Adverse Effects of GLP-1 Receptor Agonists Filippatos, Theodosios D; Panagiotopoulou, Thalia V; Elisaf, Moses S
The review of diabetic studies,
01/2014, Letnik:
11, Številka:
3-4
Journal Article
Recenzirano
Odprti dostop
Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 ...diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of GLP-1 receptor agonists with pancreatitis, pancreatic cancer, and thyroid cancer. However, several meta-analyses failed to confirm a cause-effect relation between GLP-1 receptor agonists and the development of these adverse effects. One benefit of GLP-1 receptor agonists is that they do not cause hypoglycemia when combined with metformin or thiazolidinediones, but the dose of concomitant sulphonylurea or insulin may have to be decreased to reduce the risk of hypoglycemic episodes. On the other hand, several case reports have linked the use of these drugs, mainly exenatide, with the occurrence of acute kidney injury, primarily through hemodynamic derangement due to nausea, vomiting, and diarrhea. The most common symptoms associated with the use of GLP-1 receptor agonists are gastrointestinal symptoms, mainly nausea. Other common adverse effects include injection site reactions, headache, and nasopharyngitis, but these effects do not usually result in discontinuation of the drug. Current evidence shows that GLP-1 receptor agonists have no negative effects on the cardiovascular risk of patients with T2D. Thus, GLP-1 receptor agonists appear to have a favorable safety profile, but ongoing trials will further assess their cardiovascular effects. The aim of this review is to analyze critically the available data regarding adverse events of GLP-1 receptor agonists in different anatomic systems published in Pubmed and Scopus. Whenever possible, certain differences between GLP-1 receptor agonists are described. The review also provides the reader with structured data that compare the rates of the most common adverse effects for each of the various GLP-1 receptor agonists.
Thiazide-induced hyponatremia is one of the main causes of decreased sodium levels in elderly individuals. This review presents the current evidence regarding the thiazide-associated hyponatremia. ...Thiazide-associated hyponatremia is observed mainly in patients with certain risk factors such as those receiving large doses of thiazides, having much comorbidity, such as heart failure, liver disease or malignancy, and taking several medications, such as non-steroidal anti-inflammatory drugs, selective serotonin re-uptake inhibitors or tricyclic antide- pressants. Sodium concentration should be monitored in patients with risk factors for developing thiazide-associated hyponatremia and clini- cians should measure promptly serum sodium levels in patients with neurologic signs indicating reduced sodium levels. The clinical and biochemical profile of patients with thiazide-associated hyponatremia may be that of extracellular volume depletion or the syndrome of inap- propriate antidiuretic hormone secretion （SIADH）. The investigation of possible thiazide-associated hyponatremia includes the exclusion of other causes of decreased sodium levels and the identification of the characteristics of hyponatremia due to thiazides （extracellular volume depletion-related or SIADH-like）. Treatment should be carefully monitored to avoid serious neurologic complications due to overcorrection. Clinicians should discourage prescribing thiazides in patients with a history of diuretic-associated hyponatremia and should prefer low doses of thiazides in patients with risk factors for developing thiazide-associated hyponatremia.
Hemostatic factors and the metabolic syndrome Kostapanos, Michael S; Florentin, Matilda; Elisaf, Moses S ...
Current vascular pharmacology,
11/2013, Letnik:
11, Številka:
6
Journal Article
Metabolic syndrome (MetS) is associated with increased risk of both atherothrombotic cardiovascular events and venous thromboembolism. The pro-thrombotic potential of MetS, may explain this ...association. In this review we discuss the relationship of MetS with hemostasis focusing on endothelial function, platelet activity, coagulation, fibrinolysis and hemorheologic markers. Endothelial-dependent vasodilatation is impaired in MetS. This is mostly mediated by a reduced expression of vasodilators (nitric oxide and prostacyclin) with a concomitant increase of vasoconstrictors (endothelin- 1, angiotensin II and thromboxane A2). Platelet activity is enhanced in MetS. A cross-talk between activated endothelium and platelets results in a pro-thrombotic vicious cycle. Enhanced coagulation together with impaired fibrinolysis is also present in MetS. This is mirrored by high fibrinogen and plasminogen activator inhibitor-1 levels. Endothelial dysfunction, expressed by high von Willebrand factor and tissue plasminogen factor levels, also contributes to this abnormality. Whole blood and plasma viscosity is increased in MetS. Lifestyle intervention can improve the MetS-related pro-thrombotic state. These measures include weight reduction and improved composition of the diet. A Mediterranean-style diet rich in olive oil, as a source of monounsaturated fat, and low saturated fat consumption may also be beneficial.
