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1.
[Application of new glucose lowering drugs: DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors].
Verburg, AFE, van den Donk, M, Wiersma, T
Nederlands tijdschrift voor geneeskunde. 2019
Abstract
A comprehensive review of the literature on DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors has resulted in small changes to the medication roadmap of the type 2 diabetes mellitus standard of the Dutch College of General Practitioners. SGLT-2 inhibitors and GLP-1 receptor agonists may have benefits related to cardiovascular outcomes in patients with high cardiovascular risk, especially in those who have experienced a cardiovascular event. However, ascribing effectiveness related to cardiovascular outcomes on the basis of a single cardiovascular safety trial is premature. Metformin, sulfonylurea derivatives and insulin are still the cornerstone of type 2 diabetes mellitus treatment in primary care.
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2.
The Role of Glucagon-Like Peptide 1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors in Reducing Cardiovascular Events in Patients with Type 2 Diabetes.
Kim, GS, Park, JH, Won, JC
Endocrinology and metabolism (Seoul, Korea). 2019;(2):106-116
Abstract
The prevalence of type 2 diabetes mellitus (T2DM), which is associated with cardiovascular morbidity and mortality, is increasing worldwide. Although there have been advances in diabetes treatments that reduce microvascular complications (nephropathy, neuropathy, retinopathy), many clinical studies have found that conventional oral hypoglycemic agents and glucose control alone failed to reduce cardiovascular disease. Thus, incretin-based therapies including glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT-2Is) represent a new area of research, and may serve as novel therapeutics for treating hyperglycemia and modifying other cardiovascular risk factors. Recently, it has been confirmed that several drugs in these classes, including canagliflozin, empagliflozin, semaglutide, and liraglutide, are safe and possess cardioprotective effects. We review the most recent cardiovascular outcome trials on GLP-1RAs and SGLT-2Is, and discuss their implications for treating patients with T2DM in terms of protective effects against cardiovascular disease.
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3.
Profile of semaglutide in the management of type 2 diabetes: design, development, and place in therapy.
Gomez-Peralta, F, Abreu, C
Drug design, development and therapy. 2019;:731-738
Abstract
Type 2 diabetes mellitus (T2DM) has become one of the leading causes of morbidity and mortality in developed countries. Low efficacy, weight gain, and hypoglycemia are the main pitfalls of previous treatments for T2DM. New therapies have been designed with the aim of improving the results in efficacy and quality of life. Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RA) increase glucose-dependent insulin secretion, decrease gastric emptying, and reduce postprandial glucagon secretion. The last GLP-1 RA approved by the US Food and Drug Administration and European Medicines Agency was semaglutide. This review describes its pharmacology, core clinical data coming from the randomized controlled trials included in the development program, proven cardiovascular benefits, safety issues, and precautions for the use of semaglutide in special populations. Additionally, an overview of the positioning of semaglutide in T2DM therapy and practical issues regarding semaglutide initiation are offered.
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4.
Comparative efficacy, safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes: Insights from the SUSTAIN 1-7 trials.
Aroda, VR, Ahmann, A, Cariou, B, Chow, F, Davies, MJ, Jódar, E, Mehta, R, Woo, V, Lingvay, I
Diabetes & metabolism. 2019;(5):409-418
Abstract
In individuals with type 2 diabetes, glycaemic control and cardiovascular risk factor management reduces the likelihood of late-stage diabetic complications. Guidelines recommend treatment goals targeting HbA1c, body weight, blood pressure, and low-density lipoprotein cholesterol. Development of new treatments for type 2 diabetes requires an understanding of their mechanism and efficacy, as well as their relative effects compared to other treatment choices, plus demonstration of cardiovascular safety. Subcutaneous semaglutide is a glucagon-like peptide-1 receptor agonist currently approved in several countries for once-weekly treatment of type 2 diabetes. Semaglutide works via the incretin pathway, stimulating insulin and inhibiting glucagon secretion from the pancreatic islets, leading to lower blood glucose levels. Semaglutide also decreases energy intake by reducing appetite and food cravings, and lowering relative preference for fatty, energy-dense foods. Semaglutide was evaluated in the SUSTAIN clinical trial programme in over 8000 patients across the spectrum of type 2 diabetes. This review details the efficacy and safety profile of semaglutide in the SUSTAIN 1-5 and 7 trials, and its cardiovascular safety profile in the SUSTAIN 6 trial. Semaglutide consistently demonstrated superior and sustained glycemic control and weight loss vs. all comparators evaluated. In SUSTAIN 6, involving patients at high risk of cardiovascular disease, semaglutide significantly decreased the occurrence of cardiovascular events compared with placebo/standard of care (hazard ratio 0.74, P < 0.001 for non-inferiority). Through a comprehensive phase 3 clinical trial program, we have a detailed understanding of semaglutide's efficacy, safety, cardiovascular effects and comparative role in the treatment of type 2 diabetes.
