Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Dialysis and Cardiovascular Disease in Patients With Stage 5 Chronic Kidney Disease.

BACKGROUND: No studies have reported the long-term outcomes of initiating sodium-glucose cotransporter-2 inhibitors (SGLT2is) in patients with estimated glomerular filtration rates less than 20 mL/min/1.73 m2 to predialysis. OBJECTIVE: To compare the risk for dialysis, cardiovascular events, and death between SGLT2i users and nonusers in patients with type 2 diabetes (T2D) and stage 5 chronic kidney disease (CKD). DESIGN: Target trial emulation study. SETTING: Taiwan's National Health Insurance Research Database (NHIRD). PARTICIPANTS: By applying sequential target trial emulation principle, 23 854 SGLT2i users and 23 892 SGLT2i nonusers were selected from the NHIRD for patients with T2D and stage 5 CKD from 1 May 2016 to 31 October 2021. MEASUREMENTS: Conditional Cox proportional hazards models were used to compare the risks for dialysis, hospitalization for heart failure, acute myocardial infarction (AMI), diabetic ketoacidosis (DKA), acute kidney injury (AKI), and all-cause mortality between SGLT2i users and nonusers. RESULTS: In the intention-to-treat model, compared with no SGLT2i use, SGLT2i use was associated with lower risks for dialysis (hazard ratio [HR], 0.34 [95% CI, 0.27 to 0.43]), hospitalization for heart failure (HR, 0.80 [CI, 0.73 to 0.86]), AMI (HR, 0.61 [CI, 0.52 to 0.73]), DKA (HR, 0.78 [CI, 0.71 to 0.85]), and AKI (HR, 0.80 [CI, 0.70 to 0.90]), but there was no difference in the risk for all-cause mortality (HR, 1.11 [CI, 0.99 to 1.24]). The Kaplan-Meier curves and subgroup analyses also showed that initiation of an SGLT2i in stage 5 CKD was associated with a lower risk for long-term dialysis than no SGLT2i use. LIMITATION: This result may not apply to patients without T2D. CONCLUSION: This emulated target trial showed that SGLT2i use was associated with a lower risk for dialysis, cardiovascular events, DKA, and AKI than no SGLT2i use in patients with T2D and stage 5 CKD. PRIMARY FUNDING SOURCE: National Health Research Institutes, Taiwan.

Effects of glucagon-like peptide-1 receptor agonists on liver-related and cardiovascular mortality in patients with type 2 diabetes.

BACKGROUND: Patients with type 2 diabetes (T2D) tend to have nonalcoholic fatty liver disease (NAFLD) with poorer prognosis. We performed this research to compare the risks of cardiovascular diseases, cirrhosis, liver-related mortality, and cardiovascular mortality between glucagon-like peptide-1 receptor agonist (GLP-1 RA) use and no-use in patients with T2D without viral hepatitis. METHODS: From January 1, 2008, to December 31, 2018, we used propensity-score matching to identify 31,183 pairs of GLP-1 RA users and nonusers from Taiwan's National Health Insurance Research Database. Multivariable-adjusted Cox proportional hazards models were used to examine the outcomes between the study and control groups. RESULTS: The median (Q1, Q3) follow-up time for GLP-1 RA users and nonusers were 2.19 (1.35, 3.52) and 2.14 (1.19, 3.68) years, respectively. The all-cause mortality incidence rate was 5.67 and 13.06 per 1000 person-years for GLP-1 RA users and nonusers, respectively. Multivariable-adjusted analysis showed that GLP-1 RA use had significantly lower risks of all-cause mortality (aHR 0.48, 95%CI 0.43-0.53), cardiovascular events (aHR 0.92, 95%CI 0.86-0.99), cardiovascular death (aHR 0.57, 95%CI 0.45-0.72), and liver-related death (aHR 0.32, 95%CI 0.13-0.75). However, there was no significant difference in the risk of liver cirrhosis development, hepatic failure, and hepatocellular carcinoma compared to GLP-1 RA no-use. CONCLUSIONS: This nationwide cohort study showed that GLP-1 RA use was associated with a significantly lower risk of all-cause mortality, cardiovascular events, and cardiovascular death in patients with T2D among Taiwan population. More prospective studies are warranted to verify our results.

Real-world effectiveness and safety of insulin glargine 100 U/mL plus lixisenatide in adults with type 2 diabetes: An international, multicentre, 12-month, prospective observational study.

