Cardiovascular & Haematological Disorders - Drug Targets - Volume 18, Issue 2, 2018

Background: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are a new class of oral antidiabetic drugs. So far, there are three agents approved for use in Europe and in the USA, two in Japan and another four agents under testing. Objective: The purpose of this study is to describe the mechanism of action and the favorable and adverse effects of SGLT-2 inhibitors. Method: A thorough review of literature indexed in PubMed, Scopus and Cochrane databases were conducted. Original papers, review papers and their relevant references in English, from 2005 to February 2017, were included. Results: The main mechanism of action is the glycosuria induced by the inhibition of SGLT-2, located in the early segment of the proximal convoluted tubule. Along with large amounts of glucose, sodium, water and uric acid are also excessively excreted in urine. These actions have various, both desired and adverse, consequent implications in kidneys, blood pressure, cardiovascular system and other systems. Moreover, SGLT-2 inhibitors act directly to organs other than the kidneys, as SGLT-2 can be expressed there. Conclusion: The underlying mechanisms responsible for the SGLT-2 inhibitor actions, are pleiotropic and occur in the kidneys, as well as in other target organs. The comprehension of these mechanisms, not only permits us to understand their actions better, but it could also help us to predict more of their undisclosed favorable actions, as well as their rare adverse effects.

Background: The treatment of diabetes remains challenging over the decades, even after the introduction of numerous novel drugs of different classes. Most patients with type 2 diabetes require a combination of multiple agents and eventually the use of insulin. The newest antidiabetic drugs, possibly with the most pleiotropic actions after metformin are the sodium-glucose cotransporter 2 (SGLT-2) inhibitors (SGLT-2i). This class has a unique mechanism inhibiting the glucose reabsorption in the proximal tubule of the kidney. Objective: The purpose of this review is to critically discuss the beneficial effect of SGLT-2i on glycemic control as monotherapy or in combination with other hypoglycemic agents. Methods: A systematic review of randomised clinical trials on SGLT-2i vs placebo, other glucoselowering drugs or insulin was performed, and studies assessing glycemic control, mainly expressed through glycated hemoglobin and fasting plasma glucose levels (FPG) were included in the review. Electronic and manual searches on MEDLINE, EMBASE and Cochrane Library were performed. Results: In our review, we mainly focused on dapagliflozin, empaglifozin and canagliflozin. All agents exhibited a sufficient reduction of HbA1c as well as FPG. Conclusions: SGLT-2i are a reliable second-line therapy of T2DM, since they can be combined safely with metformin, sulfonylures, incretin mimetics, insulin as well as in triple combinations. In many studies, they were prioritised as monotherapy with satisfying effects regarding HbA1c and FPG level reductions.

Background: Sodium-glucose co-transporters 2 inhibitors have emerged as a novel antidiabetic class of drugs offering significant ameliorating effects on a variety of cardiovascular risk factors, secondary to their mechanism of action, including blood pressure and body weight. Objective: The purpose of this article is to discuss available data on the impact of SGLT-2 inhibitors on blood pressure and body weight compared with other available anti-diabetic drugs and to present potential mechanisms mediating these effects. Methods: A comprehensive review of the literature was performed to identify studies examining the effects of SGLT-2 inhibitors on blood pressure and body weight. Results: SGLT-2 inhibition has been related with a mild decrease in blood pressure of approximately 3-5mmHg in systolic and 1-2mmHg in diastolic blood pressure. These data have been confirmed with 24h ambulatory measurements, as well. Furthermore, given the loss of calories in the urine, a mild decrease in body weight is anticipated, as well. Studies with this class of drugs noted a reduction in body weight of 2 to 3 kg, similar to the loss noted with the use of glucagon-like peptide 1 analogues, the only class of drugs that has offered significant reductions in body weight so far. Consclusion: The beneficial effects of the SGLT-2 inhibition on an abundance of cardiovascular risk factors, including blood pressure and body weight, have created great expectations for potential benefits from the cardiovascular events standpoint, a theory that was confirmed in the two available cardiovascular studies of this promising class of drugs.

Background: The impact of overt diabetes and poor glycemic control on the risk of cardiovascular disease is well established. Among patients with type 2 diabetes, several studies demonstrated a significant increase in coronary artery disease-related death and cardiovascular events associated with HbA1c levels of greater than 7% compared with lower levels. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are a novel class of anti-diabetic drugs that lower blood glucose levels through the suppression of renal glucose reabsorption thereby promoting renal glucose excretion. Objectives: To summarize data on the potential mechanisms of SGLT-2 inhibition that could exert cardiovascular benefits in patients with diabetes mellitus. Method: We conducted an in-depth literature search of SGLT-2 inhibitors and potential cardiovascular benefits and mechanisms that mediate those effects. Results: In diabetes, expression of the SGLT-2 genes is up-regulated and renal threshold increased, resulting in increased glucose reabsorption from glomerular filtrate, reducing urinary glucose excretion and worsening hyperglycemia. SGLT-2 inhibition should offer potential cardiovascular protection in diabetic patients via attenuating hyperglycemia, blood pressure, body weight, hyperuricemia, and diabetic nephropathy. Conclusion: The initial data of SGLT-2 inhibitors suggest beneficial effects on cardiovascular risk among patients with diabetes mellitus. Several mechanisms are hypothesized to mediate the abovementioned benefits. Future randomized, controlled studies are needed in order to unveil the contribution of each mechanism to these outcomes.

