Heart failure is a global public health problem, affecting a large number of individuals from low-income and middle-income countries. REPORT-HF is, to our knowledge, the first prospective global ...registry collecting information on patient characteristics, management, and prognosis of acute heart failure using a single protocol. The aim of this study was to investigate differences in 1-year post-discharge mortality according to region, country income, and income inequality.
Patients were enrolled during hospitalisation for acute heart failure from 358 centres in 44 countries on six continents. We stratified countries according to a modified WHO regional classification (Latin America, North America, western Europe, eastern Europe, eastern Mediterranean and Africa, southeast Asia, and western Pacific), country income (low, middle, high) and income inequality (according to tertiles of Gini index). Risk factors were identified on the basis of expert opinion and knowledge of the literature.
Of 18 102 patients discharged, 3461 (20%) died within 1 year. Important predictors of 1-year mortality were old age, anaemia, chronic kidney disease, presence of valvular heart disease, left ventricular ejection fraction phenotype (heart failure with reduced ejection fraction HFrEF vs preserved ejection fraction HFpEF), and being on guideline-directed medical treatment (GDMT) at discharge (p<0·0001 for all). Patients from eastern Europe had the lowest 1-year mortality (16%) and patients from eastern Mediterranean and Africa (22%) and Latin America (22%) the highest. Patients from lower-income countries (ie, ≤US$3955 per capita; hazard ratio 1·58, 95% CI 1·41–1·77), or with greater income inequality (ie, from the highest Gini tertile; 1·25, 1·13–1·38) had a higher 1-year mortality compared with patients from regions with higher income (ie, >$12 235 per capita) or lower income inequality (ie, from the lowest Gini tertile). Compared with patients with HFrEF, patients with HFpEF had a lower 1-year mortality with little variation by income level (pinteraction for HFrEF vs HFpEF <0·0001).
Acute heart failure is associated with a high post-discharge mortality, particularly in patients with HFrEF from low-income regions with high income inequality. Regional differences exist in the proportion of eligible patients discharged on GDMT, which was strongly associated with mortality and might reflect lack of access to post-discharge care and prescribing of GDMT.
Novartis Pharma.
Effect of Vildagliptin on Hepatic Steatosis Macauley, Mavin; Hollingsworth, Kieren G; Smith, Fiona E ...
The journal of clinical endocrinology and metabolism,
2015-April, Letnik:
100, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Context:
Although dipeptidyl-peptidase-4 inhibitors exert their major action via an incretin mechanism, a favorable effect of vildagliptin on lipid metabolism remains unexplained.
Objective:
The ...objective was to examine hepatic triglyceride levels and insulin sensitivity on vildagliptin.
Design:
This was a 6-month, randomized, double-blind, placebo-controlled trial.
Setting:
This was an outpatient study at a university clinical research center.
Patients:
Individuals with type 2 diabetes (n = 44) and glycated hemoglobin ≤7.6% on stable metformin therapy were included.
Intervention:
Intervention was vildagliptin 50 mg twice a day or placebo over 6 months.
Main Outcome Measures:
Main outcome measures were hepatic triglyceride levels and insulin sensitivity.
Results:
Mean fasting liver triglyceride content decreased by 27% with vildagliptin, from 7.3 ± 1.0% (baseline) to 5.3 ± 0.9% (endpoint). There was no change in the placebo group. The between-group difference in change from baseline was significant (P = .013). Mean fasting plasma glucose concentration decreased over the study period with vildagliptin vs placebo by −1.0 mmol/L (P = .018), and there was a positive correlation between these decrements and liver triglyceride in the vildagliptin group at 3 months (r = 0.47; P = .02) and 6 months (r = 0.44; P = .03). Plasma alanine aminotransferase fell from 27.2 ± 2.8 to 20.3 ± 1.4 IU/L in the vildagliptin group (P = .0007), and there was a correlation between the decrements in alanine aminotransferase and liver triglyceride (r = 0.83; P < .0001). Insulin sensitivity during the euglycemic clamp was similar in each group at baseline (3.24 ± 0.30 vs 3.19 ± 0.38 mg/kg/min) and did not change (adjusted mean change of 0.26 ± 0.22 vs 0.32 ± 0.22 mg/kg/min; P = .86). Mean body weight decreased by 1.6 ± 0.5 vs 0.4 ± 0.5 kg in the vildagliptin and placebo groups, respectively (P = .08).
