Konstantinos Imprialos

Sodium–glucose cotransporter-2 inhibitors and blood pressure decrease: a valuable effect of a novel antidiabetic class?

Diabetes mellitus is a major issue of public health, affecting more than 300 million people worldwide. Inhibitors of the sodium-glucose cotransporter-2 (SGLT-2) in the renal proximal tubule are a novel class of agents for the treatment of type 2 diabetes mellitus. Inhibition of the SGLT-2 results in reduced glucose reabsorption and improvement in glycemic control. Alongside glucose excretion, SGLT-2 inhibitors also have mild natriuretic and diuretic effects, combining actions of a proximal tubule diuretic and an osmotic diuretic; these properties are expected to lead to small blood pressure (BP) reductions. Clinical studies with dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, luseogliflozin, and tofogliflozin used either as monotherapy or add-on therapy and compared with placebo or active treatment have also examined the effect of these agents on BP as a secondary endpoint. Although with some differences between individual agents, all of the approved SGLT-2 inhibitors provided a mild but meaningful reduction in office SBP and DBP. Recent studies with the use of ambulatory blood pressure monitoring suggest that the magnitude of this BP reduction can be even greater. The aim of this review is to systematically summarize and present the studies reporting the effect of approved SGLT-2 inhibitors on BP.

Stroke paradox with SGLT-2 inhibitors: a play of chance or a viscosity-mediated reality?

Diabetes mellitus is a major risk factor for cardiovascular morbidity and mortality. Current therapeutic strategies have not provided constant beneficial cardiovascular-related results. Sodium–glucose co-transporters 2 (SGLT-2) inhibitors have emerged as a novel antidiabetic class of drugs that exert favourable results in a variety of other cardiovascular risk factors too, such as increased blood pressure and body weight. The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) study was the first trial that evaluated cardiovascular outcomes in patients with diabetes with the use of empagliflozin, a member of this new class of drugs. Empagliflozin was associated with remarkable reduction of cardiovascular morbidity and mortality and all-cause death. On the contrary, stroke incidence was slightly increased, although the result did not reach statistical significance. It could be assumed that a drug providing such beneficial effects on cardiovascular outcomes, would have also the same impact in stroke risk. This finding could theoretically be attributed to ‘play of chance’. However, an increase of haematocrit was observed in EMPA-REG and other SGLT-2 inhibitors studies. Accumulating evidence suggests a direct association between increased haematocrit and stroke risk. Could this ‘stroke paradox’ be a result of the increased haematocrit levels noted with SGLT-2 inhibitors? The aim of this review is to critically assess both possibilities, given that increased stroke rates (if indeed true) should not be neglected and unattended.

Hematocrit and Stroke: A Forgotten and Neglected Link?

&NA; Stroke is considered among the most common causes of mortality and disability, leading to dramatic socioeconomic consequences. From a pathophysiologic perspective, enhanced blood viscosity due to increased hematocrit might be associated with stroke through impaired cerebral blood perfusion. This association has remained rather neglected during previous decades, but newly emerged as an epicenter of scientific interest due to the unexpected elevation of stroke rates with sodium‐glucose cotransporter‐2 inhibitors, a new class of hypoglycemic drugs with otherwise dramatic cardiovascular benefits. The purpose of this article is to review available data on the relation between stroke and hematocrit values. Data from large observational studies point toward an increased risk for stroke in individuals with elevated hematocrit. Data also suggest that the coexistence of increased hematocrit values and hypertension significantly enhance the risk of cerebrovascular events compared with each condition alone. Additionally, high hematocrit values seem related to worse survival outcomes in post‐stroke patients. Collectively, the association between hematocrit and stroke seems to be strong and independent in high hematocrit values (>0.50) in both previously healthy individuals and post‐stroke patients, but remains less clarified in patients with normal hematocrit values.

