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Cardiovascular outcome trials of the newer anti-diabetic medications.
Acharya, T, Deedwania, P
Progress in cardiovascular diseases. 2019;(4):342-348
Abstract
Concerns of elevated cardiovascular disease (CVD) risk with some anti-diabetic medications warranted phase 4 clinical trials to demonstrate CVD safety of newly marketed anti-diabetic drugs. Although initially designed to evaluate safety, some of these CVD outcome trials (CVOTs) have in fact shown CVD benefits. New medication classes, like glucagon-like peptide 1 (GLP-1) analogues and sodium-glucose co-transporter 2 (SGLT2) inhibitors, have shown reductions in the risk of major adverse cardiovascular events (MACE) including, myocardial infarction, stroke, CV death, and heart failure (HF). Perhaps more importantly, SGLT2 inhibitors demonstrated reduction in the risk of HF hospitalizations, being the first class of anti-diabetic drugs to do so. Conversely, dipeptidyl peptidase 4 (DPP-4) inhibitors did not significantly affect atherosclerotic CVD end-points and some actually increased the risk of HF hospitalizations. Further, the adverse/beneficial CVD effects of these medications may not be class specific. This review focuses on the main results of these CVOTs while highlighting the heterogeneity of CVD end-points within each class and discusses important mechanistic insights and adverse effect profiles.
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2.
[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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3.
A Review of Cardiovascular Outcomes Trials of Glucose-Lowering Therapies and Their Effects on Heart Failure Outcomes.
Nassif, ME, Kosiborod, M
The American journal of cardiology. 2019;:S12-S19
Abstract
Type 2 diabetes mellitus has long been recognized as a major risk factor for adverse atherosclerotic cardiovascular disease events; however, recent data indicate that heart failure is now emerging as the most common and morbid cardiovascular complication of type 2 diabetes mellitus. When heart failure develops in patients with type 2 diabetes, prognosis is ominous, highlighting the need for glucose-lowering therapies that can prevent heart failure, improve outcomes, or both. Prior to 2008, there was a paucity of randomized controlled trials evaluating long-term cardiovascular outcomes with glucose-lowering therapies. This changed after guidance on the assessment of novel glucose-lowering agents was issued by both the US Food and Drug Administration and the European Medicines Agency. Since then, significant progress has been made as a result of large cardiovascular outcomes trials. Though randomized controlled trials on insulin, sulfonylureas, and metformin are still limited, cardiovascular outcomes trials on newer glucose-lowering agents have included hundreds of thousands of patients with multiple years of follow-up. The increased risk of thiazolidinediones on heart failure had been well theorized and is now established; however, the increase in heart failure hospitalization with certain dipeptidyl peptidase-4 inhibitors was unexpected. The reasons for discrepancies with regard to heart failure risk with different dipeptidyl peptidase-4 inhibitors remain unclear, and further mechanistic studies are ongoing. The role of glucagon-like peptide-1 receptor agonists among patients with heart failure also remains unclear, and their effects may differ in patients with and without established heart failure, particularly those with decompensated heart failure with reduced ejection fraction.
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4.
Mechanism by which dipeptidyl peptidase-4 inhibitors increase the risk of heart failure and possible differences in heart failure risk.
Sano, M
Journal of cardiology. 2019;(1):28-32
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral antidiabetic drugs that safely reduce the blood glucose level over the long term. In Japan, DPP-4 inhibitors have become the oral antidiabetic drugs most frequently prescribed for patients with type 2 diabetes. However, the results of several cardiovascular outcomes studies have suggested that some DPP-4 inhibitors may increase the risk of hospitalization for heart failure. In patients with diabetes, heart failure is the most frequent cardiovascular condition, and it has a negative impact on the quality of life as well as being a potentially fatal complication. Therefore, it is important to determine whether an increased risk of heart failure is associated with certain DPP-4 inhibitors or is a class effect of these drugs. This review explores the mechanism by which DPP-4 inhibitors may increase the risk of heart failure and possible differences among these drugs. The available research suggests that DPP-4 inhibitors cause sympathetic activation as a class effect and this may increase the risk of heart failure. Unlike other DPP-4 inhibitors, sitagliptin and alogliptin are mainly excreted in the urine and suppress renal sodium-hydrogen exchanger 3 activity. These two drugs did not increase the risk of hospitalization for heart failure in large-scale cardiovascular outcomes studies.
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5.
Heart failure in patients with type 2 diabetes mellitus: assessment with echocardiography and effects of antihyperglycemic treatments.