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5.
Strategies for Appropriate Selection of SGLT2-i vs. GLP1-RA in Persons with Diabetes and Cardiovascular Disease.
Dhindsa, DS, Mehta, A, Sandesara, PB, Thobani, A, Brandt, S, Sperling, LS
Current cardiology reports. 2019;(9):100
Abstract
PURPOSE OF REVIEW This review will serve to highlight the clinical rationale used in the selection of sodium-glucose cotransporter 2 inhibitors (SGLT2-i) or glucagon-like peptide 1 receptor agonists (GLP1-ra). RECENT FINDINGS SGLT2-i and GLP1-ra are the first anti-hyperglycemics to demonstrate significant cardiovascular benefit in multiple cardiovascular outcomes trials (CVOTs), with benefits that are consistent across class of medication. Diabetes is a major risk factor for morbidity and mortality from cardiovascular disease. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) and glucagon-like peptide 1 receptor agonists (GLP1-ra) are the first anti-hyperglycemics to demonstrate significant cardiovascular benefit. Given the unique side effect and benefit profiles, appropriate consideration of these agents with a focus on cardiovascular risk reduction requires an individualized approach.
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6.
Glucose-lowering therapies in patients with type 2 diabetes and cardiovascular diseases.
Prattichizzo, F, La Sala, L, Rydén, L, Marx, N, Ferrini, M, Valensi, P, Ceriello, A
European journal of preventive cardiology. 2019;(2_suppl):73-80
Abstract
Type 2 diabetes mellitus is a major risk factor for developing cardiovascular disease, and many patients with diabetes have prevalent cardiovascular complications. Recent cardiovascular outcome clinical trials suggest that certain new glucose-lowering drugs are accompanied by additional cardioprotective properties. Indeed, selected glucagon-like peptide-1 receptor agonists have a proved cardiovascular benefit in terms of a reduced incidence of ischaemic events, while sodium/glucose co-transporter-2 inhibitors have also shown significant protection, with a striking effect on heart failure and renal endpoints. These findings have been integrated in recent guidelines which now recommend prescribing (when initial metformin monotherapy fails) a glucagon-like peptide-1 receptor agonist or a sodium/glucose co-transporter-2 inhibitor with clinical trial-confirmed benefit in patients with diabetes and atherosclerotic cardiovascular disease, and a sodium/glucose co-transporter-2 inhibitor in such patients with heart failure or chronic kidney disease at initial stages. Furthermore, the new 2019 European Society of Cardiology guidelines in collaboration with the European Association for the Study of Diabetes recommend a glucagon-like peptide-1 receptor agonist or a sodium/glucose co-transporter-2 inhibitor in treatment-naive patients with type 2 diabetes mellitus with pre-existing cardiovascular disease or at high cardiovascular risk. Future research will disentangle the mechanisms underpinning these beneficial effects and will also establish to what extent these results are generalisable to the whole diabetes population. In the meantime, available evidence should prompt a wide diffusion of these two classes of drugs among patients with diabetes and cardiovascular disease. Here, we briefly summarise recent findings emerging from cardiovascular outcome clinical trials, discuss their impact on treatment algorithms and propose new possible approaches to improve our knowledge further regarding the cardiovascular effect of glucose-lowering medications.
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7.
SGLT-2 Inhibitors and GLP-1 Agonists: First-Line Therapy for Diabetes With Established Cardiovascular Disease.
Sajja, AP, Dey, AK, Guha, A, Elnabawi, Y, Joshi, AA, Kalra, A
Journal of cardiovascular pharmacology and therapeutics. 2019;(5):422-427
Abstract
There is a growing body of evidence that diabetes represents a significant and largely modifiable risk factor for cardiovascular disease (CVD). It is known to markedly increase the risk of CVD-with CVD accounting for 2 of every 3 deaths in patients with diabetes. It is suggested that once patients with diabetes develop clinical coronary disease, they have a grim prognosis. In 2008, the Food and Drug Association mandated the evidence of CV safety in any new diabetic therapy, leading to a multitude of large CV outcome trials to assess CV risk from these medications. However, several of these outcome trials with novel antidiabetic therapies have demonstrated not only safety but a clear and definite CV advantage in patients with type 2 diabetes. In this review, we discuss 2 relatively newer classes of diabetic drugs, sodium glucose cotransport 2 inhibitors and glucagon-like peptide 1 agonists, evaluate their efficacy in improving CV outcomes, and discuss the future of CV prevention with these agents.
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8.