Lifestyle Modifications in Non-Alcoholic Fatty Liver Disease and Non- Alcoholic Steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases worldwide, affecting more than 30% of general population. High-fat diets, physical inactivity and obesity, all prevalent in the western societies, are strongly associated with the development and progression of NAFLD. Current drug therapies have not consistently shown substantial beneficial effects. Thus, lifestyle modification appears to be the optimal intervention in combating the disease. Accordingly, several studies have concluded that weight loss, via increase in physical activity, and dietary interventions could potential ameliorate biochemical, histological, and structural abnormalities of non-alcoholic fatty liver disease. The aim of this review is to summarize the findings of these lifestyle intervention studies and discuss the implementation of each intervention, and its effectiveness in the management of the disease in everyday clinical practice.

The effect of SGLT2 inhibitors on cardiovascular events and renal function

ABSTRACT Introduction: Sodium-glucose co-transporters-2inhibitors have emerged as a very promising antidiabetic drug class, with data from the two available cardiovascular trials of this class suggesting remarkable benefits in terms of cardiovascular events, total mortality and renal outcomes. Areas covered: Data point toward clinically meaningful benefits from SGLT-2inhibition on a variety of cardiovascular risk factors. Empagliflozin, and to a lesser extent canagliflozin, resulted in significant reductions of an abundance of cardiovascular mortality and morbidity endpoints. SGLT-2inhibitors were also found to reduce the incidence of heart failure events and ameliorate the progression of diabetic kidney disease. However, empagliflozin was associated with a trend for stroke risk increase, that could be partially attributed to the drug-induced hematrocrit increases, while canagliflozin was related with higher amputations risk. Expert commentary: The beneficial impact of SGLT-2inhibitors on cardiovascular risk factors seem to be manifested in significant morbidity and mortality benefits. The bright future of SGLT-2inhibitors in diabetes therapeutics is overshadowed by the higher amputations risk and the potential harms in terms of stroke incidence. Further analyses of the data and future studies could unveil patients subgroups that might be more prone to such events or put to rest the concerns for this otherwise promising class of drugs.

SGLT-2 Inhibitors and Cardiovascular Risk in Diabetes Mellitus: A Comprehensive and Critical Review of the Literature

BACKGROUND Diabetes mellitus is a major cardiovascular risk factor. Despite the vast pharmaceutical armamentarium, current therapeutic options for the treatment of type 2 diabetes mellitus were unable to provide consistent cardiovascular benefits, apart for metformin. The newest antidiabetic class of drugs, the SGLT-2 inhibitors, seem to provide significant survival benefits. The aim of this review is to present available data that will clarify whether SGLT-2 inhibitors could precipitate in reducing cardiovascular risk in diabetes mellitus. METHODS A comprehensive literature search was performed to identify available data from clinical and experimental studies evaluating the impact of SGLT-2 inhibitors in cardiovascular risk factors and outcomes. RESULTS Along with a mild antihyperglycemic effect, SGLT-2 inhibitors seem to possess multi-dimensional properties, affecting positively several recognized cardiovascular risk factors such as increased blood pressure, arterial stiffness, body weight and dyslipidemia. Furthermore, preliminary data point towards additional benefits, including reduction of albuminuria in diabetic nephropathy, and reduction of oxidative markers and fatty liver disease in experimental models. The efficacy and safety profile of empagliflozin, an SGLT-2 inhibitor, was evaluated in the EMPA-REG outcome study, and the results were quite impressive. Further credence comes from the analysis of pooled data of SGLT-2 inhibitors trials that have shown similar results. CONCLUSION SGLT-2 Inhibitors seem to be related with ameliorating effects on multiple cardiovascular risk factors. The first data from the EMPA-REG outcome study are indeed very promising. Several ongoing cardiovascular studies with this novel class of drugs will shed light and enforce or question current enthusiasm.