Conclusions:
This study demonstrates that the dipeptidyl-peptidase-4 inhibitor vildagliptin brings about a clinically significant decrease in hepatic triglyceride levels during 6 months of therapy unrelated to change in body weight. There was no change in peripheral insulin sensitivity.
Twelve- and 52-Week Efficacy of the Dipeptidyl Peptidase IV Inhibitor LAF237 in Metformin-Treated Patients With Type 2 Diabetes
Bo Ahrén , MD 1 ,
Ramon Gomis , MD 2 ,
Eberhard Standl , MD 3 ,
David ...Mills , MSC 4 and
Anja Schweizer , PHD 4
1 Lund University, Lund, Sweden
2 Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain
3 Diabetes Research Institute, Munich, Germany
4 Novartis Pharma, Basel, Switzerland
Address correspondence and reprint requests to Dr. Bo Ahrén, Department of Medicine, Lund University B11 BMC, SE-221 84 Lund,
Sweden. E-mail: bo.ahren{at}med.lu.se
Abstract
OBJECTIVE —To assess the 12- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 versus placebo in patients with type
2 diabetes continuing metformin treatment.
RESEARCH DESIGN AND METHODS —We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 107 patients with type 2 diabetes with a 40-week
extension in those completing the core study and agreeing, together with the investigator, to extend treatment to 1 year.
Placebo ( n = 51) or LAF237 (50 mg once daily, n = 56) was added to ongoing metformin treatment (1,500–3,000 mg/day). HbA 1c and fasting plasma glucose (FPG) were measured periodically, and standardized meal tests were performed at baseline, week
12, and week 52.
RESULTS —In patients randomized to LAF237, baseline HbA 1c averaged 7.7 ± 0.1% and decreased at week 12 (Δ = −0.6 ± 0.1%), whereas HbA 1c did not change from a baseline of 7.9 ± 0.1% in patients given placebo (between-group difference in ΔHbA 1c = −0.7 ± 0.1%, P < 0.0001). Mean prandial glucose and FPG were significantly reduced in patients receiving LAF237 versus placebo by 2.2 ±
0.4 mmol/l ( P < 0.0001) and 1.2 ± 0.4 mmol/l ( P = 0.0057), respectively, but plasma insulin levels were not affected. At end point of the extension, the between-group differences
in change in mean prandial glucose, insulin, and FPG were −2.4 ± 0.6 mmol/l ( P = 0.0001), 40 ± 16 pmol/l ( P = 0.0153), and −1.1 ± 0.5 mmol/l ( P = 0.0312), respectively. HbA 1c did not change from week 12 to week 52 in LAF237-treated patients ( n = 42) but increased in participants given placebo ( n = 29). The between-group difference in ΔHbA 1c after 1 year was −1.1 ± 0.2% ( P < 0.0001).
CONCLUSIONS —Data from this study demonstrate that LAF237 effectively prevents deterioration of glycemic control when added to metformin
monotherapy in type 2 diabetes.
AMΔ, adjusted mean change
CIRGluPeak, corrected insulin response at peak glucose
DPP-4, dipeptidyl peptidase IV
ECG, electrocardiogram
FPG, fasting plasma glucose
GIP, glucose-dependent insulinotropic peptide
GLP-1, glucagon-like peptide 1
I/G, insulinogenic index at peak glucose
ITT, intent to treat
SAE, serious adverse event
SMBG, self-monitoring of blood glucose
Footnotes
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
Accepted September 7, 2004.
Received May 28, 2004.
