Project description:PURPOSE:The purpose of this study is to summarize the effectiveness and safety of metreleptin in patients with congenital or acquired generalized lipodystrophy. METHODS:Patients (n?=?66) aged ?6 months had lipodystrophy, low circulating leptin, and ?1 metabolic abnormality (diabetes mellitus, insulin resistance, or hypertriglyceridemia). Metreleptin dose (once or twice daily) was titrated to a mean dose of 0.10?mg/kg/day with a maximum of 0.24?mg/kg/day. Means and changes from baseline to month 12 were assessed for glycated hemoglobin (HbA1c), fasting triglycerides (TGs), and fasting plasma glucose (FPG). Additional assessments included the proportions of patients achieving target decreases in HbA1c or fasting TGs at months 4, 12, and 36, medication changes, and estimates of liver size. Treatment-emergent adverse events (TEAEs) were recorded. RESULTS:Significant mean reductions from baseline were seen at month 12 for HbA1c (-2.2%, n?=?59) and FPG (-3.0?mmol/L, n?=?59) and mean percent change in fasting TGs (-32.1%, n?=?57) (all p???0.001). Reductions from baseline over time in these parameters were also significant at month 36 (all p?<?0.001, n?=?14). At month 4, 34.8% of patients had a ?1% reduction in HbA1c and 62.5% had a ?30% reduction in fasting TGs; at month 12, 80% of patients had a ?1% decrease in HbA1c or ?30% decrease in TGs, and 66% had a decrease of ?2% in HbA1c or ?40% decrease in TGs. Of those on medications, 41%, 22%, and 24% discontinued insulin, oral antidiabetic medications, or lipid-lowering medications, respectively. Mean decrease in liver volume at month 12 was 33.8% (p?<?0.001, n?=?12). Most TEAEs were of mild/moderate severity. CONCLUSIONS:In patients with generalized lipodystrophy, long-term treatment with metreleptin was well tolerated and resulted in sustained improvements in hypertriglyceridemia, glycemic control, and liver volume.
Project description:OBJECTIVE:Patients with lipodystrophy have severe metabolic abnormalities (insulin resistance, diabetes, and hypertriglyceridemia) that may increase morbidity and mortality. Metreleptin is approved by the United States Food and Drug Administration for treatment of generalized forms of lipodystrophy. We aimed to determine the efficacy and safety of metreleptin among patients with partial lipodystrophy using an expanded-access model. METHODS:Study FHA101 (ClinicalTrials.gov identifier: NCT00677313) was an open-label, expanded-access, long-term clinical effectiveness and safety study in 23 patients with partial lipodystrophy and diabetes and/or hypertriglyceridemia with no prespecified leptin level. Metreleptin was administered subcutaneously at 0.02 mg/kg twice daily (BID) at Week 1, followed by 0.04 mg/kg BID at Week 2. Dose adjustments thereafter were based on patient response (maximum dose of 0.08 mg/kg BID). One-year changes in glycated hemoglobin (HbA1c), fasting plasma glucose, triglycerides, alanine and aspartate aminotransferases, and treatment-emergent adverse events (TEAEs) were evaluated. RESULTS:HbA1c, fasting plasma glucose, and triglycerides were numerically decreased throughout 1 year, with mean (standard error) changes from baseline of -0.88 (0.62)%, -42.0 (22.4) mg/dL, and -119.8 (84.1) mg/dL, respectively, which were greater among patients with higher baseline abnormalities. Liver enzymes did not worsen, and the most frequently observed TEAEs (? 10% incidence) were mild to moderate and included nausea (39.1%), hypoglycemia (26.1%), and urinary tract infections (26.1%)-all reported previously. There were no reports of clinically significant immune-related adverse events or new safety signals. CONCLUSIONS:Our clinical observations document the large heterogeneity and disease burden of partial lipodystrophy syndromes and suggest that metreleptin treatment benefits may extend to patients with partial lipodystrophy. Additional studies are needed to confirm these preliminary findings.