AIM: To assess the impact of insulin glargine (100 U/mL) and lixisenatide (iGlarLixi) fixed-ratio combination therapy on the overall management of glycaemia in patients with type 2 diabetes (T2D), previously inadequately controlled with oral antidiabetic drugs ± basal insulin or glucagon-like peptide-1 receptor agonists (GLP-1 RAs). MATERIALS AND METHODS: This 12-month, international, multicentre, prospective, observational study included patients (age ≥ 18 years) with T2D who had initiated iGlarLixi within 1 month prior to study inclusion. Data were collected at study inclusion, month 3, month 6 and month 12 from patient diaries, self-measured plasma glucose, and questionnaires. The primary endpoint was change in HbA1c from baseline to month 6. RESULTS: Of the 737 eligible participants (mean age: 57.8 [standard deviation: 11.2] years; male: 49%), 685 had baseline and post-baseline HbA1c data available. The least squares mean change in HbA1c from baseline to month 6 was -1.4% (standard error [95% confidence interval (CI)]: 0.05 [-1.5, -1.3]). The absolute change from baseline at month 12 was -1.7% ± 1.9% (95% CI: -1.9, -1.5). There were 72 hypoglycaemia events reported during the study period, with a very low incidence of severe hypoglycaemia (two participants [rate: 0.003 events per patient-year]). CONCLUSIONS: This real-world observational study shows that initiation of iGlarLixi in people with T2D inadequately controlled on oral antidiabetic drugs ± basal insulin or GLP-1 RAs improves glycaemic control with a low incidence of hypoglycaemia.

Residual risk of cardiovascular complications in statin-using patients with type 2 diabetes: the Taiwan Diabetes Registry Study.

BACKGROUND: The residual risks of atherosclerotic cardiovascular disease in statin-treated patients with diabetes remain unclear. This study was conducted to identify factors associated with these residual risks in patients with no prior vascular event. METHODS: Data on 683 statin-using patients with type 2 diabetes mellitus (T2DM) from the Taiwan Diabetes Registry were used in this study. Patients aged < 25 or > 65 years at the time of diabetes diagnosis and those with diabetes durations ≥ 20 years were excluded. The United Kingdom Prospective Diabetes Study risk engine (version 2.01; https://www.dtu.ox.ac.uk/riskengine/ ) was used to calculate 10-year residual nonfatal and fatal coronary heart disease (CHD) and stroke risks. Associations of these risks with physical and biochemical variables, including medication use and comorbidity, were examined. RESULTS: The 10-year risks of nonfatal CHD in oral anti-diabetic drug (OAD), insulin and OAD plus insulin groups were 11.8%, 16.0%, and 16.8%, respectively. The 10-year risks of nonfatal stroke in OAD, insulin and OAD plus insulin groups were 3.0%, 3.4%, and 4.3%, respectively. In the multivariate model, chronic kidney disease (CKD), neuropathy, insulin use, calcium-channel blocker (CCB) use, higher body mass indices (BMI), low-density lipoprotein (LDL), fasting glucose, log-triglyceride (TG), and log-alanine transaminase (ALT) levels were associated with an increased CHD risk. The residual risk of stroke was associated with CKD, neuropathy, CCB use, and lower LDL cholesterol levels, higher BMI and diastolic blood pressure. CONCLUSION: This study indicated that insulin was probably a residual risk factor of CHD but not stroke, and that there was a possible presence of obesity paradox in patients with T2DM on statin therapy. In addition to lowering TG and normalizing fasting glucose levels, lower LDL cholesterol level is better for reduction of risk of CHD on statin therapy. On the other hand, lower LDL cholesterol level could potentially be related to higher risk of stroke among populations receiving statin therapy. These findings suggest potential therapeutic targets for residual cardiovascular risk reduction in patients with T2DM on statin therapy.

Determinants of early chronic kidney disease in patients with recently diagnosed type 2 diabetes mellitus: a retrospective study from the Taiwan Diabetes Registry.

