The Associations between Kidney Function and Sexual Dysfunction among Males and Females with Type 2 Diabetes Mellitus.

Background and Objectives: Diabetic kidney disease (DKD), expressed either as albuminuria, low estimated glomerular filtration rate (eGFR) or both, and sexual dysfunction (SD), are common complications among type 2 diabetes mellitus (T2DM) patients. This study aims to assess whether an association exists between DKD and SD, erectile dysfunction (ED) or female sexual dysfunction (FSD) in a T2DM population. Materials and Methods: A cross-sectional study was designed and conducted among T2DM patients. The presence of SD was assessed using the International Index of Erectile Function and the Female Sexual Function Index questionnaires for males and females, respectively, and patients were evaluated for DKD. Results: Overall, 80 patients, 50 males and 30 females, agreed to participate. Sexual dysfunction was present in 80% of the study population. Among the participants, 45% had DKD, 38.5% had albuminuria and/or proteinuria and 24.1% had an eGFR below 60 mL/min/1.73 m2. The eGFR was associated with SD, ED and FSD. Moreover, SD and ED were proven as significant determinants for lower eGFR values in multiple linear regression analyses. DKD was associated with lower lubrication scores and eGFR was associated with lower desire, arousal, lubrication and total scores; however, the multivariate linear regression analyses showed no significant associations between them. Older age resulted in significantly lower arousal, lubrication, orgasm and total FSFI scores. Conclusions: SD is commonly encountered in older T2DM patients and DKD affects almost half of them. The eGFR has been significantly associated with SD, ED and FSD, while SD and ED were proven to be significant determinants for the eGFR levels.

Impact of Primary Aldosteronism in Resistant Hypertension.

PURPOSE OF REVIEW: In this narrative review, we aim to summarize the latest data on the association between primary aldosteronism and resistant hypertension, as well as to emphasize the necessity for screening for primary aldosteronism all patients with resistant hypertension. RECENT FINDINGS: Epidemiological data suggests that up to one out of five patients with resistant hypertension suffer from primary aldosteronism. Patients with primary aldosteronism have increased incidence of renal disease, diabetes mellitus, atrial fibrillation, and obstructive sleep apnea, as well as they are characterized by an extended target organ damage and increased cardiovascular morbidity and mortality. Specific treatments for primary hyperaldosteronism (adrenalectomy and mineralocorticoid receptor antagonists) have significant impact on blood pressure, can reverse target organ damage, and mitigate cardiovascular risk. All patients with resistant hypertension should be evaluated for primary aldosteronism. Patients diagnosed with the disease may further undergo lateralization with adrenal vein sampling in order to receive the optimal therapeutic option which results in significant improvements in quality of life and cardiovascular profile.

Effect of Empagliflozin and Dapagliflozin on Ambulatory Arterial Stiffness in Patients with Type 2 Diabetes Mellitus and Cardiovascular Co-Morbidities: A Prospective, Observational Study.

Background and Objectives: Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular disease. Arterial stiffness is an independent prognostic marker for cardiovascular disease development. We aimed at determining the effect of two different sodium-glucose co-transporter-2 (SGLT-2) inhibitors on ambulatory arterial stiffness in individuals with T2DM. Materials and Methods: In this single-center, single-arm, prospective study performed from January 2020 to August 2021, we planned to enroll adult subjects with T2DM and stable antidiabetic and antihypertensive treatment, assigned either to empagliflozin or dapagliflozin for 6 months. All eligible subjects underwent ambulatory blood pressure monitoring. We set as the primary efficacy outcome the change in ambulatory pulse wave velocity (PWV) from baseline to week 24. Results: We finally enrolled 46 diabetic subjects, with a mean age of 62.89 (8.53) years and mean T2DM duration of 9.72 (6.37) years. Thirty patients received dapagliflozin, while sixteen patients received empagliflozin. Due to COVID-19 pandemic restrictive measures during the study, the mean follow-up period extended from 6 months to 9.98 (3.27) months. Regarding the prespecified primary efficacy outcome, we found that the SGLT-2 inhibitor treatment did not have a significant effect on PWV (p = 0.65). Prior history of cardiovascular disease did not significantly affect the observed effects. Other indices of arterial stiffness, such as augmentation index and central pulse pressure, were not significantly affected, neither by empagliflozin nor by dapagliflozin. Conclusions: SGLT-2 inhibitor treatment with empagliflozin or dapagliflozin in subjects with T2DM failed to improve ambulatory PWV over a mean follow-up of 10 months. Registration number: ISRCTN88851713.

