Effects of SGLT-2 inhibitors on renin-angiotensin-aldosterone system and their correlation with glucose metabolism in type 2 diabetes mellitus patients with hypertension: A prospective study

Abstract

Background The impact of sodium-glucose cotransporter-2 inhibitors (SGLT-2is), including dapagliflozin, on the renin-angiotensin-aldosterone system (RAAS) in type 2 diabetes mellitus (T2DM) patients remains controversial, as they may either activate or inhibit RAAS, subsequently influencing glucose metabolism and the accuracy of the aldosterone-to-renin ratio (ARR) in diagnosing primary aldosteronism (PA). However, the effects of SGLT-2is therapy on RAAS and their correlation with glucose metabolism have not been well studied. Methods A cohort of 147 patients with T2DM and hypertension was prospectively recruited and categorized into two groups: diabetic kidney disease group (DKD, n = 73) and non-DKD group (n = 74), based on diagnostic criteria for diabetic complications. Patients were prescribed 10 mg dapagliflozin daily for 3 months. The primary outcome measure was the change in renin (REN) levels during outpatient visits at baseline, 1 month, and 3 months. The secondary outcome was the change in other metabolic biomarkers from baseline to the 3-month visit. To evaluate the relationship between RAAS components and various glucose metabolism indicators, including HbA1c, FBG, CP, HOMA-β, HOMA-IR, and UACR, Spearman correlation and multiple linear regression analyses were conducted at baseline and 3-month visit. Results After 3 months, the BMI, HbA1c, FBG, TG, TCHO, SBP, DBP, UACR, and HOMA-IR levels were significantly decreased, while Crea and HOMA-β were significantly increased from the baseline in both groups. Additionally, the differences from the baseline in FBG (−2.64±2.66 vs. −1.70±1.92 mmol/L) and UACR (−355.01±1534.12 vs. −4.66±7.86 mg/g) values were significantly higher in DKD group than those in non-DKD group. REN levels increased significantly from baseline at 1-month visit (4.15±7.35 vs. 2.75±8.03 ng/L; DKD vs. non-DKD; between-group difference, p<0.05), while ARR values decreased significantly from baseline at 1-month visit (−0.70±1.16 vs. −0.59±1.19; between-group difference, p>0.05) and 3-month visit (−0.45±1.15 vs. −0.42±1.07; between-group difference, p>0.05) in both groups (within-group change vs. baseline, p<0.017). Interestingly, no temporal differences were observed in ALD levels. REN levels returned to baseline after three months of treatment; yet the ARR, which was primarily influenced by REN, remained below its initial value. Multiple linear regression analysis revealed that a 100% increase in Log-ALD was associated with a 0.143 nmol/L higher CP and a 15.8% higher HOMA-IR in DKD group(p<0.05). A 100% increase in Log-REN was associated with a 0.359 mg/g lower UACR in DKD group and a 0.042 mmol/L higher FBG in non-DKD group(p<0.01). These correlations were independent of the internal interactions of RAAS but were significantly attenuated after 3 months of treatment. Conclusions The correlations between RAAS markers and glucose metabolism indices were significantly attenuated, potentially due to lowered blood glucose levels after SGLT-2is treatment. However, it is noteworthy that short-term therapy may elevate REN levels and reduce ARR, potentially resulting in false-negative outcomes in PA screening.