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Chronic kidney disease in type 1 diabetes: translation of novel type 2 diabetes therapeutics to individuals with type 1 diabetes.
Sridhar, VS, Limonte, CP, Groop, PH, Heerspink, HJL, Pratley, RE, Rossing, P, Skyler, JS, Cherney, DZI
Diabetologia. 2024;(1):3-18
Abstract
Current management of chronic kidney disease (CKD) in type 1 diabetes centres on glycaemic control, renin-angiotensin system inhibition and optimisation of risk factors including blood pressure, lipids and body weight. While these therapeutic approaches have significantly improved outcomes among people with type 1 diabetes and CKD, this population remains at substantial elevated risk for adverse kidney and cardiovascular events, with limited improvements over the last few decades. The significant burden of CKD and CVD in type 1 diabetes populations highlights the need to identify novel therapies with the potential for heart and kidney protection. Over the last decade, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide 1 receptor agonists and non-steroidal mineralocorticoid receptor antagonists have emerged as potent kidney-protective and/or cardioprotective agents in type 2 diabetes. The consistent, substantial kidney and cardiovascular benefits of these agents has led to their incorporation into professional guidelines as foundational care for type 2 diabetes. Furthermore, introduction of these agents into clinical practice has been accompanied by a shift in the focus of diabetes care from a 'glucose-centric' to a 'cardiorenal risk-centric' approach. In this review, we evaluate the potential translation of novel type 2 diabetes therapeutics to individuals with type 1 diabetes with the lens of preventing the development and progression of CKD.
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12. Retinopathy, Neuropathy, and Foot Care: Standards of Care in Diabetes-2023.
ElSayed, NA, Aleppo, G, Aroda, VR, Bannuru, RR, Brown, FM, Bruemmer, D, Collins, BS, Gibbons, CH, Giurini, JM, Hilliard, ME, et al
Diabetes care. 2023;(Suppl 1):S203-S215
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Abstract
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
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Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.
Tobias, DK, Merino, J, Ahmad, A, Aiken, C, Benham, JL, Bodhini, D, Clark, AL, Colclough, K, Corcoy, R, Cromer, SJ, et al
Nature medicine. 2023;(10):2438-2457
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Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
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Newer Glucose-Lowering Therapies in Older Adults with Type 2 Diabetes.
Bilal, A, Pratley, RE
Endocrinology and metabolism clinics of North America. 2023;(2):355-375
Abstract
Diabetes is prevalent in older adults and older adults with diabetes are more likely to have multiple comorbidities. It is, therefore, important to personalize diabetes management in this group. Newer glucose-lowering drugs, including dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists can be safely used in older patients and are preferred choices in many cases due to their safety, efficacy, and low risk of hypoglycemia.
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An Overview of Diet and Physical Activity for Healthy Weight in Adolescents and Young Adults with Type 1 Diabetes: Lessons Learned from the ACT1ON Consortium.
Bishop, FK, Addala, A, Corbin, KD, Muntis, FR, Pratley, RE, Riddell, MC, Mayer-Davis, EJ, Maahs, DM, Zaharieva, DP
Nutrients. 2023;(11)
Abstract
The prevalence of overweight and obesity in young people with type 1 diabetes (T1D) now parallels that of the general population. Excess adiposity increases the risk of cardiovascular disease, which is already elevated up to 10-fold in T1D, underscoring a compelling need to address weight management as part of routine T1D care. Sustainable weight management requires both diet and physical activity (PA). Diet and PA approaches must be optimized towards the underlying metabolic and behavioral challenges unique to T1D to support glycemic control throughout the day. Diet strategies for people with T1D need to take into consideration glycemic management, metabolic status, clinical goals, personal preferences, and sociocultural considerations. A major barrier to weight management in this high-risk population is the challenge of integrating regular PA with day-to-day management of T1D. Specifically, exercise poses a substantial challenge due to the increased risk of hypoglycemia and/or hyperglycemia. Indeed, about two-thirds of individuals with T1D do not engage in the recommended amount of PA. Hypoglycemia presents a serious health risk, yet prevention and treatment often necessitates the consumption of additional calories, which may prohibit weight loss over time. Exercising safely is a concern and challenge with weight management and maintaining cardiometabolic health for individuals living with T1D and many healthcare professionals. Thus, a tremendous opportunity exists to improve exercise participation and cardiometabolic outcomes in this population. This article will review dietary strategies, the role of combined PA and diet for weight management, current resources for PA and glucose management, barriers to PA adherence in adults with T1D, as well as findings and lessons learned from the Advancing Care for Type 1 Diabetes and Obesity Network (ACT1ON).
