SGLT2 Inhibitors Research Articles

6954 Effect Of The SARS-CoV-2 Pandemic on Metabolic Control In Patients With Type 2 Diabetes: A 5-year Cohort Follow-Up

Abstract Disclosure: D.P. Morales Rodríguez: None. M. Romero Ibarguengoitia: None. A. Garza-Silva: None. A. Rivera-Cavazos: None. I. Fernandez-Chau: None. A. Cepeda Medina: None. A. Gonzalez-Cantú: None. The SARS-CoV-2 pandemic brought a radical shift in the healthcare system and a suboptimal care for vulnerable patients, such as those with Type 2 Diabetes Mellitus (T2DM). Thus, we compared the metabolic control of patients with T2DM before and throughout 3 years of the SARS-CoV-2 pandemic, described the type of consultations and trends in attendance in various specialties, and compared the number of medications prescribed to patients before and during the pandemic. We conducted a retrospective observational cohort study on steelworkers with T2DM from a hospital in northeastern Mexico, who were treated by a multidisciplinary team from 2018 to 2022. We analyzed HbA1C levels, fasting serum glucose (FGS), low-density lipoprotein cholesterol (LDLc), blood pressure (BP) values, microalbuminuria, attendance at consultations across different specialties, and the trend in medication usage. We analyzed 999 subjects, 516 (51.7%) males, with a mean age (SD) of 60.1 (12.7) years. A significant difference was found in the proportion of controlled patients based on HbA1C with 55.5% in 2018 and 70.7% in 2022 (p<0.001). There was an increase of FGS control from 13.8% in 2018 to 56.1% in 2022 (p<0.001). LDL cholesterol control exhibited a decrease from 62.1% in 2018 to 57% in 2022 (p<0.001). Proportion of patients with systolic BP control decreased from 82.7% in 2018 to 80.1% in 2022 (p<0.001). Diastolic BP control was 89.6% in 2018 with an increase to 91.4% in 2022 (p=0.01). Microalbuminuria based control, increased from 80.5% in 2018 to 89% in 2022 (p=0.002). Telephone consultations were introduced in 2020, with 899 (90%) patients using this modality at least once, leading to a 35.8% decrease of in-person consultations (n=541,54.2%) and reaching its lowest point in 2021 (n=2, 0.2%). Throughout the follow-up period, all patients had at least one annual consultation with an internist or geriatrician based on their age group. There was an increase of endocrinology consultations from 8.5% in 2018 to 12.1% in 2022 and in cardiology from 6.9% in 2018 to 10.3% in 2022 (<0.05). There was a rise in the prescription of oral hypoglycemic agents raging from 4.9% to 14.2% between 2018 and 2020, with SGLT2 inhibitors being the highest prescribed and a 2.5% decrease in the prescription of sulfonylureas between 2018 and 2020. Similarly, there was an increase in the prescription of long-acting insulin by 5.9% between 2018 and 2020. There was a higher proportion of patients with controlled glycemic and diastolic blood pressure targets during the SARS-CoV-2 pandemic, this can be attributed to patient’s access to telemedicine and a multidisciplinary team capable of providing an appropriate medication prescription for an optimized management and improvement in patient’s quality of life. Presentation: 6/1/2024

7049 DUNNIGAN LIPODYSTROPHY AND SUCCESSFUL USE OF AID WITH U200

Abstract Disclosure: T. Kader: None. S. Seltzer: None. A. williams: None. Our patient is a 60 year old female with dunnigans partiallipodystrophy diagnosed after her niece was diagnosed and was sent to genetics; She was found to have a mutation in LMNA geneand had a heterozygous sequence variant.She was diagnosed with partial lipodystrophy and had macrovascular complications including carotid stenosis requiring surgical intervention.She was treated originally with insulin pump therapy that was sensor augmented along with glp1 agonist and sglt2 inhibitor but she developed recurrent pancreatitis and glp1 agonist was stopped. The pancreatitis was not induced by hypertriglycidemia as her levels were normal.Since then she had poorly controlled diabetes with a1c 8.7 percent and was having some hypoglycemia.;After consultation with the patient about off□ label use of AID pump technology for type 2 diabetes and off□ label use of u200 in AID pump she was willing to try and results were quite impressive with a1c falling close to 7 and time in range up to 70 percent with no lows. Her total insulin dosages were approximately 200 units q day but with u 200 she was changing every 2 days .Despite insulin resistance and dunnigan lipodystrophy this case exemplifies safety of u200 in AID pump in a patient with dunnigans lipodystrophy. It is the first of such report and more studies should be done using this technology in this rare group of patients with insulin resistance and poorly controlled diabetes. Presentation: 6/1/2024

6541 Recurrent Euglycemic Diabetic Ketoacidosis And Myonecrosis In A Patient Previously Thought To Have Type 2 Diabetes Mellitus