Renin-Angiotensin System Inhibitors and COVID-19: a Systematic Review and Meta-Analysis. Evidence for Significant Geographical Disparities.

PURPOSE OF REVIEW: While the COVID-19 pandemic is constantly evolving, it remains unclear whether the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) affects the clinical course of SARS-CoV-2 infection. For this meta-analysis, PubMed, CENTRAL, and grey literature were searched from their inception to 19 May 2020 for randomized, controlled trials or observational studies that evaluate the association between the use of either ACE inhibitors or ARBs and the risk for major clinical endpoints (infection, hospitalization, admission to ICU, death) in adult patients during the COVID-19 pandemic. In addition, a subgroup geographical analysis of outcomes was performed. Studies including less than 100 subjects were excluded from our analysis. RECENT FINDINGS: In total, 25 observational studies were included. ACE inhibitors and ARBs were not associated with increased odds for SARS-CoV-2 infection, admission to hospital, severe or critical illness, admission to ICU, and SARS-CoV-2-related death. In Asian countries, the use of ACE inhibitors/ARBs decreased the odds for severe or critical illness and death (OR = 0.37, 95% CI 0.16-0.89, I2 = 83%, and OR = 0.62, 95% CI 0.39-0.99, I2 = 0%, respectively), whereas they increased the odds for ICU admission in North America and death in Europe (OR = 1.75, 95% CI 1.37-2.23, I2 = 0%, and OR = 1.68, 95% CI 1.05-2.70, I2 = 82%, respectively). ACE inhibitors might be marginally protective regarding SARS-CoV-2-related death compared with ARBs (OR = 0.86, 95% CI 0.74-1.00, I2 = 0%). Randomized controlled trials are needed to confirm the aforementioned associations between ACE inhibitors, ARBs, and SARS-CoV-2.

Right Ventricular Function and Sexual Function: Exploring Shadows in Male and Female Patients With Heart Failure.

INTRODUCTION: Sexual health plays an important role in heart failure (HF) patients, and the relationship between HF and sexual dysfunction is well established; however, the role of right ventricular function in sexual dysfunction has not been investigated sufficiently. AIM: To investigate the potential association between right ventricular dysfunction and sexual dysfunction in both male and female patients with HF. METHODS: Patients with a clinical diagnosis of HF were evaluated in a cross-sectional study. Patients from the whole spectrum of HF were included in the study, regardless of cause, duration, and classification of HF. Sexual function in men was evaluated with the International Index of Erectile Function and in women with the Female Sexual Functioning Index. MAIN OUTCOME MEASURES: We demonstrate that right ventricular dysfunction is associated with worse sexual function in both men and women. RESULTS: 306 consecutive patients with HF participated in the study. Right ventricular systolic dysfunction ranged from 24.2-39.1% and right ventricular diastolic dysfunction from 16.1-83.1%, depending on the echocardiographic parameter that was assessed. Right ventricular systolic dysfunction assessed by tricuspid annular plane systolic excursion (TAPSE), TAPSE/pulmonary artery systolic pressure ratio, and right ventricular basal diameter was associated with a lower International Index of Erectile Function score (P = .031, P = .009, and P < .001, respectively). Multiple linear regression analysis revealed that erectile function was independently associated only with TAPSE/pulmonary artery systolic pressure ratio and tricuspid late tricuspid diastolic flow velocity wave (ß = 32.84, P = .006; and ß = -0.47, P = .026, respectively), whereas female sexual function was independently associated only with the early tricuspid diastolic flow velocity/late tricuspid diastolic flow velocity ratio (ß= -0.47, P = .026). CLINICAL IMPLICATIONS: Our study demonstrates that right ventricular dysfunction in patients with HF reflects an impaired sexual function status. Physicians should be aware of this association and closely evaluate those patients for sexual dysfunction. STRENGTHS & LIMITATIONS: We innovatively assessed the correlation between right ventricular dysfunction and sexual function using validated questionnaires. The main limitation is the relatively small sample size. CONCLUSIONS: Our study provides some new insights into the relationship between sexual dysfunction and right ventricular systolic and diastolic dysfunction in HF patients, also suggesting potential interventions to improve sexual and right ventricular function and prognosis in this population. Koutsampasopoulos K, Vogiatzis I, Ziakas A, et al. Right Ventricular Function and Sexual Function: Exploring Shadows in Male and Female Patients With Heart Failure. J Sex Med 2019;16:1199-1211.