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A new era for oral peptides: SNAC and the development of oral semaglutide for the treatment of type 2 diabetes.
Aroda, VR, Blonde, L, Pratley, RE
Reviews in endocrine & metabolic disorders. 2022;(5):979-994
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Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) were first introduced for the treatment of type 2 diabetes (T2D) in 2005. Despite the high efficacy and other benefits of GLP-1RAs, their uptake was initially limited by the fact that they could only be administered by injection. Semaglutide is a human GLP-1 analog that has been shown to significantly improve glycemic control and reduce body weight, in addition to improving cardiovascular outcomes, in patients with T2D. First approved as a once-weekly subcutaneous injection, semaglutide was considered an ideal peptide candidate for oral delivery with a permeation enhancer on account of its low molecular weight, long half-life, and high potency. An oral formulation of semaglutide was therefore developed by co-formulating semaglutide with sodium N-(8-[2-hydroxybenzoyl]amino)caprylate, a well-characterized transcellular permeation enhancer, to produce the first orally administered GLP-1RA. Pharmacokinetic analysis showed that stable steady-state concentrations could be achieved with once-daily dosing owing to the long half-life of oral semaglutide. Upper gastrointestinal disease and renal and hepatic impairment did not affect the pharmacokinetic profile. In the phase III PIONEER clinical trial program, oral semaglutide was shown to reduce glycated hemoglobin and body weight compared with placebo and active comparators in patients with T2D, with no new safety signals reported. Cardiovascular efficacy and safety are currently being assessed in a dedicated outcomes trial. The development of an oral GLP-1RA represents a significant milestone in the management of T2D, providing an additional efficacious treatment option for patients.
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Cardiovascular Outcome Trials with Glucose-Lowering Drugs.
Thethi, TK, Bilal, A, Pratley, RE
Current cardiology reports. 2021;(7):75
Abstract
PURPOSE OF REVIEW This review summarizes recent cardiovascular outcome trials (CVOTs) with glucose-lowering drugs. RECENT FINDINGS The majority of recent CVOTs with glucose-lowering drugs have tested dipeptidyl peptidase-4 inhibitors (DPP4-i), glucagon-like peptide-1 receptors agonists (GLP1-RA), and sodium-glucose cotransporter 2 inhibitors (SGLT2i), but studies have also been performed with other agents including thiazolidinediones and insulin. All CVOTs with DPP4-I, GLP1-RA, and SGLT2-i have demonstrated the cardiovascular (CV) safety of these agents compared to usual care. However, certain GLP1-RAs (liraglutide, subcutaneous semaglutide, albiglutide, dulaglutide) and SGLT2-i (empagliflozin, canagliflozin) have demonstrated a CV benefit, showing significant reductions in composite cardiovascular outcomes. Furthermore, all SGLT2-i also significantly decreased the risk for hospitalization for heart failure. Results from these studies have altered clinical guidelines worldwide and have resulted in new indications for some glucose-lowering drugs. In patients with T2D and high risk for CVD, GLP-1RA or SGLT2-i with proven cardiovascular benefit are recommended, irrespective of glycemic control.
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GLP-1 Analogs and DPP-4 Inhibitors in Type 2 Diabetes Therapy: Review of Head-to-Head Clinical Trials.