BACKGROUND: We tried to identify the risk factor associate with early chronic kidney disease (CKD) in recently diagnosed type 2 diabetes mellitus patients by utilizing real-world data from Taiwan Diabetes Registry. MATERIALS AND METHODS: Patients with type 2 diabetes mellitus recently diagnosed within 1 year. We divided the study participants into control group and early CKD group. Early CKD was defined as either CKD stage G1 with albuminuria, CKD stage G2 with albuminuria, or CKD stage G3a regardless of albuminuria (Urine-albumin to creatinine ratio (UACR) ≥ 3 mg/mmol). Control group was defined as CKD G1 or CKD G2 without albuminuria. Logistic regression analyses were used to compare differences in clinical characteristics between the subgroups. Linear regression models were employed to examine the factors predicting estimated glomerular filtration rate (eGFR) and UACR. RESULTS: Total 2217 patients with recently diagnosed type 2 diabetes mellitus were included. 1545 patients were assigned to control group and 618 patients were assigned to the early CKD group. Age (odds ratio (OR) 1.215, 95% confidence interval [CI] 1.122-1.316), systolic blood pressure (OR 1.203, 95% CI 1.117-1.296), glycated hemoglobin (OR 1.074, 95% CI 1.023-1.129) and triglyceride (OR 2.18, 95% CI 1.485-3.199) were found to be significant risk factors. Further, presence of bidirectional association between UACR and eGFR was found. CONCLUSIONS: We reported factors associated with early CKD in recently diagnosed type 2 diabetes mellitus patients. Variables that associated with eGFR and UACR were identified respectively, included a mutual influence between UACR and eGFR.

Sodium-Glucose Cotransporter-2 Inhibitors and Nephritis Among Patients With Systemic Lupus Erythematosus.

Importance: Lupus nephritis is a major complication of systemic lupus erythematosus (SLE). Randomized clinical trials have shown nephroprotective and cardioprotective effects of sodium-glucose cotransporter-2 inhibitors (SGLT2is). Objective: To investigate whether the use of SGLT2is is associated with the onset and progression of lupus nephritis and other kidney and cardiac outcomes in patients with SLE and type 2 diabetes. Design, Setting, and Participants: This multicenter cohort study used the US Collaborative Network of the TriNetX clinical data platform to identify patients with SLE and type 2 diabetes from January 1, 2015, to December 31, 2022. Data collection and analysis were conducted in September 2023. Exposures: Individuals were categorized into 2 groups by SGLT2i use or nonuse with 1:1 propensity score matching. Main Outcomes and Measures: The Kaplan-Meier method and Cox proportional hazards regression models were used to calculate the 5-year adjusted hazard ratios (AHRs) of lupus nephritis, dialysis, kidney transplant, heart failure, and mortality for the 2 groups. Results: From 31 790 eligible participants, 1775 matched pairs of SGLT2i users and nonusers (N = 3550) were selected based on propensity scores. The mean (SD) age of matched participants was 56.8 (11.6) years, and 3012 (84.8%) were women. SGLT2i users had a significantly lower risk of lupus nephritis (AHR, 0.55; 95% CI, 0.40-0.77), dialysis (AHR, 0.29; 95% CI, 0.17-0.48), kidney transplant (AHR, 0.14; 95% CI, 0.03-0.62), heart failure (AHR, 0.65; 95% CI, 0.53-0.78), and all-cause mortality (AHR, 0.35; 95% CI, 0.26-0.47) than SGLT2i nonusers. Conclusions and Relevance: In this cohort study of patients with SLE and type 2 diabetes, SGLT2i users had a significantly lower risk of lupus nephritis, dialysis, kidney transplant, heart failure, and all-cause mortality than nonusers. The findings suggest that SGLT2is may provide some nephroprotective and cardioprotective benefits.

Metformin and the risks of cellulitis, foot infections, and amputation in patients with type 2 diabetes.

BACKGROUND: Patients with diabetes tend to have cellulitis, foot infections, and amputation. We conducted this research to compare the risks of cellulitis, foot infections, and amputation between metformin no-use and use in persons with type 2 diabetes. METHODS: Using propensity score matching, we identified 23 234 pairs of metformin nonusers and users from the National Health Insurance Research Database of Taiwan, since January 1, 2000, to December 31, 2017. Cox proportional hazards models were adopted to examine the risks of incident cellulitis, recurrent cellulitis, foot infections, and amputation between metformin use and no-use. RESULTS: The mean follow-up period of metformin use and no-use was 6.31 (3.93) and 5.54 (3.97) years, respectively. Compared with metformin no-use, the adjusted hazard ratio and 95% confidence interval for metformin use in cellulitis development, recurrent cellulitis, foot infections, and amputation were 1.08 (1.04-1.12), 1.33 (1.14-1.55), 1.91 (1.75-2.09), and 1.88 (1.35-2.62), respectively. The longer cumulative duration of metformin usage had association with higher risks of these outcomes than metformin no-use. CONCLUSION: This population-based cohort study revealed that metformin use had association with significantly higher risks of incident cellulitis, recurrent cellulitis, foot infections, and amputation than metformin no-use in patients with type 2 diabetes.

