Usage Pattern of Glimepiride/Metformin Fixed-dose Combination in Type 2 Diabetes Patients with CVD or at Risk of CVD: An Experience in Indian Setting

Background: Diabetes is associated with almost twofold increased risk of cardiovascular diseases (CVD). The present case-based questionnaire survey evaluated the treatment pattern and clinical experience of healthcare professionals in prescribing glimepiride/metformin fixed-dose combination (FDC) to type 2 diabetes mellitus (T2DM) patients with CVD or those patients who are at risk of CVD in the Indian settings. Material and methods: A retrospective, multicenter, observational, case-based questionnaire survey was conducted in Indian healthcare centers using medical records of patients having T2DM, with CVD or are at risk of CVD, who were prescribed any strength of glimepiride/metformin FDC. Data was collected from the patients’ medical records and was analyzed using statistical tests. Results: A total of 680 patients with T2DM with CVD or at risk of CVD were included in this study. Mean duration of diabetes in the patients was 5.7 ± 4.8 years. About 68.5% patients had hypertension, 47.9% had dyslipidemia, 25.4% had coronary artery disease (CAD), 3.6% had transient ischemic attack (TIA), 4.8% had peripheral arterial disease (PAD) and 2.9% had heart failure. Around 18.1% patients had CVD after diabetes was diagnosed, while 81.9% presented with cardiovascular (CV) issues at the time of diabetes diagnosis. All patients received glimepiride/metformin FDC as first-line therapy. About 68.2% patients on glimepiride/metformin FDC had blood pressure within optimal limits. A large proportion of patients had improvement in glycemic parameters. Weight change was noted in 18.4% of the patients overall. Of these, 59.2% had reduction in weight. There were no major adverse events and treatment efficacy and tolerability were reported as good to excellent for 94.6% and 92.9% patients, respectively. Conclusion: This case-based questionnaire survey demonstrates the usage pattern of various strengths of glimepiride/metformin FDC and the clinicians’ practice approach regarding early initiation of this combination in Indian patients with diabetes who have or are at risk of CVD

Do baseline characteristics and treatments account for geographical disparities in the outcomes of patients with newly diagnosed atrial fibrillation? The prospective GARFIELD-AF registry.

OBJECTIVE: In patients with newly diagnosed atrial fibrillation (AF), do baseline risk factors and stroke prevention strategies account for the geographically diverse outcomes. DESIGN: Global Anticoagulant Registry in the FIELD-Atrial Fibrillation is a prospective multinational non-interventional registry of patients with newly diagnosed AF (n=52 018 patients). SETTING: Investigator sites (n=1317) were representative of the care settings/locations in each of the 35 participating countries. Treatment decisions were all determined by the local responsible clinicians. PARTICIPANTS: The patients (18 years and over) with newly diagnosed AF had at least 1 investigator-determined stroke risk factor and patients were not required to meet specific thresholds of risk score for anticoagulant treatment. MAIN OUTCOMES AND MEASURES: Observed 1-year event rates and risk-standardised rates were derived. RESULTS: Rates of death, non-haemorrhagic stroke/systemic embolism and major bleeding varied more than three-to-four fold across countries even after adjustment for baseline factors and antithrombotic treatments. Rates of anticoagulation and antithrombotic treatment varied widely. Patients from countries with the highest rates of cardiovascular mortality and stroke were among the least likely to receive oral anticoagulants. Beyond anticoagulant treatment, variations in the treatment of comorbidities and lifestyle factors may have contributed to the variations in outcomes. Countries with the lowest healthcare Access and Quality indices (India, Ukraine, Argentina, Brazil) had the highest risk-standardised mortality. CONCLUSION: The variability in outcomes across countries for patients with newly diagnosed AF is not accounted for by baseline characteristics and antithrombotic treatments. Residual mortality rates were correlated with Healthcare Access and Quality indices. The findings suggest the management of patients with AF needs to not only address guideline indicated and sustained anticoagulation, but also the treatment of comorbidities and lifestyle factors. TRIAL REGISTRATION NUMBER: NCT01090362

Combination therapy with oral treprostinil for pulmonary arterial hypertension. A double-blind placebo-controlled clinical trial

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy. Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response. Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56–0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro–brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil–assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12–60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting. Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening. Clinical trial registered with www.clinicaltrials.gov (NCT01560624)

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8–13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05–6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50–75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. Funding Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry

BACKGROUND: The Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012–2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3–2.3) versus 2.3 (IQR 1.8–2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32–9.35) vs 4.34 (4.16–4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF

Proprotein convertase subtilisin kexin 9 inhibitors: Current status and future directions

The discovery of proprotein convertase subtilisin kexin 9 (PCSK9) has considerably changed the therapeutic options in the field of lipid management. PCSK9 reduces low-density lipoprotein receptor (LDLR) recycling, leading to a decrease of LDL cholesterol (LDL-C) receptors on the surface of hepatocytes and a subsequent increase of circulating LDL-C levels. Among the various approaches to PCSK9 inhibition, human data are only available for inhibition of PCSK9 binding to LDLR by monoclonal antibodies. In Phase II studies, the two most advanced monoclonal antibodies in development (alirocumab and evolocumab) decreased atherogenic lipoproteins very effectively and were well tolerated. Sixty percent to seventy percent of reduction in LDL-C was observed, especially when subcutaneous injections were performed regularly every 2 weeks. No significant side effects were observed, with the exception of injection-site reactions. Three large Phase III programs with the new anti-PCSK9 antibodies are currently underway in patients with acute coronary syndrome and LDL-C inadequately controlled by standard treatments. In this review, we will discuss the effect of PCSK9 inhibition, its current status, and future perspectives

The role of optimal medical therapy in patients with stable coronary artery disease

Coronary artery disease (CAD) is a leading cause of mortality and morbidity around the globe. The fact that prevalence and mortality due to CAD are declining in developed countries cannot be held true in developing countries. Almost fourfold increase in CAD prevalence has been reported in India in the past 40 years. This incidence is likely to increase further in the coming years. The heterogeneity of the disease presentation is an important challenge in the management of these patients, and the current therapies are not universally effective in controlling these symptoms. Even with the advancements in medical therapies over the last two decades, it is unclear whether percutaneous coronary intervention (PCI) provides a prognostic advantage over optimal medical therapy (OMT) in the management of stable angina patients. The current review primarily focuses on the use of OMT for stable CAD patients and also discusses the role of coronary revascularization, especially PCI, in the management of these patients. This is based on evidence-based recommendations and guidelines

Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)

Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. Findings Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53·6%] women) from 56 countries were included in the study. Of these, 31 798 (75·4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84·2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46·2 years (IQR 34·3–58·0); median age at diagnosis of familial hypercholesterolaemia was 44·4 years (32·5–56·5), with 40·2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17·4% (2·1% for stroke and 5·2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81·1%) were receiving statins and 3691 (21·2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5·43 mmol/L (IQR 4·32–6·72) among patients not taking lipid-lowering medications and 4·23 mmol/L (3·20–5·66) among those taking them. Among patients taking lipid-lowering medications, 2·7% had LDL cholesterol lower than 1·8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin–kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1·8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p<0·001). Interpretation Familial hypercholesterolaemia is diagnosed late. Guideline-recommended LDL cholesterol concentrations are infrequently achieved with single-drug therapy. Cardiovascular risk factors and presence of coronary disease were lower among non-index cases, who were diagnosed earlier. Earlier detection and greater use of combination therapies are required to reduce the global burden of familial hypercholesterolaemia. Funding Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron