Developing and Establishing Biomechanical Variables as Risk Biomarkers for Preventable Gait-Related Falls and Assessment of Intervention Effectiveness.

The purpose of this review is to position the emerging clinical promise of validating and implementing biomechanical biomarkers of falls in fall prevention interventions. The review is framed in the desirability of blunting the effects of the rapidly growing population of older adults with regard to the number of falls, their related injuries, and health care costs. We propose that biomechanical risk biomarkers may be derived from systematic study of the responses to treadmill-delivered perturbations to both identify individuals with a risk of specific types of falls, such as trips and slips as well as quantifying the effectiveness of interventions designed to reduce that risk. The review follows the evidence derived using a specific public health approach and the published biomedical literature that supports trunk kinematics as a biomarker as having met many of the criteria for a biomarker for trip-specific falls. Whereas, the efficacy of perturbation training to reduce slip-related falls by older adults appears to have been confirmed, its effectiveness presently remains an open and important question. There is a dearth of data related to the efficacy and effectiveness of perturbation training to reduce falls to the side falls by older adults. At present, efforts to characterize the extent to which perturbation training can reduce falls and translate the approaches to the clinic represents an important research opportunity.

Complete Tracheal Ring Deformity. A Translational Genomics Approach to Pathogenesis.

Rationale: Complete tracheal ring deformity (CTRD) is a rare congenital abnormality of unknown etiology characterized by circumferentially continuous or nearly continuous cartilaginous tracheal rings, variable degrees of tracheal stenosis and/or shortening, and/or pulmonary arterial sling anomaly.Objectives: To test the hypothesis that CTRD is caused by inherited or de novo mutations in genes required for normal tracheal development.Methods: CTRD and normal tracheal tissues were examined microscopically to define the tracheal abnormalities present in CTRD. Whole-exome sequencing was performed in children with CTRD and their biological parents ("trio analysis") to identify gene variants in patients with CTRD. Mutations were confirmed by Sanger sequencing, and their potential impact on structure and/or function of encoded proteins was examined using human gene mutation databases. Relevance was further examined by comparison with the effects of targeted deletion of murine homologs important to tracheal development in mice.Measurements and Main Results: The trachealis muscle was absent in all of five patients with CTRD. Exome analysis identified six de novo, three recessive, and multiple compound-heterozygous or rare hemizygous variants in children with CTRD. De novo variants were identified in SHH (Sonic Hedgehog), and inherited variants were identified in HSPG2 (perlecan), ROR2 (receptor tyrosine kinase-like orphan receptor 2), and WLS (Wntless), genes involved in morphogenetic pathways known to mediate tracheoesophageal development in mice.Conclusions: The results of the present study demonstrate that absence of the trachealis muscle is associated with CTRD. Variants predicted to cause disease were identified in genes encoding Hedgehog and Wnt signaling pathway molecules, which are critical to cartilage formation and normal upper airway development in mice.

Evaluation of the self-directed format of Walk With Ease in patients with systemic lupus erythematosus: the Walk-SLE Pilot Study.

OBJECTIVE: To conduct a proof-of-concept pilot evaluation of the self-directed format of Walk With Ease (WWE), a 6-week walking program developed for adults with arthritis, in patients with systemic lupus erythematosus (SLE). METHODS: This was a single arm, 6-week pre- and post-evaluation of the self-directed WWE program to assess feasibility, tolerability, safety, acceptability, and effectiveness. Adult patients with physician-diagnosed SLE were recruited to participate during regularly scheduled visits to an academic rheumatology clinic. Self-reported outcomes of pain, stiffness, and fatigue were assessed by visual analog scales (VAS) and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-fatigue) scale at baseline and at completion of the 6-week program. Patients also completed a satisfaction survey at the end of the program. Multivariate linear regression models were used to calculate mean changes between baseline and 6-week follow-up scores, adjusting for covariates. Mean change scores were used to estimate effect sizes (ES). RESULTS: At 6 weeks, 48 of the 75 recruited participants completed the WWE program. Participants experienced modest improvements in stiffness and fatigue (ES = 0.12 and ES = 0.23, respectively, for VAS scores; ES = 0.16 for FACIT-fatigue score) following the intervention. The majority of participants reported satisfaction with the program (98%) and benefitted from the workbook (96%). CONCLUSIONS: The self-directed format of WWE appears to reduce stiffness and fatigue in patients with SLE. It also seems to be a feasible and acceptable exercise program to patients with SLE. Larger studies are needed to confirm these findings.

Evaluation of cephalexin failure rates in morbidly obese patients with cellulitis.

