Daily Endocrinology Research Analysis

OBJECTIVE: Glycemic management metrics derived from continuous glucose monitoring (CGM) are increasingly recognized as important therapeutic targets. We performed one of the first comparisons of CGM metrics and achievement of CGM targets among four classes of glucose-lowering medications in combination with metformin. RESEARCH DESIGN AND METHODS: The Glycemia Reduction Approaches in Diabetes (GRADE) study randomly assigned participants with type 2 diabetes and taking metformin to add one of four glucose-lowering medications (insulin glargine, glimepiride, liraglutide, or sitagliptin) and followed them for glycemic outcomes for 5 ± 1.3 years. A 2-week masked CGM analysis was conducted midstudy in 1,080 participants to evaluate CGM metrics, 24-h ambulatory glucose profile, and achievement of consensus goals. Treatment effects among the four groups were compared. RESULTS: The sitagliptin and liraglutide groups had the highest time in range 70-180 mg/dL (TIR70-180) and the lowest time below range <70 mg/dL (TBR<70) and percentage coefficient of variation (%CV). The glimepiride group had the lowest TIR70-180, and the highest %CV, TBR<70, and number of CGM-derived hypoglycemic events (P < 0.001), and was the only drug showing daytime hypoglycemia. Sitagliptin and liraglutide were best for achieving consensus goals of very low TBR<54 <1% and the combined metric of TIR70-180 >70% and TBR<70 <4% (P < 0.001). When stratified by HbA1c, mean glucose did not differ among treatments, but %CV and TBR<70 were higher with glargine and glimepiride within each HbA1c stratum. CONCLUSIONS: Incretin class drugs had the lowest %CV, the least hypoglycemia, and best achievement of CGM-based glycemic targets. CGM metrics and profiles provide clinical insights, beyond HbA1c, to guide diabetes management.

BACKGROUND: Urinary epidermal growth factor (uEGF) is a marker of tubular repair capacity. Lower uEGF-to-creatinine ratio (uEGF/Cr) levels associate with kidney disease progression in patients with type 2 diabetes at early stages of chronic kidney disease (CKD). In these patients, sodium-glucose cotransporter 2 inhibitors (SGLT2i) are associated with increased tubular EGF expression. In this study, we aimed to extend these findings to a broad CKD population with and without type 2 diabetes at various stages of CKD. METHODS: We measured EGF in stored urine samples at baseline and year 1 in participants from the CANVAS, CREDENCE, and DAPA-CKD clinical trials. Associations of baseline and longitudinal uEGF/Cr with the composite kidney outcome (sustained ≥40% eGFR decline, kidney failure, or kidney-related death) were assessed using multivariable Cox regression, and associations with annual eGFR decline using a two-slope linear mixed-effects model. Treatment effects of SGLT2i on uEGF/Cr over time were analyzed with analysis of covariance. RESULTS: In participants with type 2 diabetes from the CANVAS and CREDENCE trials (N = 5978), higher baseline uEGF/Cr was associated with a lower risk of the composite kidney outcome (hazard ratio per 2-fold higher uEGF/Cr: 0.87 [95% CI 0.80, 0.94]). SGLT2i attenuated the decline in uEGF/Cr over 1-year compared to placebo by 6.7% (95% CI 2.5, 10.8). Increases in uEGF/Cr from baseline to year 1 were independently associated with a reduced risk of the kidney outcome, even after accounting for 1-year changes in albuminuria, eGFR, and other clinical variables. Replication analyses showed similar results in the DAPA-CKD trial (N = 2450), with consistent findings in participants with and without diabetes. CONCLUSIONS: These results extend previous findings, supporting uEGF/Cr as a robust, independent biomarker of tubular health and kidney risk across diverse CKD populations. SGLT2i attenuate uEGF/Cr decline, and early changes in uEGF/Cr provide prognostic information beyond albuminuria.

IMPORTANCE: Thiazide diuretics are a cornerstone for the treatment of hypertension, but their use is associated with development of hyponatremia. Women and older adults are particularly vulnerable, but population-based estimates of absolute risk are largely absent. Such data are a prerequisite for a robust risk-benefit assessment in the clinical setting. OBJECTIVE: To compare new use of thiazide diuretics with calcium channel blockers (CCBs) and subsequent risk of hyponatremia among different age groups and between the sexes. DESIGN, SETTING, AND PARTICIPANTS: This propensity score-matched cohort study included 159 080 individuals 18 years or older in the Stockholm Sodium Cohort, a research database established to investigate the association between thiazide and hyponatremia among individuals in Stockholm, Sweden, between July 1, 2006, and December 31, 2018. Statistical analysis was performed between January 2025 and January 2026. EXPOSURE: Newly initiated treatment with thiazide diuretics and CCBs. MAIN OUTCOMES AND MEASURES: The primary outcome was profound hyponatremia (ie, a sodium concentration <125 mEq/L). Secondary outcomes were sodium concentrations less than 130 mEq/L and less than 135 mEq/L. RESULTS: A total of 79 540 individuals (median age, 63 years [IQR, 54-72 years]; 41 275 women [51.9%]) initiating thiazide treatment were propensity score matched with 79 540 individuals (median age, 63 years [IQR, 54-72 years]; 41 168 women [51.8%]) receiving CCBs. The cumulative incidence of profound hyponatremia was 0.80% (95% CI, 0.74%-0.87%) for thiazide users and 0.46% (95% CI, 0.41%-0.51%) for CCB users during the first 2 years of treatment. The occurrence of profound hyponatremia with thiazide treatment was higher among women (cumulative incidence, 1.04% [95% CI, 0.94%-1.15%) and individuals 80 years or older (cumulative incidence, 2.40% [95% CI, 2.07%-2.73%]). Thus, among women 80 years or older, the number needed to harm (NNH) was 53 (95% CI, 41-73) for developing sodium concentrations less than 125 mEq/L, 28 (95% CI, 22-38) for concentrations less than 130 mEq/L, and 16 (95% CI, 13-20) for concentrations less than 135 mEq/L. This was in marked contrast with women younger than 65 years, for whom the corresponding NNH was 790 (95% CI, 408-11 966) for developing sodium concentrations less than 125 mEq/L, 818 (95% CI, 303-∞) for concentrations less than 130 mEq/L, and 120 (95% CI, 78-261) for concentrations less than 135 mEq/L. CONCLUSIONS AND RELEVANCE: In this cohort study comprising 159 080 individuals, the association between newly initiated thiazide diuretics and hyponatremia was negligible among individuals younger than 65 years of age. In contrast, among older adults, especially among women, the association was substantial. The results may incentivize the prescriber toward choosing an alternative antihypertensive treatment. If thiazides are initiated, subsequent monitoring of serum sodium concentrations should be considered.