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Pharmacological treatment of hyperglycemia in type 2 diabetes.
Taylor, SI, Yazdi, ZS, Beitelshees, AL
The Journal of clinical investigation. 2021;(2)
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Abstract
Diabetes mellitus is a major public health problem, affecting about 10% of the population. Pharmacotherapy aims to protect against microvascular complications, including blindness, end-stage kidney disease, and amputations. Landmark clinical trials have demonstrated that intensive glycemic control slows progression of microvascular complications (retinopathy, nephropathy, and neuropathy). Long-term follow-up has demonstrated that intensive glycemic control also decreases risk of macrovascular disease, albeit rigorous evidence of macrovascular benefit did not emerge for over a decade. The US FDA's recent requirement for dedicated cardiovascular outcome trials ushered in a golden age for understanding the clinical profiles of new type 2 diabetes drugs. Some clinical trials with sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP1) receptor agonists reported data demonstrating cardiovascular benefit (decreased risk of major adverse cardiovascular events and hospitalization for heart failure) and slower progression of diabetic kidney disease. This Review discusses current guidelines for use of the 12 classes of drugs approved to promote glycemic control in patients with type 2 diabetes. The Review also anticipates future developments with potential to improve the standard of care: availability of generic dipeptidylpeptidase-4 (DPP4) inhibitors and SGLT2 inhibitors; precision medicine to identify the best drugs for individual patients; and new therapies to protect against chronic complications of diabetes.
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The Effects of Glucagon-Like Peptide-1 Receptor Agonists and Dipeptydilpeptidase-4 Inhibitors on Blood Pressure and Cardiovascular Complications in Diabetes.
Yaribeygi, H, Farrokhi, FR, Abdalla, MA, Sathyapalan, T, Banach, M, Jamialahmadi, T, Sahebkar, A
Journal of diabetes research. 2021;:6518221
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) agonists are a class of newly introduced antidiabetic medications that potentially lower blood glucose by several molecular pathways. DPP-4 inhibitors are the other type of novel antidiabetic medications which act by preventing GLP-1 inactivation and thereby increasing the activity levels of GLP-1, leading to more glucose-induced insulin release from islet β-cells and suppression of glucagon release. Most patients with diabetes have concurrent hypertension and cardiovascular disorder. If antihyperglycemic agents can attenuate the risk of hypertension and cardiovascular disease, they will amplify their overall beneficial effects. There is conflicting evidence on the cardiovascular benefits of GLP-1R induction in laboratory studies and clinical trials. In this study, we have reviewed the main molecular mechanisms by which GLP-1R induction may modulate the cardiovascular function and the results of cardiovascular outcome clinical trials.
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Glucose-lowering action through targeting islet dysfunction in type 2 diabetes: Focus on dipeptidyl peptidase-4 inhibition.
Ahrén, B
Journal of diabetes investigation. 2021;(7):1128-1135
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibition is a glucose-lowering medication for type 2 diabetes. It works through stimulation of insulin secretion and inhibition of glucagon secretion in a glucose-dependent manner, resulting in lowered fasting and postprandial glycemia with low risk of hypoglycemia. As impaired insulin secretion and augmented glucagon secretion are key factors underlying hyperglycemia in type 2 diabetes, DPP-4 inhibition represents a therapy that targets the underlying mechanisms of the disease. If insufficient in monotherapy, it can preferably be used in combination with metformin, which targets insulin resistance, and also in combination with sodium-glucose cotransporter 2 inhibition, thiazolidinediones and insulin, which target other mechanisms. In individuals of East Asian origin, islet dysfunction is of particular importance for the development of type 2 diabetes. Consequently, it has been shown in several studies that DPP-4 is efficient in these populations. This mini-review highlights the islet mechanisms of DPP-4 inhibition, islet dysfunction as a key factor for hyperglycemia in type 2 diabetes and that, consequently, DPP-4 is of particular value in populations where islet dysfunction is central, such as in individuals of East Asian origin.
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Renoprotective Effects of Incretin-Based Therapy in Diabetes Mellitus.
Yaribeygi, H, Atkin, SL, Montecucco, F, Jamialahmadi, T, Sahebkar, A
BioMed research international. 2021;:8163153
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists are recently discovered antidiabetic drugs with potent hypoglycemic effects. Among different mechanisms of activity, these compounds were shown to reduce blood glucose by suppression of glucagon secretion and stimulation of glucose-dependent insulin secretion. These antidiabetic agents have a minor risk of hypoglycemia and have been suggested as a second-line therapy to be added to metformin treatment to further optimize glycemic control in diabetes. More recently, scientific evidence suggests that GLP-1 receptor agonists may particularly afford protection from diabetic nephropathy through modulation of the molecular pathways involved in renal impairment and so improve renal function. This additional benefit adds further weight for these compounds to become promising drugs not only for glycemic control but also to prevent diabetic complications. In this review, we have updated evidence on the beneficial effects of GLP-1 receptor agonists on diabetic nephropathy and detailed the underlying pathophysiological mechanisms.