Effect of SGLT-2 inhibitors on cardiac autonomic function in type 2 diabetes mellitus: a meta-analysis of randomized controlled trials.

BACKGROUND: Cardiac autonomic neuropathy (CAN) is a common complication of type 2 diabetes mellitus (T2DM). We sought to determine whether sodium-glucose co-transporter-2 (SGLT-2) inhibitors affect indices of CAN in patients with T2DM. METHODS: We searched for parallel group or cross-over randomized controlled trials (RCTs) enrolling adult subjects with T2DM, assigned to a SGLT-2 inhibitor versus placebo or active comparator and addressing their effect on CAN. PubMed, Cochrane Library and gray literature sources were searched. We set as primary efficacy outcome the change in the low-frequency-to-high-frequency (LF/HF) ratio. We set as secondary efficacy outcomes: first, the change in the standard deviation of all 5 min mean normal RR intervals and second, the change in the square root of the mean of the sum of the squares of differences between adjacent RR intervals (r-MSSD). Protocol has not been registered at a publicly available repository. RESULTS: We pooled data from four RCTs in a total of 247 subjects with T2DM. SGLT-2 inhibitor treatment did not have a significant effect on LF/HF ratio (MD = - 0.11, 95% CI - 0.35 to 0.12, I2 = 0%, p = 0.36). SGLT-2 inhibitor treatment did not have a significant impact either on SDNN (MD = - 2.83, 95% CI - 7.41 to 1.75, I2 = 31%, p = 0.23), or on r-MSSD (MD = - 0.14, 95% CI - 3.52 to 3.25, I2 = 46%, p = 0.94). Overall risk of bias was graded as low across the selected RCTs. CONCLUSION: SGLT-2 inhibitor treatment in patients with T2DM does not seem to provide any significant beneficial effect on CAN indices.

The Impact of Metabolic Syndrome Components on Erectile Function in Patients with Type 2 Diabetes.

Erectile dysfunction is commonly encountered in diabetic patients and in patients with metabolic syndrome; however, only a few studies have assessed patients with metabolic syndrome and type 2 diabetes mellitus (T2DM) regarding their sexual function. The purpose of this study is to examine the effect of metabolic syndrome and its components on the erectile function of T2DM patients. A cross-sectional study including T2DM patients was conducted from November 2018 until November 2020. Participants were evaluated for the presence of metabolic syndrome and their sexual function was assessed using the International Index of Erectile Function (IIEF) questionnaire. A total of 45 consecutive male patients participated in this study. Metabolic syndrome was diagnosed in 84.4% and erectile dysfunction (ED) in 86.7% of them. Metabolic syndrome was not associated with ED or ED severity. Among metabolic syndrome components, only high-density lipoprotein cholesterol (HDL) was associated with ED [x2 (1, n = 45) = 3.894, p = 0.048; OR = 5.5 (95% CI: 0.890-33.99)] and with the IIEF erectile function scores (median 23 vs. 18, U = 75, p = 0.012). Multiple regression analyses showed that HDL was non-significantly associated with the IIEF erectile function scores. In conclusion, among T2DM patients HDL is associated with ED.

