Real-world effectiveness of sodium-glucose cotransporter-2 inhibitors on the progression of chronic kidney disease in patients without diabetes, with and without albuminuria.

AIM: To examine the renal effects of sodium-glucose cotransporter-2 (SGLT2) inhibition among non-diabetic individuals with chronic kidney disease (CKD) in a real-world setting. METHODS: We collected de-identified data on adults without diabetes and with an estimated glomerular filtration rate (eGFR) of 25-60 mL/min/1.73 m2, who initiated the SGLT2 inhibitors dapagliflozin or empagliflozin between September 2020 and November 2022 at Maccabi Healthcare Services, an Israeli health maintenance organization. We assessed the effects of SGLT2 inhibitors on renal function (changes in eGFR slope/time). Index date was defined as the date of the first dispensing of SGLT2 inhibitors. Annual baseline slope was calculated using all eGFR measurements during the 2 years prior to index date (median = 7 measurements), while annual follow-up slope was calculated from all evaluations during 90-900 days post index date, along with baseline measurement at index date (median = 6 measurements). Paired t tests were used to compare differences between baseline and follow-up annual slopes. RESULTS: Of a total of 354 participants with CKD, without diabetes, who received SGLT2 inhibitors and were followed for a median of 527 days, the mean age was 72.8 ± 11.8 years, 26% were female, and 91% used renin-angiotensin system blockade. The mean eGFR was 45.4 ± 9.5 mL/min/1.73 m2. The mean body mass index was 29.1 ± 5.4 kg/m2. During the year before index date, 146 participants (41%) had a urinary albumin to creatinine ratio (UACR) <30 mg/g, 81 (23%) had a UACR of 30-300 mg/g, 74 (21%) had a UACR >300 mg/g, and 53 (15%) had no UACR evaluation. The mean eGFR slope over time was -5.6 ± 7.7 mL/min/1.73 m2 per year at baseline, which improved to -1.7 ± 6.8 mL/min/1.73 m2 per year after SGLT2 inhibitor administration (p <0.001). This effect was independent of UACR. CONCLUSION: In a real-world study of primarily older non-diabetic adults with CKD, SGLT2 inhibition was associated with a slower rate of kidney function decline, regardless of baseline UACR level.

Safety and Effectiveness of Sodium-Glucose Co-transporter 2 Inhibitors on Glycemic Control in Patients with Type 2 Diabetes Mellitus Fasting during Ramadan: A Review.

This review evaluates the current evidence on the safety and efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with type 2 diabetes mellitus (T2DM) fasting during Ramadan. All studies included in the review were conducted in Asia and the Middle East. Overall, the evidence suggests that SGLT2 inhibitors are a safe and effective treatment option for most T2DM patients fasting during Ramadan. The average incidence of symptomatic hypoglycemia is 12.5%, but ranges from 0.7% to 27%, depending on the study population and concomitant use of other medications. The risk of hypoglycemia is increased when SGLT2 inhibitors are used in combination with insulin and/or sulfonylureas. Therefore, patients taking SGLT2 inhibitors in combination with insulin and/or sulfonylureas can take steps to mitigate this risk, such as having their insulin and/or sulfonylurea doses adjusted and being closely monitored for hypoglycemia. Patients taking SGLT2 inhibitors may be at increased risk of dehydration. To mitigate the risk of dehydration, patients should be advised to consume adequate fluids during the fast-breaking hours. Further research is warranted to validate these findings and extend their applicability to high-risk populations and other regions of the world.

Safety and effectiveness of sodium-glucose co-transporter 2 inhibitors on glycemic control in patients with type 2 diabetes mellitus fasting during Ramadan: a review This review delves into the existing evidence regarding the safety and efficacy of sodium-glucose co-transporter 2 (SGLT2) inhibitors for patients with type 2 diabetes mellitus (T2DM) who observe Ramadan fasting. The studies reviewed were conducted exclusively in Asia and the Middle East. Overall, the gathered evidence suggests that SGLT2 inhibitors constitute a safe and effective treatment option for most T2DM patients fasting during Ramadan. While a slightly elevated risk of dehydration compared to other medications may exist, this is generally well-tolerated. To mitigate the risk of dehydration, patients should be advised to consume adequate fluids during the fast-breaking hours. However, further research is warranted to validate these findings and extend their applicability to high-risk populations and other world regions.

