substrates for DPP-4. DPP-4 inhibitors like sitagliptin are orally administered drugs that improve glycemic control by preventing the rapid degradation of incretin hormones, thereby resulting in postprandial increases in levels of biologically active intact GLP-1 and GIP [82, 83].
Sitagliptin is an orally-bioavailable selective DPP-4 inhibitor – the first one approved by the FDA – that was discovered through the optimization of a class of beta-aminoacid-derived DPP-4 inhibitors. It lowers DPP-4 activity in a sustained manner following once daily administration, preserves the circulating levels of intact GIP and GLP1 following meals in both acute and chronic studies and reduces blood glucose levels without significant increases in hypoglycemia . Thus, the drug works by inhibiting the inactivation of the incretin GLP-1 and GIP by DPP-4. By preventing GLP-1 and GIP inactivation, GLP-1 and GIP are able to potentiate the secretion of insulin and suppress the release of glucagon by the pancreas. As the blood glucose level approaches normal, the amounts of insulin released and glucagon suppressed diminishes thus tending to prevent an overshoot and subsequent hypoglycemia which is seen with some other oral hypoglycemic agents.
Several additional DPP4 inhibitors, like saxagliptin, vildagliptin and alogliptin are currently investigated. Vildagliptin is the second DPP-4 inhibitor approved in Europe. Similarly to sitagliptin, vildagliptin has pharmacokinetic properties that support a once daily dosing regimen. Alogliptin in combination with pioglitazone, in an experimental model, improves glycemic control, lipid profiles, and increases pancreatic insulin content . Whereas hepatic insufficiency does not seem to alter pharmacokinetics of these compounds, dose adjustments are required in patients with renal impairment, at least for sitagliptin . Their beneficial effects are 1. increase circulating levels of GLP-1 in animals and humans; 2. increase the genesis, proliferation and differentiation of beta cells; 3. inhibit apoptosis of these cells; 4. enhance insulin secretion; 5. reduce fasting glucose; 6. reduce postparandial glucose; 7. reduce HbA1c levels.
In comparison to DPP-4 inhibitors, incretin mimetic agents have more pharmacological specificity but require subcutaneous injections. As with DPP-4 inhibitors, improvements in glycemic control were achieved with either no weight gain or with weight loss. Considering the impact of obesity on diabetes, along with weight gain that generally accompanies the use of insulin, insulin secretagogues, and insulin sensitizers, interventions with favorable effects on weight are likely to become increasingly important.
It should be pinpointed that there is a risk of potential adverse effects of DPP-4 inhibitors, especially on the immune system: an increased relative risk of 34% for all-cause infections after sitagliptin treatment was observed. Although, the risk of increased infection appears small, its consequences when translated into clinical practice with millions of T2DM patients treated could be considerable . Thus, while DPP-4 inhibitors present some advantages over other antidiabetic agents, long-term data on potential cardiovascular effects are needed before widespread use of these drugs is recommended.
Dual and pan-PPAR agonists
There are three PPARs subtypes which are commonly designated PPAR alpha, PPAR gamma and PPAR beta/delta. PPAR alpha activation increases HDL cholesterol synthesis, stimulates "reverse" cholesterol transport and reduces triglycerides. PPAR gamma activation results in insulin sensitization and antidiabetic action. Until recently, the biological role of PPAR beta/delta remained unclear. However, treatment of obese animals by specific PPAR delta agonists results in normalization of metabolic parameters and reduction of adiposity. Combined treatments with PPAR gamma and alpha agonists may potentially improve insulin resistance and alleviate atherogenic dyslipidemia, whereas PPAR delta properties may prevent the development of overweight which typically accompanies "pure" PPAR gamma ligands. Clearly, an optimal PPAR agent with improved safety profile that provides both effective glycemic and lipid control is needed. Compounds that affect both PPAR-alpha and PPAR-gamma, particularly with an optimized balance of agonist activity, might prove especially beneficial for patients with T2DM .