Risk Scores and Prediction Models in Chronic Heart Failure: A Comprehensive Review.

BACKGROUND: Heart failure affects a substantial proportion of the adult population, with an estimated prevalence of 1-2% in developed countries. Over the previous decades, many prediction models have been introduced for this specific population in an attempt to better stratify and manage heart failure patients. OBJECTIVE: The aim of this study is the systematic review of recent, relevant literature regarding risk scores or prediction models in ambulatory patients with an established diagnosis of chronic heart failure. METHODS: We conducted a systematic search of the literature in PubMed and CENTRAL from their inception up till December 2019 for studies assessing the performance of risk scores and prediction models and original research studies. Grey literature was searched as well. This review is reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. RESULTS: We included 16 eligible studies in this systematic review. Major heart failure risk scores derived from large heart failure populations were among the included studies. Due to significant heterogeneity regarding the main endpoints, a direct comparison of the included prediction scores was inevitable. The majority referred to patients with heart failure with reduced ejection fraction, while only two out of 16 prediction scores have been developed exclusively for heart failure patients with preserved ejection fraction. Ischemic heart disease was the most common aetiology of heart failure in the included studies. Finally, more than half of the prediction scores have not been externally validated. CONCLUSION: Prediction models aiming at heart failure patients with a preserved or mid-range ejection fraction are lacking. Prediction scores incorporating recent advances in pharmacotherapy should be developed in the future.

Cardiovascular efficacy and safety of dipeptidyl peptidase-4 inhibitors: A meta-analysis of cardiovascular outcome trials.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are a generally safe and well tolerated antidiabetic drug class with proven efficacy in type 2 diabetes mellitus (T2DM). Recently, a series of large, randomized controlled trials (RCTs) addressing cardiovascular outcomes with DPP-4 inhibitors have been published. AIM: To pool data from the aforementioned trials concerning the impact of DPP-4 inhibitors on surrogate cardiovascular efficacy outcomes and on major cardiac arrhythmias. METHODS: We searched PubMed and grey literature sources for all published RCTs assessing cardiovascular outcomes with DPP-4 inhibitors compared to placebo until October 2020. We extracted data concerning the following "hard" efficacy outcomes: fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, hospitalization for heart failure, hospitalization for unstable angina, hospitalization for coronary revascularization and cardiovascular death. We also extracted data regarding the risk for major cardiac arrhythmias, such as atrial fibrillation, atrial flutter, ventricular fibrillation and ventricular tachycardia. RESULTS: We pooled data from 6 trials in a total of 52520 patients with T2DM assigned either to DPP-4 inhibitor or placebo. DPP-4 inhibitors compared to placebo led to a non-significant increase in the risk for fatal and non-fatal myocardial infarction [risk ratio (RR) = 1.02, 95%CI: 0.94-1.11, I 2 = 0%], hospitalization for heart failure (RR = 1.09, 95%CI: 0.92-1.29, I 2 = 65%) and cardiovascular death (RR = 1.02, 95%CI: 0.93-1.11, I 2 = 0%). DPP-4 inhibitors resulted in a non-significant decrease in the risk for fatal and non-fatal stroke (RR = 0.96, 95%CI: 0.85-1.08, I 2 = 0%) and coronary revascularization (RR = 0.99, 95%CI: 0.90-1.09, I 2 = 0%), Finally, DPP-4 inhibitors demonstrated a neutral effect on the risk for hospitalization due to unstable angina (RR = 1.00, 95%CI: 0.85-1.18, I 2 = 0%). As far as cardiac arrhythmias are concerned, DPP-4 inhibitors did not significantly affect the risk for atrial fibrillation (RR = 0.95, 95%CI: 0.78-1.17, I 2 = 0%), while they were associated with a significant increase in the risk for atrial flutter, equal to 52% (RR = 1.52, 95%CI: 1.03-2.24, I 2 = 0%). DPP-4 inhibitors did not have a significant impact on the risk for any of the rest assessed cardiac arrhythmias. CONCLUSION: DPP-4 inhibitors do not seem to confer any significant cardiovascular benefit for patients with T2DM, while they do not seem to be associated with a significant risk for any major cardiac arrhythmias, except for atrial flutter. Therefore, this drug class should not be the treatment of choice for patients with established cardiovascular disease or multiple risk factors, except for those cases when newer antidiabetics (glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors) are not tolerated, contraindicated or not affordable for the patient.