Background: Diabetic nephropathy is a crucial microvascular complication of diabetes mellitus that is associated with elevated cardiovascular risk. SGLT-2 inhibitors are a new class of hypoglycemic drugs that positively affect several risk factors of cardiorenal damage. Objectives: The study aimed to review and critically discuss available data on the association of SGLT-2 inhibitors treatment with kidney function, progress of diabetic kidney disease, and renal related outcomes, as well to unveil potential mechanisms of action that mediate such effects. Method: We conducted a comprehensive search of the literature on the renal related effects of SGLT-2 inhibitors, to compose a narrative mini-review. Results: The administration of SGLT-2 inhibitors was observed to exert beneficial effects on a wide cluster of risk factors of chronic kidney disease, such as hyperglycemia, blood pressure, serum uric acid, and body weight. Data from the first two large, randomized, clinical trials of SGLT-2 inhibitors conducted to address the renal related outcomes of SGLT-2 inhibitors suggest substantial benefits on estimated glomerular filtration rate decline and albuminuria. Conclusion: The initial data suggest clinically meaningful benefits of the SGLT-2 inhibitors in diabetic patients in relevance with chronic kidney disease. Future, well-designed randomised clinical trials need to be further investigated such as nephroprotective outcomes, that if confirmed, could lead to new perspectives in the management of diabetic nephropathy.

Background: Available hypoglycemic-agents enable physicians to achieve consistent glycemic-control, but effects on cardiovascular-outcomes have been marginal or questionable. SGLT-2 inhibitors emerged as a novel antidiabetic drug class with remarkable cardiovascular benefits, and significant improvement in the prevention and progression of HF. Objective: The purpose of this article is to critically review the effect of SGLT-2 inhibitors on HFoutcomes and the potential underlying mechanisms. Method: We conducted a thorough review of the literature. The studies addressing the impact of SGLT-2 inhibitors on HF and potential underlying mechanisms were identified. Additionally, we reviewed the references of the identified original papers. Results: The EMPA-REG OUTCOME trial was the first cardiovascular safety study of this drug class that assessed among other outcomes, the impact of SGLT-2 inhibition on HF. Empagliflozin was associated with significant reductions of the risks for hospitalization or death from HF in patients with- and without-HF. Similar benefits were noted from a large-cohort study assessing the effect of SGLT-2 inhibitors on HF-outcomes in real-life. Potential mechanisms include the SGLT-2 inhibitors-induced lowering of blood pressure, the decrease in visceral obesity and the amelioration of arterial stiffness. Improvements of left ventricular mass and diastolic dysfunction may also be implicated in the manifestation of HF-benefits. Lastly, the SGLT-2 inhibitors-related higher ketones bioavailability might offer a better “fuel” to the myocardium. Conclusion: The pleiotropic effects of SGLT-2 inhibitors seem to be translated in significant improvement of HF-related outcomes. On-going trials will provide further information on the impact of these agents in various high- and low-risk populations.

Background: Type 2 diabetes mellitus (T2DM) is associated with substantially increased risk for cardiovascular events, including ischemic stroke. In turn, ischemic stroke represents a leading cause of mortality and long-term disability worldwide. The recent class of glucose-lowering agents is sodium-glucose cotransporter 2 (SGLT-2) inhibitors, which act through inhibition of glucose reabsorption in the kidney, resulting in glucose excretion without stimulating insulin release. Accumulating data suggests that these agents improve multiple risk factors for ischemic stroke except their glucose-lowering effect. Objective: In the present review, the pleiotropic actions of SGLT-2 inhibitors are summarized and their potential implications on ischemic stroke prevention are discussed. Methods: We performed a comprehensive search of the literature in terms of SGLT-2 inhibitors efficacy on ischemic stroke and traditional risk factors of cerebrovascular disease. Results: Several studies consistently showed that SGLT-2 inhibitors reduce blood pressure, induce weight loss, increase high-density lipoprotein cholesterol levels and reduce triglyceride levels. In addition, they improve several emerging cardiovascular risk factors, most notably arterial stiffness, albuminuria and oxidative stress. However, in the only trial that evaluated the effects of these agents on the incidence of ischemic stroke, empagliflozin did not reduce the risk of first or recurrent stroke despite a significant reduction in cardiovascular and all-cause mortality. Conclusion: Despite the multiple pleiotropic effects of SGLT-2 inhibitors, these agents do not appear to affect stroke risk. Ongoing large trials with longer follow-up will evaluate whether the pleiotropic effects of this class will translate into benefits in ischemic stroke prevention.