Difficulties of Preoperative Diagnosis of Cribriform Morular Thyroid Carcinoma.

Background: Cribriform morular thyroid carcinoma has been recently renamed in the 2022 WHO classification as a thyroid tumor of uncertain histogenesis. The epidemiologic, pathological, and pathophysiological characteristics distinguish it from papillary thyroid carcinoma (PTC). Preoperative genetic testing plays a role in facilitating the differential diagnosis. Methods: This report presents a confirmed case of cribriform morular thyroid carcinoma. Initially, fine-needle aspiration cytology suggested a diagnosis of PTC. However, a genetic analysis did not reveal the typical mutations associated with follicular-cell-derived neoplasms. Results: A 31-year-old woman was found to have a thyroid nodule at the left lobe measuring 11.8 × 10.2 × 12.4 mm. Ultrasonography indicated a hypoechoic, solid nodule with regular margins. Cytology revealed a papillary structure of tall cells, leading to a PTC diagnosis. Nevertheless, the genetic analysis failed to detect mutations such as BRAF V600E, NRAS Q61R, NRAS Q61K, HRAS Q61R, or HRAS Q61K mutation or the fusion of CCDC6-RET, NCOA4-RET, PAX8-PPARG, ETV6-NTRK3, TPM3-NTRK1, IRF2BP2-NTRK1, or SQSTM1-NTRK1 in the aspirated follicular cells. The patient subsequently underwent total thyroidectomy with central lymph node dissection. Pathological examination revealed a cribriform pattern of spindle-shaped cells with morular areas. Immunohistochemical staining showed positive results for ß-catenin and TTF-1, except in the morular regions, and negative results for PAX8, thyroglobulin, and BRAF (clone VE1). The diagnosis was confirmed to be cribriform morular thyroid carcinoma. Conclusion: Significant cytological similarity exists between PTC and cribriform morular thyroid carcinoma. Preoperative genetic analysis is important to differentiate these two diseases. Cribriform morular thyroid carcinoma can be differentiated from common follicular-cell-derived tumors by the absence of typical mutations; the presence of nuclear and cytoplasmic expressions of ß-catenin; the presence of TTF-1, except in morular areas; and the absence of thyroglobulin.

Assessment of iodine nutritional status and gestational thyroid function reference ranges during the first trimester of pregnancy in Taiwan.

BACKGROUND: Iodine nutrition is critical for fetal neurodevelopment in the first trimester of pregnancy, a period associated with dramatic changes in thyroid function. The aim of this study was to evaluate iodine nutritional status and thyroid function reference ranges in the first trimester in Taiwan. METHODS: Pregnant women aged 20 years and above in the first trimester were recruited in Taipei Veterans General Hospital, Taiwan from March 2019 to July 2022. Each participant provided a spot urine sample for measurement of urinary iodine concentration (UIC) and a blood sample for checkup of thyroid function and thyroid autoantibodies. A simple food frequency questionnaire was also completed. RESULTS: A total of 209 women with a mean age of 32.9 ± 4.4 years were enrolled. The median UIC was 160.9 µg/L (interquartile range [IQR]: 105.0-246.2 µg/L), indicating overall iodine sufficiency. The gestational thyroid function reference ranges were: thyroid stimulating hormone (TSH) (median: 0.93 [0.007-2.9] µIU/mL), free T4 (1.3 [0.93-2.2] ng/dL), free T3 (3.0 [2.3-5.0] ng/dL), total T4 (9.9 [6.4-16.9] ng/dL), and total T3 (135 [88-231] ng/dL). If the nonpregnant reference range of serum TSH was used, eight women (4.8%) would be misclassified as having subclinical hyperthyroidism, and two women (1.2%) with subclinical hypothyroidism would be missed. In multivariate analysis, nulliparous (adjusted odds ratio [OR] from model 1-3: 2.02, 2.05, 2.02; 95% CI, 1.08-3.77, 1.10-3.81, 1.11-3.66; p = 0.027, 0.023, 0.022, respectively) and multivitamin nonusers (adjusted OR from model 1-3: 1.86, 1.85, 1.78; 95% CI, 1.04-3.34, 1.03-3.32, 1.004-3.71; p = 0.038, 0.039, 0.049, respectively) had increased odds of having lower UIC levels <150 µg/L. CONCLUSION: The iodine nutritional status in the first trimester is adequate in Taiwan; however, certain subgroups such as nulliparous and multivitamin nonusers are still at risk for iodine deficiency. Gestational thyroid function reference ranges are needed for correct diagnosis of thyroid dysfunction in pregnancy.