Dysmetabolic Iron Overload in Metabolic Syndrome.

BACKGROUND: We sought to determine the association of dysmetabolic iron overload syndrome (DIOS) with metabolic syndrome (MetS). METHODS: Several studies have shown that DIOS is associated with Mets, mainly through the pathogenesis of its components: type 2 diabetes mellitus (T2DM), essential hypertension, non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (POS). RESULTS: Serum ferritin levels increase proportionally according to the degree of insulin resistance (IR) and the number of components of Mets. Moreover, DIOS predicts the onset of T2DM and NAFLD. Dysregulation of iron metabolism in DIOS is due to a multifactorial and dynamic process triggered by an unhealthy diet, facilitated by environmental and genetic cofactors, and resulting in a bidirectional relation between the liver and visceral adipose tissue (VAT). Iron removal combined with a healthy diet improved both insulin sensitivity and beta-cell function, but had no significant effect on blood glucose; however, phlebotomy therapy might be considered with conflicting results. CONCLUSION: Iron overload is closely associated with metabolic syndrome and its components; however, it remains under-appreciated in everyday clinical practice. Diet and lifestyle modification offer some clinical benefit; however, it is not adequate for successful management of the disease. The results of phlebotomy remain controversial, underlying the necessity of further efforts in this field.

Microvascular Complications of Type 2 Diabetes Mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic, non communicable, multisystem disease that has reached epidemic proportions. Chronic exposure to hyperglycaemia affects the microvasculature, eventually leading to diabetic nephropathy, retinopathy and neuropathy with high impact on the quality of life and overall life expectancy. Sexual dysfunction is an often-overlooked microvascular complication of T2DM, with a complex pathogenesis originating from endothelial dysfunction. OBJECTIVE: The purpose of this review is to present current definitions, epidemiological data and risk factors for diabetic retinopathy, nephropathy, neuropathy and sexual dysfunction. We also describe the clinical and laboratory evaluation that is mandatory for the diagnosis of these conditions. METHODS: A comprehensive review of the literature was performed to identify data from clinical studies for the prevalence, risk factors and diagnostic methods of microvascular complications of T2DM. RESULTS: Diabetic nephropathy and retinopathy affect approximately 25% of patients with T2DM; diabetic neuropathy is encountered in almost 50% of the diabetic population, while the prevalence of erectile dysfunction ranges from 35-90% in diabetic men. The duration of T2DM along with glycemic, blood pressure and lipid control are common risk factors for the development of these complications. Criteria for the diagnosis of these conditions are well established, but exclusion of other causes is mandatory. CONCLUSION: Early detection of microvascular complications associated with T2DM is important, as early intervention leads to better outcomes. However, this requires awareness of their definition, prevalence and diagnostic modalities.

Hypertension in Metabolic Syndrome: Novel Insights.