Use of prescription opioids in Israel and socio-economic correlations between 2010 and 2020.

BACKGROUND: The use of opioids has increased dramatically over the past several years in Israel. The aim of this study was to explore the trends of opioid consumption in Israel over a decade (2010-2020) stratified by socioeconomic status (SES), residence in the periphery, and ethnic background. METHODS: This cross-sectional study included all adult Maccabi Healthcare Services (MHS) patients who filled at least one prescription for opioids during the past decade. In order to standardize dosages and compare different opioid medications, we used the Morphine Milligram Equivalent (MME) conversion factor. We performed The Mann-Kendall test with autocorrelation correction to assess each trend. We then checked the differences between the trends with the Mann-Whitney test (for periphery) and the Kruskal Wallis (for SES and ethnic background). RESULTS: Between the years 2010-2020, 261,270 MHS members met the study's inclusion criteria. The proportions of opioids consumption were 23.9/1000 patients in 2010 and 27.6/1000 patients in 2020, representing a 15% increase. The average daily consumption of opioids was 4.6 and 10.5 MME in 2010 and 2020, respectively, an increase of 227%. The daily MME during 2020 was higher for residents of the periphery compared to non-periphery residents (daily MME of 14.0 compared to 10.1, respectively). Average daily MME increased gradually during the study period for all levels of SES; the values were highest for the low SES group and the lowest for the high SES group (daily MME in 2020 for the lowest, middle, and high SES groups were 15.2 vs. 11.8 vs. 6.7 respectively). CONCLUSIONS: This study highlights that the primary concern in the increase of opioid use is the increasing dosages. The increase in the number of patients using opioids is also significant but to a minor extent. These phenomena disproportionately impact vulnerable populations. Education programs should be offered to physicians regarding the possible harms of long-term use of opioids. These programs should emphasize the risk factors associated with the development of opioid use disorder (OUD) and the caution needed when increasing dosages or switching to higher-potency drugs. Pain clinics and centers for rehabilitation for patients with chronic pain or OUD should be available, not only in central areas but also in the periphery of the country. These clinics and centers should use a holistic approach and a multidisciplinary team that includes specialists in pain and addiction. They should be financially accessible for patients from low SES group and provide solutions in multiple languages.

Common Bacterial Infections during the 3-Month Period after SARS-CoV-2 Infection: A Retrospective Cohort Study.

INTRODUCTION: Correlations between SARS-CoV-2 and bacterial infections have mainly been studied in hospitals, and these studies have shown that such interactions may be lethal for many. In the context of community flora, less is known of the trends and consequences of viral infections relative to subsequent bacterial infections. PURPOSE: This study aims to explore the prevalence and characteristics of bacterial infections in the three months following SARS-CoV-2 infections, in a community, real-world setting. METHODS: In this retrospective cohort study, we compared patients who completed a polymerase chain reaction (PCR) test or an antigen test for SARS-CoV-2 during January 2022, the peak of the Omicron wave, and examined bacterial infections following the test. We searched these cases for diagnoses of the following four bacterial infections for three months following the test: Group A Streptococcus (GAS) pharyngitis, pneumonia, cellulitis, and urinary tract infections (UTI). RESULTS: During January 2022, 267,931 patients tested positive and 261,909 tested negative for SARS-CoV-2. Test-positive compared to test-negative patients were significantly younger (42.5 years old vs. 48.5 years old, p < 0.001), smoked less, and had fewer comorbidities (including ischemic heart disease, diabetes mellitus, hypertension, chronic obstructive pulmonary disease, and chronic renal failure). In the multivariable analysis, test-positive patients had an increased risk for GAS pharyngitis (adjusted odds ratio [aOR] = 1.25, 95% CI 1.14-1.38, p-value < 0.001) and pneumonia (aOR = 1.25, 95% CI 1.15-1.35, p-value < 0.001), a trend towards an increased prevalence of UTI (aOR = 1.05, 95% CI 0.99-1.12, p-value = 0.092), and lower risk for cellulitis (aOR = 0.92, 95% CI 0.86-0.99, p-value < 0.05). CONCLUSIONS: A history of SARS-CoV-2 infection in the past three months increased susceptibility to respiratory tract bacterial infections and the prevalence of UTI.