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COVID-19 and comorbidities: A role for dipeptidyl peptidase 4 (DPP4) in disease severity?
Bassendine, MF, Bridge, SH, McCaughan, GW, Gorrell, MD
Journal of diabetes. 2020;(9):649-658
Abstract
The coronavirus disease 2019 (COVID-19) pandemic is caused by a novel betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), similar to SARS-CoV and Middle East respiratory syndrome (MERS-CoV), which cause acute respiratory distress syndrome and case fatalities. COVID-19 disease severity is worse in older obese patients with comorbidities such as diabetes, hypertension, cardiovascular disease, and chronic lung disease. Cell binding and entry of betacoronaviruses is via their surface spike glycoprotein; SARS-CoV binds to the metalloprotease angiotensin-converting enzyme 2 (ACE2), MERS-CoV utilizes dipeptidyl peptidase 4 (DPP4), and recent modeling of the structure of SARS-CoV-2 spike glycoprotein predicts that it can interact with human DPP4 in addition to ACE2. DPP4 is a ubiquitous membrane-bound aminopeptidase that circulates in plasma; it is multifunctional with roles in nutrition, metabolism, and immune and endocrine systems. DPP4 activity differentially regulates glucose homeostasis and inflammation via its enzymatic activity and nonenzymatic immunomodulatory effects. The importance of DPP4 for the medical community has been highlighted by the approval of DPP4 inhibitors, or gliptins, for the treatment of type 2 diabetes mellitus. This review discusses the dysregulation of DPP4 in COVID-19 comorbid conditions; DPP4 activity is higher in older individuals and increased plasma DPP4 is a predictor of the onset of metabolic syndrome. DPP4 upregulation may be a determinant of COVID-19 disease severity, which creates interest regarding the use of gliptins in management of COVID-19. Also, knowledge of the chemistry and biology of DPP4 could be utilized to develop novel therapies to block viral entry of some betacoronaviruses, potentially including SARS-CoV-2.
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Long-term efficacy of gliflozins versus gliptins for Type 2 Diabetes after metformin failure: a systematic review and network meta-analysis.
Zilli, RW, Rached, CDA, Silva, FPD, Baena, RC
Revista da Associacao Medica Brasileira (1992). 2020;(4):458-465
Abstract
After metformin failure in treatment for diabetes type 2, there is no trivial option for adjuvant medication. The last two oral class medications, gliflozins and gliptins, have different mechanisms of action but have never been compared in long run studies. The aim of the present meta-analysis is to assess the overall long-term efficacy of these drugs after metformin failure. A systematic review and meta-analysis were performed, including all trials with a duration of over 2 years, comparing gliflozins or gliptins after metformin failure in type 2 diabetes. Data Sources: Pubmed (Medline), Embase, Lilacs, and the Cochrane Library from inception through July 2016 without language restrictions. The longest study period found in the literature was 4 years. We selected 1 article on empagliflozin, 1 on dapagliflozin, and 1 on saxagliptin with missing data. After one year of treatment, over 50% of the patients presented HbA1c > 7%. Efficacy rate after 4 years of empagliflozin (23%) was better than dapagliflozin (5%) and saxagliptin (7%); however, it presented statistically non-significant values for HbA1c (7.4 and 7.3% between gliflozins), and missing data for saxaglifozin. Nonetheless, empagliflozin performed better than glimepiride in the 4-year period (standardized mean difference SMD 0.4, confidence interval CI 95% 0.23 to 0.56). The failure of the secondary treatment using gliflozins occurs in less than one year of treatment (less than 50% of the patients presenting HbA1c > 7 %). Empagliflozin offered better glycemic control compared to sulfonylureas but was similar to dapagliflozin.
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[Still a role for DPP-4 inhibitors in 2020?].
