Effects of Dietary Sodium and Protein Intake on Glomerular Filtration Rate in Subjects with Type 2 Diabetes Treated with Sodium-Glucose Cotransporter 2 Inhibitors

Abstract

Background Approximately one-fourth of patients treated with sodium-glucose cotransporter 2 inhibitors (SGLT2i) experience an acute estimated glomerular filtration rate (eGFR) reduction of more than 10% (“dippers”). High sodium and protein intake can increase intraglomerular pressure and predispose to a decline in renal function. We investigated whether measured creatinine clearance (CrCl) is a sensitive enough method to detect the initial dip of GFR and if dietary sodium and protein intake might influence the extent of the early change in GFR.

Methods 28 subjects with type 2 diabetes (T2D) were enrolled. For sodium and urea determination, 24-h urinary samples were collected to estimate sodium and protein intake respectively before and 1, 3 and 6 months after SGLT2i initiation.

Results Mean CrCl was 83.23±25.52 mL/min/1.73 m² (eGFR 67.32±16.07) and dropped by 19% at month 1 (eGFR by 6%). Dippers were 64 and 40%, according to CrCl and eGFR, respectively. Exploring the potential correlation between changes in renal function and salt intake, ΔCrCl and baseline urinary sodium were inversely related at month 1 (r=−0,61; p<0.01), at month 3 (r=–0.51; p=0.01) and month 6 (r=−0,48; p<0.05). Likewise, an inverse correlation between ΔCrCl and baseline urinary urea was demonstrated at months 1 and 3 (r=−0.46; p<0.05 for both); at month 6, a similar trend was observed (r=–0.47; p=0.054).

Conclusions The present study suggests that a higher dietary sodium and protein intake may amplify the extent of the early dip in GFR, as detected with measured CrCl, in diabetic patients undergoing SGLT2i treatment.

Key words

SGLT2 inhibitors - estimated GFR - creatinine clearance - salt intake - protein intake

Publication History

Received: 04 January 2023
Received: 17 February 2023

Accepted: 21 February 2023

Accepted Manuscript online:
23 February 2023

Article published online:
17 May 2023

• References

• 1 McGuire DK, Shih WJ, Cosentino F. et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: A meta-analysis. JAMA Cardiol 2021; 6: 148-158
• 2 Heerspink HJL, Karasik A, Thuresson M. et al. Kidney outcomes associated with use of SGLT2 inhibitors in real-world clinical practice (CVD-REAL 3): A multinational observational cohort study. Lancet Diabetes Endocrinol 2020; 8: 27-35
• 3 Vallon V, Verma S. Effects of SGLT2 inhibitors on kidney and cardiovascular function. Annu Rev Physiol 2021; 83: 503-528
• 4 Weir MR, Chrysant SG, McCarron DA. et al. Influence of race and dietary salt on the antihypertensive efficacy of angiotensin-converting enzyme inhibitor or a calcium channel antagonist in salt-sensitive hypertensives. Hypertension 1998; 31: 1088-1096
• 5 Nunoi K, Sato Y, Kaku K. et al. Renal effects of a sodium-glucose cotransporter 2 inhibitor, tofogliflozin, in relation to sodium intake and glycaemic status. Diabetes Obes Metab 2019; 21: 1715-1724
• 6 Kinguchi S, Wakui H, Ito Y. et al. Relationship between basal sodium intake and the effects of dapagliflozin in albuminuric diabetic kidney disease. Sci Rep 2021; 11: 951
• 7 Lin J, Hu FB, Curhan GC. Associations of diet with albuminuria and kidney function decline. Clin J Am Soc Nephrol 2010; 5: 836-843
• 8 Esmeijer K, Geleijnse JM, de Fijter JW. et al. Dietary protein intake and kidney function decline after myocardial infarction: The Alpha Omega Cohort. Nephrol Dial Transplant 2020; 35: 106-115
• 9 van der Aart-van der Beek AB, Cherney D, Laverman GD. et al. Renal haemodynamic response to sodium-glucose cotransporter-2 inhibition does not depend on protein intake: An analysis of three randomized controlled trials. Diabetes Obes Metab 2021; 23: 1961-1967
• 10 Kraus BJ, Weir MR, Bakris GL. et al. Characterization and implications of the initial estimated glomerular filtration rate ‘dip’ upon sodium-glucose cotransporter-2 inhibition with empagliflozin in the EMPA-REG OUTCOME trial. Kidney Int 2021; 99: 750-762
• 11 Wheeler DC, Stefánsson BV, Jongs N. et al. DAPA-CKD Trial Committees and Investigators. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: A prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol 2021; 9: 22-31
• 12 EMPA-KIDNEY Collaborative Group. Herrington WG, Staplin N, Wanner C. et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2022 Epub ahead of printPMID: 36331190
• 13 De Nicola L, Gabbai FB, Garofalo C. et al. Nephroprotection by SGLT2 inhibition: Back to the future?. J Clin Med 2020; 97: 2243
• 14 Scholtes RA, Muskiet MHA, van Baar MJB. et al. Natriuretic effect of two weeks of dapagliflozin treatment in patients with type 2 diabetes and preserved kidney function during standardized sodium intake: Results of the DAPASALT Trial. Diabetes Care 2021; 44: 440-447
• 15 Zinman B, Wanner C, Lachin JM. et al. EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117-2128
• 16 Wiviott SD, Raz I, Bonaca MP. et al. DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019; 380: 347-357
• 17 Perkovic V, de Zeeuw D, Mahaffey KW. et al. Canagliflozin and renal outcomes in type 2 diabetes: Results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol 2018; 6: 691-704
• 18 Laville M. Back off to better blow up: Acute GFR decrease at SGLT-2 inhibitor initiation. Kidney Int 2021; 99: 814-816
• 19 Huang SH, Sharma AP, Yasin A. et al. Hyperfiltration affects accuracy of creatinine eGFR measurement. Clin J Am Soc Nephrol 2011; 6: 274-280
• 20 Holtkamp FA, de Zeeuw D, Thomas MC. et al. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int 2011; 80: 282-287
• 21 Perkovic V, Jardine MJ, Neal B. et al. CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380: 2295-2306
• 22 Alicic RZ, Johnson EJ, Tuttle KR. SGLT2 Inhibition for the prevention and treatment of diabetic kidney disease: A review. Am J Kidney Dis 2018; 72: 267-277