Effects of tofogliflozin on adrenocorticotropic hormone, renin and aldosterone, and cortisol levels in elderly patients with diabetes mellitus

Higashikawa, Toshihiro; Ito, Tomohiko; Mizuno, T.; Ishigami, Keiichirou; Kuroki, Kengo; Maekawa, Naoto; Usuda, Daisuke; Morita, Takuro; Hamada, Kazu; Takagi, Susumu; Takeshima, Kento; Yamada, Shinya; Sangen, Ryusho; Izumida, Toshihide; Mori, Hajime; Kiyosawa, Jun; Saito, Atsushi; Iguchi, Masaharu; Nakahashi, Takeshi; Kasamaki, Yuji; Fukuda, Akira; Kanda, Tsugiyasu; Okuro, Masashi

doi:10.1097/md.0000000000027638

Cited by 6 publications

(10 citation statements)

References 31 publications

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“…actions [ 121 ]. It was recently reported that the SGLT-2 inhibitor tofogliflozin decreased serum ACTH and cortisol levels in subjects with type 2 diabetes, indicating that tofogliflozin also influences the HPA axis [ 122 ]. Moreover, metformin, an insulin-sensitizer used as the first-line drug for treating type 2 diabetes, does not only lower plasma insulin and glucose levels, but also can reduce ACTH levels and cortisol [ 123 , 124 ].…”

Section: Can Hyperinsulinemia-induced Activation Of the Hpa Axis Be M...mentioning

confidence: 99%

New Insights into the Role of Insulin and Hypothalamic-Pituitary-Adrenal (HPA) Axis in the Metabolic Syndrome

Janssen

2022

IJMS

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Recent data suggests that (pre)diabetes onset is preceded by a period of hyperinsulinemia. Consumption of the “modern” Western diet, over-nutrition, genetic background, decreased hepatic insulin clearance, and fetal/metabolic programming may increase insulin secretion, thereby causing chronic hyperinsulinemia. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, polycystic ovarian syndrome, and Alzheimer’s disease. Recent data suggests that the onset of prediabetes and diabetes are preceded by a variable period of hyperinsulinemia. Emerging data suggest that chromic hyperinsulinemia is also a driving force for increased activation of the hypothalamic-adrenal-pituitary (HPA) axis in subjects with the metabolic syndrome, leading to a state of “functional hypercortisolism”. This “functional hypercortisolism” by antagonizing insulin actions may prevent hypoglycemia. It also disturbs energy balance by shifting energy fluxes away from muscles toward abdominal fat stores. Synergistic effects of hyperinsulinemia and “functional hypercortisolism” promote abdominal visceral obesity and insulin resistance which are core pathophysiological components of the metabolic syndrome. It is hypothesized that hyperinsulinemia-induced increased activation of the HPA axis plays an important etiological role in the development of the metabolic syndrome and its consequences. Numerous studies have demonstrated reversibility of hyperinsulinemia with lifestyle, surgical, and pharmaceutical-based therapies. Longitudinal studies should be performed to investigate whether strategies that reduce hyperinsulinemia at an early stage are successfully in preventing increased activation of the HPA axis and the metabolic syndrome.

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Section: Can Hyperinsulinemia-induced Activation Of the Hpa Axis Be M...mentioning

confidence: 99%

New Insights into the Role of Insulin and Hypothalamic-Pituitary-Adrenal (HPA) Axis in the Metabolic Syndrome

Janssen

2022

IJMS

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“…Most of the studies were male predominant. Two studies did not provide data on hypertensive prevalence 18 , 25 . One study did not report data on mean HbA1c and mean BMI 24 .…”

Section: Resultsmentioning

confidence: 99%

“…One study did not report data on mean HbA1c and mean BMI 24 . Two studies did not report data on mean systolic and diastolic blood pressure 18 , 25 , while one study did not report data on mean eGFR 23 . Among the studies, six types of SGLT2i were used: empagliflozin, ipragliflozin, canagliflozin, dapagliflozin, tofogliflozin, and luseogliflozin.…”

Section: Resultsmentioning

confidence: 99%

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Effect of sodium-glucose cotransporter-2 inhibitors on aldosterone and renin levels in diabetes mellitus type 2 patients: a systematic review and meta-analysis

