Effects of 26 weeks of treatment with empagliflozin versus glimepiride on the myocardial glucose metabolic rate in patients with type 2 diabetes: The randomized, open‐label, crossover, active‐comparator FIORE trial

Succurro, Elena; Vizza, Patrizia; Papa, Anselmo; Miceli, Sofia; Cicone, Francesco; Fiorentino, Teresa Vanessa; Sciacqua, Angela; Andreozzi, Francesco; Veltri, Pierangelo; Cascini, Giuseppe Lucio; Sesti, Giorgio

doi:10.1111/dom.14816

Cited by 9 publications

(6 citation statements)

References 67 publications

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“…The present findings are in agreement with those of previous studies showing the mechanisms of SGLT2 inhibitors on myocardial glucose metabolism assessed by PET with 18 F-FDG combined with euglycemic-hyperinsulinemic clamp [39][40][41]. A previous study showed that 4-week treatment with dapagliflozin reduced epicardial adipose tissue glucose uptake in patients with T2DM and stable coronary artery disease improving myocardial flow reserve [39].…”

Section: Discussionsupporting

confidence: 93%

Sex-specific differences in myocardial glucose metabolic rate in non-diabetic, pre-diabetic and type 2 diabetic subjects

Succurro,

Vizza,

Cicone

et al. 2024

Cardiovasc Diabetol

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Background Evidence has shown that women with type 2 diabetes (T2DM) have a higher excess risk for cardiovascular disease (CVD) than men with T2DM. Subjects with either T2DM or prediabetes exhibit myocardial insulin resistance, but it is still unsettled whether sex-related differences in myocardial insulin resistance occur in diabetic and prediabetic subjects. Methods We aimed to evaluate sex-related differences in myocardial glucose metabolic rate (MRGlu), assessed using dynamic PET with 18F-FDG combined with euglycemic-hyperinsulinemic clamp, in subjects with normal glucose tolerance (NGT; n = 20), prediabetes (n = 11), and T2DM (n = 26). Results Women with prediabetes or T2DM exhibited greater relative differences in myocardial MRGlu than men with prediabetes or T2DM when compared with their NGT counterparts. As compared with women with NGT, those with prediabetes exhibited an age-adjusted 35% lower myocardial MRGlu value (P = 0.04) and women with T2DM a 74% lower value (P = 0.006), respectively. Conversely, as compared with men with NGT, men with T2DM exhibited a 40% lower myocardial MRGlu value (P = 0.004), while no significant difference was observed between men with NGT and prediabetes. The statistical test for interaction between sex and glucose tolerance on myocardial MRGlu (P < 0.0001) was significant suggesting a sex-specific association. Conclusions Our data suggest that deterioration of glucose homeostasis in women is associated with a greater impairment in myocardial glucose metabolism as compared with men. The sex-specific myocardial insulin resistance could be an important factor responsible for the greater effect of T2DM on the excess risk of cardiovascular disease in women than in men.

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Section: Discussionsupporting

confidence: 93%

Sex-specific differences in myocardial glucose metabolic rate in non-diabetic, pre-diabetic and type 2 diabetic subjects

Succurro,

Vizza,

Cicone

et al. 2024

Cardiovasc Diabetol

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“…This is in line with the study published by Latva-Rasku and colleagues, which demonstrated that 8-week treatment with dapagliflozin does not affect tissue insulin sensitivity and MGU as measured with PET in T2D patients [ 25 ], but contrasts with other studies which instead described an increase in insulin sensitivity [ 26 – 28 ]. Succurro et al [ 29 ] recently demonstrated that T2D patients randomized to empagliflozin showed a significant reduction in MGU during hyperinsulinemic euglycemic clamp after 26 weeks of treatment as compared to patients randomized to glimepiride who showed an increase in MGU. Empagliflozin treatment was also associated with a significant increase in WBGU compared to glimepiride, which induced a reduction in WBGU.…”

Section: Discussionmentioning

confidence: 99%

Dapagliflozin improves myocardial flow reserve in patients with type 2 diabetes: the DAPAHEART Trial: a preliminary report