WHAT IS KNOWN AND OBJECTIVE: Identification of adequate antimicrobial dosing regimens for morbidly obese patients is essential given the simultaneous increase in morbid obesity and cellulitis prevalence in recent years. Insufficient data currently exist to describe the effectiveness of extrapolating traditional antibiotic dosing strategies to morbidly obese patients with cellulitis. The primary objective of this study was to compare therapeutic failure rates in non-obese and morbidly obese patients with cellulitis when treated with cephalexin at standard dosing. METHODS: This was a single-centre, retrospective cohort analysis. Adult patients hospitalized or under inpatient observation at a 1265-bed academic medical centre who received cephalexin monotherapy for non-purulent cellulitis from 2005 to 2015 were evaluated for inclusion. Patients were divided into two cohorts based on body mass index (BMI), where BMI <30 kg/m(2) was defined as non-obese and BMI ≥40 kg/m(2) as morbidly obese. Patients with critical risk factors for purulent or polymicrobial cellulitis were excluded. The primary outcome, therapeutic failure, was defined as a need for extended or additional antimicrobial therapy, surgical intervention, emergency department visit, or re-hospitalization within two to thirty days after cephalexin initiation. RESULTS AND DISCUSSION: A total of 94 patients (69 non-obese and 25 morbidly obese) met inclusion and exclusion criteria, which was below the estimated sample size needed to reach desired power. The rate of therapeutic failure in the morbidly obese group was similar to the non-obese group (20% vs. 14·5%, P = 0·53). Patients most commonly had extended or additional antibiotics prescribed in response to therapeutic failure with cephalexin. WHAT IS NEW AND CONCLUSION: Cephalexin failure rates for cellulitis did not differ statistically between morbidly obese and non-obese patients. The underpowered nature of this study is a limitation. Until further study with a larger sample size is completed, empiric adjustment of cephalexin dosing based solely on BMI may not be necessary.

Step detection using multi- versus single tri-axial accelerometer-based systems.

Multiple sensors are often considered necessary for increased step count accuracy. However, subject adherence to device-wear increases using a minimal number of activity monitors (AMs). The study aims were to determine and compare the validity of using multiple AMs versus a single AM to detect steps by comparison to video using a modification of an algorithm previously developed for a four-accelerometer AM system capable, unlike other algorithms, of accurate step detection for gait velocities as low as 0.1 m s(-1). Twelve healthy adults wore ankle, thigh and waist AMs while performing walking/jogging trials at gait velocities from 0.1-4.8 m s(-1) and a simulated free-living dynamic activities protocol. Nineteen older adults wore ankle and waist AMs while walking at velocities from 0.5-2.0 m s(-1). As little as one AM (thigh or waist) accurately detected steps for velocities >0.5 m s(-1). A single ankle AM accurately detected steps for velocities ⩾0.1 m s(-1). Only the thigh AM could not accurately detect steps during the dynamic activities. Only the thigh-ankle combination or single waist AM could accurately distinguish between walking and jogging steps. These laboratory-based results suggest that the presented algorithm can accurately detect steps in a free-living environment using only one ankle or waist AM.

Long-term efficacy of sitagliptin as either monotherapy or add-on therapy to metformin: improvement in glycemic control over 2 years in patients with type 2 diabetes.

OBJECTIVE: To evaluate the efficacy of once daily sitagliptin 100 mg as monotherapy or as add-on to metformin in patients with type 2 diabetes mellitus (T2DM) over 2 years of treatment. RESEARCH DESIGN AND METHODS: The monotherapy analysis used pooled 104 week data from 64 patients in two randomized, double-blind trials evaluating the safety and efficacy of sitagliptin monotherapy. Data used were from patients who were randomized to sitagliptin 100 mg/day, were not on an antihyperglycemic agent at the screening visit, had baseline A1C of 7.0%-10.0%, and had Week 104 A1C measurements. The add-on to metformin analysis used pooled data from 347 patients in two randomized double-blind trials evaluating the safety and efficacy of sitagliptin + metformin combination therapy. Data used were from patients who were randomized to sitagliptin 100 mg/day + metformin ≥1500 mg/day, had baseline A1C of 7%-10%, and had Week 104 A1C measurements. Excluded from either analysis were patients who discontinued prior to 2 years (e.g., due to lack of efficacy, a need for rescue medications, or adverse experiences). Analysis endpoints were A1C, fasting plasma glucose (FPG), HOMA-ß, proinsulin/insulin (P/I) ratio, and for monotherapy, 2 hour post-meal plasma glucose (PMG). RESULTS: For the pooled monotherapy cohort, after 2 years of treatment, mean A1C, FPG, and 2 hour PMG decreased from baseline values of 7.9%, 156 mg/dL, and 223 mg/dL to 6.9%, 143 mg/dL, and 191 mg/dL, respectively, while HOMA-ß increased from 67% to 85% and P/I ratio improved from 0.57 to 0.28. For the pooled add-on to metformin cohort, after 2 years of treatment, mean A1C and FPG decreased from baseline values of 7.7% and 160 mg/dL to 6.9% and 140 mg/dL, respectively, while HOMA-ß increased from 50% to 62% and P/I ratio improved from 0.33 to 0.28. These analyses are limited in that only patients who were able to complete 104 weeks of study were included. CONCLUSION: In the subset of patients with T2DM who maintained and completed treatment for 2 years with sitagliptin as monotherapy or as add-on to metformin, improvements in glycemic control and measures of ß-cell function were observed over the course of treatment.

