Immunogenicity, Efficacy, and Safety of Biosimilar Insulin Glargine (Gan & Lee Glargine) Compared With Originator Insulin Glargine (Lantus) in Patients With Type 1 Diabetes After 26 Weeks Treatment.

OBJECTIVE: To compare the immunogenicity, safety, and efficacy of Gan & Lee insulin glargine (GL Glargine) with that of the originator insulin glargine (Lantus) in patients with type 1 diabetes mellitus (T1DM). METHODS: This was a phase 3, multicenter, randomized, open-label, equivalence study. Five hundred seventy-six subjects with T1DM were randomized 1:1 to receive either GL Glargine or Lantus treatment for 26 weeks. The primary end point was the percentage of subjects in each treatment group who developed treatment-induced anti-insulin antibody after baseline and up to visit week 26, which was evaluated using a country-adjusted logistic regression model. The study also compared the changes in glycated hemoglobin, and adverse events including hypoglycemia. RESULTS: The percentage of subjects positive for treatment-induced anti-insulin antibody by Week 26 was 25.8% in the GL Glargine treatment group and 25.3% in the Lantus treatment group, with a 90% confidence interval (-5.4, 6.5) of the difference in proportions that fell completely between the similarity margins (-11.3, 11.3). The least squares mean difference between treatment groups for changes in glycated hemoglobin was -0.08 (90% confidence interval: -0.23, 0.06), and the other immunogenicity and safety profiles were comparable. CONCLUSION: GL Glargine demonstrated similar immunogenicity, efficacy, and safety compared to Lantus over 26 weeks in patients with T1DM.

DCRM 2.0: Multispecialty practice recommendations for the management of diabetes, cardiorenal, and metabolic diseases.

The spectrum of cardiorenal and metabolic diseases comprises many disorders, including obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), dyslipidemias, hypertension, and associated comorbidities such as pulmonary diseases and metabolism dysfunction-associated steatotic liver disease and metabolism dysfunction-associated steatohepatitis (MASLD and MASH, respectively, formerly known as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis [NAFLD and NASH]). Because cardiorenal and metabolic diseases share pathophysiologic pathways, two or more are often present in the same individual. Findings from recent outcome trials have demonstrated benefits of various treatments across a range of conditions, suggesting a need for practice recommendations that will guide clinicians to better manage complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. To meet this need, we formed an international volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM 2.0 Practice Recommendations, an updated and expanded revision of a previously published multispecialty consensus on the comprehensive management of persons living with DCRM. The recommendations are presented as 22 separate graphics covering the essentials of management to improve general health, control cardiorenal risk factors, and manage cardiorenal and metabolic comorbidities, leading to improved patient outcomes.

Cardio-renal-metabolic disease in primary care setting.

In the primary care setting providers have more tools available than ever before to impact positively obesity, diabetes, and their complications, such as renal and cardiac diseases. It is important to recognise what is available for treatment taking into account diabetes heterogeneity. For those who develop type 2 diabetes (T2DM), effective treatments are available that for the first time have shown a benefit in reducing mortality and macrovascular complications, in addition to the well-established benefits of glucose control in reducing microvascular complications. Some of the newer medications for treating hyperglycaemia have also a positive impact in reducing heart failure (HF). Technological advances have also contributed to improving the quality of care in patients with diabetes. The use of technology, such as continuous glucose monitoring systems (CGM), has improved significantly glucose and glycated haemoglobin A1c (HbA1c) values, while limiting the frequency of hypoglycaemia. Other technological support derives from the use of predictive algorithms that need to be refined to help predict those subjects who are at great risk of developing the disease and/or its complications, or who may require care by other specialists. In this review we also provide recommendations for the optimal use of the new medications; sodium-glucose co-transporter-2 inhibitors (SGLT2i) and Glucagon-like peptide-receptor agonists 1 (GLP1RA) in the primary care setting considering the relevance of these drugs for the management of T2DM also in its early stage.

Cardiovascular Outcomes in Patients With Diabetes and Kidney Disease: JACC Review Topic of the Week.

Chronic kidney disease (CKD) and cardiovascular disease (CVD) have a significant inter-relationship in patients with diabetes. Controlling blood pressure, dyslipidemia, and glucose levels is a common treatment approach to managing CVD risk in patients with CKD and diabetes; despite strict control, however, a high residual risk remains. This review focuses on patients who require pharmacotherapy, in whom new and existing cardiorenal therapies (renin-angiotensin-aldosterone system inhibitors, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and nonsteroidal mineralocorticoid receptor antagonists) with differing mechanisms of action and safety profiles can reduce cardiovascular risk beyond the outcomes achieved with blood pressure, dyslipidemia, or glycemic control alone. Several treatment guidelines have been updated recently to reflect new evidence. Studies of these cardiorenal agents used in combination are ongoing, and results are awaited with interest, with the hope that potential synergistic effects may lead to further improvements in cardiovascular outcomes.

