Sodium-glucose Transport Protein 2 Inhibitors Research Articles

Real-world evidence of the effects of sodium-glucose co-transporter 2 inhibitors on the dosing of diuretics in patients with heart failure: a retrospective cohort study.

Background: Heart failure (HF) was estimated to impact approximately 64 million individuals worldwide in 2017 and is predicted to rise in the coming years. Therefore, the aim of our study was to evaluate the effects of sodium-glucose transport protein 2 (SGLT2) inhibitors on the dosing of diuretics among individuals diagnosed with HF. Methods: A retrospective cohort study was conducted at Security Forces Hospital in Riyadh, Saudi Arabia, between January 2018 and August 2022. The study included adult patients who were diagnosed with heart failure and received dapagliflozin and/or diuretic. A descriptive analysis was conducted to identify significant differences between both groups by using the chi-square test for categorical variables and the Student's t-test for continuous variables. A logistic regression model was also run to identify the odds of each event. Statistical significance was indicated by p values less than .05. Results: Overall reduction in diuretics was reported in 68 patients in the SGLT2 inhibitors plus diuretic therapy group, while in the diuretic therapy group 25 patients reported overall reduction in diuretics (OR = 4.81, 95% [2.74-8.45]). The reduction of the loop dose level was reported by 58 patients in the SGLT2 inhibitors plus diuretic group and by 25 patients in the diuretic group (OR = 3.48, 95% [1.98-6.11]). The discontinuation of thiazide was reported by 16 patients in the SGLT2 inhibitors plus diuretic therapy group, but by only two patients in the diuretic group (OR = 9.04, 95% [2.03-40.19]). After 6 months, ejection fraction was increased by 2.74 in the SGLT2 inhibitors plus diuretic group (p = .0019) and decreased by 2.56 in the diuretic group (p = .0485), both of which were statistically significant. The mean dose changes were decreased by 14.52 in the SGLT2 inhibitors plus diuretic group (p < .0001), which was statistically significant. Conclusion: Treatment with SGLT2 inhibitors plus diuretic significantly reduced the patients' diuretic requirements. Therefore, our finding supports the theoretical concept of minimizing the level of diuretic upon the initiation of SGLT2 inhibitors.

Why have SGLT2 Inhibitors Failed to Achieve the Desired Success in COVID-19?

The SARS-CoV-2 virus emerged towards the end of 2019 and caused a major worldwide pandemic lasting at least 2 years, causing a disease called COVID-19. SARS-CoV-2 caused a severe infection with direct cellular toxicity, stimulation of cytokine release, increased oxidative stress, disruption of endothelial structure, and thromboinflammation, as well as angiotensin-converting enzyme 2 (ACE2) down-regulation-mediated renin-angiotensin system (RAS) activation. In addition to glucosuria and natriuresis, sodium-glucose transport protein 2 (SGLT2) inhibitors (SGLT2i) cause weight loss, a decrease in glucose levels with an insulin-independent mechanism, an increase in erythropoietin levels and erythropoiesis, an increase in autophagy and lysosomal degradation, Na+/H+-changer inhibition, prevention of ischemia/reperfusion injury, oxidative stress and they have many positive effects such as reducing inflammation and improving vascular function. There was great anticipation for SGLT2i in treating patients with diabetes with COVID-19, but current data suggest they are not very effective. Moreover, there has been great confusion in the literature about the effects of SGLT2i on COVID-19 patients with diabetes . Various factors, including increased SGLT1 activity, lack of angiotensin receptor blocker co-administration, the potential for ketoacidosis, kidney injury, and disruptions in fluid and electrolyte levels, may have hindered SGLT2i's effectiveness against COVID-19. In addition, the duration of use of SGLT2i and their impact on erythropoiesis, blood viscosity, cholesterol levels, and vitamin D levels may also have played a role in their failure to treat the virus. This article aims to uncover the reasons for the confusion in the literature and to unravel why SGLT2i failed to succeed in COVID-19 based on some solid evidence as well as speculative and personal perspectives.

Effect of Heart Failure Pharmacotherapies in Patients with Heart Failure with Mildly Reduced Ejection Fraction.

