Diabetes mellitus (DM) and its chronic complications are the major world health problem having a rising trend in the whole world. It is believed that currently 366 millions of people suffer from DM worldwide, and by the year 2030 the number of diabetics will increase to 552 million. The number of patients with DM rises in all countries and 80% percent of the world’s population suffering from diabetes live in developing countries or newly industrialized countries. (1)

The prevalence of DM in Croatia in the age group between 18-65 years is 6.1%. The total number of persons suffering from DM in 2010 was approximately 316,000, of whom over 190,000 patients have the disease discovered, while nearly 123,000 have the disease undiscovered. (2)

The recently published paper shows (3) that over 90% of patients with DM treated at the Center for Diabetes in the Bjelovar- Bilogora County suffer from type 2 of DM. The greatest number of patients was treated with oral medications (43%). 38% of patients take oral agents and insulin and 15% of patients were treated only by insulin. According to the guidelines of the Croatian Diabetes Association, metformin (Glucophage ®, Aglurab®, Siofor®, Belformin®, Gluformin®) was immediately included in the treatment of type 2 DM, accompanied by changes in a life style. (4, 5) The guidelines also suggest that in the case of failure to meet the objectives of treatment after 3-6 months (“reachability” of generally stated goals of treatment should be individualized for each patient), sulfonylurea (Diaprel MR®, Gliclada®, Glica®, Amaryl®, Dibiglim®, Diapirid ®, Glimepirid PharmaS®, Glibenclamid Genericon®, Glurenorm®), repaglinid, (Novonorm®, Reglinid®, Repaglinid PharmaS®), pioglitazone (Pioglitazone Pliva®), dipeptidyl peptidase- 4 inhibitors (Januvia®, Galvus®, Trajenta®), alpha-glucosidase- inhibitors acarbose (Glucobay®) or even glucagone like peptide-1 analogue (Byetta®, Victosa®) could be prescribed as the second line therapy, drugs that can no longer be inexpensive therapy (5). Also, the guidelines suggest controversies about the cardiovascular risks in using oral medications for the treatment of diabetes.5 This urges us to be rational in prescribing these medications to cardiovascular patients.

The combination of metformin and the sulfonylurea is a relatively common combination in the treatment of type 2 DM. This combination lowers the value of Hba1c by 1.3%.5 Data on increased mortality for cardiovascular events while administering this combination of drugs is controversial.5 The Italian observational study in subjects treated with metformin and glibencamide showed a significantly higher mortality rate (8.7%) compared to the group receiving metformin combined with repaglinide (3.1%), gliclazide (2.1%) and glimepiride (0.4%). (6)

The Canadian study by Juurlink et al. compared the cardiovascular events in elderly patients treated with either glibencamide (older generation with sulfonylurea, 1,690 patients) or gliclazide (the more recent generation of sulfonylurea, 984 patients) for 2 years’ period. Among elderly patients hospitalized for acute myocardial infarction or percutaneous coronary intervention, the administration of glibenclamide compared with gliclazide was not associated with an increased cardiovascular risk. (7)

The literature notes that inhibiting ATP-sensitive potassium channels, sulfonylureas increase the risk of death and heart failure in patients with acute coronary syndrome. The Study Nagendran et al studying a database of patients with coronary syndrome, found no increased risk of death or heart failure. (8) Meta-analysis of the Italian authors that studied major cardiovascular events in diabetic patients treated with sulfonylurea in 115 studies found a higher incidence of strokes in patients with DM treated with sulfonylurea, thereby not recording an increased overall incidence of major cardiovascular events at the same time. (9)

Intensive glycemic control using gliclazide in the study ADVANCE10 with reduction of HbA1c by 6.5% yielded a 10% reduction in macro- and microvascular events and 21% reduction in the number of diabetic nephropathies. This effect of gliclazide is partly attributed to its antioxidant properties. (10)

The report on 15 studies that analyzed the impact of sulfonylurea in cardiovascular events did not record an increase in the incidence of cardiovascular events. (11)

Metformin, a drug from the group of biguanides is today considered to be the basis of pharmacological treatment of type 2 DM. Therefore, it is to be administered immediately after the discovery of the disease accompanied by the changes in the life style and diet as recommended by the Croatian and all international guidelines for the treatment of type 2 DM. (5)

