SGLT2i reduces left ventricular mass in T2DM patients with LVH
A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes: the DAPA-LVH
Introduction and methods
A class effect of SGLT2i members on hospitalization for heart failure (HHF) has been suggested, as consistent effects of SGLT2 inhibitors have been observed in multiple trials enrolling T2DM patients. The recent DAPA-HF trial [1] demonstrated that the SGLT2i dapagliflozin reduced incidence of CVD and worsening heart failure in patients with HFrEF, with and without TDM, suggesting that benefit of SGLT2i is independent of glycemic control.
The precise mechanisms of SGLT2i however are unclear and may include natriuresis, reduction in interstitial edema, reduction of preload and afterload, improvement of renal function and cardiorenal physiology, inhibition of cardiac sodium-hydrogen exchange, and improved cardiac bioenergetics [2]. Reduction in preload and afterload may reduce left ventricular wall stress and lead to beneficial cardiac remodeling by regression of left ventricular hypertrophy (LVH).
The ‘proof of concept’ randomized controlled DAPA-LVH trial was performed to examine whether dapagliflozin causes regression of left ventricular mass in T2DM patients and LVH, assessed using cardiac magnetic resonance imaging (MRI). Exploratory secondary outcomes were body weight and composition, BP and insulin resistance, which are all potentially implicated in the pathophysiology of LVH in T2DM. 66 Patients were enrolled in this single-center trial in Tayside, Scotland and randomized to dapagliflozin or placebo. Cardiac and abdominal MRIs were performed at baseline and after 10-12 months (mean treatment period was 11.9 months).
Main results
- Change in LVM in the dapagliflozin group was -3.95 ± 4.85 g and in the placebo group -1.13 ± 4.55 g (P=0.018), leading to an absolute mean difference of -2.82 g (95%CI: -5.13 to -0.51).
- LVH regression by dapagliflozin was greater in those with an above median LVMI (LVM index) at baseline (mean change of -3.88 g, 95% CI: -7.15 to -0.61, P = 0.021).
- Dapagliflozin treatment resulted in reduction in LVM indexed to height, height¹∙⁷, height²∙⁷, compared to placebo. Also, LVM indexed to baseline body surface area (BSA) was more reduced by dapagliflozin compared to placebo (change in LVMI BSA: dapagliflozin group -2.06 g/m² vs. placebo group -0.65 g/m²; P = 0.019) leading to an estimated mean difference of -2.41 g/m² (95%CI: -2.58 to -0.24).
- 24-h ambulatory SBP and nocturnal SBP were reduced by dapagliflozin compared to placebo (mean difference in 24-h ambulatory SBP was -3.6 mmHg, 95%CI: -6.4 to -0.8; P = 0.012 and mean difference in nocturnal SBP was -4.4 mmHg, 95%CI: to – 7.9 to -0.8; P=0.017).
- There was a moderate correlation between change in LVM and change in ambulatory 24 SBP and nocturnal SBP (r=0.415, P=0.001, and r=0.321, P=0.012, respectively).
- Dapagliflozin reduced visceral adipose tissue (VAT) and subcutaneous adipose tissue (SCAT), and VAT/SCAT ratio compared to placebo. There was a strong correlation between change in LVM and change in VAT (r=0.592, P<0.001) and a moderate correlation between change in LVM and change in SCAT (r=0.360, P=0.006).
- Dapagliflozin significantly reduced weight, fasting glucose, glycated hemoglobin, hsCRP, improved HOMA-IR and raised hemoglobin and hematocrit levels compared to placebo.
Conclusion
LVM regression was observed after 1-year treatment with dapagliflozin compared to placebo, measured by cardiac MRI, in T2DM patients with LVH. These findings indicate that dapagliflozin can facilitate cardiac reverse remodeling, which may partly explain the cardiobeneficial effects observed with this SGLT2 inhibitor.
In addition, measures of body weight, VAT, SCAT, 24-h ambulatory and nocturnal SBP and insulin resistance were significantly reduced by dapagliflozin compared to placebo. These biomarkers may be involved in the pathophysiology of LVH in T2DM.
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