Abstract Disclosure: K. Haridas: None. M.M. McConnell : None. Introduction: Euglycemic diabetic ketoacidosis (DKA) is a well-recognized complication with the use of sodium linked cotransport of glucose-2 (SGLT2) inhibitors. Diabetic myonecrosis is a rare complication of diabetes mellitus caused by spontaneous death of muscle due to microvascular ischemia. Clinical Case: A 48-year-old male diagnosed with Type 2 Diabetes Mellitus with HbA1c 11.3%, treated with Empagliflozin and basal-bolus insulin was admitted to the hospital with left thigh pain and anorexia. Physical examination was notable for BMI of 19kg/m2 and left lateral thigh induration. Laboratory evaluation revealed venous pH 7.1, bicarbonate 10mmol/L (20-30), anion gap 32mmol/L(8-12), glucose 168mg/dl (65-99), ESR 67mm/h (<=12), Creatinine Kinase 31 U/L (63-473), glucosuria (4+) and ketonuria (4+). He was diagnosed with euglycemic DKA due to SGLT2 inhibitor. He was also diagnosed with Type 1 Diabetes Mellitus (T1DM) based on undetectable C-peptide and GAD antibody titer 64.3IU/ml(<5). MRI of the left thigh revealed an area of diabetic myonecrosis, measuring 11cm. He was treated with continuous insulin infusion. On hospital day 3, after resolution of the anion gap metabolic acidosis, transition was made to basal-bolus insulin. On hospital day 5, recurrent euglycemic DKA was diagnosed with bicarbonate 15mmol/L, anion gap 18mmol/L, beta-hydroxybutyrate 49.6mg/dl (<=3mg/dl), glucose 185mg/dl, glucosuria (4+) and ketonuria (4+). Continuous insulin infusion was restarted. On hospital day 8, transition was made to subcutaneous insulin. Diabetic myonecrosis was initially managed conservatively with analgesics, aspirin, and physical therapy. Due to worsening leukocytosis on hospital day 13, Ceftriaxone was started and surgical debridement was performed, revealing a loculated abscess within necrotic muscle. Empagliflozin was discontinued at discharge. Discussion: The risk of euglycemic DKA with SGLT2i use is increased in patients with T1DM and decreased oral intake, and insults like trauma or surgery as seen in this patient. Although the half-life of empagliflozin is 12 to 14 hours, there have been case reports of persistent or recurrent euglycemic DKA for 7-12 days from the time of last dose. The continued glucosuria and ketonuria in this patient with serum glucose levels below the renal threshold confirmed the recurrence. Diabetic myonecrosis usually affects the muscles of the proximal lower extremities and is seen in patients with poorly controlled diabetes with microvascular complications, between one and two decades after diagnosis, as in this patient. Conclusion: A high index of suspicion for recurrent euglycemic DKA must be maintained in patients who have new or persistent high anion gap metabolic acidosis until 2 weeks from last dose of SGLT2 inhibitor. Diabetic myonecrosis, especially if complicated by abscess formation, may require surgical intervention. Presentation: 6/1/2024

8075 Euglycemic Diabetic Ketoacidosis Associated With Cocaine Use

Abstract Disclosure: N.N. Solanki: None. A.N. Kiani: None. M. Feldman: None. Euglycemic diabetic ketoacidosis (EDKA) is characterized by increased anion gap metabolic acidosis, ketonemia or ketonuria, and normal blood glucose levels (<200 mg/dL). Due to the absence of hyperglycemia, it commonly presents as a diagnostic and therapeutic dilemma. EDKA is commonly associated with decreased caloric intake, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, recent use of insulin, heavy alcohol consumption, chronic liver disease, glycogen storage disorders, and drug-induced intoxication. Cocaine use is a lesser-known etiology for EDKA. We present a case of a 64-year-old female with a history of type 2 diabetes mellitus who presented with complaints of decreased oral intake for two days secondary to nausea and vomiting and productive cough for one week, along with cocaine use. Despite an extensive history of diabetes and no recent SGLT-2 inhibitor use, her labs were consistent with euglycemic DKA. Her imaging and further investigations revealed respiratory syncytial virus pneumonia. The patient was initially managed for starvation ketoacidosis with fluid resuscitation with no improvement in acidosis and later treated with DKA protocol with rapid correction of her anion gap metabolic acidosis. This case highlights the challenges associated with diagnosing and treating EDKA. Early initiation of DKA protocol should be considered in diabetic patients presenting with euglycemia with high anion gap metabolic acidosis with a clinical picture of starvation and cocaine use. Presentation: 6/3/2024

8647 Reversal Of Left Atrial Dilation In Heart Failure With Preserved Ejection Fraction (HFpEF) Treated With A GLP-1 Receptor Agonist And A Mineralocorticoid Receptor Antagonist