Leccisotti

Cinti

Sorice

et al. 2022

Cardiovasc Diabetol

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Objective Cardiovascular (CV) outcome trials have shown that in patients with type 2 diabetes (T2D), treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) reduces CV mortality and hospital admission rates for heart failure (HF). However, the mechanisms behind these benefits are not fully understood. This study was performed to investigate the effects of the SGLT-2i dapagliflozin on myocardial perfusion and glucose metabolism in patients with T2D and stable coronary artery disease (coronary stenosis ≥ 30% and < 80%), with or without previous percutaneous coronary intervention (> 6 months) but no HF. Methods This was a single-center, prospective, randomized, double-blind, controlled clinical trial including 16 patients with T2D randomized to SGLT-2i dapagliflozin (10 mg daily) or placebo. The primary outcome was to detect changes in myocardial glucose uptake (MGU) from baseline to 4 weeks after treatment initiation by [(18)F]2-deoxy-2-fluoro-D-glucose (FDG) PET/CT during hyperinsulinemic euglycemic clamp. The main secondary outcome was to assess whether the hypothetical changes in MGU were associated with changes in myocardial blood flow (MBF) and myocardial flow reserve (MFR) measured by 13N-ammonia PET/CT. The study was registered at eudract.ema.europa.eu (EudraCT No. 2016-003614-27) and ClinicalTrials.gov (NCT 03313752). Results 16 patients were randomized to dapagliflozin (n = 8) or placebo (n = 8). The groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, renal and heart function). There was no significant change in MGU during euglycemic hyperinsulinemic clamp in the dapagliflozin group (2.22 ± 0.59 vs 1.92 ± 0.42 μmol/100 g/min, p = 0.41) compared with the placebo group (2.00 ± 0.55 vs 1.60 ± 0.45 μmol/100 g/min, p = 0.5). Dapagliflozin significantly improved MFR (2.56 ± 0.26 vs 3.59 ± 0.35 p = 0.006 compared with the placebo group 2.34 ± 0.21 vs 2.38 ± 0.24 p = 0.81; pint = 0.001) associated with a reduction in resting MBF corrected for cardiac workload (p = 0.005; pint = 0.045). A trend toward an increase in stress MBF was also detected (p = 0.054). Conclusions SGLT-2 inhibition increases MFR in T2D patients. We provide new insight into SGLT-2i CV benefits, as our data show that patients on SGLT-2i are more resistant to the detrimental effects of obstructive coronary atherosclerosis due to increased MFR, probably caused by an improvement in coronary microvascular dysfunction. Trial registration EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752

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“…We acknowledge that the present study has several limitations that should be addressed in the near future regarding the interactions of different treatment drugs with insulin-related plaque accumulation. As proposed by previous works [ 37 , 38 , 39 ], antidiabetic and antihypertensive drugs could have interfered with the myocardial glucose metabolism and therefore their relationship with T2D-related CACs should be independently studied. Moreover, antiaggregant therapy could be useful to avoid CACs and presents itself as a very good alternative to avoid the counter-effects of insulin intake [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Insights into Insulin Resistance and Calcification in the Myocardium in Type 2 Diabetes: A Coronary Artery Analysis

Martín-Saladich

Simó

Aguadé-Bruix

et al. 2023

IJMS

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Type 2 diabetes (T2D) is responsible for high incidence of cardiovascular (CV) complications leading to heart failure. Coronary artery region-specific metabolic and structural assessment could provide deeper insight into the extent of the disease and help prevent adverse cardiac events. Therefore, in this study, we aimed at investigating such myocardial dynamics for the first time in insulin-sensitive (mIS) and insulin-resistant (mIR) T2D patients. We targeted global and region-specific variations using insulin sensitivity (IS) and coronary artery calcifications (CACs) as CV risk factor in T2D patients. IS was computed using myocardial segmentation approaches at both baseline and after an hyperglycemic–insulinemic clamp (HEC) on [18F]FDG-PET images using the standardized uptake value (SUV) (ΔSUV = SUVHEC − SUVBASELINE) and calcifications using CT Calcium Scoring. Results suggest that some communicating pathways between response to insulin and calcification are present in the myocardium, whilst differences between coronary arteries were only observed in the mIS cohort. Risk indicators were mostly observed for mIR and highly calcified subjects, which supports previously stated findings that exhibit a distinguished exposure depending on the impairment of response to insulin, while projecting added potential complications due to arterial obstruction. Moreover, a pattern relating calcification and T2D phenotypes was observed suggesting the avoidance of insulin treatment in mIS but its endorsement in mIR subjects. The right coronary artery displayed more ΔSUV, whilst plaque was more present in the circumflex. However, differences between phenotypes, and therefore CV risk, were associated to left descending artery (LAD) translating into higher CACs regarding IR, which could explain why insulin treatment was effective for LAD at the expense of higher likelihood of plaque accumulation. Personalized approaches to assess T2D may lead to more efficient treatments and risk-prevention strategies.

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Effects of 26 weeks of treatment with empagliflozin versus glimepiride on the myocardial glucose metabolic rate in patients with type 2 diabetes: The randomized, open‐label, crossover, active‐comparator FIORE trial

Cited by 9 publications

References 67 publications

Sex-specific differences in myocardial glucose metabolic rate in non-diabetic, pre-diabetic and type 2 diabetic subjects

Sex-specific differences in myocardial glucose metabolic rate in non-diabetic, pre-diabetic and type 2 diabetic subjects

Dapagliflozin improves myocardial flow reserve in patients with type 2 diabetes: the DAPAHEART Trial: a preliminary report

Insights into Insulin Resistance and Calcification in the Myocardium in Type 2 Diabetes: A Coronary Artery Analysis

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