Naoki Kumashiro

Capivasertib, an AKT (protein kinase B) inhibitor, in combination with fulvestrant, reduces the risk of progression in recurrent breast cancer; however, it frequently leads to hyperglycemia by disrupting the insulin signaling pathways. Insulin-based therapies are generally ineffective in this setting and may worsen cancer outcomes. Herein, we report a case of capivasertib-induced diabetes successfully managed with insulin-independent glucose-lowering agents while capivasertib therapy was continued. A 57-year-old female with a body mass index of 23.0 kg/m² developed hyperglycemia one month after initiating capivasertib, with a glycosylated hemoglobin (HbA1c) level of 7.3%. A 75-g oral glucose tolerance test (OGTT) confirmed the diagnosis of diabetes according to the American Diabetes Association diagnostic criteria, demonstrating a fasting glucose level of 173 mg/dL, a two-hour glucose level of 512 mg/dL, and marked hyperinsulinemia. The markedly elevated glucose levels observed during the OGTT likely reflect severe drug-induced hyperglycemia associated with AKT inhibition, rather than a typical OGTT response in untreated diabetes. Treatment with empagliflozin (10 mg/day, a sodium-glucose cotransporter-2 inhibitor) and voglibose (0.4 mg/day, an alpha-glucosidase inhibitor) improved the HbA1c level to 6.3% within two months. After five months, a repeat OGTT showed improvement, shifting from the level of diabetes to impaired glucose tolerance, with substantially reduced insulin levels. This case may represent one of the early reports describing the successful management of capivasertib-induced diabetes with insulin-independent glucose-lowering agents, suggesting a potential strategy for managing AKT inhibitor-induced hyperglycemia.

Aims: To compare the effects of baseline background characteristics in patients treated with dapagliflozin and sitagliptin in the DIVERSITY‐CVR study and to analyse the time in range (TIR), a metric for glycaemic control. Materials and methods: This prospective, randomized, multicentre study included 340 Japanese patients with early‐stage type 2 diabetes. To examine the effects of dapagliflozin and sitagliptin on glycaemic variability, we re‐examined the primary endpoint (glycated haemoglobin [HbA1c] < 7.0%, body weight loss ≥ 3.0%, and avoidance of hypoglycaemia) achievement rate in participants stratified by baseline background characteristics. Results: Sitagliptin was significantly superior in achieving HbA1c level P < 0.05), with no significant differences in other subgroups. In the lower BMI group, the rate of achievement of TIR > 70% after 24‐week treatment was significantly higher with sitagliptin than with dapagliflozin (91.9% vs. 69.4%; P < 0.05). In contrast, dapagliflozin was superior to sitagliptin in achieving TIR > 70% in the higher BMI group (85.7% vs. 52.9%; P < 0.01). Conclusion: In Japanese patients with early‐stage type 2 diabetes, sitagliptin was associated with improved TIR in patients with a lower BMI. Dapagliflozin was effective in patients with a higher BMI.

Aim: To compare the effects of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors and dipeptidyl peptidase‐4 inhibitors on ectopic fat accumulation and tissue‐specific insulin sensitivity. Materials and Methods: This randomized controlled trial enrolled 44 patients with type 2 diabetes (T2D) and non‐alcoholic fatty liver disease (NAFLD). They were randomly assigned to receive either empagliflozin 10 mg/day or sitagliptin 100 mg/day for 12 weeks. The primary endpoint was the change in intrahepatic lipid content (IHL) measured using proton magnetic resonance spectroscopy ( ¹ H‐MRS). The secondary endpoints included intramuscular and extramuscular lipid content seen in ¹ H‐MRS, body composition seen through dual‐energy X‐ray absorptiometry and tissue‐specific insulin sensitivity shown through hyperinsulinaemic‐euglycaemic clamp using stable isotopic glucose. Liver biopsy samples were pathologically evaluated at baseline. Results: At baseline, the mean duration of diabetes, HbA1c level and IHL were 3.7 years, 7.2% and 20.9%, respectively. The median NAFLD activity score was 3.0. IHL was significantly more decreased in the empagliflozin group than that in the sitagliptin group (between‐group difference was −5.2% ± 1.1% and −1.9% ± 1.2%, respectively, (95% confidence interval); −3.3 (−6.5, −0.1), P = .044). However, there were no significant between‐group differences in the change of insulin sensitivity in the liver, muscle or adipose tissues. Interestingly, hepatic insulin sensitivity was significantly increased only in the empagliflozin group and was significantly negatively associated with the change in IHL. Conclusions: Empagliflozin significantly improves hepatic steatosis compared with sitagliptin, and this may protect against subsequent hepatic insulin resistance. Early administration of SGLT2 inhibitors is preferable for T2D patients with NAFLD.