The study sought to comprehensively investigate the effect of heart failure (HF) pharmacotherapies in patients with heart failure with mildly reduced ejection fraction (HFmrEF). In the absence of randomized controlled trials, guideline recommendations concerning HF-related therapies in patients with HFmrEF are limited. Consecutive patients hospitalized with HFmrEF were retrospectively included at one institution from 2016 to 2022. The prognostic value of treatment with beta-blockers (BB), angiotensin-converting enzyme inhibitors, receptor blockers or receptor-neprilysin inhibitor (ACEi/ARB/ARNI), mineralocorticoid receptor antagonists (MRA) and sodium-glucose transport protein 2 inhibitors (SGLT2i) was investigated for all-cause mortality at 30 months (median follow-up) and HF-related rehospitalization. 2,109 patients with HFmrEF were included. Treatment with BB (27.0% vs. 35%; HR = 0.737; 95% CI 0.617-0.881; p = 0.001), ACEi/ARB/ARNI (25.9% vs. 37.6%; HR = 0.612; 95% CI 0.517-0.725; p = 0.001) and SGLT2i (11.9% vs. 29.5%; HR = 0.441; 95% CI 0.236-0.824; p = 0.010) was associated with lower risk of 30-months all-cause mortality, which was still demonstrated after multivariable adjustment and propensity score matching. In contrast, MRA treatment was not associated with long-term prognosis. The risk of HF-related rehospitalization was not affected by HF pharmacotherapies. Finally, the lowest risk of long-term all-cause mortality was observed in patients with combined use of BB, ACEi/ARB/ARNI and SGLT2i (HR = 0.456; 95% CI 0.227-0.916; p = 0.027). BB, ACEi/ARB/ARNI and SGLT2i were independently associated with lower risk of all-cause mortality in patients with HFmrEF, specifically when applied as combined "HF triple therapy". Randomized studies are needed to investigate the effect of HF-related pharmacotherapies in patients with HFmrEF.

Effectiveness and safety of the combination of sodium-glucose transport protein 2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of observational studies.

Randomized controlled trials and real-world studies suggest that combination therapy with sodium-glucose transport protein 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is associated with improvement in fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), systolic blood pressure (SBP), body mass index (BMI), and total cholesterol levels. However, a systematic review of available real-world evidence may facilitate clinical decision-making in the real-world scenario. This meta-analysis assessed the safety and effectiveness of combinations of SGLT2is + GLP-1RAs with a focus on their cardioprotective effects along with glucose-lowering ability in patients with type 2 diabetes mellitus (T2DM) in a real-world setting. Electronic searches were performed in the PubMed/MEDLINE, PROQuest, Scopus, CINAHL, and Google Scholar databases. Qualitative analyses and meta-analyses were performed using the Joanna Briggs Institute SUMARI software package and Review Manager v5.4, respectively. The initial database search yielded 1445 articles; of these, 13 were included in this study. The analyses indicated that SGLT2is + GLP-1RAs combinations were associated with significantly lower all-cause mortality when compared with individual therapies (odds ratio [95% confidence interval [CI] 0.49 [0.41, 0.60]; p < 0.00001). Significant reductions in BMI (- 1.71 [- 2.74, - 0.67]; p = 0.001), SBP (- 6.35 [- 10.17, - 2.53]; p = 0.001), HbA1c levels (- 1.48 [- 1.75, - 1.21]; p < 0.00001), and FPG (- 2.27 [- 2.78, - 1.76]; p < 0.00001) were associated with the simultaneous administration of the combination. Changes in total cholesterol levels and differences between simultaneous and sequential combination therapies for this outcome were not significant. This systematic review and meta-analysis based on real-world data suggests that the combination of SGLT2is + GLP-1RAs is associated with lower all-cause mortality and favorable improvements in cardiovascular, renal, and glycemic measurements. The findings drive a call-to-action to incorporate this combination early and simultaneously in managing T2DM patients and achieve potential cardiovascular benefits and renal protection.

Safety and Tolerability of SGLT2 Inhibitors in Cardiac Amyloidosis-A Clinical Feasibility Study.