Abstract Disclosure: M. Marino: None. L.S. Phillips: Advisory Board Member; Self; Diasyst, Inc.. Research Investigator; Self; Abbvie, Research Support, Jansen Pharmaceuticals, Research Support, Novo Nordisk, Research Support, Abbott Laboratories, Research Support, GlaxoSmithKline, Research Support, Sanofi-Aventis, Research Support, Pfizer, Inc.. Background: HFpEF is a major public health problem, since contributors include age, hypertension, hyperglycemia, and inactivity - and the US population is aging, hypertension and hyperglycemia are often inadequately treated, and inactivity is common. Moreover, management is difficult, since few medications have improved outcomes, and there is little long-term experience with sodium-glucose co-transporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and mineralocorticoid receptor antagonists. Clinical Case: In October 2010, a 69-year-old male with a history of lung adenocarcinoma with left lower lobe segmentectomy, prostate cancer post prostatectomy, and well-managed hypertension and hyperglycemia experienced severe shortness of breath while running on a track as part of his routine exercise. A left heart catheterization was performed to determine if the symptoms reflected inadequate perfusion, revealing only 30% stenosis in the left anterior descending coronary artery, ruling out coronary disease as the primary etiology. However, the left ventricular end diastolic pressure (LVEDP) was elevated (25 mmHg vs. normal <12), indicating heart failure. A transthoracic echocardiogram (TTE) in December 2010 revealed a normal left ventricular ejection fraction (EF 65%), a severely dilated left atrium [left atrial volume index (LAVI) 57 mL/m2 vs. normal <34], and diastolic dysfunction [flow velocity across the mitral valve (E/A ratio 1.61 and E/e’ 7.26). The patient was given pioglitazone 30mg daily before and nebivolol 2.5mg BID after the TTE, but in March 2011, a TTE showed an EF of 57% with persistent left atrial dilation (LAVI 50 mL/m2). A dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin 100mg daily) was begun August 2011, changed to liraglutide 1.8mg daily in December 2011, and eplerenone 75mg daily was begun February 2012. In June 2012, the LAVI was markedly improved (39 mL/m2). The nebivolol was switched to irbesartan 225mg daily in August 2012, and canagliflozin 300mg daily was added September 2013. A repeat TTE in March 2014 found an EF of 60%, and showed that the LAVI had returned to normal (34 mL/m2). During this period, mean blood pressure was 111/67 mmHg, LDL cholesterol 57 mg/dL, and HbA1c 5.4%, indicating that inadequate risk factor management was unlikely to be contributing to the diastolic dysfunction. Presently, the patient takes semaglutide, pioglitazone, telmisartan, empagliflozin, and eplerenone, continues to exercise vigorously, and a recent TTE showed an EF of 62% with mild left atrial dilation (LAVI 36.6). Conclusion: Left atrial dilation was improved after addition of a GLP-1 receptor agonist and a mineralocorticoid receptor antagonist, prior to use of an SGLT-2 inhibitor. Future investigations are needed to further understand the cardiovascular utility of these medications - beyond glycemic control and electrolyte balance. Presentation: 6/3/2024

Recent trends in GLP-1 RA and SGLT2i use among people with type 2 diabetes and atherosclerotic cardiovascular disease in the USA

IntroductionThis study aimed to assess recent trends in the US use of glucagon-like peptide-1 receptor agonist (GLP-1 RA) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) in people with type 2 diabetes...

Association between prescription drugs and all-cause mortality risk in the UK population.

Although most drugs currently approved are meant to treat specific diseases or symptoms, it has been hypothesized that some might bear a beneficial effect on lifespan in healthy older individuals, outside of their specific disease indication. Such drugs include, among others, metformin, SGLT2 inhibitors and rapamycin. Since 2006, the UK biobank has recorded prescription medication and mortality data for over 500'000 participants, aged between 40 and 70 years old. In this work, we examined the impact of the top 406 prescribed medications on overall mortality rates within the general population of the UK. As expected, most drugs were linked to a shorter lifespan, likely due to the life-limiting nature of the diseases they are prescribed to treat. Importantly, a few drugs were associated with increased lifespans, including notably Sildenafil, Atorvastatin, Naproxen and Estradiol. These retrospective results warrant further investigation in randomized controlled trials.

SGLT-2 Inhibitors Versus GLP-1 Receptor Agonists Effects on Kidney and Clinical Outcomes in Veterans with Type 2 Diabetes.