Dynamic balance assessment during gait in spinal pathologies - a literature review.

UNLABELLED: The role of the spine as a gait stabilizer is essential. Dynamic assessment, while walking, might provide complementary data to improve spinal deformity management. The aim of this paper was to review spine dynamic behavior and the various methods that have been used to assess gait dynamic balance in order to explore the consequences of spinal deformities while walking. A review was performed by obtaining publications from five electronic databases. All papers reporting pathological or non-pathological spine dynamic behavior during gait and dynamic balance assessment methods were included. Sixty articles were selected. Results varied widely according to pathologies, study conditions, and balance assessment techniques. Three methods assessing dynamic stability during gait were identified: local-orbital dynamic stability, tri-axial accelerometry, and dynamic stability margin. Data from conventional gait analysis techniques were established essentially for scoliosis and low back pain, but they do not assess specific consequences on gait dynamic balance. Three techniques investigate gait dynamic balance and have been validated in normal subjects. Further investigations need to be performed for validation in spinal pathologies as well as the value for clinical practice. LEVEL OF EVIDENCE: Level IV.

A comparison of glycaemic effects of sitagliptin and sulfonylureas in elderly patients with type 2 diabetes mellitus.

INTRODUCTION: In the USA, 45% of patients with type 2 diabetes mellitus (T2DM) are elderly (≥ 65 years old). In general, use of sulfonylurea increases with patient age as does the associated risk for hypoglycaemia, and the consequences of hypoglycaemia can be more pronounced in elderly patients. Sitagliptin, a DPP-4 inhibitor, improves glycaemic control in adult patients of all ages with T2DM, with a low risk of hypoglycaemia when used alone or in combination with other antidiabetic agents that are not generally associated with hypoglycaemia when used independently. METHODS: In a post hoc analysis, pooled data from elderly patients who participated in one of three double-blind studies comparing the effects of therapy with sitagliptin (100 mg/day) vs. sulfonylurea (in titrated doses) were analysed for changes from baseline in HbA1c, fasting plasma glucose (FPG), and body weight and for the incidence of reported symptomatic hypoglycaemia. In these studies, patients on diet alone or metformin were randomised to sitagliptin or glipizide for 104 weeks (studies 1 and 2) or glimepiride for 30 weeks (study 3). The analysis included 372 elderly patients who completed a trial through 25 or 30 weeks. RESULTS: Both HbA1c and FPG decreased from baseline with each treatment, with no statistically significant differences between treatments. A significantly lower incidence of reported hypoglycaemia was observed with sitagliptin compared with sulfonylurea (6.2% vs. 27.8%; p < 0.001). Body weight decreased significantly with sitagliptin but not with sulfonylurea. Significantly more patients on sitagliptin than on sulfonylureas achieved a composite end-point of >0.5% HbA1c reduction with no reported hypoglycaemia or increase in body weight (44.1% vs. 16.0%; p < 0.001). CONCLUSION: In this analysis of elderly patients with T2DM, compared with sulfonylurea, sitagliptin provided similar glycaemic efficacy with less hypoglycaemia and with body weight loss.

Novel associations between FAAH genetic variants and postoperative central opioid-related adverse effects.