Gilbert, MP, Pratley, RE
Frontiers in endocrinology. 2020;:178
Abstract
The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells in response to the presence of nutrients in the small intestines. These homones facilitate glucose regulation by stimulating insulin secretion in a glucose dependent manner while suppressing glucagon secretion. In patients with type 2 diabetes (T2DM), an impaired insulin response to GLP-1 and GIP contributes to hyperglycemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors block the breakdown of GLP-1 and GIP to increase levels of the active hormones. In clinical trials, DPP-4 inhibitors have a modest impact on glycemic control. They are generally well-tolerated, weight neutral and do not increase the risk of hypoglycemia. GLP-1 receptor agonists (GLP-1 RA) are peptide derivatives of either exendin-4 or human GLP-1 designed to resist the activity of DPP-4 and therefore, have a prolonged half-life. In clinical trials, they have demonstrated superior efficacy to many oral antihyperglycemic drugs, improved weight loss and a low risk of hypoglycemia. However, GI adverse events, particularly nausea, vomiting, and diarrhea are seen. Both DPP-4 inhibitors and GLP-1 RAs have demonstrated safety in robust cardiovascular outcome trials, while several GLP-1 RAs have been shown to significantly reduce the risk of major adverse cardiovascular events in persons with T2DM with pre-existing cardiovascular disease (CVD). Several clinical trials have directly compared the efficacy and safety of DPP-4 inhibitors and GLP-1 RAs. These studies have generally demonstrated that the GLP-1 RA provided superior glycemic control and weight loss relative to the DPP-4 inhibitor. Both treatments were associated with a low and comparable incidence of hypoglycemia, but treatment with GLP-1 RAs were invariably associated with a higher incidence of GI adverse events. A few studies have evaluated switching patients from DPP-4 inhibitors to a GLP-1RA and, as expected, improved glycemic control and weight loss are seen following the switch. According to current clinical guidelines, GLP-1RA and DPP-4 inhibitors are both indicated for the glycemic management of patients with T2DM across the spectrum of disease. GLP-1RA may be preferred over DPP- 4 inhibitors for many patients because of the greater reductions in hemoglobin A1c and weight loss observed in the clinical trials. Among patients with preexisting CVD, GLP-1 receptor agonists with a proven cardiovascular benefit are indicated as add-on to metformin therapy.
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Obesity in Type 1 Diabetes: Pathophysiology, Clinical Impact, and Mechanisms.
Corbin, KD, Driscoll, KA, Pratley, RE, Smith, SR, Maahs, DM, Mayer-Davis, EJ, ,
Endocrine reviews. 2018;(5):629-663
Abstract
There has been an alarming increase in the prevalence of obesity in people with type 1 diabetes in recent years. Although obesity has long been recognized as a major risk factor for the development of type 2 diabetes and a catalyst for complications, much less is known about the role of obesity in the initiation and pathogenesis of type 1 diabetes. Emerging evidence suggests that obesity contributes to insulin resistance, dyslipidemia, and cardiometabolic complications in type 1 diabetes. Unique therapeutic strategies may be required to address these comorbidities within the context of intensive insulin therapy, which promotes weight gain. There is an urgent need for clinical guidelines for the prevention and management of obesity in type 1 diabetes. The development of these recommendations will require a transdisciplinary research strategy addressing metabolism, molecular mechanisms, lifestyle, neuropsychology, and novel therapeutics. In this review, the prevalence, clinical impact, energy balance physiology, and potential mechanisms of obesity in type 1 diabetes are described, with a special focus on the substantial gaps in knowledge in this field. Our goal is to provide a framework for the evidence base needed to develop type 1 diabetes-specific weight management recommendations that account for the competing outcomes of glycemic control and weight management.
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Treatment of type 2 diabetes mellitus in the older adult: a review.
Pratley, RE, Heller, SR, Miller, MA
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2014;(7):722-36
Abstract
OBJECTIVE This review summarizes the particular challenges of diabetes in older individuals and the evidence base guiding the selection of treatment targets and strategies in this population. METHODS An in-depth literature search was conducted to identify the evidence base from randomized, controlled, and population-based epidemiological studies, as well as guidelines derived from expert opinion. RESULTS Older patients are a highly heterogeneous population with respect to the pathogenesis and course of diabetes and, as a group, manifest significant comorbidities that impact treatment goals and strategies. There is a lack of consensus regarding "optimal" glucose targets in older patients with diabetes. Hypoglycemia is more common in the older patient, contributes to increased morbidity and reduced quality of life, and limits treatment in many cases. Duration of diabetes, comorbidities, life expectancy, and functional status are other important factors to consider when identifying appropriate glycemic goals and choosing an antihyperglycemic agent for older patients with type 2 diabetes mellitus (T2DM). CONCLUSION Current, limited treatment recommendations in older patients with T2DM are based on expert opinion due to the general lack of evidence from randomized controlled trials. This underscores the importance of individualizing pharmacologic therapy in these patients with a focus on the risk-to-benefit ratio. Additional trials in older patients are needed to assess drug safety, efficacy, and dosing.