Glucagon-like peptide-1 receptor agonists and risk of sight-threatening retinopathy in Taiwanese population: A propensity based cohort study.

AIMS: To compare the risk of vision-threatening retinopathy between glucagon-like peptide-1 receptor agonists (GLP-1 RA) use and no use in patients with type 2 diabetes. METHODS: Using propensity score matching, we identified 27,506 pairs of GLP-1 RA users and non-users, 3904 pairs of GLP-1 RA and dipeptidyl peptidase-4 inhibitors (DPP-4i) users, 10,985 pairs of GLP-1 RA and sodium-glucose cotransporter-2 inhibitors (SGLT2i) users, 2542 pairs of GLP-1 RA and sulfonylurea, respectively, from Taiwan's National Health Insurance Research Database from January 1, 2009 to December 31, 2018. We used Cox proportional hazards models to compare the risk of vision-threatening retinopathy between GLP-1 RA use and other matched groups. RESULTS: In the matched cohorts, the time-varying exposure analysis showed that GLP-1 RA use was not associated with an increased risk of vision-threatening retinopathy compared to GLP-1 RA non-use (aHR 0.96, 95 % CI 0.89-1.03). New-user and active-comparator analyses showed that GLP-1 RA was associated with a significantly lower risk of vision-threatening retinopathy than DPP-4i (aHR 0.8, 95 % CI 0.66-0.97) but had no significant association with this risk compared to SGLT2i (aHR 1.09, 95 % CI 0.96-1.24) or sulfonylureas (aHR 0.79, 95 % CI 0.49-1.06). CONCLUSIONS: This nationwide cohort study showed that GLP-1 RA use was not associated with an increased risk of vision-threatening retinopathy compared to non- GLP-1 RA use, and GLP-1 RA could significantly lower the risk of vision-threatening retinopathy than DPP-4i.

Recent progress in unraveling cardiovascular complications associated with primary aldosteronism: a succinct review.

This comprehensive review offers a thorough exploration of recent advancements in our understanding of the intricate cardiovascular complications associated with Primary Aldosteronism (PA). PA encompasses a spectrum of conditions characterized by hypertension and excessive production of aldosterone operating independently of the renin-angiotensin system. Given its association with an elevated risk of cardiovascular and cerebrovascular complications, as well as a higher incidence of metabolic syndrome in comparison to individuals with essential hypertension (EH), an accurate diagnosis of PA is of paramount importance. This review delves into the intricate interplay between PA and cardiovascular health and focuses on the key pathophysiological mechanisms contributing to adverse cardiac outcomes. The impact of different treatment modalities on cardiovascular health is also examined, offering insights into potential therapeutic approaches. By highlighting the significance of recognizing PA as a significant contributor to cardiovascular morbidity, this review emphasizes the need for improved screening, early diagnosis, and tailored management strategies to both enhance patient care and mitigate the burden of cardiovascular diseases. The findings presented herein underscore the growing importance of PA in the context of cardiovascular medicine and emphasize the potential for translating these insights into targeted interventions to improve patient outcomes.

Electrochemical Skin Conductance by Sudoscan in Non-Dialysis Chronic Kidney Disease Patients.