Opioid effects are potentiated by cannabinoid agonists including anandamide, an endocannabinoid. Inter-individual variability in responses to opioids is a major clinical problem. Multiple deaths and anoxic brain injuries occur every year because of opioid-induced respiratory depression (RD) in surgical patients and drug abusers of opioids and cannabinoids. This study aimed to determine specific associations between genetic variants of fatty acid amide hydrolase (FAAH) and postoperative central opioid adverse effects in children undergoing tonsillectomy. This is a prospective genotype-blinded observational study in which 259 healthy children between 6 and 15 years of age who received standard perioperative care with a standard anesthetic and an intraoperative dose of morphine were enrolled. Associations between frequent polymorphisms of FAAH and central postoperative opioid adverse effects including, RD, postoperative nausea and vomiting (PONV) and prolonged stay in Post Anesthesia Recovery Room (postoperative anesthesia care unit, PACU) due to RD and PONV were analyzed. Five specific FAAH single nucleotide polymorphisms (SNPs) had significant associations with more than twofold increased risk for refractory PONV (adjusted P<0.0018), and nominal associations (P<0.05) with RD and prolonged PACU stay in white children undergoing tonsillectomy. The FAAH SNP, rs324420, is a missense mutation with altered FAAH function and it is linked with other FAAH SNPs associated with PONV and RD in our cohort; association between PONV and rs324420 was confirmed in our extended cohort with additional 66 white children. Specific FAAH polymorphisms are associated with refractory PONV, opioid-related RD, and prolonged PACU stay due to opioid adverse effects in white children undergoing tonsillectomy.

Efficacy and safety of initial combination treatment with sitagliptin and pioglitazone--a factorial study.

AIM: To evaluate the efficacy and safety of initial combination therapy of sitagliptin 100 mg/day coadministered with all marketed doses of pioglitazone in patients with type 2 diabetes. METHODS: Patients with A1c ≥7.5 and ≤11.0% were randomized among seven arms that received, once daily, 100 mg sitagliptin alone; 15, 30 or 45 mg pioglitazone alone, or 100 mg sitagliptin plus 15, 30 or 45 mg pioglitazone for 54 weeks. The primary endpoint was change from baseline in A1c at week 24. Protocol-specified analyses compared combination therapies with monotherapies at respective dose-strengths and combination of sitagliptin plus pioglitazone 30 mg with pioglitazone 45 mg monotherapy. Post-hoc analyses compared sitagliptin plus pioglitazone 15 mg with pioglitazone monotherapy at the two higher doses. RESULTS: Initial combination therapy with sitagliptin and pioglitazone provided significantly greater reductions in A1c (0.4-0.7% differences) and other glycaemic endpoints than either monotherapy at the same doses. Combining sitagliptin with low-dose pioglitazone generally produced greater glycaemic improvements than higher doses of pioglitazone monotherapy (0.3-0.4% differences in A1c). Combination therapy was generally well tolerated; adverse events (AEs) of hypoglycaemia were reported with similar incidence (7.8-11.1%) in all treatment groups over the 54 weeks of study; oedema was reported in 0.5% of patients in the sitagliptin monotherapy group and 2.7-5.3% among pioglitazone-treated groups. Significant weight gain was observed in all combination-treated groups compared with the sitagliptin monotherapy group. CONCLUSIONS: Initial combination therapy with sitagliptin and pioglitazone provided better glycaemic control than either monotherapy and was generally well tolerated.

Sitagliptin and pioglitazone provide complementary effects on postprandial glucose and pancreatic islet cell function.

AIMS: The effects of sitagliptin and pioglitazone, alone and in combination, on α- and ß-cell function were assessed in patients with type 2 diabetes. METHODS: Following a 6-week diet/exercise period, 211 patients with HbA1c of 6.5-9.0% and fasting plasma glucose of 7.2-14.4 mmol/l were randomized (1 :1 :1 : 1) to sitagliptin, pioglitazone, sitagliptin + pioglitazone or placebo. At baseline and after 12 weeks, patients were given a mixed meal followed by frequent blood sampling for measurements of glucose, insulin, C-peptide and glucagon. RESULTS: After 12 weeks, 5-h glucose total area under the curve (AUC) decreased in all active treatments versus placebo; reduction with sitagliptin + pioglitazone was greater versus either monotherapy. The 5-h insulin total AUC increased with sitagliptin versus all other treatments and increased with sitagliptin + pioglitazone versus pioglitazone. The 3-h glucagon AUC decreased with sitagliptin versus placebo and decreased with sitagliptin + pioglitazone versus pioglitazone or placebo. Φ(s), a measure of dynamic ß-cell responsiveness to above-basal glucose concentrations, increased with either monotherapy versus placebo and increased with sitagliptin + pioglitazone versus either monotherapy. The insulin sensitivity index (ISI), a composite index of insulin sensitivity, improved with pioglitazone and sitagliptin + pioglitazone versus placebo. The disposition index, a measure of the relationship between ß-cell function and insulin sensitivity, improved with all active treatments versus placebo. CONCLUSIONS: Sitagliptin and pioglitazone enhanced ß-cell function (increasing postmeal Φ(s)), and sitagliptin improved α-cell function (decreasing postmeal glucagon) after 12 weeks in patients with type 2 diabetes. Through these complementary mechanisms of action, the combination of sitagliptin and pioglitazone reduced postmeal glucose more than either treatment alone.

