Abstract
Classical non-insulin antihyperglycemic drugs currently approved for the treatment of type 2 diabetes mellitus (T2DM) comprise five groups: biguanides, sulfonylureas, meglitinides, glitazones and alpha-glucosidase inhibitors. Novel compounds are represented by the incretin mimetic drugs like glucagon like peptide-1 (GLP-1), the dipeptidyl peptidase 4 (DPP-4) inhibitors, dual peroxisome proliferator-activated receptors (PPAR) agonists (glitazars) and amylin mimetic drugs. We review the cardiovascular effects of these drugs in an attempt to improve knowledge regarding their potential risks when treating T2DM in cardiac patients. Metformin may lead to lethal lactic acidosis, especially in patients with clinical conditions that predispose to this complication, such as recent myocardial infarction, heart or renal failure. Sulfonylureas exert their effect by closing the ATP-dependent potassium channels. This prevents the opening of these channels during myocardial ischemia, impeding the necessary hyperpolarization that protects the cell. The combined sulfonylurea/metformin therapy reveals additive effects on mortality in patients with coronary artery disease (CAD). Meglitinides effects are similar to those of sulfonylureas, due to their almost analogous mechanism of action. Glitazones lower leptin levels, leading to weight gain and are unsafe in NYHA class III or IV. The long-term effects of alpha-glucosidase inhibitors on morbidity and mortality rates is yet unknown. The incretin GLP-1 is associated with reductions in body weight and appears to present positive inotropic effects. DPP-4 inhibitors influences on the cardiovascular system seem to be neutral and patients do not gain weight. The future of glitazars is presently uncertain following concerns about their safety. The amylin mimetic drug paramlintide, while a satisfactory adjuvant medication in insulin-dependent diabetes, is unlikely to play a major role in the management of T2DM.Summarizing the present information it can be stated that 1. Four out the five classical oral antidiabetic drug groups present proven or potential cardiac hazards; 2. These hazards are not mere 'side effects', but biochemical phenomena which are deeply rooted in the drugs' mechanism of action; 3. Current data indicate that the combined glibenclamide/metformin therapy seems to present special risk and should be avoided in the long-term management of T2DM with proven CAD; 4. Glitazones should be avoided in patients with overt heart failure; 5, The novel incretin mimetic drugs and DPP-4 inhibitors – while usually inadequate as monotherapy – appear to be satisfactory adjuvant drugs due to the lack of known undesirable cardiovascular effects; 6. Customized antihyperglycemic pharmacological approaches should be implemented for the achievement of optimal treatment of T2DM patients with heart disease. In this context, it should be carefully taken into consideration whether the leading clinical status is CAD or heart failure.
Highlights
Diabetes mellitus threatens to become a global health crisis; treating diabetes and its complications is going to dominate future health care expenditures
Current data indicate that the combined glibenclamide/metformin therapy seems to present special risk and should be avoided in the long-term management of Type 2 diabetes mellitus (T2DM) with proven coronary artery disease (CAD); 4
Glitazones should be avoided in patients with overt heart failure; 5, The novel incretin mimetic drugs and dipeptidyl peptidase 4 (DPP-4) inhibitors – while usually inadequate as monotherapy – appear to be satisfactory adjuvant drugs due to the lack of known undesirable cardiovascular effects; 6
Summary
Diabetes mellitus threatens to become a global health crisis; treating diabetes and its complications is going to dominate future health care expenditures. Combination therapy is known to promote additional blood glucose reduction but there is as yet no evidence that these or another antidiabetic formulations are beneficial in preventing or delaying macrovascular disease These observations are in keeping with the UKPDS reports demonstrating excess risk of all-cause mortality in the whole diabetic population receiving combined therapy, especially in patients in whom metformin was added at an early stage [54]. 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 Following approval of a given therapy for a chronic condition, large prospective, randomized, placebo-controlled trials designed to check its long-term safety and effectiveness require many years to be completed, and sometimes such studies are not performed at all This is the case with this combined treatment in CAD patients.
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