Statins exert beneficial effects on cardiovascular CV outcomes as well as on inflammation and oxidative stress. The widespread use of statins for both primary and secondary CV disease prevention is ...based on the evidence from large randomized controlled trials. The benefits of statin treatment outweigh any harm in high risk patients. In this narrative review, we provide an update on several aspects of statin treatment based on the most recent evidence in this field.
Recent studies suggest that the cholesterol content of HDL (high density lipoproteins) may provide limited information on their antiatherogenic properties and that the composition and particles’ ...structure provide more information on their functionality. We used NMR-based (nuclear magnetic resonance-based) lipidomics to study the relationships of serum HDL-C (HDL-cholesterol) levels with the lipid composition of HDL particles in three groups of subjects selected on the basis of their HDL-C levels. Subjects with low and high HDL-C levels exhibited differences in HDL lipidome compared to those with normal HDL-C levels. In pattern recognition analysis, the discrimination power among all groups was of high significance. The low HDL-C group presented enrichment of the core in triglycerides and depletion in cholesterol esters, whereas the high HDL-C group showed a decrease in triglycerides content. Additionally, as HDL-C increases, all lipid classes are esterified with higher percentage of unsaturated than saturated fatty acids. In addition to the aforementioned differences, the surface layer is enriched in sphingomyelin and free cholesterol in the high HDL-C level group. NMR-based lipidomic analysis of HDL can be particularly useful since it provides insights into molecular features and helps in the characterization of the atheroprotective function of HDL lipoproteins and in the identification of novel biomarkers of cardiovascular risk.
Non-alcoholic fatty liver disease(NAFLD) is a common health problem with a high mortality burden due to its liver- and vascular-specific complications. It is associated with obesity, high-fat diet as ...well as with type 2 diabetes mellitus(T2DM) and metabolic syndrome(MetS).Impaired hepatic fatty acid(FA) turnover together with insulin resistance are key players in NAFLD pathogenesis. Peroxisome proliferator-activated receptors(PPARs)are involved in lipid and glucose metabolic pathways.The novel concept is that the activation of the PPARαsubunit may protect from liver steatosis. Fenofibrate, by activating PPARα, effectively improves the atherogenic lipid profile associated with T2DM and MetS. Experimental evidence suggested various protective effects of the drug against liver steatosis. Namely, fenofibraterelated PPARα activation may enhance the expression of genes promoting hepatic FA β-oxidation. Furthermore, fenofibrate reduces hepatic insulin resistance. It also inhibits the expression of inflammatory mediators involved in non-alcoholic steatohepatitis pathogenesis.These include tumor necrosis factor-α, intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1and monocyte chemoattractant protein-1. Consequently, fenofibrate can limit hepatic macrophage infiltration. Other liver-protective effects include decreased oxidative stress and improved liver microvasculature function. Experimental studies showed that fenofibrate can limit liver steatosis associated with high-fat diet,T2DM and obesity-related insulin resistance. Few studies showed that these benefits are also relevant even in the clinical setting. However, these have certain limitations. Namely, these were uncontrolled, their sample size was small, fenofibrate was used as a part of multifactorial approach, while histological data were absent.In this context, there is a need for large prospective studies, including proper control groups and full assessment of liver histology.
Fenofibrate and the kidney: an overview Kostapanos, Michael S.; Florentin, Matilda; Elisaf, Moses S.
European journal of clinical investigation,
20/May , Letnik:
43, Številka:
5
Journal Article
Recenzirano
Background
Fenofibrate has been used for the management of atherogenic dyslipidaemia for many years. Reports of fenofibrate‐associated increases in serum creatinine (SCr) levels raised concerns ...regarding deleterious effects on renal function.
Design
In this narrative review, we discuss available literature on the effect of fenofibrate on the kidney.