Use of a Poroelastic Model to Predict Intramuscular Pressure.

Measurement of individual muscle tension in a clinical setting has yet to be achieved. Previous investigators have suggested that the tension in skeletal muscle, comprised of approximately 70% fluid, could be determined using interstitial muscle fluid pressure (IMP). A computational model is needed to aid in understanding IMP distribution in muscles of varying geometry and contractile states without exhaustive testing. The first aim of this study was to determine a set of transversely isotropic material properties (i.e., permeability, relaxed modulus, and drained Poisson's ratio) for excised skeletal muscle using inverse finite element analysis with a poroelastic constitutive formulation on tension data from either longitudinal or transverse uniaxial load-relaxation tests of skeletal muscle tissue. The second aim was to compare pore pressure estimated from a model to experimental pressure measurements to assess its ability to accurately predict IMP. Results of this study indicated that skeletal muscle was transversely isotropic under load-relaxation as demonstrated by significant differences in the drained Poisson's ratio. It was also noted that the drained Poisson's ratios under both longitudinal and transverse loading were negative in these tests of excised muscle tissue. Pore pressure calculated with this model provided a good prediction of the development of IMP. These results point to the benefit of using a poroelastic model of skeletal muscle to predict IMP.

A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni-corrected threshold (P<1 × 10(-4)). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P=0.0004) and UBCH7 protein expression (P=0.0068). The results suggest that variants carried on the SLE-associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.

Identification of novel coding mutation in C1qA gene in an African-American pedigree with lupus and C1q deficiency.

OBJECTIVES: Homozygous C1q deficiency is an extremely rare condition and strongly associated with systemic lupus erythematosus. To assess and characterize C1q deficiency in an African-American lupus pedigree, C1q genomic region was evaluated in the lupus cases and family members. METHODS: Genomic DNA from patient was obtained and C1q A, B and C gene cluster was sequenced using next generation sequencing method. The identified mutation was further confirmed by direct Sanger sequencing method in the patient and all blood relatives. C1q levels in serum were measured using sandwich ELISA method. RESULTS: In an African-American patient with lupus and C1q deficiency, we identified and confirmed a novel homozygote start codon mutation in C1qA gene that changes amino acid methionine to arginine at position 1. The Met1Arg mutation prevents protein translation (Met1Arg). Mutation analyses of the patient's family members also revealed the Met1Arg homozygote mutation in her deceased brother who also had lupus with absence of total complement activity consistent with a recessive pattern of inheritance. CONCLUSION: The identification of new mutation in C1qA gene that disrupts the start codon (ATG to AGG (Met1Arg)) has not been reported previously and it expands the knowledge and importance of the C1q gene in the pathogenesis of lupus especially in the high-risk African-American population.

Efficacy and safety of initial combination therapy with sitagliptin and pioglitazone in patients with type 2 diabetes: a 54-week study.

