Identification of subgroups of patients with type 2 diabetes with differences in renal function preservation, comparing patients receiving sodium-glucose co-transporter-2 inhibitors with those receiving dipeptidyl peptidase-4 inhibitors, using a supervised machine-learning algorithm (PROFILE study): A retrospective analysis of a Japanese commercial medical database.

AIMS: To investigate the effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors vs. dipeptidyl peptidase-4 (DPP-4) inhibitors on renal function preservation (RFP) using real-world data of patients with type 2 diabetes in Japan, and to identify which subgroups of patients obtained greater RFP benefits with SGLT2 inhibitors vs. DPP-4 inhibitors. METHODS: We retrospectively analysed claims data recorded in the Medical Data Vision database in Japan of patients with type 2 diabetes (aged ≥18 years) prescribed any SGLT2 inhibitor or any DPP-4 inhibitor between May 2014 and September 2016 (identification period), in whom estimated glomerular filtration rate (eGFR) was measured at least twice (baseline, up to 6 months before the index date; follow-up, 9 to 15 months after the index date) with continuous treatment until the follow-up eGFR. The endpoint was the percentage of patients with RFP, defined as no change or an increase in eGFR from baseline to follow-up. A proprietary supervised learning algorithm (Q-Finder; Quinten, Paris, France) was used to identify the profiles of patients with an additional RFP benefit of SGLT2 inhibitors vs. DPP-4 inhibitors. RESULTS: Data were available for 990 patients prescribed SGLT2 inhibitors and 4257 prescribed DPP-4 inhibitors. The proportion of patients with RFP was significantly greater in the SGLT2 inhibitor group (odds ratio 1.27; P = 0.01). The Q-Finder algorithm identified four clinically relevant subgroups showing superior RFP with SGLT2 inhibitors (P < 0.1): no hyperlipidaemia and eGFR ≥79 mL/min/1.73 m2 ; eGFR ≥79 mL/min/1.73 m2 and diabetes duration ≤1.2 years; eGFR ≥75 mL/min/1.73 m2 and use of antithrombotic agents; and haemoglobin ≤13.4 g/dL and LDL cholesterol ≥95.1 mg/dL. In each profile, glycaemic control was similar in the two groups. CONCLUSION: SGLT2 inhibitors were associated with more favourable RFP vs. DPP-4 inhibitors in patients with certain profiles in real-world settings in Japan.

Humanistic and economic burden of cardiovascular disease related comorbidities and hypoglycaemia among patients with type 2 diabetes in Japan.

AIM: This study aims to examine the humanistic and economic burden of cardiovascular disease (CVD)-related comorbidities and hypoglycaemia among respondents with type 2 diabetes (T2D) in Japan. METHODS: This study used the Japan National Health and Wellness Survey 2016 database. Respondents who self-reported a physician-diagnosed T2D were included. Respondents with or without the condition of interest (CVD-related comorbidities or hypoglycaemia) were compared via generalized linear models in terms of the outcome variables: (1) health-related quality of life (HRQoL), (2) work productivity and activity impairment, (3) healthcare resource utilization and (4) economic costs. RESULTS: A total of 1478 survey respondents reported a diagnosis of T2D (mean age 63.6 ±â€¯10.6 years, mean HbA1c 6.91 ±â€¯1.1%). Of whom, 804 subjects (54.4%) had at least one CVD related comorbidities, and 369 subjects (29.3%) reported experiences of hypoglycaemia episodes. Patients with CVD-related comorbidities or hypoglycaemia episodes had worse HRQoL, more work and activity impairment, increased health care visits, and higher costs. CONCLUSIONS: CVD related comorbidities and hypoglycaemia remains a significant humanistic and economic burden in patients with T2D. The findings suggested that appropriate T2D management with proper medication choice are important to control CVD related comorbidities and hypoglycaemia among T2D patients to alleviate the burden.

Reduction of postprandial glucose by lixisenatide vs sitagliptin treatment in Japanese patients with type 2 diabetes on background insulin glargine: A randomized phase IV study (NEXTAGE Study).