In patients treated with metformin, already after six months’ treatment, it was observed a significantly reduced number of DM macrovascular complications, such as coronary incidents, strokes or deaths associated with DM. (12) Like any medicine, metformin has contraindications. It should not be administered to patients with creatinine clearance less than 60 ml/min, with severe liver failure, in alcoholics, patients with pancreatitis and all hypoxic conditions involving heart failure, respiratory failure and severe peripheral vascular disease (gangrene). (5)

Potential adverse effect of metformin on endothelial recovery after placement of drug eluting stents after the coronary intervention is described in the article by Habib et al. It was observed that metformin and mTOR (mammalian target of rapamycin) inhibitors (sirolimus) used in drug eluting stents have adverse molecular effects. It affects the endothelial recovery after coronary intervention S6K (ribosomal S6 kinase) dependent mechanism. Patients who take metformin and have the mTOR inhibitor drug-eluting stent are potentially at a higher risk of delayed endothelialization of the blood vessel and are at a higher risk for stent thrombosis. (13)

Preclinical studies have shown that metformin inhibits myocardial ischemia and has effects on reperfusion, regardless of its effect on the blood glucose level. This cardioprotective effect is mediated by activation of RISK (Reperfusion Injury Salvage Kinase) metabolic pathway and increased formation of adenosine. (14) The administration of metformin can potentially improve the outcome of cardiovascular events, even in patients without DM. (14) The study on the animal model (rats) who were chronically receiving 300mg of metformin a day showed that the administration of metformin enhanced the resistance to myocardial ischemic injury by a mechanism independent of the glucose reduction. This shows the positive effect of metformin on the structure of the mitochondria, which is mediated by the activation of AMPK (AdenosinMonoPhosphate-activated protein kinase) of metabolic pathway. (15) The study results indicating that metformin limits the size of myocardial infarction, suggest that the patients suffering from myocardial ischemia can benefit from the administration of metformin, even if they have no DM. (16)

Insulin resistance is the underlying pathogenetic disorder in DM type 2. The improvement of insulin sensitivity can be achieved by using drugs that have an impact on the genetic mechanisms. These are the thiazolidinediones (glitazones)- PPAR-gamma ligands, known as pioglitazone on our market. Glitazones are activators of nuclear transcription factor (peroxysome proliferator-activated receptor gamma, PPARgamma) that regulate the transcription of genes responsible for insulin involved in the control of formation of glucose utilization carrier and fat metabolism. Due to its mechanism of action, one of the most significant side effects in the use of glitazones is the weight gain. This is partly a consequence of fluid retention, which can have an impact on a potential heart failure. (5) The contraindications to the use of pioglitazone are congestive heart failure of any degree (NYHA class I-IV), liver disease, creatinine clearance <4ml/min, pregnant and breasting women, diabetic ketoacidosis, bladder cancer being active or a history of bladder cancer, hematuria. (5)

The literature suggests many favorable pleiotropic effects of administration of pioglitazone such as a favorable effect on epithelial dysfunction, lowering of blood pressure, correction of lipid metabolism, lowering of the level of inflammatory cytokines and protrombotic factors. (17) Compared with metformin, already after 16 weeks of administration, pioglitazone showed a greater reduction in the level of CRP, and other inflammation markers, thrombogenecity factors and oxidative stress. (18)

Consequently, due to these antiatherogenic effects, pioglitazone reduces mortality, myocardial infarction and stroke. (18) This is particularly worth noting for the comparison with rosiglitazone, the drug from the same group that was withdrawn from the market a few years ago due to an increased risk of heart failure, myocardial infarction and total mortality. (19) Meta-analysis of cardiovascular effects clearly indicates the negative effect of rosiglitazone on cardiovascular events compared to pioglitazone, which does not have such an effect. (19)

Repaglinide is currently the only agent from the group of analogs of sulfonylurea available in the Croatian market. It can be administered with a meal as a monotherapy or as a dual therapy with alpha-glucosidase inhibitors, DPP 4 inhibitors, thiazolidinediones and GLP 1 analogs. (5) However, in concomitant administration of metformin, there is no guarantee that the treatment will not cause an increased cardiovascular risk, especially in patients with coronary heart disease. (5)