AIM: To assess the 54-week efficacy of initial combination therapy with sitagliptin and pioglitazone, compared with pioglitazone monotherapy, and to assess safety in these groups during the 30 weeks after the dosage of pioglitazone was increased from 30 to 45 mg/day, in drug-naÏve patients with type 2 diabetes mellitus and inadequate glycaemic control [haemoglobin A1c (HbA1c) 8-12%]. METHODS: Following a 24-week, randomized, double-blind, parallel-group study (Sitagliptin Protocol 064, Clinicaltrials.gov: NCT00397631; Yoon KH, Shockey GR, Teng R et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and pioglitazone on glycaemic control and measures of beta-cell function in patients with type 2 diabetes. Int J Clin Pract 2011; 65: 154-164) in which patients were treated with the combination of sitagliptin 100 mg/day and pioglitazone 30 mg/day or monotherapy with pioglitazone 30 mg/day, patients entered a 30-week extension study. In the extension study, the pioglitazone dose was increased from 30 to 45 mg/day in both groups. Depending upon treatment allocation, patients took one tablet of sitagliptin 100 mg or matching placebo daily. Pioglitazone was administered in an open-label fashion as a single 45-mg tablet taken once daily. Patients not meeting specific glycaemic goals in the extension study were rescued with metformin therapy. Efficacy and safety results for the extension study excluded data after initiation of rescue therapy. RESULTS: Of the 520 patients initially randomized, 446 completed the base study and, of these, 317 entered the extension. In this extension study cohort, the mean reductions from baseline in HbA1c and fasting plasma glucose (FPG) at the end of the base study (week 24) were -2.5% and -62.1 mg/dl with the combination of sitagliptin 100 mg and pioglitazone 30 mg versus -1.9% and -48.7 mg/dl with pioglitazone monotherapy. At the end of the extension study (week 54), the mean reduction in haemoglobin A1c (HbA1c) was -2.4% with the combination of sitagliptin 100 mg and pioglitazone 45 mg versus -1.9% with pioglitazone monotherapy [between-group difference (95% CI) = -0.5% (-0.8, -0.3)] and the mean reduction in FPG was -61.3 mg/dl versus -52.8 mg/dl, respectively [between-group difference (95% CI) = -8.5 mg/dl (-16.3, -0.7)]. Safety and tolerability of initial treatment with the combination of sitagliptin and pioglitazone and pioglitazone monotherapy were similar. As expected, increases in body weight from baseline were observed in both treatment groups at week 54: 4.8 and 4.1 kg in the combination and monotherapy groups, respectively [between-group difference (95% CI) = 0.7 kg (-0.7, 2.1)]. CONCLUSION: In this study, initial combination therapy with sitagliptin 100 mg and pioglitazone 30 mg increased to 45 mg after 24 weeks led to a substantial and durable incremental improvement in glycaemic control compared with initial treatment with pioglitazone monotherapy during a 54-week treatment period. Both initial combination therapy with sitagliptin and pioglitazone and pioglitazone monotherapy were generally well tolerated (Clinicaltrials.gov: NCT01028391).

Role of MYH9 and APOL1 in African and non-African populations with lupus nephritis.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and organ damage. Lupus nephritis (LN) is one of the most severe manifestations of SLE. Multiple studies reported associations between renal diseases and variants in the non-muscle myosin heavy chain 9 (MYH9) and the neighboring apolipoprotein L 1 (APOL1) genes. We evaluated 167 variants spanning MYH9 for association with LN in a multiethnic sample. The two previously identified risk variants in APOL1 were also tested for association with LN in European-Americans (EAs) (N = 579) and African-Americans (AAs) (N = 407). Multiple peaks of association exceeding a Bonferroni corrected P-value of P < 2.03 × 10(-3) were observed between LN and MYH9 in EAs (N = 4620), with the most pronounced association at rs2157257 (P = 4.7 × 10(-4), odds ratio (OR) = 1.205). A modest effect with MYH9 was also detected in Gullah (rs8136069, P = 0.0019, OR = 2.304). No association between LN and MYH9 was found in AAs, Asians, Amerindians or Hispanics. This study provides the first investigation of MYH9 in LN in non-Africans and of APOL1 in LN in any population, and presents novel insight into the potential role of MYH9 in LN in EAs.

Effect of initial combination therapy with sitagliptin and metformin on ß-cell function in patients with type 2 diabetes.

AIM: To examine the effect of sitagliptin and metformin, alone and in combination, on modelled parameters of ß-cell function in patients with type 2 diabetes. METHODS: The data used in the present analyses are from a 104-week study, which included a 24-week, placebo- and active controlled phase followed by a 30-week, active controlled, continuation phase and an additional 50-week, active controlled extension phase. Patients were randomised to one of six blinded treatments: sitagliptin 50 mg + metformin 1000 mg b.i.d., sitagliptin 50 mg + metformin 500 mg b.i.d., metformin 1000 mg b.i.d., metformin 500 mg b.i.d., sitagliptin 100 mg q.d. or placebo. Patients on placebo were switched in a blinded manner to metformin 1000 mg b.i.d. at week 24. Subsets of patients volunteered to undergo frequently sampled meal tolerance tests at baseline and at weeks 24, 54 and 104. ß-cell responsivity was assessed with the C-peptide minimal model. The static component (Φ(s)) estimates the rate of insulin secretion related to above-basal glucose concentration. The dynamic component (Φ(d)) is related to the rate of change in glucose. The total index (Φ(total)) represents the overall response to a glycaemic stimulus and is calculated as a function of Φ(s) and Φ(d). Insulin sensitivity was estimated with the Matsuda index (ISI). The disposition index, which assesses insulin secretion relative to the prevailing insulin sensitivity, was calculated based on the Φ(total) and ISI. RESULTS: At week 24, substantial reductions in postmeal glucose were observed with all active treatment groups relative to the placebo group. Φ(s), Φ(total) and the disposition index were significantly improved from baseline at week 24 with all active treatments relative to placebo. Generally larger effects were observed with the initial combination of sitagliptin and metformin relative to the monotherapy groups. When expressed as median percent change from baseline, Φ(s) increased from baseline by 137 and 177% in the low- and high-dose combination groups and by 85, 54, 73 and -9% in the high-dose metformin, low-dose metformin, sitagliptin monotherapy and placebo groups, respectively. At weeks 54 and 104, the combination treatment groups continued to demonstrate greater improvements in ß-cell function relative to their respective monotherapy groups. CONCLUSIONS: After 24 weeks of therapy, relative to placebo, initial treatment with sitagliptin or metformin monotherapy improved ß-cell function; moreover, initial combination therapy demonstrated larger improvements than the individual monotherapies. Improvements in ß-cell function were found with treatments for up to 2 years.