Sodium-glucose transport protein 2 inhibitors (SGLT2i) slow the progression of renal dysfunction and improve the prognosis of patients with heart failure. Amyloidosis constitutes an important subgroup for which evidence is lacking. Amyloidotic fibrils originating from misfolded transthyretin and light chains are the causal agents in ATTR and AL amyloidosis. In these most frequent subtypes, cardiac involvement is the most common organ manifestation. Because cardiac and renal function frequently deteriorate over time, even under best available treatment, SGLT2i emerge as a promising treatment option due to their reno- and cardioprotective properties. We retrospectively analyzed patients with cardiac amyloidosis, who received either dapagliflozin or empagliflozin. Out of 79 patients, 5.1% had urinary tract infections; 2 stopped SGLT2i therapy; and 2.5% died unrelated to the intake of SGLT2i. No genital mycotic infections were observed. As expected, a slight drop in the glomerular filtration rate was noted, while the NYHA functional status, cardiac and hepatic function, as well as the 6 min walk distance remained stable over time. These data provide a rationale for the use of SGLT2i in patients with amyloidosis and concomitant cardiac or renal dysfunction. Prospective randomized data are desired to confirm safety and to prove efficacy in this increasingly important group of patients.

The Prevention of Diabetic Ketoacidosis in Patients with Type 2 Diabetes on Sodium-Glucose Transport Protein 2 Inhibitors

Background: Sodium-Glucose Transport Protein 2 Inhibitors (SGLT2Is) effectively control diabetes. Diabetic ketoacidosis (DKA) has been reported as a life-threatening adverse effect due to SGLT2Is use. Aim: This study aims to review the current evidence of incidence, predisposing factors and the prevention of DKA in T2DM patients on SGLT2Is use. Methods and Materials: Two reviewers have conducted a search strategy of studies published in English between August 2012 and November 2020, in EBSCOhost, Google Scholar, PubMed, Science Direct and Wiley. Two reviewers independently assessed the eligibility and quality of the studies and extracted the data. Results: 85 studies were identified in the initial search; 75 records were removed and finally, 10 studies were included. Only studies discussing the prevention of DKA in T2DM patients on SGLT2Is were selected, extracted and categorized into main domains that included SGLT2Is use inT2DM patients and DKA (50%), SGLT2Is use in T2DM patients (20%), the clinical presentation of DKA (20%) and DKA prevention (10%). Six studies showed SGLT2Is increased the risk of DKA with very low rates in two studies. The precipitating factors of DKA in all included studies were revealed asstopping or reducing insulin, trauma, infection, surgery, severe acute illness, vigorous exercise, dehydration, low carbohydrate intake and excessive alcohol intake. In two studies DKA can be prevented by wakefulness and education, in one study by closed follow-up, in one study by regular monitoring and adjustment of medications and in two studies by recognition of patients at risk. Conclusions: This review summarized the prevention of DKA in T2DM patients on SGLT2Is use with consideration of incidence, a summary of evidence and predisposing factors. Physicians, health care providers and patients should be aware of SGLT2Is use, regular follow up, precipitating factors, symptoms, signs and prevention of DKA. Keywords: Sodium-Glucose Transport Protein 2 Inhibitors SGLT2Is, Type 2 diabetes mellitus, Diabetic Ketoacidosis, Scoping Review.

Prescribing patterns of adjunctive therapy for the treatment of type 1 diabetes mellitus among Australian endocrinologists.

Many people living with type 1 diabetes (type 1 diabetes mellitus (T1DM)) do not meet glycaemic targets. Adjunctive therapies have both risks and metabolic benefits and may have a role in selected patients. To review the prescribing patterns of adjunctive therapy for the treatment of T1DM diabetes in Australia. We conducted an online survey of Australian endocrinologists and endocrinology registrars. We surveyed the frequency of, motivations and concerns regarding the prescription of metformin, dipeptidyl peptidase-4 (DPP-IV) inhibitors, sodium-glucose transport protein 2 (SGLT-2) inhibitors and glucagon-like peptide 1 receptor agonist (GLP1RA) in T1DM. Fifty-two practitioners participated. Most respondents (94%) had prescribed adjuncts for the treatment of T1DM in some form. Weight (89%), large insulin doses (73%), glycaemic variability (52%), high HbA1c (48%) and the presence of cardiovascular disease (48%) were the most common factors determining the use of adjuncts. The most commonly prescribed adjuncts were metformin (94%) and SGLT-2 inhibitors (65%). Respondents who had never prescribed an SGLT-2 inhibitor (n = 18) reported risk of diabetic ketoacidosis (DKA) (100%), off-label status (39%), lack of evidence (39%), withdrawal of support from the European Medicines Agency (17%) and cost (17%) as factors contributing to their decision. Thirty-one respondents (60%) had prescribed a GLP1RA. Among those who had never prescribed a GLP1RA (n = 21), off-label status (57%), lack of evidence (48%), cost (38%) and expected lack of efficacy (14%) were factors affecting their decision. Only five respondents (10%) had prescribed a DPP-IV inhibitor. Australian endocrinologists commonly prescribe adjuncts to address cardiometabolic concerns in T1DM. DKA risk and off-label status are significant factors contributing to reluctance to prescribe.