Early intervention and intensive management of patients with diabetes, cardiorenal, and metabolic diseases.

Increasing rates of obesity and diabetes have driven corresponding increases in related cardiorenal and metabolic diseases. In many patients, these conditions occur together, further increasing morbidity and mortality risks to the individual. Yet all too often, the risk factors for these disorders are not addressed promptly in clinical practice, leading to irreversible pathologic progression. To address this gap, we convened a Task Force of experts in cardiology, nephrology, endocrinology, and primary care to develop recommendations for early identification and intervention in obesity, diabetes, and other cardiorenal and metabolic diseases. The recommendations include screening and diagnosis, early interventions with lifestyle, and when and how to implement medical therapies. These recommendations are organized into primary and secondary prevention along the continuum from obesity through the metabolic syndrome, prediabetes, diabetes, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), atherosclerotic cardiovascular disease (ASCVD) and atrial fibrillation, chronic kidney disease (CKD), and heart failure (HF). The goal of early and intensive intervention is primary prevention of comorbidities or secondary prevention to decrease further worsening of disease and reduce morbidity and mortality. These efforts will reduce clinical inertia and may improve patients' well-being and adherence.

Icosapent ethyl for reduction of persistent cardiovascular risk: a critical review of major medical society guidelines and statements.

INTRODUCTION: REDUCE-IT demonstrated that adding 4 g/day of icosapent ethyl (IPE; purified ethyl ester of eicosapentaenoic acid [EPA]) to statins substantially reduced cardiovascular disease (CVD) events, with few adverse effects. These data prompted numerous leading medical societies across five continents, including the American College of Cardiology, the European Society of Cardiology, and the Japanese Circulation Society, to update their guidelines or scientific/consensus statements to recommend use of IPE for primary and secondary prevention of CVD events. AREAS COVERED: This review discusses the incorporation of IPE into international guidelines and scientific statements, noting areas of consensus and distinction. As background, this review also describes the CVD benefits and risks of IPE as a statin adjunct, and outlines current data regarding the potential mechanisms of CVD risk reduction by EPA (as IPE) beyond triglyceride reduction. EXPERT OPINION/COMMENTARY: IPE is unique among 'triglyceride-lowering' treatments in having strong CVD outcomes data and, therefore, a broad international consensus among professional medical society guidelines and statements endorsing its use for CVD risk reduction in patients generally meeting REDUCE-IT inclusion criteria. IPE should be considered for CVD prevention as a statin adjunct in all such patients.Plain Language SummaryCardiovascular disease (CVD) remains the leading cause of death worldwide. Statin monotherapy is conventionally used first-line to reduce the risk of CV events, such as heart attacks and strokes, in patients with elevated cholesterol. However, considerable risk remains despite appropriate control of cholesterol levels with a statin. Consequently, research has focused on treatment of additional therapeutic targets to reduce this remaining CV risk. One such target is elevated blood triglyceride levels. Unfortunately, most drugs that lower triglyceride levels, such as niacin, fibrates, and mixed omega-3 fatty acids, have not reduced the risk of cardiovascular events in clinical trials when added to statin therapy. However, the omega-3 fatty acid eicosapentaenoic acid ('EPA') administered in highly purified form as icosapent ethyl (IPE) has emerged as the first omega-3 fatty acid, and the first triglyceride-lowering agent to prevent CV events when added to statins. This was demonstrated most notably in the pivotal REDUCE-IT trial, in which IPE reduced the risk of major CV events by 25% in high-risk patients with mildly to moderately elevated triglyceride levels despite statin-controlled cholesterol levels. The mechanisms responsible for this reduction in CV events appear to go far beyond lowering triglyceride levels alone. In light of the positive results from the REDUCE-IT trial, IPE was approved for CV disease risk reduction globally, including in the United States, Canada, European Union, and the United Kingdom, and its use is being increasingly endorsed in United States and international statements and guidelines for managing CV risk. Despite minor differences among guidelines, there is strong consensus that IPE should be considered for use in CVD prevention in all patients who meet the proposed criteria.