Results
Most clinical studies showed a rapid (within weeks) raising effect of fenofibrate on SCr levels. This was often accompanied by declined estimated glomerular filtration rate. Risk predictors of this adverse effect might include increased age, impaired renal function and high‐dose treatment. Also, the concomitant use of medications affecting renal hemodynamics (e.g. angiotensin‐converting enzyme‐inhibitors (ACEi) and angiotensin receptor blockers) may predispose to fenofibrate‐associated increased SCr levels. Interestingly, SCr increases by fenofibrate were transient and reversible even without treatment discontinuation. Furthermore, fenofibrate was associated with a slower progression of renal function impairment and albuminuria in a long‐term basis. Also, fenofibrate might be protective against pathological changes in diabetic nephropathy and hypertensive glomerulosclerosis. In this context, it is uncertain whether fenofibrate‐associated increase in SCr levels mirrors true renal function deterioration. Several theories have been expressed. The most dominant one involved the inhibition of renal vasodilatory prostaglandins reducing renal plasma flow and glomerular pressure. Increased creatinine secretion or reduced creatinine clearance by fenofibrate was also suggested. These hypotheses should be settled by further studies.
Conclusions
Fenofibrate may not be a nephrotoxic drug. However, a close monitoring of SCr levels is relevant especially in high‐risk patients. Increases in SCr levels ≥30% can impose treatment discontinuation.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors inhibit glucose re-absorption in the proximal renal tubules. These drugs also affect many anthropometric and metabolic parameters with various ...mechanisms of action. Areas covered: We present the available evidence regarding these effects. SGLT2 inhibitors can decrease body weight mainly due to a reduction of total fat mass. SGLT2 inhibitors can decrease blood pressure levels and serum uric acid levels and may also reduce the degree of diabetes-related albuminuria. These effects may have contributed in the beneficial cardiovascular effects seen in the EMPA-REG OUTCOME trial. On the other hand, the SGLT2 inhibition-induced natriuresis and osmotic diuresis could lead to a decrease of extracellular volume. A small increase in serum low-density lipoprotein cholesterol has been observed with SGLT2 inhibitors. A small increase in serum phosphate concentration has been reported with these drugs due to increased phosphate reabsorption, which combined with an increase in serum parathormone may adversely affect bone homeostasis. In rare cases, SGLT2 inhibitors administration may be followed by euglycemic diabetic ketoacidosis. Expert opinion: SGLT2 inhibitors improve many aspects of human metabolism and may be beneficial in diabetic patients if certain precautions are followed by clinicians during the administration of these drugs.
Pioglitazone and cancer: angel or demon? Kostapanos, Michael S; Elisaf, Moses S; Mikhailidis, Dimitri P
Current pharmaceutical design,
2013, Letnik:
19, Številka:
27
Journal Article
Recenzirano
After the withdrawal of troglitazone and rosiglitazone, pioglitazone remains the sole thiazolidinedione (TZD) still available. Pioglitazone is efficacious in improving glycemic control and reduce the ...risk of cardiovascular events. Although generally well-tolerated, pioglitazone was withdrawn by some national medicines agencies (e.g. in France and Germany) due to reports of increased incidence of bladder cancer. In this article, we review the literature on the association between pioglitazone and cancer in several sites, including the bladder. Pioglitazone, like other TZDs, increased differentiation, inhibited growth and proliferation, while provoked apoptosis in various cancer cells, including bladder cancer, in vitro and in vivo. However, a rat-specific carcinogenic effect of pioglitazone on the bladder was noted in vivo. Clinical data for the risk of various cancer sites mostly come from observational studies and are subject to bias. An increased risk for bladder cancer by pioglitazone was suggested by retrospective analyses. This risk was associated with the time of exposure and the age, by identifying 24 months and 65 years, respectively, as time 'thresholds' above which this risk becomes relevant. In contrast, no increased risk for bladder cancer was associated with pioglitazone in randomized clinical trials. Pioglitazone was associated with increased incidence of melanoma and non-Hodgkin lymphoma and decreased risk of renal cancer in one cohort study. These findings need to be re-evaluated on a prospective basis. There is no convincing evidence that pioglitazone increases or decreases the risk of cancer in other sites. In contrast, it was suggested that this drug may be useful either in the treatment of cancer complications or as an adjunct to chemotherapeutic agents. Considering the clinical benefit from the use of pioglitazone it is reasonable to wait until data from ongoing clinical trials are available before reaching definitive conclusions. Nevertheless, the potential for increased risk of bladder cancer should be taken into consideration, especially in the presence of other risk factors for bladder carcinogenesis (e.g. smoking).
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