Effects of anti-diabetes medications on cardiovascular and kidney outcomes in Asian patients with type 2 diabetes: a rapid evidence assessment and narrative synthesis.

BACKGROUND: The cardiovascular and kidney safety of glucose-lowering drugs is a key concern in type 2 diabetes (T2D). We evaluated cardiorenal outcomes with glucose-lowering drugs in Asian patients, who comprise over half of T2D cases globally. RESEARCH DESIGN AND METHODS: A rapid evidence assessment was conducted for phase III or IV, double-blind, randomized clinical trials of glucose-lowering drugs reporting cardiovascular or kidney outcomes for Asian T2D patients (Embase, Medline, Cochrane Library databases: 1 January 2008-14 June 2020). RESULTS: Fifty-four publications reported exploratory data for Asians from 18 trials of dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose co-transporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and insulin analogs. SGLT2 inhibitors and several GLP-1 receptor agonists were associated with reduced cardiovascular risk in Asian T2D patients, while DPP-4 inhibitors exhibited cardiovascular safety. SGLT2 inhibitors also appeared to reduce renal risk; however, kidney outcomes were lacking for DPP-4 inhibitors other than linagliptin and GLP-1 receptor agonists in Asian patients. Insulin data were inconclusive as the only trial conducted used different types of insulin as both treatment and comparator. CONCLUSIONS: Cardiorenal outcomes with glucose-lowering drugs in Asian T2D patients were similar to outcomes in the overall multinational cohorts of these trials. DPP-4 inhibitors appear to demonstrate cardiovascular safety in Asians, while SGLT2 inhibitors and some GLP-1 receptor agonists may reduce cardiorenal and cardiovascular risk, respectively.

Validity of Claims Diagnosis Codes for Cardiovascular Diseases in Diabetes Patients in Japanese Administrative Database.

BACKGROUND: Observational studies using large claims databases for diabetes patients have been increasingly conducted. While validation of outcomes is important in such studies, validation studies from Japan are still scarce and small in scale with questions remaining on the representativeness of their findings. We examined the positive predictive value (PPV) of outcomes that often develop in type 2 diabetes patients: cardiovascular outcomes including congestive heart failure (CHF), myocardial infarction (MI), stroke-related diseases, and renal outcomes including end stage renal disease (ESRD), and death using a large Japanese database containing administrative claims and electronic medical record (EMR) data. PATIENTS AND METHODS: We used patient-level administrative claims data from 2003 and EMR data from 1985 to the most recent data up to December 2018 provided by Real World Data Co., Ltd. The database consisted of data from over 200 hospitals including ≥12 million uniquely identifiable patients. Among patients who had ≥1 type 2 diabetes diagnosis in the EMR, those who had administrative claims for each outcome were identified, and then the PPV was calculated for each outcome using the EMR as the gold standard. RESULTS: The numbers of patients identified for each outcome were 1,700 for MI, 2,027 for hemorrhagic stroke, 3,722 for ESRD, 4,723 for ischemic stroke, 5,404 for CHF, 6,678 for any type of stroke, and 10,815 for death. PPVs ranged from 67.4% for ESRD, 78.7% for MI, 80.3% for death, 85.7% for ischemic stroke, 88.9% for any type of stroke, 89.9% for hemorrhagic stroke, and 95.7% for CHF. A post hoc analysis showed PPV for ESRD as 83.8%. CONCLUSION: This large-scale validation study on diagnosis in administrative claims showed reasonable PPVs for the outcomes. We believe that the definitions of outcomes can be considered to be appropriate for future studies using Japanese administrative claims data.

Empagliflozin as adjunct to insulin in Japanese participants with type 1 diabetes: Results of a 4-week, double-blind, randomized, placebo-controlled phase 2 trial.

AIMS: This phase 2, double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov NCT02702011) with 4 sites in Japan investigated the pharmacodynamics (PD), pharmacokinetics (PK) and safety profile of empagliflozin in Japanese participants with type 1 diabetes mellitus (T1DM) as adjunctive therapy to insulin. MATERIALS AND METHODS: Participants using multiple daily injections of insulin for ≥12 months, with HbA1c of 7.5%-10.0%, entered a 2-week, open-label, placebo run-in period, followed by a 4-week, double-blind period during which participants were randomized 1:1:1:1 to receive empagliflozin 2.5 mg (n = 13), empagliflozin 10 mg (n = 12), empagliflozin 25 mg (n = 12) or placebo (n = 11). The primary objective was to assess the effect of empagliflozin vs placebo on urinary glucose excretion (UGE) after 7 days of treatment. RESULTS: PD: Empagliflozin resulted in a dose-dependent significant increase in 24-hour UGE compared with placebo (UGE placebo-corrected mean [95% confidence interval] change from baseline: 2.5 mg, 65.10 [43.29, 86.90] g/24 h; 10 mg, 81.19 [58.80, 103.58] g/24 h; 25 mg, 98.11 [75.91, 120.31] g/24 h). After 4 weeks of treatment, UGE increase was associated with improved glycaemic control, reduced body weight and decreased insulin needs. Empagliflozin treatment also resulted in dose-dependent increases in serum ketone bodies and free fatty acids. PK: Plasma empagliflozin levels increased in a dose-dependent manner and peaked at 1.5 hours. In this short study, empagliflozin was well tolerated, with no increase in rate of hypoglycaemia and no diabetic ketoacidosis events reported. CONCLUSIONS: Based on this short-duration phase 2 study, the PK/PD profile of empagliflozin in Japanese participants with T1DM is comparable to that of non-Japanese participants.

Epigenetic control of cardiomyocyte production in response to a stress during the medaka heart development.

The size and morphology of organs are largely determined by a genetic program. However in some cases, an epigenetic mechanism influences the process of organ development. Particularly, epigenetic factors such as hemodynamic stress and blood pressure affect the morphogenesis of cardiac chambers and valves. Here, we report that the epigenetic influences affect the cardiomyocyte production. Taking advantage of longer developmental period of medaka fish, we could examine the later emerging tissue responses to the defect of ventricular beating, which occurred in the hozuki (hoz) mutant that harbors the mutated ventricular myosin heavy chain (vmhc) gene. The mutant showed a remarkable ventricular enlargement, and we showed that this enlargement was due to an excess production of ventricular cardiomyocytes in addition to the lack of concentric chamber growth. By experimental blockade of blood flow, we demonstrated that an elevated cardiac pressure was responsible for the aberrant cardiomyocyte production. From these data, we propose that the epigenetic tissue response to a stressed situation controls the production of cardiomyocytes to attain a fine tuning of heart formation.