Naoki Kumashiro

Effectiveness of dapagliflozin on vascular endothelial function and glycemic control in patients with early-stage type 2 diabetes mellitus: DEFENCE study

AbstractBackgroundRecent studies reported that sodium glucose cotransporter 2 (SGLT2) inhibitors can potentially reduce the risk of cardiovascular mortality in patients with type 2 diabetes mellitus (T2DM). However, there is little or no information on the therapeutic effects of SGLT2 inhibitors on the progression of atherosclerosis. This dapagliflozin effectiveness on vascular endothelial function and glycemic control (DEFENCE) study was designed to determine the effects of dapagliflozin, a SGLT2 inhibitor, on endothelial function in patients with early-stage T2DM.MethodsDEFENCE is a prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative clinical trial. Between October 2015 and August 2016, 80 T2DM patients treated with 750xa0mg of metformin (hemoglobin A1c ≥6.0 and <8.0%, nxa0=xa080) were enrolled and randomized to receive either 1500xa0mg/day metformin (the metformin group, nxa0=xa040), or 750xa0mg/day metformin supplemented with 5xa0mg/day dapagliflozin (the dapagliflozin group, nxa0=xa040), for 16xa0weeks. The primary endpoint was a change in flow-mediated dilation (FMD) from baseline to the end of the 16-week treatment period. The secondary outcomes include changes in indexes of glycemic control, lipid metabolism, and oxidative stress, body composition, and safety evaluation.ResultsAlthough FMD tended to improve only in the dapagliflozin group, ΔFMD was comparable between the two groups. Analysis of patients with HbA1c >7.0% showed significant improvement of FMD in the dapagliflozin group than metformin group (Pxa0<xa00.05). HbA1c, fasting plasma glucose, plasma glucagon, and body weight significantly decreased in both groups. Interestingly, urine 8-hydroxy-2′-deoxyguanosin, a biomarker of oxidative stress, was significantly lower in the dapagliflozin group than metformin group at 16xa0weeks (Pxa0<xa00.001).ConclusionsDapagliflozin add-on therapy to metformin for 16xa0weeks improved endothelial function, as assessed by FMD, in patients with inadequately controlled early-stage T2DM. Improvement in oxidative stress may contribute to the improvement in FMD.n Trial registration University Hospital Medical Information Network Clinical Trial Registry (UMIN000018754)

Linagliptin improves endothelial function in patients with type 2 diabetes: A randomized study of linagliptin effectiveness on endothelial function

The present multicenter, prospective, controlled, open and randomized three‐arm parallel study was designed to compare the effects of linagliptin with those of metformin on endothelial function.

Glycemic Variability in Type 1 Diabetes Compared with Degludec and Glargine on the Morning Injection: An Open-label Randomized Controlled Trial

IntroductionOptimal adjustment of basal insulin to overcome hypoglycemia and glycemic variability (GV) depends on its duration of action and peak-less profile. Owing to the ability of long-acting basal insulin to avoid hypoglycemia, we titrated pre-meal glucose to normal fasting blood glucose, 80–110xa0mg/dL (4.5–6.1xa0mmol/L), and post-meal glucose to 80–140xa0mg/dL (4.5–7.8xa0mmol/L). The purpose of this study was to evaluate two basal insulin analogues degludec (IDeg) and glargine (IGlar), injected in the morning, for GV using continuous glucose monitoring (CGM) in type 1 diabetes (T1DM).MethodsIn this crossover study, 20 Japanese patients with T1DM (age 54xa0±xa016xa0years, disease duration 16xa0±xa08xa0years, BMI 24xa0±xa04xa0kg/m2, HbA1c 7.4xa0±xa00.8%) were randomized into one of two different starting regimens, and CGM was conducted on three consecutive days during the last week of each 12-week titration period. Treatment satisfaction was assessed at the end of each treatment period using the Diabetes Therapy-Related Quality of Life Questionnaire (DTR-QOL).ResultsThere were no differences in HbA1c, total insulin dosage, body weight changes, and basal to bolus ratio between the IDeg and IGlar arms. The day-to-day variability in fasting interstitial GV on the CGM curves was significantly less in the IDeg than IGlar treatment period (25.9xa0±xa022.0 vs. 43.8xa0±xa030.1xa0mg/dl, pxa0=xa00.04). Other markers of GV, calculated by the EasyGV software, including mean amplitude of glycemic excursions (MAGE), J-index, total and nocturnal hypoglycemia were not different between the two treatment periods. The score of “satisfaction with treatment”, a subdomain of the DTR-QOL system, was higher in the IDeg period.ConclusionThus, the morning injection of the two long-acting insulin analogues seemed similar with regard to the magnitude of hypoglycemia in T1DM, but treatment with IDeg was associated with lower day-to-day variation in glucose level. These results suggest that IDeg is safe with minimal morning GV in patients with T1DM.Clinical trial registrationJapanese Clinical Trials Registry, UMIN000012358.