Aims/Introduction: We investigated the potential use of canagliflozin, in comparison with liraglutide, as an alternative to bolus insulin in patients with well‐controlled type 2 diabetes mellitus receiving multiple daily insulin injection therapy.Materials and Methods: In 40 patients, with glycated hemoglobin (HbA1c) levels <7.5% controlled by multiple daily insulin injection therapy, all bolus insulin was randomly switched to canagliflozin (100 mg/day) or liraglutide (0.3–0.9 mg/day) for 24 weeks. Basal insulin was continued with dose adjustment according to a predefined algorithm. The end‐points were the change in the HbA1c level, glycemic variability assessed by continuous glucose monitoring, body mass index, insulin dose, quality of life (QOL) and safety assessments. Factors influencing the changes in QOL were also assessed using a simple regression analysis.Results: The change in HbA1c from baseline was comparable between the treatments. Both treatments maintained the HbA1c level to the baseline levels with stable glucose variability and no severe hypoglycemia for 24 weeks, decreased total insulin dose, and significantly increased the QOL score. The change in QOL was significantly associated with injection frequency.Conclusions: For patients with well‐controlled type 2 diabetes mellitus, under the support of basal insulin, complex insulin regimens can be simplified by replacing all bolus insulin with once‐daily canagliflozin or liraglutide, which improves patients’ QOL.

Background: While the cardioprotective benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been established in patients with cardiovascular disease (CVD), their advantages over other anti-diabetic drugs at earlier stages remain unclear. We compared the cardioprotective effects of empagliflozin, an SGLT2 inhibitor, with those of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, focusing on cardiac fat accumulation, cardiac function, and cardiac metabolism in patients with early-stage type 2 diabetes mellitus (T2DM) without CVD complications. Methods: This was a prospective, randomized, open-label, blinded-endpoint, parallel-group trial that enrolled 44 Japanese patients with T2DM. The patients were randomized for 12-week administration of empagliflozin or sitagliptin. Pericardial fat accumulation and myocardial triglyceride content were evaluated by magnetic resonance imaging and proton magnetic resonance spectroscopy, respectively. Echocardiography, ¹²³I-β-methyl-iodophenyl pentadecanoic acid myocardial scintigraphy, and laboratory tests were performed at baseline and after the 12-week treatment period. Results: The patients were middle-aged (50.3 ± 10.7 years, mean ± standard deviation) and overweight (body mass index 29.3 ± 4.9 kg/m²). They had a short diabetes duration (3.5 ± 3.2 years), HbA1c levels of 7.1 ± 0.8%, and preserved cardiac function (ejection fraction 73.8 ± 5.0%) with no vascular complications, except for one baseline case each of diabetic nephropathy and peripheral arterial disease. After the 12-week treatment, no differences from baseline were observed between the two groups regarding changes in pericardial, epicardial, and paracardial fat content; myocardial triglyceride content; cardiac function and mass; and cardiac fatty acid metabolism. However, considering cardiometabolic biomarkers, high-density lipoprotein cholesterol and ketone bodies, including β-hydroxybutyric acid, were significantly increased, whereas uric acid, plasma glucose, plasma insulin, and homeostasis model assessment of insulin resistance were significantly lower in the empagliflozin group than in the sitagliptin group (p < 0.05). Conclusions: Although the effects on cardiac fat and function were not statistically different between the two groups, empagliflozin exhibited superior effects on cardiometabolic biomarkers, such as uric acid, high-density lipoprotein cholesterol, ketone bodies, and insulin sensitivity. Therefore, when considering the primary preventive strategies for CVD, early supplementation with SGLT2 inhibitors may be more beneficial than DPP-4 inhibitors, even in patients with early-stage T2DM without current CVD complications. Clinical Trial Registration: UMIN000026340; registered on February 28, 2017. https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000030257