DIABETES CARE
Context:
The dipeptidyl peptidase-4 inhibitor, vildagliptin, inhibits glucagon secretion at hyperglycemia but appears to enhance glucagon counterregulation during hypoglycemia in type 2 diabetes.
...Objective:
The objective of the investigation was to study whether vildagliptin also improves α-cell function in type 1 diabetes (T1D).
Patients and Methods:
The study was a single-center, double-blind, randomized, placebo-controlled crossover study involving 28 patients with C-peptide negative and antibody positive T1D 21 males, seven females, glycosylated hemoglobin 57.9 mmol/mol (7.5%). Patients received vildagliptin (50 mg twice a day) or placebo as an add-on to their insulin therapy for 4 wk each. On d 28 of the respective treatment period, patients were served a standard meal (500 kcal) to raise the circulating incretin hormone levels followed by a hyperinsulinemic hypoglycemic clamp at 2.5 mmol/liter.
Main Outcome Measure:
The increase in plasma glucagon levels during the 30-min hypoglycemic clamp (min 165–195 of the test) was measured.
Results:
During the meal, glucagon levels were lower with vildagliptin than with placebo (120 min area under the curveglucagon 2.4 ± 0.2 vs. 2.6 ± 0.2 nmol/liter × minutes, P = 0.022 for between group difference). In contrast, during hypoglycemia, the glucagon counterregulation was not reduced by vildagliptin (increase in glucagon 1.5 ± 1.0 pmol/liter with vildagliptin vs. 1.7 ± 0.8 pmol/liter with placebo, P = NS). In addition, the counterregulatory responses in epinephrine, norepinephrine, cortisol, and pancreatic polypeptide were not different between the treatments. During the 4-wk treatment period, vildagliptin reduced the mean glycosylated hemoglobin, whereas there was no change with placebo between group difference was −3.4 ± 1.0 mmol/mol (−0.32 ± 0.09%; P = 0.002) from baseline of 57.9 mmol/mol (7.5%).
Conclusions:
Vildagliptin, although inhibiting glucagon secretion during hyperglycemia, does not compromise the glucagon counterregulatory response during hypoglycemia in T1D.
Management of Type 2 Diabetes in Treatment-Naive Elderly Patients
Benefits and risks of vildagliptin monotherapy
Richard E. Pratley , MD 1 ,
Julio Rosenstock , MD 2 ,
F. Xavier Pi-Sunyer , MD 3 ,
...Mary Ann Banerji , MD 4 ,
Anja Schweizer , PHD 5 ,
Andre Couturier , MSC 6 and
Sylvie Dejager , MD, PHD 6
1 Vermont College of Medicine, Burlington, Vermont
2 Dallas Diabetes and Endocrine Center, Dallas, Texas
3 St. Lukes-Roosevelt Hospital, New York, New York
4 State University of New York Downstate Medical Center, Brooklyn, New York
5 Novartis Pharma AG, Basel, Switzerland
6 Novartis Pharmaceuticals Corporation, East Hanover, NJ
Address correspondence and reprint requests to Anja Schweizer, PhD, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland.
E-mail: anja.schweizer{at}novartis.com
Abstract
OBJECTIVE —The purpose of this study was to evaluate the efficacy and safety of vildagliptin in elderly patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS —Efficacy data from five double-blind, randomized, placebo- or active-controlled trials of ≥24 weeks’ duration were pooled.
Effects of 24-week vildagliptin monotherapy (100 mg daily) were compared in younger (<65 years, n = 1,231) and older (≥65 years, n = 238) patients. Safety data from eight controlled clinical trials of ≥12-weeks’ duration were pooled; adverse event profiles
in younger ( n = 1,890) and older ( n = 374) patients were compared.