Characteristics of hepatic insulin‐sensitive nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) plays a crucial role in type 2 diabetes and hepatocellular carcinoma. The major underlying pathogenesis is hepatic insulin resistance. The aim of the present study was to characterize patients with NAFLD with paradoxically normal hepatic insulin sensitivity relative to patients with NAFLD with hepatic insulin resistance. We recruited 26 patients with NAFLD and divided them into three groups ranked by the level of hepatic insulin sensitivity (HIS; high‐HIS, mid‐HIS, low‐HIS), as assessed by the hyperinsulinemic‐euglycemic clamp studies using stable isotope. Hepatic insulin sensitivity of the high‐HIS group was identical to that of the non‐NAFLD lean control (clamped percent suppression of endogenous glucose production, 91.1% ± 5.2% versus 91.0% ± 8.5%, respectively) and was significantly higher than that of the low‐HIS group (66.6% ± 7.5%; P < 0.01). Adiposity (subcutaneous, visceral, intrahepatic, and muscular lipid content), hepatic histopathology, and expression levels of various genes by using liver biopsies, muscle, and adipose tissue insulin sensitivity, plasma metabolites by metabolomics analysis, putative biomarkers, and lifestyles were assessed and compared between the high‐HIS and low‐HIS groups. Among these, adipose tissue insulin sensitivity assessed by clamped percent suppression of free fatty acid, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites, such as citric acid and cis‐aconitic acid, were significantly higher in the high‐HIS group compared to the low‐HIS group. In contrast, there were no differences in adiposity, including intrahepatic lipid content assessed by proton magnetic resonance spectroscopy (28.3% ± 16.1% versus 20.4% ± 9.9%, respectively), hepatic histopathology, other putative biomarkers, and lifestyles. Conclusion: High levels of adipose tissue insulin sensitivity, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites are unique characteristics that define patients with hepatic insulin‐sensitive NAFLD regardless of intrahepatic lipid content. (Hepatology Communications 2017;1:634–647)

Acute suppurative thyroiditis in infected thyroid cyst in an adult patient under hemodialysis

Acute suppurative thyroiditis (AST) accompanied by an abscess is a rare clinical case. Hemodialysis patients are at risk for infections. Sepsis mortality was from 100 to 300 times higher for chronic dialysis patients than that for the general public. Thus, special care should be taken against infection in patients under hemodialysis.

Acute focal bacterial nephritis in an occupational allergy

A 50-year-old male professional noodle maker with an allergy to soba (buckwheat noodles) was admitted to the emergency room with high fever. 2 months earlier he had a mild stiff shoulder for a week. At the time of admission, the patient had a temperature of 38·8°C and oliguria. Laboratory fi ndings showed a white-blood-cell count of 18 800 per μL (normal value 4400–11 000 per μL), C-reactive protein 16·3 mg/dL (<0·3 mg/dL), procalcitonin 2·44 μg/L (<0·1 μg/L), creatinine 147·5 μmol/L (60–110 μmol/L), plasma glucose 56·4 mmol/L (5·6 mmol/L), HbA1c 14·7% (<5·7 %), and 100 urinary leucocytes cells per high-power fi eld without red blood cells and sediment. Contrast-enhanced CT showed wedge-shaped masslike hypodense lesions, resembling acute focal bacterial nephritis (AFBN; fi gure part A). Meticillin-sensitive Staphylococcus aureus (MSSA), common in skin infections, was found in blood (arterial and venous) and urine samples. Levofl oxacin 500 mg per day and intravenous insulin were started, leading to substantial clinical improvement. However, 7 days after starting levofl oxacin treatment, the patient developed rapidly worsening pain of the left acromioclavicular joint with high fever. A subsequent CT scan showed extensive masses in the deltoid muscle and lateral humeral condyle that extended downwards into the brachioradialis muscle (fi gure part B). Cultured glenohumeral joint fl uid repeatedly grew MSSA. The results of a gallium-67 scan showed diff use uptake at the glenohumeral joint to the lateral humerus (fi gure part C). The antibiotics were changed to cefazolin 6 g/day continuously for 6 weeks for osteomyelitis according to WHO guidelines. He recovered during the 6 weeks and all infected lesions healed. Although MSSA is a common pathogen of bacterial soft-tissue infection, there was no remarkable skin manifestation. Therefore, hypersensitive reaction to soba and diabetes might be relevant in the pathogenesis of blood-borne AFBN. The patient with skin allergy had enhanced colonisation of S aureus, increasing production of potent exotoxin; toxin might act as a risk for blood-borne AFBN adding to diabetes.