Clinical Outcomes of Diabetic Ketoacidosis in Type 2 Diabetes Patients with and without SGLT2 Inhibitor Treatment: A Retrospective Study.

AIM: This study aimed to compare the clinical course and outcomes of DKA in T2DM patients who received treatment with SGLT2 inhibitors versus those who did not. METHODS: A retrospective analysis was conducted on T2DM patients who were admitted to the Rambam Health Care Campus with DKA between 7/2015 and 9/2020. Demographic, clinical, and laboratory data were obtained from electronic medical records. Outpatient mortality was monitored until 12/2022. RESULTS: Of 71 T2DM patients admitted with DKA, 16 (22.5%) were on SGLT2 inhibitor treatment upon admission. SGLT2 inhibitor users had a higher BMI and were less likely to be treated with insulin. During hospitalization, the rates of acute kidney injury, concomitant infections, and inpatient mortality among SGLT2 inhibitor users were comparable to non-users. The median follow-up period was 35.1 months for the SGLT2 inhibitor users and 36.7 months for non-users. The long-term mortality from any cause was lower among the SGLT2 inhibitor users (12.5% vs. 52.7%, p = 0.004). In Cox regression analysis, SGLT2 inhibitor use was associated with a lower risk of long-term mortality from any cause (HR = 0.19, p = 0.04). CONCLUSION: T2DM patients with DKA who received SGLT2 inhibitors had lower long-term mortality from any cause compared to those who did not receive SGLT2 inhibitors.

A beneficial role of GLP-1 receptor agonist therapy in ABCC8-MODY (MODY 12).

Maturity-onset diabetes of the young (MODY) is an inherited form of diabetes resulting from a mutation in a single gene. ABCC8-MODY is caused by mutations in the ABCC8 gene, which encodes sulfonylurea receptor 1 (SUR1), a regulatory component of the ATP-sensitive potassium (KATP) channel found in beta cells. In ABCC8-MODY, mutations in the ABCC8 gene interfere with insulin secretion in response to glucose. Recent evidence suggests that therapy with GLP-1 receptor agonists (GLP-1 RAs) may be beneficial in ABCC8-MODY. This report presents a successful treatment of a 49-year-old woman diagnosed with ABCC8-MODY using the GLP-1 RA semaglutide. The patient, who had been previously receiving insulin therapy, experienced significant improvements in glycemic control and weight loss after transitioning to semaglutide. GLP-1 RAs potentially enhance insulin secretion in ABCC8-MODY by activating multiple signaling pathways involved in insulin secretion. The report highlights the potential of GLP-1 RA therapy as an alternative to sulfonylureas and insulin for individuals with ABCC8-MODY. GLP-1 RAs have previously demonstrated benefits in other forms of MODY. Understanding the molecular mechanisms through which GLP-1 RAs promote insulin secretion, including their effects on KATP channels and activation of PKA and Epac signaling, offers valuable insights into their therapeutic effects.

Cardiometabolic risk factors among children and adolescents with overweight and Class 1 obesity: A cross-sectional study. Insights from stratification of Class 1 obesity.

Context: Severe childhood obesity is associated with increased prevalence of cardiometabolic risk factors (CMRFs). Among children with Class 1 obesity, higher BMI may indicate greater cardiometabolic risk. Class 1 obesity reflects a wide spectrum of BMI values. Each 10% increase in BMI above the 95th percentile is equivalent to an average increase of 2.15 kg/m2 and 2.75 kg/m2 in BMI among children and adolescents, respectively. Such increments may be of clinical importance. Objectives: The study aimed to determine the prevalence and clustering of CMRFs in children and adolescents with BMI 110%-119% of the 95th BMI percentile. Methods: A cross-sectional analysis of data, from an Israeli health maintenance organization, of children and adolescents (5-17 years) with overweight or Class 1 obesity, and at least one measurement of lipid profile during Jan/2020-May/2021. CMRFs were defined as abnormal lipid profile, elevated alanine aminotransferase, hypertension, and prediabetes or diabetes. Study groups included overweight and Class 1 Obesity-A (BMI < 110%) and Obesity-B (BMI ≥ 110%) of the 95th BMI percentile. Results: Of 7211 subjects included, 40.2% were overweight, 50.3% obesity-A, and 9.5% obesity-B. Multivariable analyses showed that children and adolescents from the Obesity-B group had increased odds for higher triglycerides, LDL cholesterol, and ALT levels; and lower HDL cholesterol levels, as compared to Obesity-A. The odds of prediabetes (insignificant) tended to be higher in the Obesity-B group, which was associated with increased CMRFs clustering. Conclusions: Among children and adolescents with Class 1 obesity, BMI ≥ 110% of the 95th percentile was associated with higher prevalence and clustering of CMRFs.