Project description:AIMS/INTRODUCTION:Relationships between cardiometabolic risk and glycemia have rarely been studied in people under clinical evaluation and treatment for cardiometabolic risk and with prediabetes. We investigated relationships between glycemia and cardiometabolic risk factors in clinic participants with prediabetes. MATERIALS AND METHODS:This was a cross-sectional analysis of data collected at a center in Thailand. Clinic attendees were at high risk of diabetes or cardiovascular disease, with hemoglobin A1c (HbA1c) 39-<48 mmol/mol or fasting plasma glucose (FPG) 5.6-<7.0 mmol/L. The relationships between glycemia and cardiometabolic risk factors were explored. RESULTS:Of 357 participants, two or more insulin resistance-related metabolic disturbances were present in 84%; 61% took a statin and 75% an antihypertensive agent. Independently of age, sex, adiposity, medication use, possible non-alcoholic fatty liver disease and sex-glycemia interaction, neither FPG nor HbA1c were associated with variation in any other cardiometabolic risk factors. High-density lipoprotein cholesterol decreased with HbA1c in women (female-HbA1c interaction, P = 0.03) but, unexpectedly, increased with FPG in men (male-FPG interaction, P = 0.02). CONCLUSIONS:Overall, in Thai people treated for high cardiometabolic risk and with prediabetes defined by FPG and/or HbA1c, neither FPG nor HbA1c were associated with other cardiometabolic risk factors. However, according to sex, high-density lipoprotein cholesterol showed the expected relationship with glycemia in women, but the reverse in men.
Project description:The efficacy of using fasting plasma glucose (FPG) alone as a preferred screening test for diabetes has been questioned. This study was aimed to evaluate whether the use of serum advanced glycation end products-peptides (sAGEP) would help to improve the efficacy of FPG in diabetes screening among high-risk Chinese subjects with FPG <7.0 mmol/L. FPG, 2-h plasma glucose (2h-PG), serum glycated haemoglobin A1c (HbA1c), and sAGEP were measured in 857 Chinese subjects with risk factors for diabetes. The areas under receiver operating characteristic (ROC) curves generated by logistic regression models were assessed and compared to find the best model for diabetes screening in subjects with FPG <7.0 mmol/L. The optimal critical line was determined by maximizing the sum of sensitivity and specificity. Among the enrolled subjects, 730 of them had FPG <7.0 mmol/L, and only 41.7% new diabetes cases were identified using the 1999 World Health Organization FPG criterion (FPG ?7.0 mmol/L). The area under ROC curves generated by the model on FPG-sAGEP was the largest compared with that on FPG-HbA1c, sAGEP, HbA1c or FPG in subjects with FPG <7.0 mmol/L. By maximizing the sum of sensitivity and specificity, the optimal critical line was determined as 0.69×FPG + 0.14×sAGEP = 7.03, giving a critical sensitivity of 91.2% in detecting 2h-PG ?11.1 mmol/L, which was significantly higher than that of FPG-HbA1c or HbA1c. The model on FPG-sAGEP improves the efficacy of using FPG alone in detecting diabetes among high-risk Chinese subjects with FPG <7.0 mmol/L, and is worth being promoted for future diabetes screening.
Project description:AIMS/HYPOTHESIS:Partial lipodystrophy (PL) is most commonly characterized by loss of subcutaneous fat in the extremities with preservation of truncal fat and is associated with insulin resistance, diabetes and hyperlipidaemia. Recombinant human leptin (r-metHuLeptin) therapy has been shown to be effective in treating metabolic abnormalities associated with congenital or acquired generalized lipodystrophy and PL associated with lamin A/C (LMNA) gene mutations or highly active antiretroviral therapy (HAART). Our aim was to assess the effectiveness of leptin therapy in treating metabolic complications of PL associated with heterozygous peroxisome proliferator activated receptor gamma (PPARG) mutations. This is the first report to detail the clinical response of a patient with PL due to a PPARG mutation treated with r-metHuLeptin. METHODS:A 36-year-old female with PL associated with a heterozygous PPARG mutation complicated by poorly controlled diabetes and severe, refractory hypertriglyceridaemia was enrolled in a National Institutes of Health (NIH) protocol to evaluate the role of r-metHuLeptin in lipodystrophy. The patient received escalating doses of r-metHuLeptin until a dose 0.12 mg/kg/day was reached. Metabolic parameters, including serum chemistries, fasting blood glucose, glycated haemoglobin (HbA1c), lipid profile, an oral glucose tolerance test (OGTT), an insulin tolerance test (ITT), liver volume, percentage body fat and energy expenditure were followed at regular time intervals over 18 months of therapy. RESULTS:Eighteen months of r-MetHuLeptin therapy was associated with a marked improvement in glucose homeostasis as evidenced by normalization of the fasting blood glucose (baseline = 8.3 mmol/l; 18 months = 4.9 mmol/l), lowering of HbA1c (baseline = 9.9%; 18 months = 7.2%) and improved tolerance to an oral glucose load. In addition, a striking amelioration in the patient's refractory, severe hypertriglyceridaemia was observed (baseline = 21.15 mmol/l; 18 months = 5.96 mmol/l). CONCLUSION:r-MetHuLeptin is effective in treating metabolic complications associated with PL due to PPARG mutations. In the context of previously published work, our findings suggest that the response to r-MetHuLeptin is independent of the aetiology in lipodystrophy.