Initial therapy with the fixed-dose combination of sitagliptin and metformin results in greater improvement in glycaemic control compared with pioglitazone monotherapy in patients with type 2 diabetes.

AIMS: To evaluate the efficacy and safety of initial therapy with a fixed-dose combination (FDC) of sitagliptin and metformin compared with pioglitazone in drug-naÏve patients with type 2 diabetes. METHODS: After a 2-week single-blind placebo run-in period, patients with type 2 diabetes, HbA1c of 7.5-12% and not on antihyperglycaemic agent therapy were randomized in a double-blind manner to initial treatment with a FDC of sitagliptin/metformin 50/500 mg twice daily (N = 261) or pioglitazone 30 mg per day (N = 256). Sitagliptin/metformin and pioglitazone were up-titrated over 4 weeks to doses of 50/1000 mg twice daily and 45 mg per day, respectively. Both treatments were then continued for an additional 28 weeks. RESULTS: From a mean baseline HbA1c of 8.9% in both groups, least squares (LS) mean changes in HbA1c at week 32 were -1.9 and -1.4% for sitagliptin/metformin and pioglitazone, respectively (between-group difference = -0.5%; p < 0.001). A greater proportion of patients had an HbA1c of <7% at week 32 with sitagliptin/metformin vs. pioglitazone (57% vs. 43%, p < 0.001). Compared with pioglitazone, sitagliptin/metformin treatment resulted in greater LS mean reductions in fasting plasma glucose (FPG) [-56.0 mg/dl (-3.11 mmol/l) vs. -44.0 mg/dl (-2.45 mmol/l), p < 0.001] and in 2-h post-meal glucose [-102.2 mg/dl (-5.68 mmol/l) vs. -82.0 mg/dl (-4.56 mmol/l), p < 0.001] at week 32. A substantially greater reduction in FPG [-40.5 mg/dl (-2.25 mmol/l) vs. -13.0 mg/dl (-0.72 mmol/l), p < 0.001] was observed at week 1 with sitagliptin/metformin vs. pioglitazone. A greater reduction in the fasting proinsulin/insulin ratio and a greater increase in homeostasis model assessment of ß-cell function (HOMA-ß) were observed with sitagliptin/metformin than with pioglitazone, while greater decreases in fasting insulin and HOMA of insulin resistance (HOMA-IR), and a greater increase in quantitative insulin sensitivity check index (QUICKI) were observed with pioglitazone than with sitagliptin/metformin. Both sitagliptin/metformin and pioglitazone were generally well tolerated. Sitagliptin/metformin led to weight loss (-1.4 kg), while pioglitazone led to weight gain (3.0 kg) (p < 0.001 for the between-group difference). Higher incidences of diarrhoea (15.3% vs. 4.3%, p < 0.001), nausea (4.6% vs. 1.2%, p = 0.02) and vomiting (1.9% vs. 0.0%, p = 0.026), and a lower incidence of oedema (1.1% vs. 7.0%, p < 0.001), were observed with sitagliptin/metformin vs. pioglitazone. The between-group difference in the incidence of hypoglycaemia did not reach statistical significance (8.4 and 4.3% with sitagliptin/metformin and pioglitazone, respectively; p = 0.055). CONCLUSION: Compared with pioglitazone, initial therapy with a FDC of sitagliptin and metformin led to significantly greater improvement in glycaemic control as well as a higher incidence of prespecified gastrointestinal adverse events, a lower incidence of oedema and weight loss vs. weight gain.

Efficacy and safety of sitagliptin and the fixed-dose combination of sitagliptin and metformin vs. pioglitazone in drug-naïve patients with type 2 diabetes.