The correlation between testosterone, inflammation and cytokine status in type-2 diabetes men.

Type 2 diabetes mellitus (T2DM) is believed to cause hypogonadism through increasing pro-inflammatory cytokines. Tumour necrosis factor-α (TNF-α) is a primary cytokine associated with T2DM. The study explored the association between total testosterone (TT) level and cytokines status in 53 adult males, 27 T2DM (T2DM group) and 26 non-T2DM (control group). Blood samples evaluated fasting plasma glucose, HbA1c, insulin, HOMA-IR, FSH, LH, TT, prolactin, estradiol, cortisol, cortisol-binding globulin, C-reactive protein and eight cytokines (Interferon-gamma, IL-10, IL-13, IL-17A, IL-4, IL-23, IL-6, TNF-α). Data are presented as a median with interquartile interval. TT concentration was lower in the T2DM group [10.9 nmol/L (7.1-12.2) vs. 12.3 nmol/L (10.7-14.9) in control, p = 0.008]. CRP and cortisol in T2DM patients were higher than in control (p = 0.031 and 0.041 respectively). TT was negatively correlated with HOMA-IR, body mass index (BMI) and FSH (p = 0.028, 0.019 and 0.006 respectively). Multiple linear regression models showed that lower TT values were predictable by a linear combination of the independent variables: TNF-α, BMI and T2DM (p = 0.047, 0.023 and 0.019 respectively). High CRP and cortisol levels in T2DM patients suggest an inflammatory state. TT levels associated with TNF-α suggest a role of this cytokine in the aetiology of hypogonadism in T2DM patients.

Screening for non-classic congenital adrenal hyperplasia in women: New insights using different immunoassays.

Context: The 250µg-cosyntropin stimulation test (CST) is used to diagnose non-classic congenital adrenal hyperplasia (NCCAH). The current recommendation is to perform CST when follicular 17-hydroxyprogesterone (17OHP) is 6-30 nmol/L, a cutoff derived from radioimmunoassay (RIA). Recently, enzyme-linked immunosorbent assay (ELISA) has replaced RIA. Objectives: We aimed to (1) determine the RIA and ELISA-based 17OHP cutoffs at which CST should be performed, (2) identify predictors of NCCAH. Methods: A retrospective study at an Israeli Health Maintenance Organization. Data were retrieved from women with suspected NCCAH, referred for CST during 2001-2020. NCCAH was defined as a stimulated 17OHP >30 nmol/L. Serum 17OHP levels were assayed by RIA from 1/2000-3/2015, and by ELISA from 4/2015-12/2020. ROC curves were generated and optimal 17OHP thresholds were determined. Multivariate analysis was performed. Results: CST was performed in 2409 women (1564 in RIA, 845 in ELISA). NCCAH was diagnosed in 4.7% of the RIA group and 7.5% of the ELISA group. The optimal basal 17OHP cutoff values predicting NCCAH were 6.1 nmol/L in RIA (sensitivity=93.2%, specificity=91.7%) and 8.2 nmol/L in ELISA (sensitivity=93.7%, specificity=92.3%). In multivariate analysis, higher basal 17OHP, lower LH: FSH ratio, and oligomenorrhea were predictors of NCCAH in RIA. Higher basal 17OHP, androstenedione, and total testosterone were predictors of NCCAH in ELISA. A lower LH: FSH ratio showed similar trend in ELISA. Conclusions: Optimal RIA-based basal 17OHP cutoff was comparable with that recommended in guidelines. The results suggest adopting a higher 17OHP cutoff when using ELISA. LH : FSH ratio improves the negative predictive value of basal 17OHP.