Project description:The prevalence of diabetes in Singapore is high. Screening to facilitate early detection and intervention has been shown to be cost-effective. Current clinical practice guidelines in Singapore recommend screening with fasting plasma glucose (FPG), followed by an oral glucose tolerance test (OGTT) in those with FPG 6.1-6.9?mmol/L. Glycated haemoglobin A1c (HbA1c) has robust stability at ambient temperature, and can be performed on non-fasted capillary blood samples, making it an attractive potential alternative for screening. However, limitations of HbA1c include differential performance in different races, and its performance as a screening test has not been well characterized in Asian populations. This study compares HbA1c and FPG as diabetes screening modalities in 3540 community-dwelling Singapore residents of Chinese, Malay and Indian race to detect diabetes mellitus diagnosed based on blood glucose (FPG???7.0?mmol/L, 2?hr OGTT???11.1?mmol/L). The area under the receiver-operating-characteristic curve (AUC) was higher for FPG compared to HbA1c in the overall population and age, race and age-race strata, but these differences were not statistically significant. HbA1c >?=?7.0% identified 95% of individuals with diabetes mellitus, and the remainder had impaired glucose tolerance (IGT). HbA1c cut-off at 6.1% had better sensitivity (0.825) to FPG at 6.1?mmol/L. The positive predictive value of HbA1c at 6.1% was 40-50% in different age-race combinations with a negative predictive value of about 98%. If follow-up screening with FPG is used, a lower cut-off at 5.6?mmol/L is appropriate in identifying people with pre-diabetes, as about 85% of people with HbA1c 6.1-6.9% and FPG 5.6-6.9?mmol/L had IFG/IGT or diabetes in the study sample. HbA1c is an appropriate alternative to FPG as a first-step screening test, and the combination of Hba1c?>?=?6.1% and FPG?>?=?5.6?mmol/L would improve the identification of individuals with diabetes mellitus and prediabetes.
Project description:AIM:Higher haemoglobin levels and differences in glucose metabolism have been reported among high-altitude residents, which may influence the diagnostic performance of HbA1c . This study explores the relationship between HbA1c and fasting plasma glucose (FPG) in populations living at sea level and at an altitude of > 3000 m. METHODS:Data from 3613 Peruvian adults without a known diagnosis of diabetes from sea-level and high-altitude settings were evaluated. Linear, quadratic and cubic regression models were performed adjusting for potential confounders. Receiver operating characteristic (ROC) curves were constructed and concordance between HbA1c and FPG was assessed using a Kappa index. RESULTS:At sea level and high altitude, means were 13.5 and 16.7 g/dl (P > 0.05) for haemoglobin level; 41 and 40 mmol/mol (5.9% and 5.8%; P < 0.01) for HbA1c ; and 5.8 and 5.1 mmol/l (105 and 91.3 mg/dl; P < 0.001) for FPG, respectively. The adjusted relationship between HbA1c and FPG was quadratic at sea level and linear at high altitude. Adjusted models showed that, to predict an HbA1c value of 48 mmol/mol (6.5%), the corresponding mean FPG values at sea level and high altitude were 6.6 and 14.8 mmol/l (120 and 266 mg/dl), respectively. An HbA1c cut-off of 48 mmol/mol (6.5%) had a sensitivity for high FPG of 87.3% (95% confidence interval (95% CI) 76.5 to 94.4) at sea level and 40.9% (95% CI 20.7 to 63.6) at high altitude. CONCLUSION:The relationship between HbA1c and FPG is less clear at high altitude than at sea level. Caution is warranted when using HbA1c to diagnose diabetes mellitus in this setting.