AIM: The efficacy and safety of sitagliptin (SITA) monotherapy and SITA/metformin (MET) vs. pioglitazone (PIO) were assessed in patients with type 2 diabetes and moderate-to-severe hyperglycaemia (A1C = 7.5-12.0%). METHODS: In an initial 12-week phase (Phase A), 492 patients were randomised 1 : 1 in a double-blind fashion to SITA (100 mg qd) or PIO (15 mg qd, up-titrated to 30 mg after 6 weeks). In Phase B (28 additional weeks), the SITA group was switched to SITA/MET (up-titrated to 50/1000 mg bid over 4 weeks) and the PIO group was up-titrated to 45 mg qd RESULTS: At the end of Phase A, mean changes from baseline were -1.0% and -0.9% for A1C; -26.6 mg/dl and -28.0 mg/dl for fasting plasma glucose; and -52.8 mg/dl and -50.1 mg/dl for 2-h post-meal glucose for SITA and PIO, respectively. At the end of Phase B, improvements in glycaemic parameters were greater with SITA/MET vs. PIO: -1.7% vs. -1.4% for A1C (p = 0.002); -45.8 mg/dl vs. -37.6 mg/dl for fasting plasma glucose (p = 0.03); -90.3 mg/dl vs. -69.1 mg/dl for 2-h postmeal glucose (p = 0.001); and 55.0% vs. 40.5% for patients with A1C < 7% (p = 0.004). A numerically higher incidence of gastrointestinal adverse events and a significantly lower incidence of oedema were observed with SITA/MET vs. PIO. The incidence of hypoglycaemia was similarly low in both groups. Body weight decreased with SITA/MET and increased with PIO (-1.1 kg vs. 3.4 kg; p < 0.001). CONCLUSION: Improvements in glycaemic control were greater with SITA/MET vs. PIO, with weight loss vs. weight gain. Both treatments were generally well tolerated.

A treatment strategy implementing combination therapy with sitagliptin and metformin results in superior glycaemic control versus metformin monotherapy due to a low rate of addition of antihyperglycaemic agents.

AIMS: Combination therapy with sitagliptin and metformin has shown superior efficacy compared with metformin monotherapy. In this study, we compare two strategies: initial combination therapy with sitagliptin/metformin as a fixed-dose combination (FDC) and initial metformin monotherapy, with the option to add additional antihyperglycaemic agents (AHAs) in either treatment arm during the second phase of the study in order to reach adequate glycaemic control. METHODS: We evaluated the sitagliptin and metformin FDC compared with metformin monotherapy over 44 weeks in 1250 patients with type 2 diabetes mellitus in a two-part, double-blind, randomized, controlled clinical trial. The initial 18-week portion (Phase A) of this study in which additional AHAs were only allowed based on prespecified glycaemic criteria, has been previously reported. Here, we present results from the 26-week Phase B portion of the study during which double-blind study medication continued; however, unlike Phase A, during Phase B investigators were unmasked to results for haemoglobin A1C (HbA1c) and fasting plasma glucose (FPG) and directed to manage glycaemic control by adding incremental AHA(s) as deemed clinically appropriate. RESULTS: There were 1250 patients randomized in the study with 965 completing Phase A and continuing in Phase B. Among patients receiving sitagliptin/metformin FDC or metformin monotherapy, 8.8% and 16.7% received additional AHA therapy, respectively. Although glycaemic therapy in both groups was to have been managed to optimize HbA1c reductions with the option for investigators to supplement with additional AHAs during Phase B, patients randomized to initial therapy with sitagliptin/metformin FDC had larger reductions of HbA1c from baseline compared with patients randomized to initial metformin monotherapy [least squares (LS) mean change: -2.3% and -1.8% (p < 0.001 for difference) for sitagliptin/metformin FDC and metformin monotherapy groups, respectively]. A significantly larger reduction in FPG from baseline was observed in the sitagliptin/metformin FDC group compared with the metformin monotherapy group (p = 0.001). Significantly more patients in the sitagliptin/metformin FDC group had an HbA1c of less than 7.0% or less than 6.5% compared with those on metformin monotherapy. Both treatment strategies were generally well tolerated, with a low and similar incidence of hypoglycaemia in both groups and lower incidences of abdominal pain and diarrhoea in the sitagliptin/metformin FDC group compared with the metformin monotherapy group. CONCLUSIONS: A strategy initially implementing combination therapy with sitagliptin/metformin FDC was superior to a strategy initially implementing metformin monotherapy, even when accounting for the later addition of supplemental AHAs. Sitagliptin/metformin FDC was generally well tolerated.