Outcomes of pituitary apoplexy: a comparison of microadenomas and macroadenomas.

PURPOSE: We aimed to assess clinical characteristics of apoplexy of pituitary microadenomas compared to macroadenomas. METHODS: We retrieved clinical records of patients > 18 years old, hospitalized in Rambam hospital between January 2001 and October 2017, with pituitary apoplexy and follow-up of at least one year. We compared clinical course and outcomes of apoplexy between patients with microadenomas and macroadenomas, and between patients who received conservative or surgical treatment. Statistical analysis was done using Fisher's exact and Mann-Whitney tests. RESULTS: Twenty-seven patients with pituitary apoplexy were included in the final analysis: mean age was 40.7 ± 12.5 years, 13(48%) were female, 7(26%) had microadenomas, and 21(78%) harbored clinically nonfunctioning pituitary adenomas. Upon admission, hyponatremia, random cortisol level of < 200 nmol/L, and secondary hypothyroidism, were evident in 6/20, 8/18, and 4/18 patients with macroadenoma and 1/5, 2/5, and 1/6 patients with microadenoma, respectively (P = 1.0). Hypogonadotropic hypogonadism was evident in 9/12 men with macroadenoma. In 12 macroadenoma patients, the tumor abutted the optic chiasm, of whom eight had visual field defects. Fifteen patients with macroadenoma and two with microadenoma underwent transsphenoidal surgery. Median follow-up was 3 years. At last follow-up visit, patients with microadenoma had lower rates of corticotropic deficiency or secondary hypothyroidism compared to macroadenoma patients (1/7 vs. 13/20 respectively, p = 0.033). Only two patients with macroadenomas had persistent visual field defects. Outcomes were comparable between conservative and surgical treatment groups. CONCLUSIONS: Long term pituitary hormone deficiencies are more common in pituitary apoplexy patients with macroadenomas. Apoplexy of pituitary microadenoma carries a more favorable prognosis.

Hypoglycemia in diabetes: An update on pathophysiology, treatment, and prevention.

Hypoglycemia is a common complication in patients with diabetes, mainly in those treated with insulin, sulfonylurea, or glinide. Impairments in counterregulatory responses and hypoglycemia unawareness constitute the main risk factors for severe hypoglycemia. Episodes of hypoglycemia are associated with physical and psychological morbidity. The fear of hypoglycemia constitutes a barrier that impairs the patient's ability to reach good glycemic control. To prevent hypoglycemia, much effort must be invested in patient education regarding risk factors, warning signs, and treatment of hypoglycemia at an early stage, together with setting personalized goals for glycemic control. In this review, we present a comprehensive update on the treatment and prevention of hypoglycemia in type 1 and type 2 diabetic patients.

Interactions between antihyperglycemic drugs and the renin-angiotensin system: Putative roles in COVID-19. A mini-review.

BACKGROUND: Diabetes mellitus is associated with a more severe course of coronavirus disease 2019 (COVID-19). The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes angiotensin-converting enzyme II (ACE2) receptor for host cell entry. We aimed to assess the interactions between antihyperglycemic drugs and the renin-angiotensin system (RAS) and their putative roles in COVID-19. METHODS: A literature search was performed using Pubmed to review the interrelationships between hyperglycemia, RAS and COVID-19, and the effects of antihyperglycemic medications. RESULTS: The RAS has an essential role in glucose homeostasis and may have a role in COVID-19-induced lung injury. Some antihyperglycemic medications modulate RAS and might hypothetically alleviate the deleterious effect of angiotensin II on lung injury. Furthermore, most antihyperglycemic medications showed anti-inflammatory effects in animal models of lung injury. CONCLUSIONS: Some antihyperglycemic medications might have protective effects against COVID-19-induced lung injury. Early insulin therapy seems very promising in alleviating lung injury.

Effects of sodium glucose co-transporter 2 inhibitors on genital infections in female patients with type 2 diabetes mellitus- Real world data analysis.