The primary aim compared kidney endpoints between patients with type 2 diabetes (T2D) 36 months after initiation on a sodium-glucose cotransporter-2 inhibitor (SGLT2i) or a GLP-1 receptor agonist (GLP-1RA). Secondary aims compared estimated glomerular filtration rate (eGFR), hemoglobin A1c (HbA1c), weight, and urine albumin-to-creatinine ratio (UACR) changes. We conducted a retrospective cohort study of propensity score matched veterans with T2D, baseline eGFR>20mL/min/1.73m2, and initiated on a SGLT2i vs GLP-1RA between 4/1/2009-9/1/2020. Cox proportional hazard models were constructed to evaluate effectiveness between both groups on composite endpoint (decline of >=40% in eGFR from baseline, ESRD event, and all-cause mortality) and its components adjusting for baseline characteristics. Spline models were constructed to evaluate eGFR change and linear mixed effects models were constructed to evaluate changes in HbA1c, weight, and UACR. We used an intent-to-treat (ITT) approach as our main analysis followed by a per-protocol (PP) approach excluding veterans who discontinued or switched therapy during the study period. A total of 29,146 propensity score matched veterans were included in SGLT2i and GLP-1RA groups (14,573 per group). In the ITT and PP analyses, veterans initiated on SGLT2i had a 35% (HR=0.65; 95% CI: 0.62, 0.68) and 34% (HR=0.66; 95% CI: 0.62, 0.69) reduction in the hazard of experiencing the composite endpoint compared to veterans initiated on GLP-1RA adjusting for baseline characteristics, respectively. Between 6-36 months, we found an improved chronic eGFR slope with SGLT2i compared to GLP-1RA in both ITT and PP analyses; +1.19 mL/min/1.73 m2 (95% CI: 0.93, 1.45) and +1.29 mL/min/1.73m2 (95% CI: 1.01, 1.57), respectively. The annual difference in chronic eGFR slope in both ITT and PP analyses were +0.97 mL/min/1.73m2/year (95% CI: 0.82, 1.11) and +1.08 mL/min/1.73m2/year (95% CI: 0.92, 1.25). Improved HbA1c, weight loss and UACR were reported for both groups. In this real-world study, veterans with T2D initiated on SGLT2i were associated with reduced hazard of experiencing mortality, worsening eGFR, or developing ESRD and improved glycemic, metabolic, and renal endpoints compared to GLP-1RA use.

The role of coronary microcirculation in heart failure with preserved ejection fraction: An unceasing odyssey.

Heart failure with preserved ejection fraction (HFpEF) represents an entity with complex pathophysiologic pathways, among which coronary microvascular dysfunction (CMD) is believed to be an important orchestrator. Research in the field of CMD has highlighted impaired vasoreactivity, capillary rarefaction, and inflammation as potential mediators of its development. CMD can be diagnosed via several noninvasive methods including transthoracic echocardiography, cardiac magnetic resonance, and positron emission tomography. Moreover, invasive methods such as coronary flow reserve and index of microcirculatory resistance are commonly employed in the assessment of CMD. As far as the association between CMD and HFpEF is concerned, numerous studies have highlighted the coexistence of CMD in the majority of HFpEF patients. Additionally, patients affected by both conditions may be facing an adverse prognosis. Finally, there is limited evidence suggesting a beneficial effect of renin-angiotensin-aldosterone system blockers, ranolazine, and sodium-glucose cotransporter-2 inhibitors in CMD, with further evidence being awaited regarding the impact of other pharmacotherapies such as anti-inflammatory agents.

Hypoglycemic drugs, circulating inflammatory proteins, and gallbladder diseases: A mediation mendelian randomization study

BackgroundThe relationship of hypoglycemic drugs, inflammatory proteins and gallbladder diseases remain unknown. MethodsFour hypoglycemic drugs were selected as exposure: glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter 2 inhibitors (SGLT-2i), and metformin. The outcome were two gallbladder diseases: cholecystitis and cholelithiasis. Mendelian Randomization (MR) was employed to determine the association between hypoglycemic drugs and gallbladder diseases. ResultsDPP-4i and SGLT-2i had no effect on cholecystitis and cholelithiasis. However, a causal relationship was found between inhibition of ETFDH gene, a target of metformin expressed in cultured fibroblasts, and cholelithiasis (OR: 0.84, 95 %CI: (0.72,0.97), p = 0.021), as well as between GLP1R expression in the brain caudate basal ganglia and cholecystitis (OR: 1.29, 95 %CI: (1.11,1.49), p = 0.001). The effect of ETFDH inhibition on cholelithiasis through Interleukin-10 receptor subunit beta (IL-10RB) levels and Neurotrophin-3 (NT-3) levels, with a mediated proportion of 8 % and 8 %, respectively. ConclusionMetformin plays a protective role in cholelithiasis, while GLP-1RA have a harmful effect on the risk of cholecystitis. Metformin may reduce the risk of cholelithiasis by modulating the levels of Neurotrophin-3 (NT-3) and Interleukin-10 receptor subunit beta (IL-10RB). Further clinical and mechanistic studies are required to confirm these findings.