To cope the high glycemic variability (GV) is crucial in the management of multiple daily insulin (MDI) in diabetes. We compared the effect of low dose metformin 750mg/d adding vildagliptin 100mg/d (DPP4+LMET) or the high dose metformin 1500mg/d (HMET), in type 2 diabetes (T2D) with MDI, evaluating GV by continuous glucose monitoring (CGM). Single center, open-label, 12 weeks - 2 period crossover design. Twenty T2D with inadequately controlled (7.0% <HbA1c ≦9.0%) with MDI + LMET were enrolled. Primary endpoints were GV and hypoglycemia derived from CGM performed after each 12 weeks treatment periods. There was no significant difference in HbA1c, body weight changes, total daily dose of insulin. DPP4+LMET compared to the HMET, significantly reduced the calculated GV value, mean (7.15±1.3 vs 7.82±1.6, p<0.05), standard deviation (1.78±0.55 vs 2.27±1.11, p=0.03), continuous overlapping net glycemic action (6.44±1.28 vs 7.12±1.69, p<0.05), J-Index (26.7±11.0 vs 34.9±19.8, p<0.05), high blood glucose index (3.01±1.96 vs. 6.73±4.85, p=0.02), and mean amplitude of glycemic excursions (4.53±1.35 vs 5.50±2.34, p=0.03). The GV metrics with hypoglycemia and nocturnal hypoglycemia were not significantly different. DPP4+LMET decreased GV associated with hyperglycemia. Adding DPP4 inhibitor to the lower dose of metformin is an alternative approach to the stable GV in MDI.

Background: Few prospective studies have compared the cardiovascular benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors. We aimed to clarify the efficacy of dapagliflozin versus sitagliptin for modulating cardiometabolic risk factors including high glycated hemoglobin (HbA1c) levels, hypoglycemia, and body weight. Methods: This prospective, randomized, open-label, blinded-endpoint, parallel-group trial enrolled 340 Japanese patients with early-stage type 2 diabetes receiving metformin alone or no glucose-lowering agents, who were randomized to receive dapagliflozin or sitagliptin for 24 weeks. The primary endpoint was the proportion of patients who achieved the composite endpoint of HbA1c level maintenance < 7.0% (53 mmol/mol), avoidance of hypoglycemia (maintenance of sensor glucose ≥ 3.0 mmol/L or ≥ 54 mg/dL), and ≥ 3.0% body weight loss from baseline. Secondary endpoints included components of the primary endpoint, other metabolic indices, and glucose variability indices measured using flash glucose monitoring. Results: Clinical characteristics of patients were age, 58.1 ± 12.2 years; known duration of diabetes, 5.8 ± 6.1 years; body weight, 74.7 ± 14.2 kg; body mass index, 27.9 ± 4.1 kg/m²; and HbA1c level, 7.8 ± 0.8% at baseline. The achievement ratio of primary endpoint was significantly higher in the dapagliflozin group than in the sitagliptin group (24.4% vs. 13.8%, P < 0.05). While the rates of HbA1c level maintenance < 7.0% (53 mmol/mol) and avoidance of hypoglycemia were comparable between the groups (49.4 vs. 50.0% and 88.7 vs. 92.3% for dapagliflozin vs. sitagliptin, respectively), body weight loss of ≥ 3.0% was significantly achieved in the dapagliflozin group (54.4 vs. 19.6%, P < 0.001). Moreover, dapagliflozin was superior to sitagliptin regarding several secondary endpoints that modulate cardiometabolic risk, namely reducing fasting plasma glucose, insulin, uric acid, increasing high-density lipoprotein cholesterol, and suppressing the increase in serum creatinine and the decrease in estimated glomerular filtration rate. On the other hand, sitagliptin was superior to dapagliflozin in suppressing glucose variability. Conclusions: Compared to sitagliptin, dapagliflozin was significantly more effective at improving cardiometabolic risk factors, suggesting that SGLT2 inhibitors might be more suitable than DPP-4 inhibitors for preventing cardiovascular events in patients with early-stage but inadequately controlled type 2 diabetes. Trial registration Trial number, UMIN000028014; registered on June 30, 2017