Echocardiographic Parameters During Long and Short Interdialytic Intervals in Hemodialysis Patients

BACKGROUND The long interdialytic interval in thrice-weekly hemodialysis is associated with excess cardiovascular risk. However, the mechanisms behind these adverse consequences are not fully understood. This study investigated the interdialytic changes in right and left ventricular function during the 2- and 3-day intervals. STUDY DESIGN Observational study with 2 random crossover sequences of recordings: 3-day followed by 2-day interval or vice versa. SETTINGS & PARTICIPANTS 41 stable patients with end-stage renal disease on standard thrice-weekly hemodialysis therapy. PREDICTOR 3-day (long) versus 2-day (short) interdialytic interval. OUTCOME Interdialytic change in echocardiographic indexes of left and right ventricular function. MEASUREMENTS 2-dimensional echocardiographic and tissue Doppler imaging studies were performed with a Vivid 7 cardiac ultrasound system at the start and end of the 3- and 2-day interdialytic intervals. RESULTS During both intervals studied, elevations in cardiac output, stroke volume, left ventricular mass index, and peak early diastolic velocities of the left ventricle were evident. Interdialytic weight gain (3.0±1.7 vs 2.4±1.3 [SD] kg) and inferior vena cava diameter increase (0.54±0.3 vs 0.25±0.3) were higher during the 3-day versus the 2-day interval (P<0.001). Left ventricular systolic and diastolic function indexes were generally no different between interdialytic intervals. In contrast, interdialytic increases in left and right atrial volume, right ventricular systolic pressure (RVSP; 15.3±10.2 vs 4.7±5.2mmHg; P<0.001), and tricuspid regurgitation maximum velocity (0.46±0.45 vs 0.14±0.33m/s; P=0.001) were significantly greater during the 3- versus the 2-day interval. Multivariable analysis suggested that changes in interdialytic weight gain, right ventricle diastolic function, and pulmonary vascular resistance were determinants of the change in RVSP. LIMITATIONS Observational study design. CONCLUSIONS Excess volume accumulation over the long interdialytic interval in hemodialysis patients results in higher left and right atrial enlargement and RVSP elevation, which clinically corresponds to pulmonary circulation overload, providing one plausible pathway for the excess mortality risk during this period.

Sexual Dysfunction, Cardiovascular Risk and Effects of Pharmacotherapy

BACKGROUND Sexual dysfunction affects millions of people with an increasing prevalence, worldwide. The pathophysiology of the disease shares several similarities with cardiovascular disease (CVD), including atherosclerosis, endothelial dysfunction, structural vascular damage and subclinical inflammation. Erectile dysfunction (ED) and female sexual dysfunction are common among patients with CVD and risk factors such as hypertension, diabetes, obesity and metabolic syndrome. Given the common pathogenesis of the diseases, ED is an independent prognostic factor of future ED events. Patients with overt ED or risk factors are usually treated with several drugs for the management of these conditions. Several of these drugs have been evaluated for their effect on sexual activity. RESULTS AND CONCLUSION Among the antihypertensive drugs, diuretics and beta-blockers seem to exert a detrimental impact on sexual function, with nebivolol being the only beta-blocker with favorable properties through an increase in nitric oxide bioavailability. In contrast, renin-angiotensin system inhibitors and calcium-channel blockers have a neutral effect on sexual activity. Hypoglycemic drugs have been less evaluated in the ED setting, with metformin, pioglitazone and liraglutide presenting favorable results. Statins on the other hand have not provided consistent results with observational studies suggesting a detrimental role in sexual activity and a few randomized studies indicating a neutral or even beneficial effect on erectile function.

Canagliflozin and Hypertension: Is It the Optimal Choice for All Hypertensive Patients?