Caironi, V, Jornayvaz, FR, Gariani, K
Revue medicale suisse. 2020;(697):1186-1190
Abstract
DPP-4 inhibitors are a well-established treatment for type 2 diabetes. They act by improving glycemic control through the incretin system. This class of molecules are well-tolerated and are associated with a low risk of hypoglycemia. Yet, their efficacy in glycemic control is rather moderate and they don't offer a benefit in terms of cardiovascular or renal protection. Even if they have a good safety profile, it is important to pay attention to the risk of cardiac failure and pancreatitis. This article provides an overview of the use of DPP-4 inhibitors in 2020.
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Cardiovascular Safety and Benefits of Noninsulin Antihyperglycemic Drugs for the Treatment of Type 2 Diabetes Mellitus: Part 2.
Yandrapalli, S, Malik, A, Horblitt, A, Pemmasani, G, Aronow, WS, Frishman, WH
Cardiology in review. 2020;(5):219-235
Abstract
Ideal drugs to improve outcomes in type 2 diabetes mellitus (T2DM) are those with antiglycemic efficacy, as well as cardiovascular safety that has to be determined in appropriately designed cardiovascular outcome trials as mandated by regulatory agencies. The more recent antihyperglycemic medications have shown promise with regards to cardiovascular disease (CVD) risk reduction in T2DM patients at a high cardiovascular risk. Sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists are associated with better cardiovascular outcomes and mortality in T2DM patients than are dipeptidylpeptidase-4 inhibitors, leading to the Food and Drug Administration's approval of empagliflozin to reduce mortality, and of liraglutide to reduce CVD risk in high-risk T2DM patients. For heart failure outcomes, sodium glucose cotransporter-2 inhibitors are beneficial, while glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors are neutral. Ongoing and planned randomized controlled trials of these newer drugs should clarify the possibility of class effects and of CVD risk reduction benefits in low-moderate cardiovascular risk patients. While we eagerly await the results on ongoing studies, these medications should be appropriately prescribed in T2DM patients with baseline CVD or those at a high CVD risk after carefully evaluating the elevated risk for adverse events like gastrointestinal disturbances, bladder cancer, genital infections, and amputations. Studies to understand the pleotropic and novel pathophysiological mechanisms demonstrated by the sodium glucose cotransporter-2 inhibitors will shed light on the effects of the modulation of microvascular, inflammatory, and thrombotic milieu for improving the CVD risk in T2DM patients. This is part 2 of the series on noninsulin antihyperglycemic drugs for the treatment of T2DM.
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Oral antidiabetes agents for the management of inpatient hyperglycaemia: so far, yet so close.
Koufakis, T, Mustafa, OG, Zebekakis, P, Kotsa, K
Diabetic medicine : a journal of the British Diabetic Association. 2020;(9):1418-1426
Abstract
BACKGROUND Hyperglycaemia is an ongoing challenge in hospital settings and is associated with poor outcomes. Current recommendations for the management of inpatient hyperglycaemia suggest insulin as the main glucose-lowering treatment choice and limit the administration of oral antidiabetes agents to a small proportion of cases because of safety concerns. AIM: To present and critically appraise the available evidence on the use of oral antidiabetes agents in the hospital setting and the risk-benefit balance of such an approach in the era of cardiovascular outcomes trials. METHODS PubMed, Embase and Google Scholar databases were searched to identify relevant published work. Available evidence on the efficacy and the safety profile of oral agents in the context of their use in hospitalized individuals are summarized and discussed in this narrative review. RESULTS There is no robust evidence to suggest the use of metformin, thiazolidinediones, sulfonylureas and sodium-glucose co-transporter-2 inhibitors in the hospital setting, although some of their effects on acute outcomes deserve further evaluation in future studies. However, the use of dipeptidyl peptidase-4 inhibitors in inpatients with type 2 diabetes is supported by a few, well-designed, randomized controlled trials. These trials have demonstrated good safety and tolerability profiles, comparable to insulin glucose-lowering efficacy, and a reduction in insulin dose when dipeptidyl peptidase-4 inhibitors are co-administered with insulin, in individuals with mild to moderate hyperglycaemia and a stable clinical condition. CONCLUSION The administration of dipeptidyl peptidase-4 inhibitors to specific groups of inpatients might be a safe and effective alternative to insulin.
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Infectious complications of newer agents in the fight against diabetes.
Stover, KR, Hugh, E, Sherman, JJ, Malinowski, SS, Berdahl, GJ, Riche, DM
The Nurse practitioner. 2020;(11):17-24
Abstract
Infectious complications have been reported with antidiabetic medications. Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors have been associated with upper respiratory tract infections and urinary tract infections. Sodium-glucose cotransporter 2 inhibitors have been associated with lower limb amputations, urinary tract infections, genital mycotic infections, and Fournier gangrene.