Manosroi

Danpanichkul

Atthakomol

2022

Sci Rep

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The effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on plasma aldosterone concentration (PAC) and plasma renin activity (PRA) levels are still inconclusive. This meta-analysis aimed to demonstrate the changes in PAC and PRA levels after the use of SGLT2i in type 2 diabetes patients. A search for relevant publications was performed using PubMed/Medline, Scopus, Cochrane, and Embase databases from their inception through May 2022. Inclusion criteria were studies that contained data on crude PAC and PRA levels before and after the use of SGLT2i in adult type 2 diabetes patients. Standardized mean difference (SMD) with a 95% confidence interval (95% CI) was calculated. Data was separately analyzed by study design: randomized controlled study (RCT) and non-randomized controlled study (non-RCT). Ten studies involving 380 patients were included with two RCT and eight non-RCT. Serum PAC levels showed no significant change after the use of SGLT2i in both RCT and non-RCT. Significantly higher PRA levels were observed after the use of SGLT2i in both RCT and non-RCT with SMD of 0.40 ng/mL/hr; 95% CI (0.06, 0.74) and SMD of 0.36 ng/mL/hr; 95%CI (0.17, 0.55), respectively. Subgroup analysis found significantly higher PRA levels after the use of SGLT2i (SMD 0.45 ng/mL/hr; 95% CI (0.18, 0.71)) only in subgroups that used for three months or less. The use of SGLT2i in diabetes mellitus type 2 patients can affect PRA levels, especially during short-term use. PRA levels should be interpreted with caution in this population.

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“…Other researchers have also reported that the progression of carotid atherosclerosis was associated with serum or urinary cortisol levels [ 32 – 34 ]. Interestingly, a recent study revealed that administration of tofogliflozin decreased both serum ACTH and cortisol levels in patients with T2DM, indicating that tofogliflozin influences the hypothalamic–pituitary–adrenal pathway in this population [ 35 ]. Therefore, SGLT2 inhibitors may be related to the attenuation of carotid atherosclerosis via reduction of serum cortisol levels.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the effect of tofogliflozin on the tissue characteristics of the carotid wall—a sub-analysis of the UTOPIA trial

Katakami

Mita

Maeda

et al. 2022

Cardiovasc Diabetol

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Background Since sodium-glucose cotransporter 2 (SGLT2) inhibitors have a pleiotropic antiatherogenic effect, they are expected to attenuate the progression of atherosclerosis. However, whether SGLT2 inhibitors affect the tissue characteristics of the human arterial wall remains unclear. This study aimed to evaluate the effects of tofogliflozin, a selective SGLT2 inhibitor, on the tissue characteristics of the human arterial wall in type 2 diabetes (T2DM) patients without apparent cardiovascular disease (CVD). Methods The present study was a post hoc analysis based on data obtained from the Using Tofogliflozin for Possible Better Intervention against Atherosclerosis for Type 2 Diabetes Patients (UTOPIA) trial, which was a multicenter prospective, randomized, open-label, blinded-endpoint study conducted to evaluate the efficacy of tofogliflozin in preventing the progression of atherosclerosis in patients with T2DM. We evaluated the longitudinal change in the ultrasonic tissue characteristics of the carotid wall using gray-scale median (GSM), an established index of ultrasonic tissue characteristics. The right and left intima-medial areas were delineated, and the GSM values were evaluated (right GSM-CCA and left GSM-CCA). The average values of the right and left carotid arteries were defined as “mean GSM-CCA value.” Results In a mixed-effects model for repeated measures, mean GSM-CCA, along with the right and left GSM-CCA values, did not significantly change in either the tofogliflozin (n = 168) or conventional treatment group (n = 169). In addition, the tofogliflozin and conventional treatment groups did not significantly differ regarding the change of the mean GSM-CCA (mean difference [95% CI] − 1.24[− 3.87, 1.38], P = 0.35), along with the right (mean difference [95% CI] − 2.33[− 5.70, 1.05], P = 0.18) and the left GSM-CCA (mean difference [95% CI] − 0.29 [− 3.53, 2.95], P = 0.86) values. Similar findings were obtained even after adjusting for traditional cardiovascular risk factors and/or the administration of drugs at baseline. Conclusions The tissue characteristics of the carotid arterial wall did not change in either the tofogliflozin or conventional treatment group during the 104-week treatment period, and there was no significant difference between the treatment groups. Clinical trial registration UMIN000017607 (https://www.umin.ac.jp/icdr/index.html)

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Effects of tofogliflozin on adrenocorticotropic hormone, renin and aldosterone, and cortisol levels in elderly patients with diabetes mellitus

Cited by 6 publications

References 31 publications

New Insights into the Role of Insulin and Hypothalamic-Pituitary-Adrenal (HPA) Axis in the Metabolic Syndrome

New Insights into the Role of Insulin and Hypothalamic-Pituitary-Adrenal (HPA) Axis in the Metabolic Syndrome

Effect of sodium-glucose cotransporter-2 inhibitors on aldosterone and renin levels in diabetes mellitus type 2 patients: a systematic review and meta-analysis

Evaluation of the effect of tofogliflozin on the tissue characteristics of the carotid wall—a sub-analysis of the UTOPIA trial

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