Iwakura, K
Journal of echocardiography. 2019;(4):177-186
Abstract
Heart failure is one of the major cardiovascular complications in patients with type 2 diabetes mellitus (T2DM) and increases the risk of morbidity and mortality. Although active management for heart failure is needed in patients with T2DM, traditional treatment and some new class of antihyperglycemic drugs, such as glucagon-like peptide-1 receptor agonists or dipeptidyl peptidase-4 inhibitors, could not reduce the risk of heart failure. Recent major trials demonstrated sodium-glucose co-transporter-2 (SGLT2) inhibitors improve prognosis of T2DM patients through prevention of heart failure. Both heart failure with reduced ejection fraction and that with preserved ejection fraction (HFpEF) is observed in T2DM patients, and HFpEF is often overlooked and misdiagnosed in these population. Left ventricular hypertrophy, left atrial dilatation, diastolic dysfunction, and subclinical systolic dysfunction indicated as reduced global longitudinal strain are major abnormalities on echocardiography in patients with diabetic cardiomyopathy. These structural and functional changes are also prevalent in the general patients with T2DM, and those with these abnormalities have higher incidence of heart failure than those without them. Glycemic control might improve some of these abnormalities on echocardiography, but it is still unclear whether their improvement could be associated with risk reduction for heart failure. At now, there are only limited data on the effects of DPP-4 inhibitors or SGLT2 inhibitors on echocardiography in T2DM patients. Large-scale trials are needed to clarify how antihyperglycemic drugs affect echocardiographic parameters.
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6.
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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Current treatment options for nonalcoholic fatty liver disease.
Shetty, A, Syn, WK
Current opinion in gastroenterology. 2019;(3):168-176
Abstract
PURPOSE OF REVIEW Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the United States and is strongly associated to the metabolic syndrome. In this review, we will discuss the evidence behind the current recommendations on lifestyle modifications and available treatment options for NAFLD. RECENT FINDINGS The unrelenting rise in obesity and diabetes epidemic has led to a large healthcare burden from NAFLD and it is projected to continue to grow over the next two decades. Lifestyle modification that leads to weight loss is effective at treating NAFLD, but these modifications require a multidisciplinary approach for success in the real world. Multiple pharmacologic treatment options have been studied with promising results, but none have been approved for treatment in the United States. Clinical trials are on-going to study further pharmacologic treatment alternatives. SUMMARY NAFLD is the most common chronic liver disease in United States, and an independent risk factor for mortality. Implementation of lifestyle modifications through a multidisciplinary approach and careful selection of patients for pharmacologic interventions will be essential for successful management of NAFLD.
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Diabetes Care for Patients Experiencing Homelessness: Beyond Metformin and Sulfonylureas.
Brooks, LK, Kalyanaraman, N, Malek, R
The American journal of medicine. 2019;(4):408-412
Abstract
On any given night in the United States, an estimated 553,742 people are homeless. Applying a broader definition of homelessness that includes unstably housed people, an estimated 1.5% of Americans experience homelessness in a given year. Rates of diabetes are increasing among individuals experiencing homelessness. The social, psychological, and physical challenges of homelessness not only contribute to the rate of diabetes, but also complicate management. Unstable housing, limited medical resources, food insecurity, and competing priorities are barriers to diabetes care among patients experiencing homelessness. Homeless patients with diabetes more frequently develop specific comorbidities that require special attention, such as cardiovascular disease, substance abuse, depression, and foot wounds. The Affordable Care Act gave states the option to expand Medicaid to those earning up to 138% of the federal poverty level. This addressed a gap in coverage for low-income individuals not eligible for Medicaid or employer-sponsored insurance. With increased insurance coverage, this has increased the variety of medications available to treat hyperglycemia from type 2 diabetes beyond metformin, sulfonylureas, and insulin. Several of the newer classes of medications have advantages for patients experiencing homelessness, but also have special considerations in this vulnerable patient population. This narrative review will provide a review of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide agonists, sodium glucose cotransporter-2 inhibitors, and thiazolidinediones in individuals experiencing homelessness.
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9.
New Agents for the Treatment of Type 2 Diabetes.
Libianto, R, Ekinci, EI
Critical care clinics. 2019;(2):315-328
Abstract
The Renaissance of glucose-lowering therapies has arrived with multiple agents that lower blood glucose and demonstrate cardiovascular and renal benefits in people with type 2 diabetes. This article summarizes these new classes of therapies, including the sodium glucose co-transporter-2 inhibitors, glucagon-like peptide-1 agonists, and dipeptidyl peptidase-4 inhibitors. Their cardiovascular safety profile, effects on glycemic, weight, and renal outcomes are discussed. As more options become available to treat type 2 diabetes, clinicians need to be aware of the advantages of each class of medications, beyond their glycemic lowering effects. The safety profiles are summarized in this article.
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10.
Dipeptidyl peptidase-4 inhibitors (DPP-4i) combined with vitamin D3: An exploration to treat new-onset type 1 diabetes mellitus and latent autoimmune diabetes in adults in the future.
Pinheiro, MM, Pinheiro, FMM, Trabachin, ML
International immunopharmacology. 2018;:11-17
Abstract
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by destruction of pancreatic beta cells through cell injury caused primarily by cytotoxic T lymphocytes (CD8+). The pathophysiological basis of T1DM seems to be an imbalance between a reduced function of T regulatory lymphocytes and an increased inflammatory activity of Th17 lymphocytes caused by increased production of inflammatory cytokines, as IL-1β, IL-6, IL-17 and IFN-gamma due to environmental factors and genetic predisposition. The preservation of the reserve of beta cells in new-onset T1DM and latent autoimmune diabetes in adults (LADA) by immunomodulation in addition to the incretin effect seems to be possible with an association of DPP-4 inhibitors and vitamin D3. In this review, we discuss the effects of both drugs on the immune system and on beta cell function and their eventual additive effects in preserving the residual function of beta cells in new-onset T1DM and LADA.