BACKGROUND: Metabolic syndrome (MetS) is characterized by the simultaneous presence of obesity, hypertension, dyslipidemia and hyperglycemia in an individual, leading to increased cardiovascular disease (CVD) risk. It affects almost 35% of the US adult population, while its prevalence increases with age. Elevated blood pressure is the most frequent component of the syndrome; however, until now, the optimal antihypertensive regiment has not been defined. OBJECTIVE: The purpose of this review is to present the proposed definitions for the metabolic syndrome, as well as the prevalence of hypertension in this condition. Moreover, evidence regarding the metabolic properties of the different antihypertensive drug classes and their effect on MetS will be displayed. METHODS: A comprehensive review of the literature was performed to identify data from clinical studies for the prevalence, pathophysiology and treatment of hypertension in the metabolic syndrome. RESULTS: Hypertension is present in almost 80% of patients with metabolic syndrome. The use of thiazide diuretics and b-blockers has been discouraged in this population; however, new evidence suggests their use under specific conditions. Calcium channel blockers seem to exert a neutral effect on MetS, while renin-angiotensin system inhibitors are believed to be of the most benefit, although differences exist between the different agents of this category. CONCLUSION: Controversy still exists regarding the optimal antihypertensive treatment for hypertension in MetS. Due to the high prevalence of hypertension in this population, more data from clinical trials are needed in the future.

Renovascular Hypertension: Novel Insights.

Renovascular hypertension (RVH) remains among the most prevalent and important, but also potentially reversible, causes of secondary hypertension. The predominant causes of renal artery stenosis (RAS) are atherosclerotic renovascular arterial stenosis (ARAS) and renal fibromuscular dysplasia. This condition can lead to progressive renal injury, cardiovascular complications and 'flash pulmonary edema'. Duplex Doppler ultrasonography, computed tomographic angiography and magnetic resonance angiography are the most commonly used diagnostic methods. There are three therapeutic options available: medical therapy including renin-angiotensin-aldosterone system antagonists, lipid-lowering agents, and antiplatelet therapy, percutaneous angioplasty with or without stent placement and surgical revascularization. Three large trials failed to demonstrate the superiority of renal artery revascularization over pharmaceutical therapy in controlling blood pressure and preserving renal function. For this reason, today revascularization is only recommended for patients with progressive worsening of renal function, recurrent 'flash pulmonary edema' and rapid increase in antihypertensive requirement in patients with previously well-controlled hypertension. However, more properly designed trials are needed in order to identify which patient populations would probably benefit from renal revascularization.

Treatment strategies for hypertension in patients with type 1 diabetes.

INTRODUCTION: Type 1 diabetes mellitus (T1DM) is a chronic, autoimmune disease that is characterized by total absence of insulin production. Hypertension is a common comorbidity in T1DM with complex pathophysiology, while it is also a well-recognized risk factor for the development of cardiovascular disease (CVD), as well as other microvascular diabetic complications. AREAS COVERED: The purpose of this review is to present the current definitions, epidemiological data and prevalence rates of hypertension in T1DM, as well as to describe current therapeutic options. EXPERT OPINION: Hypertension affects around a third of the type 1 diabetic population, with higher prevalence rates in older individuals with longer disease duration. Although hypertension affects a substantial proportion of T1DM individuals, blood pressure control rates are disappointingly low. Alongside lifestyle modification, antihypertensive treatment should be initiated in those with blood pressure above 140/90 mmHg, with a systolic blood pressure target of 130 mmHg and lower, if tolerated. In those with established CVD or diabetic nephropathy, systolic blood pressure targets below 130 mmHg should be pursued. Initial pharmacotherapy should consist of a renin-angiotensin-aldosterone system inhibitor. There is an urgent need for good quality data regarding proper antihypertensive treatment initiation, optimal BP targets and optimal antihypertensive treatment for better clinical outcomes.

Efficacy and safety of renal denervation for the management of arterial hypertension: A systematic review and meta-analysis of randomized, sham-controlled, catheter-based trials.