AIM: To evaluate the pharmacodynamics of lixisenatide once daily vs sitagliptin once daily in Japanese patients with type 2 diabetes receiving insulin glargine U100. MATERIALS AND METHODS: This multicentre, open-label, phase IV study (NEXTAGE Study; ClinicalTrials.gov number, NCT02200991) randomly assigned 136 patients to either lixisenatide once daily via subcutaneous injection (10 µg initially increased weekly by 5 up to 20 µg) or once-daily oral sitagliptin 50 mg. The primary endpoint was the change in postprandial glucose (PPG) exposure 4 hours after a standardized breakfast (PPG area under the plasma glucose concentration-time curve [AUC0:00-4:00h ]) from baseline to day 29. RESULTS: Lixisenatide reduced PPG exposure to a statistically significantly greater extent than sitagliptin: least squares (LS) mean change from baseline in PPG AUC0:00-4:00h was -347.3 h·mg/dL (-19.3 h·mmol/L) in the lixisenatide group and -113.3 h·mg/dL (-6.3 h·mmol/L) in the sitagliptin group (LS mean between-group difference -234.0 h·mg/dL [-13.0 h·mmol/L], 95% confidence interval -285.02 to -183.00 h·mg/dL [-15.8 to -10.2 h·mmol/L]; P < .0001). Lixisenatide led to significantly greater LS mean reductions in maximum PPG excursion than sitagliptin (-122.4 vs -46.6 mg/dL [-6.8 vs -2.6 h·mmol/L]; P < .0001). Change-from-baseline reductions in exposure to C-peptide, fasting glycoalbumin levels, and the gastric emptying rate were greater in the lixisenatide than in the sitagliptin group. The incidence of treatment-emergent adverse events was higher with lixisenatide (60.9%) than with sitagliptin (16.4%), with no serious events or severe hypoglycaemia reported. CONCLUSION: Lixisenatide reduced PPG significantly more than sitagliptin, when these agents were added to basal insulin glargine U100, and was well tolerated.

Assessment of quality of life in patients with type 2 diabetes mellitus before and after starting biphasic insulin aspart 30 (BIAsp 30) therapy: IMPROVE study in Japan.

AIMS: To evaluate treatment satisfaction before and after starting biphasic insulin aspart 30 (BIAsp 30) therapy in patients with type 2 diabetes mellitus (T2D) in the IMPROVE study Japan using the Diabetes Medication Satisfaction (DiabMedSat) questionnaire. METHODS: The DiabMedSat questionnaire assesses overall satisfaction with drug therapy for diabetes treatment in three domains: burden, efficacy and symptoms. Patients previously treated by oral anti-diabetic drugs in the IMPROVE study Japan answered the DiabMedSat questionnaires at baseline (week 0) and week 26 after starting BIAsp 30 treatment. RESULTS: The mean scores for each domain at weeks 0 and 26, respectively, were: burden, 64.5 and 67.5 (p = 0.041); efficacy, 55.0 and 61.5 (p < 0.001); and symptoms, 70.9 and 68.1 (p = 0.049). The overall scores were 63.4 and 65.6, respectively (p = 0.079). With regard to burden, bothersome aspects were significantly improved with BIAsp 30 treatment at week 26, compared with treatment with oral anti-diabetic drugs at week 0. Major hypoglycemic episodes were very rare; most hypoglycemic events were minor and occurred during the daytime. CONCLUSIONS: The study results indicate that BIAsp 30 does not adversely affect QOL in Japanese patients at insulin initiation.

Genetic suppression of ghrelin receptors activates brown adipocyte function and decreases fat storage in rats.