The role of anti-diabetic drugs in NAFLD. Have we found the Holy Grail? A narrative review

PurposeNon-alcoholic fatty liver disease (NAFLD) has become a leading cause of liver disease, affecting 30% of the global population. NAFLD prevalence is particularly high in obese individuals and patients with type 2 diabetes mellitus (T2DM). NAFLD ranges from simple fat deposition in the liver to necroinflammation and fibrosis (non-alcoholic steatohepatitis (NASH)), NASH-cirrhosis, and/or hepatocellular carcinoma. Insulin resistance plays a key role in NAFLD pathogenesis, alongside dysregulation of adipocytes, mitochondrial dysfunction, genetic factors, and changes in gut microbiota. Since insulin resistance is also a major predisposing factor of T2DM, the administration of anti-diabetic drugs for the management of NAFLD seems reasonable.MethodsIn this review we provide the NAFLD-associated mechanisms of action of some of the most widely used anti-diabetic drugs, namely metformin, pioglitazone, sodium-glucose transport protein-2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor analogs (GLP1 RAs), and dipeptyl-peptidase-4 inhibitors (DPP4i) and present available data regarding their use in patients with NAFLD, with and without T2DM.ResultsBoth metformin and DPP4i have shown rather contradictory results, while pioglitazone seems to benefit patients with NASH and is thus the only drug approved for NASH with concomitant significant liver fibrosis by all major liver societies. On the other hand, SGLT2i and GLP1 RAs seem to be beneficiary in patients with NAFLD, showing both remarkable results, with SGLT2i proving to be more efficient in the only head-to-head study so far.ConclusionIn patients with NAFLD and diabetes, pioglitazone, GLP1 RAs, and SGLT2i seem to be logical treatment options. Larger studies are needed before these drugs can be recommended for non-diabetic individuals.

The role of sodium-glucose transport Protein-2 (Sglt-2) inhibitor on albuminuria and the progressive of diabetic kidney disease

Diabetes mellitus (DM) is a non-communicable disease with an increasing incidence every year. Sodium-Glucose Transport Protein-2 (SGLT-2) inhibitors are a class of insulin-independent antidiabetic drugs that can reduce the incidence of kidney function damage. This study aimed to determine the role of SGLT-2 inhibitor therapy in preventing the incidence of albuminuria so that it can be used as a consideration for treatment applications in type 2 DM patients. This study used the literature review method. Stages in data collection using the PRISMA method from several Journal Databases based on inclusion and exclusion criteria. SGLT-2 inhibitors are antidiabetic drugs that can help glycemic control with a good safety profile. The effectiveness of SGLT2 inhibitor class drugs has been proven to reduce the occurrence of albuminuria and impact the progression of diabetic kidney disease. Further research can be carried out to prove the benefits of this modality comprehensively.

