Recently, the management of type 2 diabetes mellitus (T2DM) has been dramatically changed by new classes of glucose-lowering drugs. Especially, the emergence of sodium-glucose cotransporter-2 inhibitor (SGLT2i) can be cited as the primary factor for this change. SGLT2i blocks glucose reabsorption in the proximal tubules of the kidney and increases glucosuria, as well as blocking sodium resorption and leading to sodium excretion in the urine [1]. A recent series of mega-scale clinical trials for SGLT2i indicated cardioprotective effects of SGLT2i [2,3,4], and some SGLT2is have now become the first-line treatment for T2DM with comorbid atherosclerotic cardiovascular disease (ASCVD) and heart failure. Furthermore, several studies have reported a lowering effect of SGLT2i on blood pressure (BP) [5]. However, it is unclear which type of patients, especially obese or non-obese, may experience a greater antihypertensive effect with SGLT2i treatment.
The present study by Tsukamoto et al. [6] retrospectively evaluated 447 Japanese patients with T2DM and chronic kidney disease (CKD) treated with SGLT2i for at least 1 year. The primary outcome was achieving the target BP (<130/80 mmHg) after SGLT2i treatment. Consequently, the body mass index (BMI) <29.1 group had significantly lower systolic and diastolic BPs after SGLT2i treatment than the BMI ≥29.1 group. Baseline BMI was associated with the antihypertensive effects of SGLT2i. The present study is clinically significant as it demonstrates that the BP-lowering effect of SGLT2i is more effective in non-obese patients. Furthermore, conversely, this study could also be interpreted as indicating the limitations of the BP-lowering effect of SGLT2i in obese patients. From previous reports [7], it was believed that BP-lowering effect of SGLT2i were more effective in obese patients. However, sub-analyses based on obesity status were not extensively reported in previous cardiovascular outcome trials. The present study is a groundbreaking research that overturns previous reports in a cohort model with propensity score matching.
Although mechanisms underlying the BP-lowering effects of SGLT2i are unclear, SGLT2i presumably acts primarily by decreasing circulating plasma volume through osmotic and natriuretic diuresis in the early stages of administration and later by suppressing sympathetic nerve activity in the long term [8, 9]. In the present study, Tsukamoto et al. proposed insufficient improvement in insulin resistance or inhibition of sympathetic nervous system hyperactivation due to “residual risk of obesity” as a potential mechanism for the insufficient BP reduction in obese patients treated with SGLT2i (Fig. 1). Furthermore, exploring the potential impact of obstructive sleep apnea, which is highly prevalent in obese patients, would be of great interest in the BP-lowering effect of SGLT2i.
In addition, what is particularly interesting in this study is the degree of BP reduction achieved with SGLT2i. SGLT2i has shown modest but significant BP-lowering effects [10]. In individuals with elevated BP, SGLT2i lower systolic BP by 3–9 mmHg [5, 11]. The magnitude of BP lowering is consistent regardless of number of background BP-lowering agents and is also observed in individuals with treatment- resistant hypertension [12, 13]. In the present study, the overall systolic BP reduction was about 9–10 mmHg (about 12 mmHg in the lower BMI group). The authors attribute this greater systolic BP reduction to the inadequate blood pressure control in the study patients. However, conversely, these findings may suggest that in non-obese patients, the BP-lowering effect of SGLT2i is sufficient even as a monotherapy.
Finally, as mentioned by the authors in the Discussion, if we assume that the mechanism underlying the inadequate BP reduction in obese patients treated with SGLT2i is attributed to “residual obesity” and increased sodium intake, then, there is a possibility that additional administration of glucagon-like peptide-1 receptor agonist (GLP-1RA) or angiotensin receptor-neprilysin inhibitors (ARNI) may be effective. In future research, studies investigating the combination therapy of GLP-1RA or ARNI for obese patients with insufficient BP reduction by SGLT2i are anticipated.
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KS received funds from Omron Health Care Ltd, Asahi Calpis Wellness Ltd, Teijin Pharma Ltd, Fukuda Lifetec Ltd.
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Shiina, K. Who benefits from the blood pressure-lowering effects of SGLT2 inhibitors in patients with type 2 diabetes mellitus and chronic kidney disease? — Obese or non-obese?. Hypertens Res 47, 681–682 (2024). https://doi.org/10.1038/s41440-023-01543-0
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DOI: https://doi.org/10.1038/s41440-023-01543-0