Disorder of Glucose Metabolism and Therapy: Implications on the Natural History of Advanced Chronic Liver Disease

Introduction: Hepatogenous diabetes (HD) is a disorder of glucose metabolism (DGM) that develops as a complication of advanced chronic liver disease (ACLD) with an estimated prevalence of 20–70%. It appears to be associated with a larger number of decompensations, but its impact on the natural history of the disease is unclear. The treatment of DGM is hampered by the fact that some therapeutic agents are associated with a risk of complications in ACLD. The aim of this work was to study DGM in a population of patients with ACLD: prevalence, liver disease decompensation episodes, mortality analysis and study of the impact of antidiabetic therapies in patients with ACLD who developed DGM. Materials and Methods: A cohort of consecutive patients with ACLD without previous DGM, who attended a Hepatology clinic in the period of January to June 2015 was selected. Follow-up was carried out for 5 years. Data on age, gender, date of diagnosis and etiology of ACLD, Child-Pugh and MELD-Na classifications at enrollment, development of DGM, and antidiabetic therapy were collected. Logistic regression models for hospitalizations due to decompensated ACLD, ascites, hepatic encephalopathy (HE), upper gastrointestinal bleeding (UGB), hepatocellular carcinoma (HCC), portal vein thrombosis (PVT), infectious complications, acute-on-chronic liver failure (ACLF), and death were built. A survival analysis for patients with and without DGM was also performed. Treatment effectiveness for patients with DGM was assessed. Results: Initially, 221 patients were included, 154 (69.7%) of whom developed DGM after the diagnosis of ACLD. DGM patients presented a significantly higher number of hospitalizations. Odds ratio (OR) for death was not significantly related with DGM. At 5 years of follow-up, 68.9% of patients with DGM were alive, against 81.8% without DGM (p = 0.087). From the 154 patients who were diagnosed with DGM, 42.9% were not receiving pharmacological treatment for DGM. Treated patients were prescribed with either biguanides (34.8%), a SGLT2 inhibitor (8.6%), or insulin (7.7%). Only 1 patient was treated with a GLP-1 analogue. A tendency of OR favoring treatment was observed for biguanides and SGLT2 inhibitors in all outcomes except ascites. In the univariable analysis, the use of biguanides was associated with lower risk of death (OR: 0.84 [95% CI: 0.73–0.96]) and HE (OR: 0.85 [95% CI: 0.73–0.98]). Conclusion: DGM occurs with high prevalence in patients with ACLD and it seems to be related to more hospitalizations, which highlights the importance of its early identification and appropriate therapeutic approach. In the absence of contraindications, biguanides should be considered for treatment of patients with ACLD and DGM as they appear to be associated with a tendency to better outcomes and may present some advantage in terms of survival.

The use of sodium-glucose cotransporter type 2 inhibitors for the treatment of chronic heart failure in cancer patients receiving cardiotoxic chemotherapy. Preliminary results.

Background. Chronic heart failure (CHF) is one of the most serious and late manifestations of cardiotoxicity during treatment with antitumor drugs in cancer patients. As of today, only 2 groups of drugs have proven significant cardioprotective effects in this category of patients: angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) and beta-blockers (BABs). Only recently has data emerged on the successful use of sodium-glucose cotransporter type 2 inhibitors (SGLT-2) in patients with CHF on anthracycline therapy.Aim. To evaluate the role of SGLT-2 inhibitors in the complex treatment of CHF in cancer patients receiving cardiotoxic chemotherapy.Methods. A prospective observational open study, including 60 patients with verified CHF who received cardiotoxic chemotherapy and dual cardioprotective therapy: ACEIs/ARBs + BABs (control group); and 56 patients who receive similar therapy with the addition of Dapagliflozin 10 mg 1 time in the morning (study group). The results were monitored after 6 months using laboratory and instrumental research methods, as well as additional control methods. Results. Troponin T, N-terminal prohormone of brain natriuretic peptide (NTproBNP) and left ventricular longitudinal strain (GLS) levels were compared in 47 patients who had completed all follow-up studies at 6 months. It was noted that the dynamics of troponin in both groups did not differ significantly (p0.753 and p0.260, respectively), and the level of NTproBNP significantly decreased in the study group by 7.8% compared to the control group (p0.006). Comparable data were obtained for GLS (a decrease in the study group by 6.5% in relative values) compared to the control group (p0.008)). 22 (46.8%) patients had CHF before the start of chemotherapy, and in 25 (53.2%) CHF arose during antitumor drug therapy. There were 17 (16%) deaths, but there were no deaths from heart failureinbothgroups.Conclusion. We believe that a decrease in the marker of heart failure and a less pronounced impairment of the longitudinal deformation of the left ventricle with the addition of SGLT-2 inhibitors to the basic therapy of CHF in cancer patients receiving cardiotoxic chemotherapy can slow down the progression of CHF.