PERIOPERATIVE DIABETIC KETOACIDOSIS ASSOCIATED WITH SODIUM-GLUCOSE CO-TRANSPORTER-2 INHIBITORS : A SYSTEMATIC REVIEW

DKA or diabetic ketoacidosis is an emergency condition caused by hyperglycemia in which excessive acid is produced in the blood. Patients with type 1 and type 2 diabetes who undergo surgery, have an infection, or are under extreme stress can also develop DKA. The body generates the hormone adrenaline to combat infection and stress, but this can have a negative effect on blood glucose levels (adrenaline is counterinsulin). This can worsen if the patient refuses to take diabetes medication or inject insulin during stressful or infectious situations. The fundamental components of the pathophysiological mechanisms at play in diabetic ketoacidosis (DKA) include shifts in hormone levels and the ensuing inflammatory response. Alterations in the concentration of hormones lead to shifts in the production and consumption of glucose, as well as an increase in lipolysis and the formation of ketone bodies. Canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin are agents approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus (DM) in adults. Acting on proteins, the four agents are SGLT2 inhibitor class agents. SGLT-2 is expressed in the kidney's proximal tubule. This may result in a decrease in filtered glucose reabsorption, a decrease in the renal threshold for glucose (RTG), and an increase in glucose excretion via urine. Diabetes patients treated with sodium–glucose transport protein 2 (SGLT2) inhibitors have also been reported to experience DKA. The results of a study indicate that DKA is uncommon among T2DM patients treated with SGLT2 inhibitors.

An Audit of Inpatient Management of Acute Decompensated Heart Failure With Reduced Ejection Fraction in General Medicine

This audit aimed to describe the use of guideline-directed medical therapies (GDMT) in patients with heart failure with reduced ejection fraction who have been hospitalised with decompensated heart failure in a tertiary hospital. Patients not on GDMT due to medical contraindications are termed to be on “rationalised medical therapy” (RMT). The primary objective was to assess the percentage of patients discharged on GDMT, RMT, or suboptimal therapy. Secondary outcomes were the prevalence of sodium-glucose transport protein 2 inhibitors (SGLT2I) use and inpatient venous thromboembolism (VTE) prophylaxis. Patients aged ≥18 years, with a left ventricular ejection fraction of <40% and admitted under General Medicine at Middlemore with an ICD-10 diagnosis of acute decompensated heart failure between 30 September 2021 and 30 March 2022 were identified. Sixty-two patients were randomly selected from an eligible population of 339 patients. Data collection was performed using the Electronic-Prescribing and Electronic Discharge Summary applications. Twenty-seven patients (44%) were discharged on GDMT, 17 (27%) were discharged on RMT, and 18 (29%) were discharged on suboptimal therapy; 8% of patients were discharged on SGLT2I, while 80% did not meet PHARMAC Special Authority criteria. A total of 69% of patients received VTE prophylaxis. Eighteen patients (29%) were on suboptimal heart failure therapy at discharge and almost 31% did not have VTE prophylaxis. This may lead to suboptimal outcomes in mortality and morbidity. A total of 80% of patients could benefit from SGLT2I therapy but did not meet special authority criteria.

Implantable cardioverter defibrillator for primary prevention in patients with non-ischemic cardiomyopathy in the era of novel therapeutic agents- meta-analysis.

Evidence regarding the mortality benefit of implantable cardioverter defibrillator (ICD) non-ischemic dilated cardiomyopathy (NIDCM) is inconsistent. The most recent randomized study, the DANISH trial, did not find improved outcomes with ICD. However, based on previous studies and meta-analyses, current guidelines still highly recommend ICD implantation in NIDCM patients. The introduction of novel medications for heart failure improved the clinical outcome dramatically. We aimed in this study to evaluate the effect of Angiotensin Receptor-Neprilysin Inhibitors (ARNi) and sodium-glucose transport protein 2 inhibitors (SGLT2i) on the mortality benefit of ICD in NIDCM. We used a previous metanalysis algorithm and added an updated comprehensive literature search in PubMed for randomized control trials that examined the mortality benefit of ICD in NIDCM vs. optimal medical treatment. The primary outcome included death from any cause. We did a meta-regression analysis to search for a single independent factor affecting mortality. Using previous data, we evaluated the theoretical effect of ICD implementation on patients treated with SGLT2 inhibitors and ARNi. No new articles were added to the results of the previous meta-analysis. 2,622 patients with NIDCM from 5 cohort studies published between 2002 and 2016 were included in the analysis. 50% of them underwent ICD implantation for primary prevention of sudden cardiac death, and 50% did not. ICD was associated with a significantly decreased risk for death from any cause compared to control (OR = 0.79, 95%CI: 0.66-0.95, p = 0.01, I2 = 0%). The theoretical addition of ARNi and the SGLT2 inhibitor dapagliflozin did not change the significant mortality effect of ICD (OR = 0.82, 95%CI: 0.7-0.9, p = 0.001, I2 = 0%) and (OR = 0.82, 95%CI: 0.7-0.9, p = 0.001, I2 = 0%). A meta-regression revealed no association between death from any cause and left bundle branch block (LBBB), use of amiodarone, use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers, year initiated enrollment, and the year ended enrollment (R2 = 0.0). In patients with NIDCM, the addition of ARNi and SGLT2i did not affect the mortality advantages of ICD for primary prevention. https://www.crd.york.ac.uk/prospero/, identifier: CRD42023403210.