The old and well known lipid-lowering fibric acid derivative bezafibrate is the first clinically tested pan-(alpha, beta/delta, gamma) PPAR activator. It is the only pan-PPAR activator with more than a quarter of a century of therapeutic experience with a good safety profile. Therefore, bezafibrate could be considered (indeed, as a "post hoc" understanding) as an "archetype" of a clinically tested pan-PPAR ligand. Bezafibrate leads to considerable raising of HDL cholesterol and reduces triglycerides, improves insulin sensitivity and reduces blood glucose level, significantly lowering the incidence of cardiovascular events and new diabetes in patients with features of the metabolic syndrome. It attenuates the progression of insulin resistance, defers the onset of overt T2DM, enhances adiponectin levels and reduces the incidence of myocardial infarction in patients with metabolic syndrome during long-term follow-up [89–95]. However, from a biochemical point of view, bezafibrate is a PPAR ligand with a relatively low potency.
Several novel and potent dual PPAR-alpha/gamma agonists (glitazars) have been clinically developed. These agents have a major effect on peripheral and hepatic insulin sensitivity, with HbA1c reductions of 0.5–2%. On the basis of their mode of action, it is expected that these agents could modulate cardiovascular risk by improving endothelial reactivity, reducing blood pressure, and improving lipid profiles . However, the emergence of different types of toxic effects in clinical trials has resulted in their failure to progress beyond phase III development. Nonetheless, no consistent safety signal has been detected, probably because PPAR-alpha and PPAR-gamma each control the expression of many proteins that are involved in a range of biological processes. For example, development of tesaglitazar was discontinued because of indications that it could cause renal impairment, muraglitazar was linked with cardiovascular safety issues, and the earlier agents ragaglitazar and farglitazar failed because of liver toxicity and tumors in rodents.
The recently reported SYNCHRONY study  aimed to establish the safety profile and glucose-lowering and lipid-modifying effects of the new compound aleglitazar . Aleglitazar significantly reduced baseline HbA1c versus placebo in a dose-dependent manner, with a 600 μg dose. Edema, hemodilution, and weight gain occurred and were dose-dependent. However, at aleglitazar doses less than 300 μg, no patients had congestive heart failure, frequency of edema was similar to placebo and less than with pioglitazone, and bodyweight gain was less than with pioglitazone. The favorable balance in the safety and efficacy profile of aleglitazar represents encouraging short-term clinical data for this agent and provides good evidence to enter phase III investigation. Thus, the future of these dual PPAR agonists is presently uncertain following former concerns about their safety. However, the favorable changes in lipids and glycemic endpoints still encourage further research.
Amylin mimetic drugs
Amylin is a synergistic partner to insulin, with which it is cosecreted from pancreatic beta cells in response to meals. Deficient amylin secretion is a well-recognized phenomenon in type 1 diabetes and in a later-stage in T2DM, in whom pancreatic insulin production is markedly reduced. Its physiological effects mimic in part those of GLP-1. Amylin suppresses glucagon – a pancreatic hormone that regulates the production of glucose by the liver – secretion from pancreatic alpha cells, thereby attenuating hepatic glucose production. It also delays gastric emptying and likely possesses a central effect to enhance satiety .
Pramlintide is a synthetic hormone for parenteral (subcutaneous) administration, resembling human amylin effects. It reduces the production of glucose by the liver by inhibiting the action of glucagon and diminishes postprandial glucose fluctuations. The drug was approved by the FDA in March 2005. While it seems to be a satisfactory adjuvant medication in insulin-dependent diabetes, it is unlikely to play a major future role in the management of T2DM .
Cardiovascular effects of the new compounds
While he main physiologic benefits demonstrated from exenatide therapy have been on indexes of glycemic control, cardiovascular effects have also been described. In experimental models, GLP-1 receptors have been demonstrated in cardiac myocytes and in certain regions of the brain that regulate autonomic function . In some cases the use of GLP-1 infusion was associated with a doubling of stroke volume and an increase in cardiac output by > 50%, as well as significant decreases in left ventricular end-diastolic volume . Encouraging results were also documented in humans , but long-term safety data are required before we fully understand any potential benefits or risks derived from the hemodynamic influences of GLP-1-based therapies.
Regarding DPP-4 inhibitors, few data are available concerning cardiovascular markers or clinical outcomes. Given the preliminary data they might be considered in individuals with impaired ventricular function. However, no clinical trials using these agents have yet been reported in this or any other group of patients with cardiovascular disease. Glitazars may yield some reduction in blood pressure . The amylin mimetic drug pramlintide did not show cardiovascular advantages or risks .