RESULTS —Mean baseline A1C and fasting plasma glucose (FPG) were significantly lower in older (70 years: 8.3 ± 0.1% and 9.6 ± 0.1
mmol/l, respectively) than in younger (50 years: 8.7 ± 0.0% and 10.5 ± 0.1 mmol/l, respectively) patients. Despite this, the
adjusted mean change from baseline (AMΔ) in A1C was −1.2 ± 0.1% in older and −1.0 ± 0.0% in younger vildagliptin-treated patients
( P = 0.092), and the AMΔ in FPG was significantly larger in older (−1.5 ± 0.2 mmol/l) than in younger (−1.1 ± 0.1 mmol/l, P = 0.035) patients. Body weight was significantly lower at baseline in older (83.4 ± 1.0 kg) than in younger (92.0 ± 0.6 kg)
patients. Weight decreased significantly in the older subgroup (AMΔ −0.9 ± 0.3 kg, P = 0.007), whereas smaller, nonsignificant decreases occurred in younger patients (AMΔ −0.2 ± 0.1 kg). Adverse event rates
were slightly higher in older than in younger subgroups but were lower among older, vildagliptin-treated subjects (63.6%)
than in the pooled active comparator group (68.1%). Vildagliptin treatment did not increase adverse events among older patients
with mild renal impairment (62.0%). Hypoglycemia was rare (0.8%) in the elderly patients, and no severe events occurred.
CONCLUSIONS —Vildagliptin monotherapy was effective and well tolerated in treatment-naive elderly patients.
AMΔ, adjusted mean change
DPP-4, dipeptidyl peptidase IV
FPG, fasting plasma glucose
GFR, glomerular filtration rate
GLP-1, glucagon-like peptide-1
OAD, oral antidiabetic drug
SAE, serious adverse event
Footnotes
Published ahead of print at http://care.diabetesjournals.org on 18 September 2007. DOI: 10.2337/dc07-1188. Clinical trial reg. nos. NCT00099905, NCT00099866, NCT00099918, NCT00101673,
NCT00101803, and NCT00120536, clinicaltrials.gov.
R.E.P. has received research grants and consulting fees from Novartis. J.R. has received research grants and consulting fees
from Novartis. F.X.P.-S. has received research grants and consulting fees from Novartis. M.A.B. has received grant support
and honoraria from Novartis.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/dc07-1188 .
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.
Accepted September 12, 2007.
Received June 21, 2007.
DIABETES CARE
Analyzing safety aspects of a drug from individual studies can lead to difficult-to-interpret results. The aim of this paper is therefore to assess the general safety and tolerability, including ...incidences of the most common adverse events (AEs), of vildagliptin based on a large pooled database of Phase II and III clinical trials.
Safety data were pooled from 38 studies of ≥ 12 to ≥ 104 weeks' duration. AE profiles of vildagliptin (50 mg bid; N = 6116) were evaluated relative to a pool of comparators (placebo and active comparators; N = 6210). Absolute incidence rates were calculated for all AEs, serious AEs (SAEs), discontinuations due to AEs, and deaths.
Overall AEs, SAEs, discontinuations due to AEs, and deaths were all reported with a similar frequency in patients receiving vildagliptin (69.1%, 8.9%, 5.7%, and 0.4%, respectively) and patients receiving comparators (69.0%, 9.0%, 6.4%, and 0.4%, respectively), whereas drug-related AEs were seen with a lower frequency in vildagliptin-treated patients (15.7% vs 21.7% with comparators). The incidences of the most commonly reported specific AEs were also similar between vildagliptin and comparators, except for increased incidences of hypoglycemia, tremor, and hyperhidrosis in the comparator group related to the use of sulfonylureas.
The present pooled analysis shows that vildagliptin was overall well tolerated in clinical trials of up to >2 years in duration. The data further emphasize the value of a pooled analysis from a large safety database versus assessing safety and tolerability from individual studies.