Impact of dronedarone on patients with atrial fibrillation and diabetes: A sub-analysis of the ATHENA and EURIDIS/ADONIS studies.

AIM: This post hoc analysis evaluated efficacy and safety of dronedarone in atrial fibrillation (AF) and atrial flutter (AFL) patients with/without diabetes. METHODS: Patients were categorized according to baseline diabetes status. Time-to-event analyses were performed using Kaplan-Meier method. Hazard-ratios were assessed using Cox models. RESULTS: 945/4628 (dronedarone = 482; placebo = 463) patients in ATHENA and 215/1237 (dronedarone = 148; placebo = 67) patients in EURIDIS/ADONIS studies had diabetes. In ATHENA, there were higher rates of CV hospitalization/death in patients with diabetes (39.5%) than without diabetes (34.7%). Incidence of first CV hospitalization/death was lower in patients with diabetes treated with dronedarone (35.1%) than placebo (44.1%), and time to this event was longer in those treated with dronedarone than placebo (log-rank p = 0.005). Median AF/AFL recurrence time was longer in patients treated with dronedarone than placebo in patients with diabetes (ATHENA: 722 vs 527 days, log-rank p = 0.004; EURIDIS/ADONIS: 100 vs 23 days, log-rank p = 0.15) or without diabetes (ATHENA: 741 vs 492 days, log-rank p < 0.0001; EURIDIS/ADONIS: 120 vs 59 days, log-rank p = 0.0002). Occurrence of any treatment-related adverse events with dronedarone was similar for patients with/without diabetes and was comparable to placebo. CONCLUSIONS: Dronedarone reduced incidence of CV hospitalization/death, AF/AFL recurrence and increased time to these events in AF/AFL patients with/without diabetes. TRIAL REGISTRATION: Not applicable, as it was a post hoc analysis. This article is based on previously conducted studies (ATHENA: NCT00174785, EURIDIS: NCT00259428, and ADONIS: NCT00259376).

DCRM Multispecialty Practice Recommendations for the management of diabetes, cardiorenal, and metabolic diseases.

Type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF)-along with their associated risk factors-have overlapping etiologies, and two or more of these conditions frequently occur in the same patient. Many recent cardiovascular outcome trials (CVOTs) have demonstrated the benefits of agents originally developed to control T2D, ASCVD, or CKD risk factors, and these agents have transcended their primary indications to confer benefits across a range of conditions. This evolution in CVOT evidence calls for practice recommendations that are not constrained by a single discipline to help clinicians manage patients with complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. The ultimate goal for these recommendations is to be comprehensive yet succinct and easy to follow by the nonexpert-whether a specialist or a primary care clinician. To meet this need, we formed a volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM Practice Recommendations, a multispecialty consensus on the comprehensive management of the patient with complicated metabolic disease. The task force recommendations are based on strong evidence and incorporate practical guidance that is clinically relevant and simple to implement, with the aim of improving outcomes in patients with DCRM. The recommendations are presented as 18 separate graphics covering lifestyle therapy, patient self-management education, technology for DCRM management, prediabetes, cognitive dysfunction, vaccinations, clinical tests, lipids, hypertension, anticoagulation and antiplatelet therapy, antihyperglycemic therapy, hypoglycemia, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), ASCVD, HF, CKD, and comorbid HF and CKD, as well as a graphical summary of medications used for DCRM.

American Association of Clinical Endocrinology Clinical Practice Guideline: The Use of Advanced Technology in the Management of Persons With Diabetes Mellitus.

OBJECTIVE: To provide evidence-based recommendations regarding the use of advanced technology in the management of persons with diabetes mellitus to clinicians, diabetes-care teams, health care professionals, and other stakeholders. METHODS: The American Association of Clinical Endocrinology (AACE) conducted literature searches for relevant articles published from 2012 to 2021. A task force of medical experts developed evidence-based guideline recommendations based on a review of clinical evidence, expertise, and informal consensus, according to established AACE protocol for guideline development. MAIN OUTCOME MEASURES: Primary outcomes of interest included hemoglobin A1C, rates and severity of hypoglycemia, time in range, time above range, and time below range. RESULTS: This guideline includes 37 evidence-based clinical practice recommendations for advanced diabetes technology and contains 357 citations that inform the evidence base. RECOMMENDATIONS: Evidence-based recommendations were developed regarding the efficacy and safety of devices for the management of persons with diabetes mellitus, metrics used to aide with the assessment of advanced diabetes technology, and standards for the implementation of this technology. CONCLUSIONS: Advanced diabetes technology can assist persons with diabetes to safely and effectively achieve glycemic targets, improve quality of life, add greater convenience, potentially reduce burden of care, and offer a personalized approach to self-management. Furthermore, diabetes technology can improve the efficiency and effectiveness of clinical decision-making. Successful integration of these technologies into care requires knowledge about the functionality of devices in this rapidly changing field. This information will allow health care professionals to provide necessary education and training to persons accessing these treatments and have the required expertise to interpret data and make appropriate treatment adjustments.