To the Editor: We have read with great interest the study by Townsend and colleagues, which provided important clinical data on the effect of canagliflozin on blood pressure (BP). Patients with type 2 diabetes are typically a group with difficult-to-control hypertension, most often in need of combination treatment to achieve BP control. The study efficiently demonstrated that canagliflozin seems to actually be an antihypertensive drug, which is in agreement with the results of several studies of impact of sodium-glucose cotransporter 2 (SGLT2) inhibitors on BP. Of note, the study demonstrated almost similar 24-hour ambulatory BP monitoring (ABPM) and office BP reductions, in contrast with data supporting that antihypertensive treatment leads to an ABPM reduction that is usually two-thirds of the office BP decrease. A meta-analysis of 44 studies assessing response to antihypertensive treatment with office and 24-hour BP measurements concluded that the average reductions in 24-hour systolic BP and diastolic BP were 36.5% and 36.8% less than the reduction in the office systolic BP and diastolic BP values, respectively. Therefore, the SGLT2 inhibitor not only demonstrated a decrease in BP but exceeded the expectations for its possible antihypertensive action. The importance of these findings are obvious and we would kindly ask the investigators to provide us with further data that could clarify several important topics on the management of hypertensive patients. First, it would be of interest to provide any differences in the efficacy of canagliflozin according to ethnicity (Hispanic/Latino vs other), especially in African American populations. It is known that patients of African ancestry exhibit greater tendency to retain sodium and have volume-dependent BP elevation. Therefore, diuretics are among the most effective BP-lowering drugs in African Americans. Second, diuretics are very useful in the management of hypertension in obese patients. A subanalysis of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial revealed that the combination of a calcium channel blocker with an angiotensin-converting enzyme inhibitor provided similar outcome benefits across the baseline adiposity status (lean, overweight, and obese). On the other hand, the combination of a diuretic with an angiotensin-converting enzyme inhibitor was associated with significantly greater benefits in obese patients than in overweight and especially in lean patients. Subsequently, a subanalysis according to baseline body mass index would specify any plausible effects of the diuretic action of the drug on BP in overweight or obese compared with lean patients (body mass index ≤25, 25–30, and >30 kg/m). Third, it is clear that canagliflozin demonstrates an important diuretic effect. Useful information could emerge through the detection of any differences in the efficacy of the drug according to baseline antihypertensive classes used, and especially whether the SGLT2 inhibitor was equally effective in patients already on therapy with diuretics and/or renin-angiotensin system inhibitors. Finally, considering the mechanism of action of canagliflozin, the simultaneous administration of the SGLT2 inhibitor with other antihypertensive agents could explain the occurrence of several adverse events. Did orthostasis, volume depletion, and renal function deterioration occur in patients already treated with diuretics or renin-angiotensin system inhibitors? The additional BP-lowering effect of canagliflozin raises high hopes for the future of this antidiabetic class of drugs. Further understanding of their impact in different subgroups is essential to help physicians individualize treatment options for their patients. Therefore, we would be deeply obliged to the authors for performing the suggested subanalyses.

Reduction of Vascular Inflammation, LDL-C, or Both for the Protection from Cardiovascular Events?

Background: Low density lipoprotein cholesterol (LDL-C) and low grade arterial inflammation are key pathogenic factors for atherosclerosis and its manifestation, cardiovascular disease (CVD). Objective: In this narrative review we assessed if decreasing LDL-C levels or inflammation or both is more effective in reducing CVD events. Results: In the Scandinavian Simvastatin Survival Study (4S), all statin trials of the 90s’ and the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) the benefit came from the LDL-C reduction. In the GREak and Atorvastatin Coronary heart disease Evaluation (GREACE), the Treating to New Targets (TNT), and the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trials both mechanisms in combination produced significant benefits. In the Atorvastatin for Reduction of MYocardial Damage during Angioplasty (ARMYDA) trials and the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) with a human antibody targeting IL-1β with no lipid lowering effect, the reduction in arterial inflammation played the only beneficial role because there was no change in lipids levels. Conclusion: Both LDL-C and inflammation reduction are beneficial to the reduction of CVD risk. However, canakinumab is a very expensive drug that only induced a 15% reduction in CVD events, thus drastically reducing the possibility for it to be used in clinical practice. Besides, canakinumab is associated with increased infections, some fatal. A potent statin with anti-inflammatory effects is probably the best choice for the majority of those needing hypolipidaemic drug therapy.