BACKGROUND: Peripheral neuropathy is prevalent among patients with chronic kidney disease (CKD). Sudoscan non-invasively detects polyneuropathy by measuring electrochemical skin conductance (ESC). We conducted a study on sudomotor function in CKD patients across various stages based on their estimated glomerular filtration rate (eGFR). METHODS: In this cross-sectional study of 700 CKD patients, all underwent Sudoscan. Pathological ESC was defined as hands < 40 µS or feet < 50 µS. Clinical neuropathy scores including Michigan Neuropathy Screening Instrument (MNSI) and Douleur Neuropathique en 4 questionnaire (DN4) were obtained. RESULTS: Among participants, 344 had diabetes and 356 did not. Hands and feet ESC decreased with CKD progression (median (IQR) in stage 1-2, 3, 4-5: 54.0 (39.0-68.0), 45.5 (30.0-63.0), 41.8 (26.5-60.5), p trend < 0.001; 64.5 (53.5-74.0), 60.5 (43.0-72.5), 55.0 (39.0-69.8), p trend < 0.001). Pathological hands and feet ESC increased in later CKD stages (stage 1-2, 3, 4-5: 26.6%, 40.9%, 45.7%, p trend < 0.001; 21.7%, 34.0%, 40.6%, p trend < 0.001). Positive hands and feet ESC-eGFR correlation existed irrespective of diabetes. Diabetic patients had lower hands and feet ESC than non-diabetics as CKD progressed. However, multivariate regression found no significant ESC-eGFR association. Sudoscan correlated with clinical neuropathy scores. CONCLUSION: Pathological sudomotor function was common in non-dialysis CKD stages 4-5. Diabetic patients had worse function. Sudomotor dysfunction progressed with renal disease but eGFR was not an independent risk factor.

Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Retinopathy in Patients With Type 2 Diabetes.

Importance: Diabetic nephropathy and diabetic retinopathy share many similarities in pathophysiological processes. Preclinical studies have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2is) have a protective role in the risk of diabetic retinopathy. Objective: To compare the risk of sight-threatening retinopathy associated with SGLT2is and other second-line glucose-lowering medications (including pioglitazone, sulfonylureas, and dipeptidyl peptidase-4 inhibitors [DPP-4is]) in patients with type 2 diabetes (T2D). Design, Setting, and Participants: This cohort study in Taiwan applied a new-user and active-comparator design. Patient demographic and clinical data were obtained from the National Health Insurance Research Database. Adult patients with newly diagnosed T2D from January 1, 2009, to December 31, 2019, were recruited and followed up until December 31, 2020. Propensity score matching was used to identify pairs of patients treated with SGLT2i vs DPP-4i, SGLT2i vs pioglitazone, and SGLT2i vs sulfonylurea from January 1, 2016, to December 31, 2019. Data were analyzed between August 18, 2022, and May 5, 2023. Exposures: Treatment with SGLT2i, DPP-4i, pioglitazone, and sulfonylureas starting on January 1, 2016. Main Outcomes and Measures: The main outcome was sight-threatening retinopathy in participants. Cox proportional hazards regression models were used to assess relative hazards of sight-threatening retinopathy between the matched case and control groups. Results: A total of 3 544 383 patients with newly diagnosed T2D were identified. After 1:1 propensity score matching, 65 930 pairs of patients treated with SGLT2i vs DPP-4i, 93 760 pairs treated with SGLT2i vs pioglitazone, and 42 121 pairs treated with SGLT2i vs sulfonylurea were identified. These matched patients included 236 574 males (58.6%), with a mean (SD) age of 56.9 (11.8) years. In the matched cohorts, SGLT2i had a significantly lower risk of sight-threatening retinopathy than DPP-4i (adjusted hazard ratio [AHR], 0.57; 95% CI, 0.51-0.63), pioglitazone (AHR, 0.75; 95% CI, 0.69-0.81), and sulfonylureas (AHR, 0.62; 95% CI, 0.53-0.71). The Kaplan-Meier curves showed that SGLT2i was associated with a significantly lower cumulative incidence of sight-threatening retinopathy than DPP-4i (3.52 vs 6.13; P < .001), pioglitazone (4.32 vs 5.76; P < .001), and sulfonylureas (2.94 vs 4.67; P < .001). Conclusions and Relevance: This cohort study found that SGLT2i was associated with a lower risk of sight-threatening retinopathy compared with DPP-4i, pioglitazone, and sulfonylureas. This finding suggests that SGLT2i may play a role not only in reduced risk of diabetic nephropathy but also in the slow progression of diabetic retinopathy in patients with T2D.

Whole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program.

Introduction: Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data. Methods: Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, or four or more medications regardless of BP (n = 1,705). A normotensive control group was defined as individuals with BP < 140/90 mmHg (n = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90 mmHg (n = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American). Results: One variant in the known HTN locus, KCNK3, was a top finding in the multi-ethnic analysis (p = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95% confidence interval) = 0.80 (0.74-0.88)]. This variant was replicated in the Vanderbilt University Medical Center's DNA repository data. Aggregate gene-based signals included the genes AGTPBP, MYL4, PDCD4, BBS9, ERG, and IER3. Discussion: Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.