A case of lean polycystic ovary syndrome with early stage of type 1 diabetes successfully treated with metformin [Rapid Communication]

Polycystic ovary syndrome (PCOS) is common in obese women with insulin resistant type 2 diabetes for which metformin treatment is getting established in addition to clomiphene. However, lean PCOS patients are sometimes accompanied with type 1 diabetes. It remains unclear whether these patients are insulin resistant and whether metformin is effective for them. A 32-year-old woman, who suffered from acne, hirsutism, and menstrual disorders since age 29, was diagnosed as PCOS by serum high LH levels and polycystic ovary on echography. Interestingly, her body mass index (BMI) had consistently been 21.0 kg/m2 since age 20. She was first treated with clomiphene for one year for infertility but it did not improve her menstrual cycle nor did she get pregnant during that period. She was then assessed with diabetes mellitus and subsequently diagnosed as type 1 diabetes with mild hyperglycemia (HbA1c 6.0%). Since her insulin secretion was still well preserved, to assess insulin sensitivity, hyperinsulinemic-euglycemic clamp test was performed and showed her to be insulin resistant. Low dose insulin and low dose metformin treatment was started without clomiphene. After her ovulation and menstrual cycle were ameliorated only one month later, her treatment was supplemented with clomiphene for the next three months enabling her to at last become pregnant. This report highlights the efficacy of metformin in lean PCOS with type 1 diabetes. Insulin therapy is essential for type 1 diabetes but hyperinsulinemia potentially exacerbates PCOS through hyperandrogenism. Metformin is therefore recommended for treatment of lean PCOS with type 1 diabetes as well as common obese PCOS with type 2 diabetes.

Efficacy and safety of repaglinide added to sitagliptin in Japanese patients with type 2 diabetes: A randomized 24-week open-label clinical trial

Although sitagliptin and repaglinide monotherapies improve postprandial hyperglycemia, the long-term effects and safety of their combination has not been examined. In this randomized 24-week trial of Japanese patients with poor control (HbA1c 7.0-8.5%) by sitagliptin, we divided 40 patients randomly into two equal groups of the repaglinide add-on to sitagliptin (ADD-ON, n=20), or sitagliptin switched to repaglinide (SWITCH, n=20). The meal tolerance test was carried out at weeks 0 and 24. The primary outcomes were changes in HbA1c and area under the curves (AUC) of glucose from the baseline to week 24. The mean change in HbA1c from baseline to week 24 was larger in the ADD-ON (-0.87±0.63%, mean±SD), compared with the SWITCH (0.03±0.65%, p=0.000). Significant improvements were noted in the mean changes in fasting glucose and AUCs of glucose in the ADD-ON vs. SWITCH (p=0.007 and p=0.000). Insulin secretion relative to glucose elevation (ISG; defined as AUC insulin/AUC glucose) increased significantly in the ADD-ON, although the mean change in fasting insulin level was significantly decreased in the ADD-ON (p=0.015 and p=0.026). The AUC of glucagon was significantly lower at 24-week relative to baseline in the ADD-ON, but was not significant in the two groups (p=0.047 and p=0.056, respectively). The combination therapy produced significant reductions in HbA1c, AUC of glucose and fasting glucose compared with switching to repaglinide without weight gain or severe hypoglycemia. The improved glycemic control with this combination therapy may be at least in part due to augmentation of repaglinide-induced insulin secretion by sitagliptin.