To clarify the role of ghrelin and its receptor (GHS-R) in the regulatory mechanism of energy metabolism, we analyzed transgenic (Tg) rats expressing an antisense GHS-R mRNA under the control of the tyrosine hydroxylase (TH) promoter. Tg rats showed lower visceral fat weight and higher O(2) consumption, CO(2) production, rectal temperature, dark-period locomotor activity, brown adipose tissue (BAT) weight and uncoupling protein 1 expression compared with wild-type (WT) rats on a standard diet. A high-fat diet for 14days significantly increased body weight, visceral fat weight, and the sizes of white and brown adipocytes in WT rats but not in Tg rats compared with the corresponding standard-diet groups. Antisense GHS-R mRNA was expressed and GHS-R expression was reduced in TH-expressing cells of the vagal nodose ganglion in Tg rats. Ghrelin administered intravenously suppressed noradrenaline release in the BAT of WT rats, but not in Tg rats. These results suggest that ghrelin/GHS-R plays an important role in energy storage by modifying BAT function and locomotor activity. As our previous study showed that peripheral ghrelin-induced noradrenaline release suppression in BAT is blocked by vagotomy, the present findings also suggest that vagal afferents transmit the peripheral ghrelin signal to the sympathetic nervous system innervating BAT.

Growth hormone-releasing hormone (GHRH) neurons in the arcuate nucleus (Arc) of the hypothalamus are decreased in transgenic rats whose expression of ghrelin receptor is attenuated: Evidence that ghrelin receptor is involved in the up-regulation of GHRH expression in the arc.

GH secretagogue (GHS)/ghrelin stimulates GH secretion by binding mainly to its receptor (GHS-R) on GHRH neurons in the arcuate nucleus (Arc) of the hypothalamus. GHRH, somatostatin, and neuropeptide Y (NPY) in the hypothalamus are involved in the regulatory mechanism of GH secretion. We previously created transgenic (Tg) rats whose GHS-R expression is reduced in the Arc, showing lower body weight and shorter nose-tail length. GH secretion is decreased in female Tg rats. To clarify how GHS-R affects GHRH expression in the Arc, we compared the numbers of GHS-R-positive, GHRH, and NPY neurons between Tg and wild-type rats. Immunohistochemical analysis showed that the numbers of GHS-R-positive neurons, GHRH neurons, and GHS-R-positive GHRH neurons were reduced in Tg rats, whereas the numbers of NPY neurons and GHS-R-positive NPY neurons did not differ between the two groups. The numbers of Fos-positive neurons and Fos-positive GHRH neurons in response to KP-102 were decreased in Tg rats. Competitive RT-PCR analysis of GHRH mRNA expression in the cultured hypothalamic neurons showed that KP-102 increased NPY mRNA expression level and that NPY decreased GHRH mRNA expression level. KP-102 increased GHRH mRNA expression level in the presence of anti-NPY IgG. GH increased somatostatin mRNA expression. Furthermore, GH and somatostatin decreased GHRH mRNA expression, whereas KP-102 showed no significant effect on somatostatin mRNA expression. These results suggest that GHS-R is involved in the up-regulation of GHRH and NPY expression and that NPY, somatostatin, and GH suppress GHRH expression. It is also suggested that the reduction of GHRH neurons of Tg rats is induced by a decrease in GHS-R expression.

Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity.

Growth hormone secretagogues (GHSs) stimulate GH secretion and food intake. GHS receptor (GHS-R) mRNA has been identified mainly in the arcuate nucleus (Arc) and ventromedial nucleus of the hypothalamus and in the pituitary. Ghrelin, an endogenous ligand for GHS-R, has recently been purified from rat stomach. Although ghrelin is also expressed in the hypothalamus, the physiological significance of the ghrelin/GHS-R system is still unknown. We have created transgenic (Tg) rats expressing an antisense GHS-R mRNA under the control of the promoter for tyrosine hydroxylase (TH), thus selectively attenuating GHS-R protein expression in the Arc. Tg rats had lower body weight and less adipose tissue than did control rats. Daily food intake was reduced, and the stimulatory effect of GHS treatment on feeding was abolished in Tg rats. GH secretion and plasma insulin-like growth factor-I levels were reduced in female Tg rats. These results suggest that GHS-R in the Arc is involved in the regulation of GH secretion, food intake, and adiposity.