Cardiovascular Outcomes and Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: Current Data and Future Prospects.

Cardiovascular (CV) disease remains the leading cause of morbidity and mortality worldwide and poses an ongoing challenge with the aging population. Elevated low-density lipoprotein cholesterol (LDL-C) is an established risk factor for atherosclerotic cardiovascular disease (ASCVD), and the expert consensus is the use of statin therapy (if tolerated) as first line for LDL-C reduction. However, patients with ASCVD may experience recurrent ischemic events despite receiving maximally tolerated statin therapy, including those whose on-treatment LDL-C remains ≥70 mg/dL, patients with familial hypercholesterolemia, high-risk subgroups with comorbidities such as diabetes mellitus, and those who have an intolerance to statin therapy. Optimal therapeutic strategies for this unmet need should deploy aggressive lipid lowering to minimize the contribution of dyslipidemia to their CV risk, particularly for very high-risk populations with additional risk factors beyond hypercholesterolemia and established ASCVD. To understand the current clinical climate and guidelines regarding ASCVD, we primarily searched PubMed for articles published in English regarding lipid-lowering therapies and CV risk reduction, including emerging therapies, and CV outcomes trials with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. This review discusses the findings of recent clinical trial evidence for CV risk reduction with cholesterol-lowering therapies, with a focus on CV outcomes trials with PCSK9 inhibitors, and considers the impact of the study results for secondary prevention and future strategies in patients with hypercholesterolemia and CV risk despite maximally tolerated statin therapy.

Glucagon-Like Peptide 1 Receptor Agonists and Heart Failure: The Need for Further Evidence Generation and Practice Guidelines Optimization.

With worsening epidemiological trends for both the incidence and prevalence of type 2 diabetes mellitus (T2DM) and heart failure (HF) worldwide, it is critical to implement optimal prevention and treatment strategies for patients with these comorbidities, either alone or concomitantly. Several guidelines and consensus statements have recommended glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter type 2 inhibitors as add-ons to lifestyle interventions with or without metformin in those at high atherosclerotic cardiovascular disease risk. However, these recommendations are either silent about HF or fail to differentiate between the prevention of HF in those at risk versus the treatment of individuals with manifest HF. Furthermore, these documents do not differentiate among those with different HF phenotypes. This distinction, even though important, may not be critical for sodium-glucose cotransporter type 2 inhibitors in view of the consistent data for benefit for both atherosclerotic cardiovascular disease- and HF-related outcomes that have emerged from the regulatory-mandated cardiovascular outcome trials for all sodium-glucose cotransporter type 2 inhibitors and the recent DAPA-HF trial (Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction)demonstrating the benefit of dapagliflozin on HF-related outcomes in patients with HF with reduced ejection fraction with or without T2DM. However, the distinction may be crucial for glucagon-like peptide-1 receptor agonists and other antihyperglycemic agents. Indeed, in several of the new statements, glucagon-like peptide-1 receptor agonists are suggested treatment not only for patients with T2DM and atherosclerotic cardiovascular disease, but also in those with manifest HF, despite a lack of evidence for the latter recommendation. Although glucagon-like peptide-1 receptor agonists may be appropriate to use in patients at risk for HF, mechanistic insights and observations from randomized trials suggest no clear benefit on HF-related outcomes and even uncertainty regarding the safety in those with HF with reduced ejection fraction. Conversely, theoretical rationales suggest that these agents may benefit patients with HF with preserved ejection fraction. Considering that millions of patients with T2DM have HF, these concerns have public health implications that necessitate the thoughtful use of these therapies. Achieving this aim will require dedicated trials with these drugs in both patients who have HF with reduced ejection fraction and HF with preserved ejection fraction with T2DM to assess their efficacy, safety, and risk-benefit profile.

Use of sodium-glucose co-transporter-2 inhibitors in patients with and without type 2 diabetes: implications for incident and prevalent heart failure.