Project description:The objective of this study was to develop quantitative models to delineate the net efficacy of taspoglutide on fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) from the response of placebo in type 2 diabetes patients, and further find pharmacodynamic potency of taspoglutide and FPG for half of maximum reduction responses of FPG and HbA1c, respectively. Several PD data about taspoglutide treatments for type 2 diabetes patients were digitalized from the published papers related with the clinical development of taspoglutide. The model based meta-analysis (MBMA) studies for FPG and HbA1c were performed with Monolix 4.2 software. The MBMA successfully described the effects of placebo and taspoglutide on pharmacological indexes of FPG and HbA1c through mono and multiple combination therapies in clinical trials. The pharmacodynamic potency (25.3 pmol/l) produced 50% of maximum responses of FPG (-2.39 mmol/l) from the responses of placebo for FPG (-0.371 mmol/l); the response change of FPG (-1.81 mmol/l) affected 50% of maximum response change (-1.74%) for HbA1c from the response of placebo (-0.253%). The leveraging prior knowledge from the longitudinal MBMA will be utilized to guide clinical development of taspoglutide and further support study designs including optimization of dose and duration of therapy.
Project description:A large proportion of patients with T2DM in China do not meet accepted HbA1c targets despite the availability of guidelines that describe a treatment pathway for achieving glycemic control. The aim of this study is to identify the fasting plasma glucose (FPG) target that will provide the highest control rate of HbA1c <7 % in Chinese patients with T2DM treated with an insulin glargine-based regimen as an adjunct to an established OAD regimen. This information will support improvements in diabetes care management in China.Approximately 934 men and women aged ?18 to ?65 years with poorly controlled T2DM will be enrolled and randomized to one of three FPG target groups; ?5.6 mmol/L, ?6.1 mmol/L, or ?7.0 mmol/L. They will be initiated on daily insulin glargine (Lantus®) in addition to their usual OAD regimen for 24 weeks. Patients will self-monitor fasting blood glucose (SM-FBG), and the study physician will titrate the basal insulin dose according to the SM-FBG results. In addition, HbA1c and safety will be recorded. We plan to statistically derive the optimal FPG target for an HbA1c of <7 %.In China, treatment strategies that would achieve an optimum balance between glycemic control (as per HbA1c) and hypoglycemia are imperative to ensure improvements in the management of T2DM. Furthermore, elucidating the contribution of FPG to HbA1c in Chinese patients with T2DM and identifying a predictable relationship between FPG and HbA1c would be a valuable tool for patient self-management of diabetes.NCT02545842 . Registered on 8 September 2015.
Project description:BACKGROUND:The discrepancy between glycosylated hemoglobin (HbA1c) and fasting plasma glucose (FPG) in clinical practice may be related to factors such as acute stress, renal dysfunction, and anemia, and its relationship with in-hospital outcomes is uncertain. The aim of this study was to investigate the association between the type of discrepancy between HbA1c and FPG and in-hospital outcomes in patients with acute coronary syndrome (ACS) and diabetes. METHODS:The Improving Care for Cardiovascular Disease in China - Acute Coronary Syndrome (CCC-ACS) project is a national, hospital-based quality improvement project with an ongoing database. Patients with ACS, diabetes and complete HbA1c and FPG values at admission were included. The consistent group included patients with HbA1c?<?6.5% and FPG?<?7.0?mmol/L or HbA1c???6.5% and FPG???7.0?mmol/L. The discrepancy group included patients with HbA1c???6.5% and FPG?<?7.0?mmol/L (increased HbA1c group) or HbA1c?<?6.5% and FPG???7.0?mmol/L (increased FBG group). RESULTS:A total of 7762 patients were included in this study. The numbers of patients in the consistent and discrepancy groups were 5490 and 2272 respectively. In the discrepancy group, increased HbA1c accounted for 77.5% of discrepancies, and increased FPG accounted for 22.5% of discrepancies. After adjusting for confounders, patients in the increased FPG group had a 1.6-fold increased risk of heart failure (OR, 1.62; 95% CI, 1.08-2.44), a 1.6-fold increased risk of composite cardiovascular death and heart failure (OR, 1.63; 95% CI, 1.09-2.43), and a 1.6-fold increased risk of composite major adverse cardiovascular and cerebrovascular events (MACCEs) and heart failure (OR, 1.56; 95% CI, 1.08-2.24) compared to patients in the increased HbA1c group. CONCLUSIONS:Patients with an increased FPG but normal HbA1c had a higher risk of in-hospital adverse outcomes than those with increased HbA1c but normal FPG. This result may indicate that when HbA1c and FPG are inconsistent in patients with ACS and diabetes, the increased FPG that may be caused by stress hyperglycemia may have a more substantial adverse effect than increased HbA1c, which may be caused by chronic hyperglycemia. These high-risk patients should be given more attention and closer monitoring in clinical practice. TRIAL REGISTRY:Clinicaltrial.gov , NCT02306616 . Registered 29 November 2014.