Dear Editor,
We read with interest the meta-analysis by Davood et al. [1], which concluded that SGLT2 inhibitors (SGLT2is) modestly reduce blood pressure (BP) without clear dose-dependency. However, we note methodological limitations that warrant discussion.
First, categorizing dosages as "low, medium, high" across different SGLT2is oversimplifies dose-response relationships. Pharmacokinetic and potency differences exist. Sato et al. found that without standardization (e.g., by urinary glucose excretion), potency differences of 2.3-fold can occur; after standardization, canagliflozin still showed 1.33-fold higher intrinsic activity [2]. Future analyses should use pharmacologically-driven dose modeling.
Second, the validity of indirect comparisons in the star-shaped network relies on transitivity. Chen et al. demonstrated that key modifiers like diabetes duration (>15 years: HR 0.78; <5 years: HR 0.65; P = 0.003) and baseline hypertension severity substantially alter treatment effects, threatening indirect comparison validity [3]. The conclusion of comparable efficacy may thus be unreliable without assessing these factors.
Third, the "non-dose-dependent" conclusion requires scrutiny. The "effect ceiling" phenomenon may explain the lack of gradient. More critically, original trials were underpowered for BP endpoints. Georgianos et al. confirmed sample sizes were based on glycemic outcomes, leading to severe underpowering for detecting BP differences. With sample sizes <200/group, the false-negative rate for dose-response reached 47% [4]. Interpreting "no significant effect" as "no dose-dependency" may be biased.
Future studies with refined dose models, rigorous transitivity checks, and BP-focused designs are needed. We believe addressing these points will strengthen future evidence synthesis.
CRediT authorship contribution statement
Yin Jian: Writing – original draft, Writing – review & editing. Bin Cao: Conceptualization, Supervision, Visualization.
Funding
The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
References
- 1.Semirani-Nezhad D., Roozbehi K., Moghadam A.S., Ebrahimi E., Salehi K., Hashempoor A., et al. Dose-dependent effects of SGLT2 inhibitors on circadian blood pressure in hypertensive patients with diabetes: a systematic review and bayesian network meta-analysis. Int. J. Cardiol. Cardiovas. Risk Prev. 2026 doi: 10.1016/j.ijcrp.2025.200569. [DOI] [Google Scholar]
- 2.Sato H., Ishikawa A., Yoshioka H., Jin R., Sano Y., Hisaka A. Model-based meta-analysis of HbA1c reduction across SGLT2 inhibitors using dose adjusted by urinary glucose excretion. Sci. Rep. 2024;14 doi: 10.1038/s41598-024-76256-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Chen J.Y., Pan H.C., Shiao C.C., Chuang M.H., See C.Y., Yeh T.H., et al. Impact of SGLT2 inhibitors on patient outcomes: a network meta-analysis. Cardiovasc. Diabetol. 2023;22:290. doi: 10.1186/s12933-023-02035-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Georgianos P.I., Agarwal R. Ambulatory blood pressure reduction with SGLT-2 inhibitors: dose-response meta-analysis and comparative evaluation with low-dose hydrochlorothiazide. Diabetes Care. 2019;42:693–700. doi: 10.2337/dc18-2207. [DOI] [PMC free article] [PubMed] [Google Scholar]