Association of SGLT2 Inhibitors with Incident Cancer: SGLT2i and Incident Cancer

AimIt remains unknown whether sodium-glucose cotransporter 2 inhibitors (SGLT2i) could be associated with incident cancer. MethodsWe analyzed individuals having diabetes and newly prescribed SGLT2i or dipeptidyl peptidase 4 inhibitors (DPP4i) in a large-scale epidemiological database. The primary outcome was the incidence of cancer. A propensity score matching algorithm was employed to compare the subsequent development of cancer between the SGLT2i and DPP4i groups. ResultsAfter 1:2 propensity score matching, 26,823 individuals (8,941 SGLT2i, 17,882 DPP4i) were analyzed. During the mean follow-up duration of 2.0 ± 1.6 years, 1,076 individuals developed cancer. SGLT2i administration was associated with a reduced risk of cancer (HR 0.80, 95% CI 0.70-0.91). Particularly, SGLT2i administration was related to a lower risk of colorectal cancer (HR 0.71, 95% CI 0.50-0.998). Our primary findings remained consistent across various sensitivity analyses, including overlap weighting analysis (HR 0.79, 95% CI 0.66-0.94), inverse probability of treatment weighting 0.75 (95% CI 0.65-0.86), and induction period settings 0.78 (95% CI 0.65-0.93). The risk of developing cancer was comparable among individual SGLT2is (P-value of 0.1738). ConclusionOur investigation using nationwide real-world data demonstrated the potential advantage of SGLT2i over DPP4i in reducing the development of cancer in individuals with diabetes.

A Highly Sensitive Inclusion Complex Based Spectrofluorimetric Method for the Determination of Certain Sodium Glucose Cotransporter-2 Inhibitors: Greenness Assessment and Application to Different Biological Fluids.

This study introduces a remarkably simple, green, and highly sensitive inclusion complex based spectrofluorimetric method for analyzing two sodium glucose cotransporter-2 (SGLT2) inhibitors: empagliflozin (EGF) and dapagliflozin (DGF). The method utilizes beta-cyclodextrin (β-CD) complexation to enhance the native fluorescence of EGF and DGF in aqueous solutions, resulting in 11.0-fold and 9.0-fold intensity increases, respectively. Fluorescence measurements were conducted at 301 nm emission following 230 nm excitation for both drugs. The method demonstrates excellent linearity (0.9994 for EGF and 0.9993 for DGF) over concentration ranges of 5.0-250.0 ng/mL and 10.0-300.0 ng/mL, with low detection limits of 1.05 and 1.38 ng/mL for EGF and DGF, respectively. The method's versatility was validated through successful application in pharmaceutical formulations, content uniformity testing, and biological fluids. This eco-friendly approach primarily uses water as a solvent and requires minimal reagents. The method's environmental impact was comprehensively evaluated using the analytical eco-scale, green analytical procedure index (GAPI), and analytical greenness metric (AGREE).

Diagnostic and therapeutic practice for HFpEF across continents and regions: An international survey.

This study aims to evaluate the worldwide variations in the diagnosis and treatment of heart failure with preserved ejection fraction (HFpEF), using an HF survey distributed internationally to physicians, including both cardiologists and non-cardiologists. A group of HF specialists designed an independent, academic web-based survey focusing on HFpEF care and diagnosis, which was distributed via scientific societies and various social networks between 1 May 2023 and 1 July 2023. The survey included 1459 physicians (1242 cardiologists and 217 non-cardiologists) from 91 countries, with a mean age of 42 (34-49) years and 61% male. Most physicians (89.2%) defined HFpEF as left ventricular ejection fraction ≥50%. Significant regional variations were observed in HFpEF management (P<0.001 for all comparisons unless stated otherwise). Cardiologists managed 63.1% of HFpEF patients overall, with significant variability across regions (P < 0.001). The estimated HFpEF prevalence was highest in Eastern Asia and Western Europe and lowest in Africa and South America. Diagnostic practices varied: natriuretic peptide use ranged from 70%-74% in Africa to 95%-97% in Southern/Western Europe. Echocardiographic parameters showed regional differences, with diastolic stress testing used most in South-Eastern Asia (47% vs. 13-36% elsewhere). HFpEF scoring systems were most common in South-Eastern Asia (78%) and least in Africa (30.1%). Coronary artery disease screening approaches differed, with Eastern Asian physicians more likely to always perform routine angiograms (52%) compared with Northern Europeans (12%). Treatment preferences also varied regionally. Sodium glucose co-transporter-2 inhibitors (SGLT2i) was the preferred first-line treatment (45%-70% across regions), followed by diuretics. In an ideal setting, 52% would primarily use SGLT2i, 33% loop diuretics, and 22% beta-blockers. Drug availability differed significantly: SGLT2i was most available (88% overall), while ARNI was least available (61%). South America and Middle Eastern/Northern Africa reported lower availability of guideline-directed therapies. Multidisciplinary HF programmes were most common in Asia (70%) and least in Africa (24%). The perceived benefit of atrial flow regulator devices also showed significant regional differences. There are considerable global variations in the diagnosis and management of HFpEF. Most physicians favour SGLT2i despite regional disparities in health care resources and guideline adherence. Harmonized practices and improved access to comprehensive care can enhance outcomes of HFpEF patients worldwide.