Up-Titration Strategy After DPP-4 Inhibitor-Based Oral Therapy for Type 2 Diabetes: A Randomized Controlled Trial Shifting to a Single-Dose GLP-1 Enhancer Versus Adding a Variable Basal Insulin Algorithm

IntroductionIt is unclear whether adding basal insulin or enhancing incretin signaling with a glucagon-like peptide-1 receptor agonist (GLP-1RA) is more effective as an up-titration strategy after dipeptidyl peptidase-4 inhibitor (DPP-4i)-based oral antidiabetic drug (OAD) therapy. GLP-1RAs can be injected without dose adjustment, unlike basal insulin. Our objective was to examine the efficacy of changing patients inadequately controlled with oral DPP-4i-based OAD therapy to injectable GLP-1RA and discontinuing the DPP4i versus adding basal insulin glargine (IGlar) with the continuation of the oral DPP4i.MethodsSixty patients with type 2 diabetes (T2DM) and glycated hemoglobin (HbA1c) between 7.0% and 10.0% on DPP-4i-based OAD therapy were randomized to either adding IGlar and remaining on the DPP-4i or liraglutide and discontinuing the DPP-4i for 24xa0weeks. Patients in the IGlar group started with 0.1xa0unit/kg and were titrated according to the algorithm. In the liraglutide group, the DPP-4i was replaced with liraglutide 0.9xa0mg/day, the maximum dose in Japan. We evaluated HbA1c, glycated albumin (GA), and anthropometrics.ResultsHbA1c was significantly lower at week 24 (−u20091.0u2009±u20090.9% in the IGlar group and −u20090.6u2009±u20090.8% in the liraglutide group), but the difference between groups was not significant. Changes in GA were similar (−u20092.9u2009±u20093.2% vs. −u20092.6u2009±u20093.2%) in both groups. Body weight (BW) was significantly lower only in the liraglutide group (+u20090.5u2009±u20092.6xa0kg vs. −u20092.2u2009±u20092.0xa0kg). The rate of minor hypoglycemic episodes was similar for both groups.ConclusionFor poorly controlled T2DM on DPP-4i-based OAD therapy, switching to single-dose liraglutide to enhance incretin signaling is as effective as dose-titrated basal IGlar, but significant BW reduction was only seen in the liraglutide group. These results suggest that enhancing incretin signaling with a single-dose injectable GLP-1 RA might be an alternative to dose-titrated basal insulin therapy in patients with T2DM poorly controlled with DPP-4i-based OAD therapy. These findings should be confirmed in a longer and larger trial.Trial RegistrationTrial Registry (UMIN-CTR) as UMIN000012224.

Rationale and design of study of dapagliflozin versus sitagliptin treatment efficacy on prevention of cardiovascular risk factors in type 2 diabetes patients: the DIVERSITY-CVR study

BackgroundRecent studies reported that sodium glucose cotransporter 2 (SGLT2) inhibitors reduced the cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (T2DM) compared to placebo in contrast to no reduction with dipeptidyl peptidase 4 (DPP4) inhibitors. However, there are no comparative studies on the effects of SGLT2 inhibitors and DPP4 inhibitors on HbA1c, body weight and hypoglycemia as risk factors of cardiovascular diseases. The aim of the present ongoing study is to compare the effects of dapagliflozin, a SGLT2 inhibitor, with those of sitagliptin, a DPP4 inhibitor, on cardiovascular risk factors in T2DM patients with inadequate glycemic control.MethodsThe study of dapagliflozin versus sitagliptin treatment efficacy on prevention of cardiovascular risk factors in T2DM patients (DIVERSITY-CVR study) is a prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative study. A total of 340 T2DM patients treated with metformin alone or with no glucose-lowering agents (hemoglobin A1c ≥u20097.0 and <u200910.0%) will be randomized into the dapagliflozin group (5–10xa0mg/day, nu2009=u2009170) and the sitagliptin group (50–100xa0mg/day, nu2009=u2009170), and treated for 24xa0weeks. The primary endpoint is the rate of achieving a composite endpoint of the following three items at 24th week; (1) HbA1cu2009<u20097.0%; (2) body weight loss of ≥u20093.0% from baseline; (3) avoidance of hypoglycemia. Hypoglycemia will be monitored using the flash glucose monitoring system. The secondary outcomes include each component of the primary endpoint, plus indices of lipid metabolism, and evaluations related to safety.ConclusionsThere is lack of solid information on differences in the therapeutic effects of SGLT2 inhibitors and DPP4 inhibitors on multiple risk factors for cardiovascular diseases. It is anticipated that the results of the DIVERSITY-CVR study provides useful clinical data on the management of patients with T2DM, including reducing the risk of CVD. The results of this study will become available in 2019.Trial registration University Hospital Medical Information Network Clinical Trial Registry (UMIN000028014). Registered 30 June 2017