Background: SGLT-2 inhibitors are a novel class of antidiabetic drugs, recently approved for the treatment of patients with T2DM. Their cardioprotective and renoprotective action, along with their beneficial effects on metabolic parameters, makes them an attractive therapeutic option. Since 2015, when the US FDA issued warning regarding the increased risk of euDKA in the setting of SGLT-2 inhibitors administration, a vivid discussion upon the direct connection between this novel class and the major metabolic complication of diabetes mellitus is still ongoing. Objectives: To present the underlying pathophysiology, associating SGLT-2 inhibitors and euDKA, and clinical data both in T1DM and in T2DM patients, in order to understand the clinical background which favors the development of euDKA. Method: We conducted a comprehensive research of the relevant literature regarding the association between SGLT-2 inhibitors in clinical practice and the events of diabetic ketoacidosis, mainly euglycemic. Results: Randomized controlled trials, meta-analyses, case series and case reports shed light on this possible connection, the background that favors euDKA, and the mediating pathophysiologic mechanisms. Many of those euDKA events developed in patients with T1DM, due to off-label use of SGLT-2 inhibitors, or in patients previously misdiagnosed as having T2DM, who in fact suffered from LADA. Conclusion: SGLT-2 inhibitors certainly predispose to euDKA, but it is unclear if, as certain precipitating factors are usually recognized on the background, DKA would also occur in the absence of an SGLT-2 inhibitor. Further investigation is required in order to establish or not SGLT- 2 inhibitors as causative factors of euDKA.

Background: Long-term diabetes causes other disease development such as cardiovascular diseases (CVD). Objective: Genetics can help us to predict cardiovascular diseases in diabetic patients. Method and Search Strategy: We searched PubMed and Google scholar for the terms: Cardiovascular disease, Diabetes, Polymorphism, Genetics from 2000 to 2017, and then included the relevant studies in our study. Discussion: Essential role of inheritance in multifactorial disease is obviously clear, however, varies by disease and by other factors such as age of disease onset and subtype of disease. CVD is a multifactorial disease which can develop in diabetes patients as a result of increase in oxidative stress. It may also increase expression of pro-inflammatory factors and induce apoptosis in cardiomyocytes. Conclusion: Predictive polymorphisms are risk estimators for CVD incidence in diabetes patients. SNPs such as 894G>T in NOS3 gene, V16 in MnSOD gene, Rs3918188 in NOS3 gene and Rs11614913 in MiR-196a2 increase the risk of CVD in diabetic patients are precious polymorphisms for CVD prediction in diabetic population. CDKN2B, MTHFR and ACE genes have polymorphisms which increase the risk of diabetes and other polymorphisms on these genes increase the risk of CVD, we suggest these genes are valuable to study and find out if there are any polymorphisms that predict CVD susceptibility in diabetic patients.

Background: Ischemia is a multifactorial disorder in which several genetic and environmental factors are involved. Platelets are the major causative agents of this disease because their elevated activity and aggregation would increase the risk of atherosclerosis and thrombosis, as well as ischemia. A number of polymorphisms in platelet receptors can increase the risk of ischemia and single-nucleotide polymorphisms (SNPs) have been detected in platelets. In addition, polymorphisms in other genes have been shown to cause platelet adhesion and aggregation that plays a role in ischemia. Patients respond differently to anti-platelet drugs which are used to treat patients with ischemia. Polymorphisms affect patients' responses to anti-platelet drugs, for instance, by increasing platelet activity and causing resistance of platelets to these drugs. Diagnosis of these polymorphisms can greatly contribute to better prediction of prognosis and response to treatment of patients, leading to more effective therapeutic strategies and a proper approach to ischemia. Conclusion: In this review, we have evaluated the role of polymorphisms involved in platelet activation and development of ischemia.

Objective: Infective endocarditis due to Enterococus Gallinarum is a rare clinical condition. We present a case of an 85 years old male with a history of the valvular disease and permanent pace maker with past medical history of repetitive urinary tract infections in the previous months, who presented to the emergency department with fever, urinary disturbances, general malaise and positive blood cultures for Enterococcus Gallinarum. Methods: Echocardiography was a useful diagnostic method in the present case, showing the vegetation on the tricuspid valve. Results: This case is notable because tricuspid valve endocarditis due to Enterococcus Gallinarum is a rare clinical condition and improves knowledge of disease and management in patients with endocarditis.