Despite the availability of a numerous antihypertensive agents, hypertension treatment and control rates remain low in many countries. The role of the sympathetic nervous system has long been recognized, but recent sham control renal denervation studies demonstrated conflicting results. In this reviewe paper, the authors performed a systematic review and meta-analysis to examine outcomes of sham-controlled studies utilizing new technologies and procedures. Six published randomized, sham-controlled studies were included in this meta-analysis. Of those, three trials used the first-generation radiofrequency renal denervation device and technique and the other three used second-generation devices and techniques. In total, 981 patients with hypertension were randomized in all 6 trials to undergo renal denervation (n = 585) or sham procedure (n = 396). Overall, renal denervation resulted in a decrease of 24-hours systolic ambulatory blood pressure (ABP) by 3.62 mm Hg (95% CI: -5.28--1.96; I2  = 0%), compared to sham procedure (GRADE: low). Renal denervation also reduced daytime systolic ABP by 5.51 mm Hg (95% CI: -7.79--3.23; I2  = 0%), compared to sham procedure but not nighttime systolic ABP. Office systolic blood pressure was reduced by 5.47 mm Hg (95% CI -8.10--2.84; I2  = 0%), compared to sham control. Further analysis demonstrated that second-generation devices were effective in reducing blood pressure, whereas the first-generation devices were not. These results indicate that effective renal denervation can result in significant and clinically meaningful blood pressure reduction. The second-generation devices provide better renal nerve ablation.

Glycemic efficacy and safety of glucagon-like peptide-1 receptor agonist on top of sodium-glucose co-transporter-2 inhibitor treatment compared to sodium-glucose co-transporter-2 inhibitor alone: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Sodium-glucose co-transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are now considered as key players in the treatment of type 2 diabetes mellitus (T2DM). The purpose of this meta-analysis was to provide precise effect estimates regarding the safety and efficacy of the addition of a GLP-1RA on top of SGLT-2i treatment. RESEARCH DESIGN AND METHODS: PubMed and CENTRAL, along with grey literature sources, were searched from their inception to May 2019 for randomized controlled trials (RCTs) with a duration ≥ 12 weeks, evaluating the safety and efficacy of addition of a GLP-1RA on a SGLT-2i compared to SGLT-2i alone in patients with T2DM. We also used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the credibility of our summary estimates. RESULTS: We identified three eligible RCTs, pooling data retrieved from 1,042 patients with T2DM in total. Administration of the maximum dose of a GLP-1RA on top of SGLT-2i treatment compared to SGLT-2i alone resulted in significant decrease in HbA1c by 0.91% (95% CI; -1.41 to -0.42) [GRADE: moderate], in body weight by 1.95 kg (95% CI; -3.83 to -0.07) [GRADE: moderate], in fasting plasma glucose by 1.53 mmol/L (95% CI; -2.17 to -0.88) [GRADE: moderate] and in systolic blood pressure levels by 3.64 mm Hg (95% CI -6.24 to -1.03). No significant effects on lipid profile and diastolic blood pressure were demonstrated. A significant increase in the risk for any hypoglycemia (RR: 2.62, 95% CI; 1.15-5.96, I2 = 33%) [GRADE: moderate] and for nausea (RR: 3.21, 95% CI; 1.36-7.54, I2 = 63%) [GRADE: moderate] and a non-significant increase in the risk for diarrhoea (RR: 1.64, 95% CI; 0.98-2.75, I2 = 0%) [GRADE: low] were documented. No other safety issues were identified. CONCLUSIONS: This meta-analysis suggests that a GLP-1RA/SGLT-2i combination, if tolerated, exerts significant beneficial effects on glycemic control and body weight loss, however increasing the risk for any hypoglycemia and gastrointestinal adverse events.

New Horizons in the Pathogenesis, Pathophysiology and Treatment of Familial Hypercholesterolaemia.

