A cardiologic approach to non-insulin antidiabetic pharmacotherapy in patients with heart disease

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.

Figure 1

Histographical display of crude all-cause mortality (percent) over a mean 7.7-year follow-up in 11,322 CAD patients – nondiabetic and diabetic – on several therapeutic regimens. Mortality in patients on a combined glibenclamide/metformin regimen was significantly higher and almost quadrupled the figures documented for nondiabetic CAD patients. Significant statistical differences were still present when comparing the group on combined pharmacotherapy with the groups on other antidiabetic regimes. ND – nondiabetics; diet – patients solely on diet; gliben – patients on glibenclamide; metfor – patients on metformin; comb – patients on a combined glibenclamide/metformin regimen. (Based on data from Ref. [45]).

Figure 2

Actuarial survival curves of all-cause mortality after multivariate analysis in the same population as in Figure 1. Multivariate analysis included age, gender, glucose, cholesterol, triglycerides, previous myocardial infarction, anginal syndrome, hypertension, functional class, previous cerebrovascular accident, peripheral vascular disease, smoking, body mass index and use of beta blockers and antiplatelet drugs. With patients on diet as reference group, the combined treatment with metformin and glibenclamide was associated with a significantly higher hazard ratio of all cause mortality: 1.53 (95% CI 120–1.96. (Modified from Ref. [45]).