Vildagliptin is a potent and selective inhibitor of dipeptidyl peptidase-IV (DPP-4), orally active, that improves glycemic control in patients with type 2 diabetes (T2DM) primarily by enhancing ...pancreatic (alpha and beta) islet function. Thus vildagliptin has been shown both to improve insulin secretion and to suppress the inappropriate glucagon secretion seen in patients with T2DM. Vildagliptin reduces HbA(1c) when given as monotherapy, without weight gain and with minimal hypoglycemia, or in combination with the most commonly prescribed classes of oral hypoglycemic drugs: metformin, a sulfonylurea, a thiazolidinedione, or insulin. Metformin, with a different mode of action not addressing beta-cell dysfunction, has been used for about 50 years and still represents the universal first line therapy of all guidelines. However, given the multiple pathophysiological abnormalities in T2DM and the progressive nature of the disease, intensification of therapy with combinations is typically required over time. Recent guidelines imply that patients will require pharmacologic combinations much earlier to attain and sustain the increasingly stringent glycemic targets, with careful drug selection to avoid unwanted adverse events, especially hypoglycemia. The combination of metformin and vildagliptin offers advantages when compared to currently used combinations with additive efficacy and complimentary mechanisms of action, since it does not increase the risk of hypoglycemia and does not promote weight gain. Therefore, by specifically combining these agents in a single tablet, there is considerable potential to achieve better blood glucose control and to improve compliance to therapy.
Background: Bone metabolism is a dynamic process that is influenced by food ingestion. Endogenous incretins have been shown to be important regulators of bone turnover. The aim of the present study ...was to assess whether a dipeptidylpeptidase (DPP)‐4 inhibitor affects markers of bone resorption and calcium homeostasis.
Methods: The present study was a single‐center, double blind, randomized clinical trail. Fifty‐nine drug‐naïve patients with type 2 diabetes (T2D) were randomized to either 1 year treatment with the DPP‐4 inhibitor vildagliptin (100 mg, once daily; n = 29) or placebo (n = 30). Patients received a standardized breakfast after measurement of serum concentrations of cross‐linked C‐terminal telopeptide (s‐CTx), a bone resorption marker influenced by food intake, before and after 50 weeks treatment.
Results: Vildagliptin did not change postprandial s‐CTx concentrations compared with pretreatment levels (between‐group ratio 1.15 ± 0.17; P = 0.320). Fasting serum alkaline phosphatase, calcium, and phosphate were also unaffected y 1 year treatment with vildagliptin.
Conclusions: Treatment with vildagliptin for 1 year was not associated with changes in markers of bone resorption and calcium homeostasis in drug‐naïve patients with T2D and mild hyperglycemia.
The temporal and spatial expression of stage‐specific genes during morphological development of fungi and higher eukaryotes is controlled by transcription factors. In this study, we report the ...cloning and functional analysis of the Candida albicans TEC1 (CaTEC1) gene, a new member of the TEA/ATTS family of transcription factors that regulates C. albicans virulence. The promoters of the type 4, 5 and 6 proteinase isogenes (SAP4–6) contain repetitive TEA/ATTS consensus sequence motifs. This finding suggests a possible role for a homologue of Saccharomyces cerevisiae TEC1 during the activation of proteinase gene expression in C. albicans. CaTEC1 is predominantly expressed in the hyphal form of C. albicans. In vitro, serum‐induced hyphal formation as well as evasion from MΦ after phagocytosis is suppressed in catec1/catec1 mutant cells. Furthermore, expression of the proteinase isogenes SAP4–6 is no longer inducible in these mutant cells. The deletion of the CaTEC1 gene attenuates virulence of C. albicans in a systemic model of murine candidiasis, although both mutant and revertant cells that were prepared from infected tissues or the vaginal mucosa grew in a hyphal morphology in vivo. CaTEC1 complements the pseudohyphal and invasive growth defect of haploid and diploid S. cerevisiae tec1/tec1 mutant cells and strongly activates the promoter of FLO11, a gene required for pseudohyphal growth. This study provides the first evidence pointing to an essential role for a member of the TEA/ATTS transcription factor family that had so far only been ascribed to function during development as a virulence regulator in microbial pathogenesis.
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