Cardiovascular effectiveness of newer glucose-lowering agents, with and without baseline lipid-lowering therapy in type 2 diabetes: A systematic meta-analysis of cardiovascular outcome trials and real-world evidence

BackgroundWhether the cardiovascular treatment benefits of sodium–glucose co-transporter 2 inhibitors (SGLT-2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) differ by baseline use of statins/lipid lowering therapy is unclear. This systematic review and meta-analysis investigated whether baseline statin use (users vs non-users) influences the cardiovascular and kidney benefits of SGLT-2is and GLP-1RAs in patients with type 2 diabetes (T2D). MethodsWe identified relevant cardiovascular outcome trials (CVOTs) and observational cohort studies from MEDLINE, Embase, the Cochrane Library, and bibliographic searches up to March 2024. The analysis pooled study-specific hazard ratios (HRs) with 95% confidence intervals (CIs) for outcomes, categorized by baseline statin use status. We also assessed the interactions between these medications and baseline statin use by calculating and pooling the ratio of HRs (RHRs) within each trial. ResultsTwenty-five articles (13 articles comprising 6 unique CVOTs and 12 articles comprising 9 unique cohort studies) were eligible. In CVOTs of SGLT-2is, the HRs (95% CIs) of MACE; composite of CVD death or hospitalisation for heart failure; stroke; and kidney events in statin users were 0.90 (0.82-1.00), 0.78 (0.60-1.02), 1.00 (0.77-1.31), and 0.60 (0.53-0.69), respectively. The corresponding estimates were similar in non-statin users. In CVOTs of GLP-1RAs, the HRs (95% CIs) for MACE in statin and non-statin users were 0.81 (0.73-0.90) and 0.92 (0.77-1.11), respectively. In observational cohort studies, SGLT-2is similarly reduced the risk of several cardiovascular and kidney outcomes in both statin and non-statin users. The estimated RHRs and p-values for interaction indicated that baseline statin use status did not significantly modify the cardio-kidney benefits of SGLT-2is and GLP-1RAs. ConclusionsAggregate analyses of intervention and real-world evidence show that SGLT-2is and GLP-1RAs provide comparable cardio-kidney benefits in patients with T2D, regardless of baseline statin use status.PROSPERO Registration: CRD42024498939

Identification of functional heterogeneity of immune cells and tubular-immune cellular interplay action in diabetic kidney disease.

Renal inflammation plays key roles in the pathogenesis of diabetic kidney disease (DKD). Immune cell infiltration is the main pathological feature in the progression of DKD. Sodium glucose cotransporter 2 inhibitor (SGLT2i) were reported to have antiinflammatory effects on DKD. While the heterogeneity and molecular basis of the pathogenesis and treatment with SGLT2i in DKD remains poorly understood. To address this question, we performed a single-cell transcriptomics data analysis and cell cross-talk analysis based on the database (GSE181382). The single-cell transcriptome analysis findings were validated using multiplex immunostaining. A total of 58760 cells are categorized into 25 distinct cell types. A subset of macrophages with anti-inflammatory potential was identified. We found that Ccl3+ (S100a8/a9 high) macrophages with anti-inflammatory and antimicrobial in the pathogenesis of DKD decreased and reversed the dapagliflozin treatment. Besides, dapagliflozin treatment enhanced the accumulation of Pck1+ macrophage, characterized by gluconeogenesis signaling pathway. Cell-cross talk analysis showed the GRN/SORT1 pair and CD74 related signaling pathways were enriched in the interactions between tubular epithelial cells and immune cells. Our study depicts the heterogeneity of macrophages and clarifies a new possible explanation of dapagliflozin treatment, showing the metabolism shifts toward gluconeogenesis in macrophages, fueling the anti-inflammatory function of M2 macrophages, highlighting the new molecular features and signaling pathways and potential therapeutic targets, which has provided an important reference for the study of immune-related mechanisms in the progression of the disease.

Euglycemic Ketoacidosis Associated with SGLT-2 Inhibitors in Non-diabetic Patients-A Narrative Review.

Euglycemic ketoacidosis is an acute, life-threatening emergency that is characterized by euglycemia, metabolic acidosis, and ketonemia. It is a well-recognized adverse event in diabetic patients taking sodium-glucose cotransporter-2 inhibitor (SGLT-2 inhibitor). However, there is limited data on SGLT-2 inhibitor-related euglycemic ketoacidosis in non-diabetic patients. The mechanism behind SGLT-2 inhibitor-associated euglycemic ketoacidosis involves a general state of starvation or relative insulin deficiency, which exacerbates the mild baseline ketonemia caused by this class of medications while normoglycemia is maintained. The incidence of euglycemic ketoacidosis will likely increase with the increasing use of SGLT-2 inhibitors for various indications in addition to diabetes mellitus type 2, predominantly for congestive heart failure (CHF). Recognizing the signs and symptoms of this life-threatening condition is essential to treat it effectively. Our objective is to comprehensively revisit the pathophysiology of euglycemic ketoacidosis associated with SGLT-2 inhibitors and the risk factors for the condition, review the available data, and summarize the reported cases of euglycemic ketoacidosis in non-diabetic patients on SGLT-2 inhibitors. Our literature search identified five articles with six cases of euglycemic ketoacidosis in non-diabetic patients who were on SGLT-2 inhibitors for heart failure with reduced ejection fraction. The common risk factor in five out of the six cases was decreased oral intake due to acute illness, fasting, or a perioperative state.