Type 2 diabetes (T2D) is associated with an increased risk of heart failure (HF), with recent reports indicating that HF with preserved ejection fraction (HFpEF) may be more common than HF with reduced ejection fraction (HFrEF) in patients with T2D. T2D and HF result in worse outcomes than either disease alone. Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) have significantly improved HF outcomes in patients with T2D and may represent a new therapeutic alternative for patients with T2D at risk for or with HF. Current guidelines recommend prevention of HF through risk factor management. Once developed, treatment of HFrEF should include neurohormonal and haemodynamic modulations; however, there are no specific treatments available for HFpEF. SGLT-2is are the first class of glucose-lowering therapy to prevent HF in clinical trials and real-world studies in patients with T2D (with or without established cardiovascular disease and with or without baseline HF). Mechanistic studies suggest that SGLT-2is have beneficial effects on both systolic and diastolic function and additional systemic effects that could benefit HF outcomes. In patients with HFrEF, SGLT-2i treatment as add-on to standard HF therapy has had beneficial effects on HF outcomes, irrespective of T2D status. These results and those of ongoing outcomes trials with SGLT-2is may help establish this drug class as a treatment for HF in patients with HFrEF and HFpEF, as well as HF in patients without T2D.

Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Management of Dyslipidemia and Prevention of Cardiovascular Disease Algorithm - 2020 Executive Summary.

The treatment of lipid disorders begins with lifestyle therapy to improve nutrition, physical activity, weight, and other factors that affect lipids. Secondary causes of lipid disorders should be addressed, and pharmacologic therapy initiated based on a patient's risk for atherosclerotic cardiovascular disease (ASCVD). Patients at extreme ASCVD risk should be treated with high-intensity statin therapy to achieve a goal low-density lipoprotein cholesterol (LDL-C) of <55 mg/dL, and those at very high ASCVD risk should be treated to achieve LDL-C <70 mg/dL. Treatment for moderate and high ASCVD risk patients may begin with a moderate-intensity statin to achieve an LDL-C <100 mg/dL, while the LDL-C goal is <130 mg/dL for those at low risk. In all cases, treatment should be intensified, including the addition of other LDL-C-lowering agents (i.e., proprotein convertase subtilisin/kexin type 9 inhibitors, ezetimibe, colesevelam, or bempedoic acid) as needed to achieve treatment goals. When targeting triglyceride levels, the desirable goal is <150 mg/dL. Statin therapy should be combined with a fibrate, prescription-grade omega-3 fatty acid, and/or niacin to reduce triglycerides in all patients with triglycerides ≥500 mg/dL, and icosapent ethyl should be added to a statin in any patient with established ASCVD or diabetes with ≥2 ASCVD risk factors and triglycerides between 135 and 499 mg/dL to prevent ASCVD events. Management of additional risk factors such as elevated lipoprotein(a) and statin intolerance is also described.

Correction to: Combining GLP-1 Receptor Agonists and Basal Insulin in Older Adults with Type 2 Diabetes: Focus on Lixisenatide and Insulin Glargine.

There are some corrections in the original article, Page 11, "/LYXUMIA" word has to be removed from the section RATIONALE FOR COMBINATION THERAPY COMPRISING GLP-1 RAs AND BASAL INSULIN.

Combining GLP-1 Receptor Agonists and Basal Insulin in Older Adults with Type 2 Diabetes: Focus on Lixisenatide and Insulin Glargine.

Estimates suggest that there are currently 122.8 million adults 65-99 years of age living with diabetes, of whom 90-95% are diagnosed with type 2 diabetes (T2D). Over the past two decades, a greater understanding of the complex and multifactorial pathogenesis of T2D has resulted in the development and introduction of new-generation classes of glucose-lowering therapies, which are now extensively endorsed by prevailing guidelines and are increasingly being used worldwide. These newer agents may further assist in the effective pharmacological management of T2D through the provision of patient-centered care that acknowledges multimorbidity and is respectful of and responsive to individual patient preferences and barriers. Given these considerations, the therapeutic approach in older patients with T2D is complex, particularly in those who have functional dependence, frailty, dementia, or who are at end-of-life. It is currently too early to draw conclusions on the long-term use of newer glucose-lowering agents in this population, as their efficacy and safety in older adults remains largely unknown. In this review, we will discuss considerations for the use of glucose-lowering treatments in older adults, with particular focus on the use of basal insulin and glucagon-like peptide-1 receptor agonists, and the rationale for the use of combination therapy comprising these agents. Finally, we will review clinical data from studies of the fixed-ratio combination of insulin glargine and lixisenatide in older patients with T2D. FUNDING: Sanofi US, Inc.