Risk of fracture with dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors in real-world use: systematic review and meta-analysis of observational studies.
Hidayat, K, Du, X, Shi, BM
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2019;(10):1923-1940
Abstract
UNLABELLED In the present meta-analysis based on real-world data, the use of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1ra), or sodium-glucose cotransporter-2 inhibitors (SGLT2i) was not associated with the risk of fracture. INTRODUCTION Cumulative evidence from randomized control trials (RCTs) with limited fracture events showed that the use of DPP-4i, GLP-1ra, or SGLT2i may not affect the risk of fracture. However, additional insights from large population-based studies with routinely collected data on fracture events and an adequate amount of fracture events are necessary to draw firm conclusions. To refine and complement the results from RCTs, a systematic review and meta-analysis of observational studies were performed to investigate the association between the use of DPP-4i, GLP-1ra, or SGLT2i and the risk of fracture in real-world settings. METHODS The PubMed and Web of Science databases were searched to identify relevant observational studies. A random-effect model was used to estimate the summary relative risks (RRs). RESULTS The use of DPP-4i (RR 0.83, 95% CI [confidence interval] 0.60, 1.14; n = 11), GLP-1ra (RR 0.65, 95% CI 0.24, 1.74; n = 4), or SGLT2i (RR 1.02, 95% CI 0.91, 1.16; n = 4) was not associated with the risk of fracture. In general, there was a consistent lack of association between the use of DPP-4i or GLP-1ra and the risk of fracture across nearly all subgroups, except for a significantly reduced risk of hip fracture with the use of GLP-1ra (RR 0.21, 95% CI 0.04, 0.98). CONCLUSIONS Cumulative real-world evidence does not support an association between the use of DPP-4i, GLP-1ra, or SGLT2i and the risk of fracture. Our findings, together with the cumulative evidence from RCTs, should reassure policy makers and medical practitioners that the use of these medications is unlikely to increase the risk of fracture among type 2 diabetes mellitus patients in general. Further studies need to investigate the long-term impact of these drugs on the fracture risk, particularly in high-risk populations.
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9.
A Review of the Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Lean Body Mass in Humans.
Sargeant, JA, Henson, J, King, JA, Yates, T, Khunti, K, Davies, MJ
Endocrinology and metabolism (Seoul, Korea). 2019;(3):247-262
Abstract
Weight loss is an important goal in the management of several chronic conditions, including type 2 diabetes mellitus, and pharmacological therapies that aid weight loss are appealing. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) are novel glucose-lowering therapies that have been shown to induce clinically significant reductions in body weight. However, this weight loss may not be attributed solely to fat mass (FM). Given the importance of skeletal muscle and lean body mass (LBM) on cardio-metabolic health and physical function, we reviewed the available literature reporting the effects of GLP-1RAs and SGLT2is on body composition. Results demonstrate that, in most circumstances, the weight loss associated with both therapies predominantly comprises a reduction in FM, although significant heterogeneity exists between studies. In over half of the studies identified, the proportion of LBM reduction ranged between 20% and 50% of total weight lost, which is consistent with diet-induced weight loss and bariatric surgery. No clear differences existed between GLP-1RAs and SGLT2is. Consequently, the loss of LBM and skeletal muscle associated with weight loss induced by GLP-1RAs and SGLT2is warrants attention. Strategies to preserve skeletal muscle and improve physical function, for example through structured exercise, are of great importance.
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10.
Glucose-lowering drugs and heart failure: implications of recent cardiovascular outcome trials in type 2 diabetes.
Cattadori, G, Pantanetti, P, Ambrosio, G
Diabetes research and clinical practice. 2019;:107835
Abstract
Heart failure (HF) is common in Type-2 diabetes mellitus (T2DM), and viceversa, leading to a mutual impact on prognosis. Knowledge about this complex interplay has dramatically changed recently, due to development of new glucose-lowering drugs, and to specific FDA and EMA Guidance mandating to perform cardiovascular outcome trials (CVOTs), aimed at establishing cardiovascular safety, for new anti-diabetic treatments before they enter the market. Such CVOTs have demonstrated that the effects of the new antidiabetic drugs on the mutual interactions between T2DM and HF may develop across different phases:Results of such trials can be summarized as: (a) all different classes of novel glucose-lowering drugs have good cardiovascular safety profile; (b) with respect to HF, DPP4 inhibitors might tend to increase risk; (c) sodium-glucose co-transporter 2 inhibitors (SGTLi), significantly reduce it; (d) glucagon-like peptide 1 receptor agonists (GLP1) tend to be neutral. These CVOTs data have led to guideline recommendations indicating appropriate therapy to T2DM patients with HF not at glycemic control target with metformin therapy.