Effectiveness of apabetalone and some other indirect epigenetic-oriented drugs in the treatment of heart failure

Epigenetic therapy for cardiovascular disease (CVD) has received increased attention from the medical community in recent years. Evidence of this is the fact that more and more controlled clinical trials evaluate the beneficial effects of: 1) direct epigenetic drugs, for example, apabetalone, and 2) repurposed drugs with possible indirect epigenetic action, for example, metformin, statins, sodium-glucose transport protein 2 (SGLT2) inhibitors and omega-3 polyunsaturated fatty acids (PUFAs) in CVD, including heart failure (HF) with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Apabetalone is the first and unique direct-acting epigenetic drug tested in patients with CVD, and the BETonMACE study showed a reduction in first hospitalization for HF (at any EF) and CVD mortality in patients with type 2 diabetes (T2D) and recent acute coronary syndrome, suggesting a possible role for this drug in secondary prevention. Patients with HFpEF appear to benefit from the addition of metformin and SGLT2 inhibitors to standard statin therapy due to their ability to reduce the death risk. In contrast, hydralazine with or without isosorbide dinitrate produced no beneficial effects. In HFrEF, metformin and SGLT2 inhibitors may reduce the risk of HF and death, while clinical trials with statins have mixed results. PUFA supplementation was associated with a significant reduction in car­diovascular risk in both HFrEF and HFpEF. However, definitive data on the benefits of direct and indirect epigenetic therapy for CVD can only be obtained from large clinical trials in the future. The purpose of this review was to provide updated information on epigenetic therapy for CVD obtained from clinical trials.

Semaglutide: new dawn for diabetics.

Madam, the growing prevalence of diabetes and obesity in Pakistan demands an optimal treatment plan to simultaneously manage the root pathologies. Semaglutide is a novel glucagon-like peptide-1 receptor agonist (GLP-1 RA) that was approved by the Food and Drug Administration (FDA) in 2017 for the treatment of type 2 diabetes and has recently, in 2020, approved for cardiovascular (CV) risk reduction in adults with T2D and known heart disease. Semaglutide has proved beneficial in terms of inducing weight loss while actively reducing blood glucose and blood pressure. It is also the first of its class to be available in an oral form in addition to the standard subcutaneous (SC) therapy. Results from various research trials indicate a superiority of Semaglutide not only among other GLP-1 RA of its class but also over insulin glargine and Sitagliptin inducing significant weight loss and reducing HbA1c and systolic blood pressure.1 It does this while continuing to offer a favorable CV profile. Studies like Sustain 6 and Pioneer 6, have demonstrated a non-inferiority and safety of SC and oral Semaglutide in CV health. At the same time while we await the completion of the SOUL and SELECT trials to confirm an added potential superiority in improving CV outcomes.2 In conclusion, Semaglutide can safely be used in patients with T2D as a monotherapy or as an add-on to metformin or insulin. The Diabetes Canada guidelines 2018 recommend using incretins like GLP1 RA, and/or Sodium-glucose transport protein 2 inhibitors (SGLT2i) when weight loss and lower risk of hypoglycemia are a targeted patient priority.3 However, Helena et al. have demonstrated more significant reductions in HbA1c and continued weight loss beyond week 26 up to week 52, with Semaglutide signifying its superiority over standard empagliflozin therapy.4 Semaglutide, although well-tolerated, has some side effects, including dizziness, headache, and gastrointestinal upset3,5 that can be reduced by gradually increasing the dose.3 Potential side effects of pancreatitis and diabetic retinopathy, however, require physicians to warrant caution as such side effects may yet have been underreported or understudied.1 Nonetheless, the beneficial effects of Semaglutide, a once-weekly SC dose, and the alternative option of an oral formulation offer ease of use for the patient. However, the lack of research and cost-effectiveness have limited its use and availability in Pakistan. Therefore, ample work must be done to introduce this important drug in our market and routine practice.