Advances in SGLT2 Inhibitors for Type 2 Diabetes Management

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have emerged as a significant class of medications for the management of type 2 diabetes mellitus, offering improved glycemic control and cardiovascular benefits. This review focuses on the development of various SGLT2 inhibitors, highlighting their chemical structures, pharmacological properties, and therapeutic potential. Methods: A comprehensive literature review was conducted, summarizing the synthesis and biological evaluation of multiple SGLT2 inhibitors, including novel compounds derived from C-aryl glucoside scaffolds, C-glucosides, and 5α-carba-β-D-glucopyranose derivatives. Studies utilized various techniques, such as click chemistry, Friedel-Crafts alkylation, and pharmacokinetic assessments, to evaluate the efficacy and selectivity of these inhibitors. Results: Several promising compounds were identified, including compound 1 (GCC5694A) with an IC50 of 0.460 nM against SGLT2 and strong selectivity for SGLT1, and compound 26, which exhibited an IC50 of 4.47 nM, surpassing dapagliflozin. Novel derivatives, such as compound 22 (IC50 = 47 nM) and compound 27, demonstrated significant inhibitory effects and selectivity profiles. Pharmacokinetic studies revealed compounds like compound 28 had enhanced half-lives compared to established drugs like sergliflozin. Additionally, compounds such as the nitric oxide-releasing dapagliflozin derivative exhibited dual anti-diabetic and anti-thrombotic properties. Conclusion: The ongoing development of SGLT2 inhibitors demonstrates substantial advancements in therapeutic options for type 2 diabetes. The structural modifications and novel compounds explored in this review highlight the potential for improved efficacy and safety profiles, suggesting that these new agents could play a vital role in diabetes management and warrant further clinical investigation.

Trends of SGLT2 inhibitors among patients with and without cancer.

113 Background: While initial indications for SGLT2 inhibitors (SGLT2i) were for management of type 2 diabetes mellitus (DM), their use has broadened with cardiovascular and renal protective properties. Given limited studies in cancer patients, we evaluated the trends of SGLT2i usage in patients with or without cancer. Methods: This study is a retrospective cohort analysis that examined electronic medical records from a global health research network, TriNetX. Our study population included patients 18 and older having one of following diagnoses: heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), chronic kidney disease (CKD), and cardiovascular disease (CVD) with DM. Cohorts were separated by cancer status, creating 8 study cohorts. The incidence of SGLT2i use was measured annually, defined as total new patients receiving an SGLT2i divided by total eligible patients for that year. Linear trend plots were created showing incidence percentage from 2016 to 2023 to compare trends in cancer patients and non-cancer patients. Results: Amongst all study cohorts, the observed yearly incidence of SGLT2i use was considerably lower from 2016 and 2019. Measured incidence did not exceed 2%, with no observable differences between cancer and non-cancer patients. From 2020 to 2023, the observed incidence dramatically increased year over year, doubling from the observed 2019 incidence for all groups. Differences in utilization between cancer non-cancer patient cohorts became visible from 2020 onward amongst patients with HFrEF, CKD, and DM with CVD. This is highlighted by differences in 2023 incidence percentages for HFrEF (13.1% Non-Cancer vs. 10.7% Cancer), CKD (10.0% Non-Cancer vs. 3.8% Cancer), and DM with CVD (7.6% Non-Cancer vs. 5.2% Cancer). Conclusions: Since 2020, there has been an uptick in SGLT2i usage across all patient cohorts, indicating increased adoption of this therapy in clinical practice. Observed incidence rates suggest that cancer patients were less likely to be prescribed SGLT2i compared to non-cancer patients. Further research is needed to understand the barriers of use and efficacy of SGLT2is in cancer patients. Yearly incidence percentage of SGLT2 inhibitor use for 8 study cohorts represented in each column; each row represents a year where incidence is reported. HFrEF HFpEF CKD CVD + DM Year Non-Cancer Cancer Non-Cancer Cancer Non-Cancer Cancer Non-Cancer Cancer 2016 0.27 0.32 0.28 0.41 0.31 0.37 0.88 0.8 2017 0.34 0.41 0.36 0.57 0.39 0.52 1.16 1.19 2018 0.45 0.53 0.41 0.5 0.46 0.49 1.28 1.14 2019 0.74 0.77 0.6 0.77 0.82 0.77 1.91 1.7 2020 1.55 1.31 0.83 1.02 1.52 1.04 2.77 2.07 2021 4.2 3.32 1.77 2.11 3.76 1.96 4.25 3.36 2022 8.85 7.02 4.04 3.84 7.3 2.89 5.99 4.36 2023 13.07 10.66 6.38 6.16 10 3.68 7.6 5.24 HFrEF= Heart Failure Reduced Ejection Fraction; HFpEF= Heart Failure Preserved Ejection Fraction; CKD= Chronic Kidney Disease; CVD + DM= Cardiovascular Disease with Diabetes Mellitus.