AIMS: Sodium glucose co-transporter 2 (SGLT2) inhibitors are associated with increased risk of genital infections. We aimed to assess incidence and risk factors associated with genital infections among female patients with type 2 diabetes mellitus (T2DM) treated with SGLT2 inhibitors. METHODS: We retrieved data on adult female patients with T2DM who initiated treatment with empagliflozin or dapagliflozin during March 2015-March 2018, in a large Israeli health maintenance organization (HMO). Genital infections were identified by diagnosis codes or relevant dispensed prescriptions. The proportion of days covered with SGLT2 inhibitors (SGLT2i-PDC) was measured. Univariate and multivariate analyses were performed to identify risk factors. RESULTS: Of 1542/6153 patients, 25.1% had events of genital infections during a mean of 2.3 years. The adjusted hazard ratio (HR) was 4.25 for the highest versus lowest SGLT2i-PDC group. Younger age, history of genital infection, and estrogen therapy were associated with increased risk of genital infections. Chronic Kidney Disease and DPP4 inhibitor therapy at baseline were associated with lower risk of genital infections. CONCLUSIONS: Potential risk factors for genital infections were identified in women initiating SGLT2 inhibitors.

Management of cystic prolactinomas: a review.

INTRODUCTION: Cystic prolactinoma is a variant of prolactin-secreting pituitary adenoma. The strategies for the management of cystic prolactinoma have not been addressed thoroughly in clinical guidelines. METHODS: A literature search was performed using Pubmed to review the current approaches to the treatment of cystic prolactinoma. RESULTS: Transsphenoidal resection is an effective and relatively safe approach for the treatment of cystic prolactinoma, however, morbidity of surgery is dependent on the skill of the surgeon. Emerging studies allude to the efficacy and safety of dopamine agonists in the management of cystic prolactinoma. Dopamine agonists are associated with considerable rates of clinical improvement and tumor shrinkage, hence reducing the need for surgical intervention. CONCLUSIONS: Recent studies suggest that dopamine agonist therapy may be an effective and safe treatment option in a considerable portion of patients with cystic prolactinomas. We suggest that dopamine agonists should be considered as a first-line therapy for cystic prolactinoma in the absence of indications for early surgical intervention.

Cabergoline treatment for recurrent Cushing's disease during pregnancy.

OBJECTIVE: Cushing's disease during pregnancy is associated with an increased risk for maternal and fetal complications. In recurrent Cushing`s disease following transsphenoidal surgery, and when re-operation is not feasible, medical treatment is usually considered. Cabergoline was found to be effective in reducing hypercortisolism in Cushing's disease. Evolving data concerning the safety of cabergoline use during pregnancy show no significant increase in the rate of complications during pregnancy or the postnatal period. METHODS: We report a 29-year-old woman, gravida 0, para 0, with recurrent Cushing`s disease, three years after transsphenoidal resection of pituitary ACTH-secreting macroadenoma. Repeated MRI revealed an empty sella with a small gadolinium-enhancing lesion, suspected to be an adenoma remnant on the medial wall of the right cavernous sinus. As the patient was not willing to undergo repeat surgical intervention, treatment with cabergoline was initiated, with a gradual dose titration up to 3.5 mg/week. Clinical improvement ensued, and 4 months later, she conceived spontaneously. After discussing treatment options with the patient, cabergoline treatment at a dose of 2 mg/week was continued throughout pregnancy. RESULTS: The patient showed complete clinical remission during pregnancy. Consecutive tests of 24-h urinary free cortisol concentration were not found to be elevated. Pregnancy and delivery were uneventful except for mild hypothyroidism observed during the second trimester. At full term the patient delivered a healthy female infant, by an elective cesarean section. CONCLUSION: This case report demonstrates that cabergoline may be an effective and safe therapeutic option for the treatment of Cushing's disease during pregnancy.

Rapid progression to cardiac tamponade in Erdheim-Chester disease despite treatment with interferon alpha.

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans histiocytosis with heterogeneous clinical manifestations. The most common presentation is bone pains typically involving the long bones. Approximately 75% of the patients develop extraskeletal involvement. Cardiac involvement is seen in up to 45% of the patients, and although, pericardial involvement is the most common cardiac pathology of this rare disease, cardiac tamponade due to ECD has been very rarely reported. We describe a case of a patient found to have ECD with multi-organ involvement and small pericardial effusion, which progressed to cardiac tamponade despite treatment with interferon alpha.