A step-by-step guide for the diagnosis and management of hyponatraemia in patients with stroke.

Hyponatraemia is common in patients with stroke and associated with adverse outcomes and increased mortality risk. The present review presents the underlying causes and provides a thorough algorithm for the diagnosis and management of hyponatraemia in stroke patients. Concomitant diseases and therapies, such as diabetes, chronic kidney disease and heart failure, along with diuretics, antidepressants and proton pump inhibitors are the most common causes of hyponatraemia in community. In the setting of acute stroke, the emergence of hyponatraemia might be attributed to the administration of hypotonic solutions and drugs (ie. mannitol and antiepileptics), poor solute intake, infections, as well as stroke-related conditions or complications, such as the syndrome of inappropriate secretion of antidiuretic hormone, cerebral salt wasting syndrome and secondary adrenal insufficiency. Diagnostically, the initial step is to differentiate hypotonic from non-hypotonic hyponatraemia, usually caused by hyperglycaemia or recent mannitol administration in patients with stroke. Determining urine osmolality, urine sodium level and volume status are the following steps in the differentiation of hypotonic hyponatraemia. Of note, specific parameters, such as fractional uric acid and urea excretion, along with plasma copeptin concentration, may further improve the diagnostic yield. Therapeutic options are based on the duration and symptoms of hyponatremia. In the case of acute or symptomatic hyponatraemia, hypertonic saline administration is recommended. Hypovolaemic chronic hyponatremia is treated with isotonic solution administration. Although fluid restriction remains the first-line treatment for the rest forms of chronic hyponatraemia, therapies increasing renal free water excretion may be necessary. Loop diuretics and urea serve this purpose in patients with stroke, whereas sodium-glucose transport protein-2 inhibitors appear to be a promising therapy. Nevertheless, it is yet unclear whether the appropriate restoration of sodium level improves outcomes in such patients. Randomized trials designed to compare therapeutic strategies in managing hyponatraemia in patients with stroke are required.

SGLT2i uptake among heart failure patients with reduced ejection fraction: ongoing prescriber hesitancy and how to address this

Abstract Background The evidence of mortality benefit from sodium-glucose transport protein 2 inhibitors (SGLT2i) in the management of heart failure with reduced ejection fraction (HFrEF) has been observed since 2019. Its first-line use in HFrEF, regardless of diabetes status, has been recommended by The European Society of Cardiology (ESC) since September 2021. Yet prescriber hesitancy surrounding SGLT2i use is still an under investigated issue resulting in centres falling short of gold-standard care. A simple review of pharmacotherapy pattern can alert clinicians to under prescribing of SGLT2i inhibitors and respond by improving adherence to guidelines. Purpose To describe the pharmacotherapy pattern of HFrEF patients attending an outpatient (Heart Failure Support Unit) HFSU in Ireland. Methods A retrospective analysis was performed in HFrEF patients actively attending the HFSU. Active attendance was considered a single engagement with the service between 1st January 2021 and 31st December 2021, and patients who have not died, been transferred to another service, or loss to follow-up. Information collected from digital records included patient demographic, comorbidities, baseline investigations, and pharmacotherapy pattern. Sensitivity analysis was performed for patients with type 2 diabetes (T2DM). Results 156 HFrEF patients were actively attending the HFSU. The mean age was 72.1 (±12.5) years and majority were male 114 (73.1%). The following pharmacotherapy pattern was revealed: angiotensin-converting enzyme inhibitors/ angiotensin II receptor blockers (ACEi/ARBs) 80 (51.3%), ARNi 55 (35.3%), β-blockers 142 (91.0%), mineralocorticoid receptor antagonist (MRA) 58 (37.2%), SGLT2i 9 (5.8%) and Ivabradine 9 (5.8%). Sensitivity analysis for T2DM patients (n=45) reveals a pattern of ACEi/ARBs 46.7%, ARNi 37.8%, β-blockers 95.6%, MRA 42.2%, SGLT2i 20.0% and Ivabradine 8.9%. All 9 instances of SGLT2i use were in T2DM patients. Since identification of SGLT2i under-prescribing, an interim review on 28th February 2022 revealed that total SGLT2i prescription had increased by 19 (211.1%), all of which were outside the T2DM population. Conclusions SGLT2i is still under prescribed for HFrEF management and prescriptions have the tendency to be restricted to T2DM patients. Identification of pharmacotherapy pattern can alert clinicians to prescriber hesitancy and increase new SGLT2i prescriptions outside the T2DM population. Funding Acknowledgement Type of funding sources: None.