BACKGROUND: Familial Hypercholesterolaemia (FH) is an autosomal-dominant genetic disease and represents the most common genetic disorder: heterozygous 1/250 births, homozygous 1/300, 000 births. FH is characterized by high to very high low-density lipoprotein cholesterol (LDL-C), which is the main cause of increased incidence of premature atherosclerotic Cardiovascular Disease (CVD) or aortic stenosis. OBJECTIVE: The aim of the review was to investigate the pathogenesis and the pathophysiology of FH. RESULTS: The most common (60-80%) FH cause is mutations of the LDL Receptor (LDLR) protein (6 classes with a different number of receptors and functionality). Moreover, mutations in apolipoprotein B (APOB) (<5%) and gain-of-function mutations of proprotein convertase subtilisin/kexin type 9 genes (PCSK9) (<1%) contribute to its pathogenesis. An Autosomal Recessive Hypercholesterolaemia (ARH) is another cause, very rare (1/2.500 births), mainly in Sardinia. The remaining patients with a clinical diagnosis of monogenic hypercholesterolaemia do not present any known genetic cause. Since FH is a significant public health problem, early diagnosis and treatment are of utmost importance. Recent studies demonstrated the influence of the LDLR mutation type in the FH phenotype, associating a more severe clinical phenotype and worse advanced CVD in patients with null mutation than those with receptor-defective mutations. This analysis completes the adequate clinical diagnosis. CONCLUSION: Both homozygous and heterozygous FH are related to mutations of LDLR (mainly), APOB, PCSK9, while other rare forms exist. All aberrations lead to the impaired removal of LDL-C from the blood leading to its accumulation and subsequent CVD earlier than in the general population.

Diabetes and lipid metabolism.

The authors review the association between diabetes mellitus (DM) and aberrations of lipid metabolism related to DM, diabetic dyslipidemia (DD). DM is considered as a major health burden worldwide and one of the most important modifiable cardiovascular disease (CVD) risk factors. This applies to both the developed and the developing countries, especially the latter. While patients with type 1 DM, 10% of all DM cases, usually do not have dyslipidemia, DD is frequent among patients with type 2 DM (T2DM) (prevalence > 75%) and is mainly a mixed dyslipidemia [increase in triglycerides (TGs), low high-density lipoprotein cholesterol (HDL-C), and small-dense (atherogenic), low-density lipoprotein cholesterol (LDL-C) particles]. The components of DD, which is characterized by quantitative (mentioned above), qualitative, and kinetic abnormalities all contributing to CVD risk, are mostly related to insulin resistance. Statins, ezetimibe, and PCSK9 inhibitors can be used in monotherapy or consecutively in combinations if needed. Statins compose the main drug. For the residual CVD risk after statin treatment, the use of statin-fibrate combinations is indicated only in patients with mixed dyslipidemia. In conclusion, DD is a major health problem worldwide. It is a significant CVD risk factor and should be treated according to current guidelines. The means today exist to normalize all quantitative, qualitative, and kinetic aberrations of DD, thereby reducing CVD risk.

Mineralocorticoid Receptor Antagonists in Essential and Resistant Hypertension.

BACKGROUND: Mineralocorticoid receptor antagonists are a second-line class of antihypertensive drugs, which have been accounted for as the optimal add-on therapy in the triple algorithm for the management of resistant hypertension. OBJECTIVES: To assess the effects of mineralocorticoid receptor antagonists in the treatment of patients with essential hypertension and resistant hypertension. METHOD: We conducted a meticulous review of the literature and comprehensive identification of the clinical trials assessing the efficacy of mineralocorticoid receptor antagonists in individuals with primary and resistant hypertension. RESULTS: MRAs have been thoroughly tested in several clinical studies in relevance to blood pressure lowering effects, over the last six decades. Accumulating data observed that MRAs resulted in a significant reduction in blood pressure level in patients with resistant hypertension. In addition, spironolactone was found to beneficially affect the management of resistant hypertension. CONCLUSION: Mineralocorticoid receptor antagonists exert a significant antihypertensive effect. Future welldesigned randomized controlled studies are greatly needed to address crucial clinical aspects in the field.