The study by Schramm et al was published 2 years ago and it followed up more than 107,000 patients with DM type 2 throughout a period of 9 years. 9,607 of patients involved in this study had a history of myocardial infarction. Compared to metformin, the administration of some older sulfonylureas (glibenclamide, glipizide and tolbutamide) was associated with increased mortality in patients with and without history of myocardial infarction. The administration of repaglinide and gliclazide compared to metformin was not associated with higher mortality rate. (20)

Also, a study conducted in Denmark on 96 lean patients with type 2 DM, which studied the level of inflammation markers (tumor necrosis factor alpha, plasminogen activator inhibitor 1 antigen, tissue plasminogen activator antigen, von Willebrand factor, soluble intracellular adhesion molecule, soluble E- selectin) in patients taking metformin or repaglinide found a higher decline in inflammatory parameters responsible for endothelial dysfunction in patients treated with metformin compared to patients treated with repaglinide. (21)

As a result of such controversial opinions on cardiovascular effects of repaglinide, the indications for the administration of these drugs must be set according to strict criteria, particularly in newly diagnosed patients with type 2 DM and patients with known coronary heart disease. (5)

The possibility to increase the level of incretin hormones in the circulation in order to reduce blood glucose opens up a new chapter in the treatment of type 2 DM. For this purpose, we use the GLP 1 analogs and DPP 4 inhibitors. DPP 4 inhibitors registered in Croatia are sitagliptin, vildagliptin and linagliptin (Table 1).

In addition to its role in lowering glucose, linagliptin tested on animal models proved to be able to reduce the areas of the affected myocardial infarction. (22) Also, compared to glimepiride (sulphonylurea), the patients treated with linagliptin had a significantly lower relative risk of cardiovascular events, particularly stroke, regardless of the fact that linagliptin causes hypoglycemia less than sulfonylureas. (23) A meta-analysis that involved 8 studies lasting more than 12 weeks analyzed cardiovascular mortality (fatal myocardial infarction, fatal stroke), nonfatal stroke, nonfatal myocardial infarction, unstable angina pectoris. The degree of risk of these primary events was significantly lower with the use of linagliptin compared with placebo and glimepiride. (23) These analyses show that the administration of linagliptin does not increase cardiovascular risks, but probably confers cardiovascular benefits in patients with DM type 2. (23)

A similar cardioprotective effect of sitagliptin was shown in the 2013 Israeli study. Patients with type 2 DM who received sitagliptin before the major cardiovascular event had significantly fewer hospital complications (postinfarction angina, myocardial reinfarction, pulmonary edema, infections, renal failure) compared to the patients treated only with metformin or other oral hypoglycemic agents. (24) The conclusion that the administration of sitagliptin does not increase cardiovascular risks is reached by the analysis of 25 randomized clinical trials. (25) Moreover, in animal models vildagliptin and sitagliptin also proved to have equal cardiovascular protective effect. (26) Rats on high fat diet, with high body mass index, high insulin levels in plasma, increased parameters of oxidative stress and dyslipidemia received vildagliptin and sitagliptin. In addition to improving these metabolic parameters, the improvement of cardiac function was also recorded. The mitochondrial dysfunction in cardiac disease was prevented and the heart rate variability was stabilized. (26)

A variety of oral medications for the treatment of type 2 DM shows that every new, available and recognizable pathophysiological mechanism is exploited in the treatment of this disease. Such a great number of molecules can certainly have a direct effect on the cardiovascular system or the effect of the risk factors in addition to blood glucose level. Generally, controversies and doubts regarding cardiovascular safety are greater for older medicines for oral treatment of type 2 DM, especially from the group of sulfonylureas. Sulfonylurea from the older group (glibenclamide) should be avoided, particularly in the combination with metformin, because cardiovascular risks seem to be rising as a result of their administration. Previous studies show that pioglitazone is a safe medicine, but clinical examination should detect patients to whom the above limitation of use might relate. Repaglinide is also a safe medicine, although there are still doubts about the safety of this medicine in patients with coronary heart disease which should be clarified by the research to follow. Studies that suggest beneficial effects on metabolic parameters and endothelial function make the more recent medicines from the group of DPP 4 inhibitors more attractive for prescribing to patients with concomitant cardiovascular disorders.