LEFT VENTRICULAR MASS PREDICTS CARDIAC REVERSE REMODELING IN PATIENTS TREATED WITH EMPAGLIFLOZIN: AN EXPLORATORY SUB-ANALYSIS OF THE EMPA-HEART CARDIOLINK-6 RANDOMIZED CONTROLLED TRIAL

LEFT VENTRICULAR MASS PREDICTS CARDIAC REVERSE REMODELING IN PATIENTS TREATED WITH EMPAGLIFLOZIN: AN EXPLORATORY SUB-ANALYSIS OF THE EMPA-HEART CARDIOLINK-6 RANDOMIZED CONTROLLED TRIAL

INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN-7 AS A MARKER OF CARDIAC REVERSE REMODELING WITH EMPAGLIFLOZIN: A SECONDARY ANALYSIS OF THE EMPA-HEART CARDIOLINK-6 RANDOMIZED CONTROLLED TRIAL

Reverse cardiac remodeling is believed to contribute to the cardiovascular benefits offered by sodium-glucose transport protein 2 inhibitors (SGLT2i). Given the association between insulin-like growth factor binding protein 7 (IGFBP7) levels and cardiac remodeling, it has been postulated that IGFBP7 may serve as a predictor for individuals who may derive greater benefit from SGLT2i therapy. This exploratory sub-analysis of the EMPA-HEART CardioLink-6 trial examined the association between serum IGFBP7 levels and reverse cardiac remodeling in patients treated with empagliflozin.

The Intersection of SGLT2 Inhibitors, Cognitive Impairment, and CKD.

Impairment in cognition and decline in kidney function often converge in the aging individual with chronic kidney disease (CKD). Cognitive impairment (CI) may be preventable through modification of health behaviors and risk factors that contribute to the vascular disease burden. CKD patients often have multiple coexisting comorbid conditions contributing to vascular risk. These comorbidities include hypertension, diabetes, cerebrovascular disease, and cardiovascular disease. Emerging evidence suggests that the management and prevention of vascular risk factors and cardiovascular diseases may indirectly contribute to the prevention of CI in CKD. Sodium glucose transport protein 2 inhibitors (SGLT2i) are emerging as the standard of care for selected individuals with CKD, type 2 diabetes (T2DM), and heart failure with rapidly expanding indications being actively investigated. In this narrative review, we examine the intriguing hypothesis that SGLT2i demonstrate potential disease modifying properties in CI among individuals with CKD.

A precision medicine approach to metabolic therapy for breast cancer in mice

Increasing evidence highlights approaches targeting metabolism as potential adjuvants to cancer therapy. Sodium-glucose transport protein 2 (SGLT2) inhibitors are the newest class of antihyperglycemic drugs. To our knowledge, SGLT2 inhibitors have not been applied in the neoadjuvant setting as a precision medicine approach for this devastating disease. Here, we treat lean breast tumor-bearing mice with the SGLT2 inhibitor dapagliflozin as monotherapy and in combination with paclitaxel chemotherapy. We show that dapagliflozin enhances the efficacy of paclitaxel, reducing tumor glucose uptake and prolonging survival. Further, the ability of dapagliflozin to enhance the efficacy of chemotherapy correlates with its effect to reduce circulating insulin in some but not all breast tumors. Our data suggest a genetic signature for breast tumors more likely to respond to dapagliflozin in combination with paclitaxel. In the current study, tumors driven by mutations upstream of canonical insulin signaling pathways responded to this combined treatment, whereas tumors driven by mutations downstream of canonical insulin signaling did not. These data demonstrate that dapagliflozin enhances the response to chemotherapy in mice with breast cancer and suggest that patients with driver mutations upstream of canonical insulin signaling may be most likely to benefit from this neoadjuvant approach.