Sodium-glucose co-transporter 2 (SGLT2) inhibitors inhibit glucose re-absorption in the proximal renal tubules. Two trials have shown significant reductions of cardiovascular (CV) events with ...empagliflozin and canagliflozin, which could not be attributed solely to their antidiabetic effects. The aim of the review is the critical presentation of suggested mechanisms/hypotheses for the SGLT2 inhibitors' cardioprotection. The search of the literature revealed many possible cardioprotective mechanisms, because SGLT2 inhibitors (i) increase natriuresis and act as diuretics with unique properties leading to a reduction in preload and myocardial stretch (the diuretic hypothesis); (ii) decrease blood pressure and afterload (the blood pressure lowering hypothesis), (iii) favor the production of ketones, which can act as a 'superfuel' in the cardiac and renal tissue (the 'thrifty substrate' hypothesis), (iv) improve many metabolic variables (the metabolic effects hypothesis), (v) exert many anti-inflammatory effects (the anti-inflammatory effects hypothesis), (vi) can act through the angiotensin II type II receptors in the context of simultaneous renin-angiotensin-aldosterone-system (RAAS) blockade leading to vasodilation and positive inotropic effects (the RAAS hypothesis), (vii) directly decrease the activity of the upregulated in heart failure Na
+
-H
+
exchanger in myocardial cells leading to restoration of mitochondrial calcium handling in cardiomyocytes (the sodium hypothesis). Additionally, some SGLT2 inhibitors exhibit also SGLT1 inhibitory action possibly resulting in an attenuation of oxidative stress in ischemic myocardium (the SGLT1 inhibition hypothesis). Thus, many mechanisms have been suggested (and possibly act cumulatively) for the cardioprotective effects of SGLT2 inhibitors.
Purpose of Review
Despite significant progress in plasma lipid lowering strategies, recent clinical trials highlight the existence of residual cardiovascular risk. Angiopoietin-like protein 3 ...(ANGPTL3) and apolipoprotein C-III (Apo C-III) have been identified as novel lipid-lowering targets.
Recent Findings
Apo C-III and ANGPTL3 have emerged as novel regulators of triglyceride (TG) and low-density lipoprotein-cholesterol (LDL-C) levels. ANGPTL3 is an inhibitor of lipoprotein lipase (LPL), reducing lipolysis of Apo B-containing lipoproteins. Loss-of-function
ANGPLT3
mutations are associated with reduced plasma cholesterol and TG, while novel ANGPLT3 inhibition strategies, including monoclonal antibodies (evinacumab),
ANGPLT3
antisense oligonucleotides (IONIS-ANGPTL3-L
Rx
), and small interfering RNA (siRNA) silencing techniques (ARO-ANG3), result in increased lipolysis and significant reductions of LDL-C and TG levels in phase I and II clinical trials. Similarly, Apo C-III inhibits LPL while promoting the hepatic secretion of TG-rich lipoproteins and preventing their clearance. Loss-of-function
APOC3
mutations have been associated with reduced TG levels. Targeting of Apo C-III with volanesorsen, an
APOC3
siRNA, results in significant reduction in plasma TG levels but possibly also increased risk for thrombocytopenia, as recently demonstrated in phase I, II, and III clinical trials. ARO-APOC3 is a novel siRNA-based agent targeting Apo C-III which is currently under investigation with regard to its lipid-lowering efficiency.
Summary
ANGPTL3 and Apo C-III targeting agents have demonstrated striking lipid-lowering effects in recent clinical trials; however, more thorough safety and efficacy data are required. Here, we evaluate the role of ANGPLT3 and Apo C-III in lipid metabolism, present the latest clinical advances targeting those molecules, and outline the remaining scientific challenges on residual lipid-associated cardiovascular risk.
Summary
Background
Glucagon‐like peptide 1 (GLP‐1) analogs regulate body weight and liver steatosis. Different body adipose tissue (AT) depots exhibit biological variability. Accordingly, GLP‐1 ...analog effects on AT distribution are unclear.
Objectives
To investigate GLP1‐analog effects on adiposity distribution.
Search methods
PubMed, Cochrane, and Scopus databases were screened for eligible randomized human trials. Pre‐defined endpoints included visceral AT (VAT), subcutaneous AT (SAT), total AT (TAT), epicardial AT (EAT), liver AT (LAT), and waist‐to‐hip ratio (W:H). Search was conducted until May 17, 2022.
Data collection and analysis
Data extraction and bias assessment were performed by two independent investigators. Treatment effects were estimated using random effects models. Analyses were performed on Review Manager v5.3.
Main results
Out of the 367 screened studies, 45 were included in the systematic review and 35 were used in the meta‐analysis. GLP‐1 analogs reduced VAT, SAT, TAT, LAT, and EAT, with non‐significant effects on W:H. Overall bias risk was low.
Conclusions
GLP‐1 analog treatment reduces TAT, affecting most studied AT depots, including the pathogenic VAT, EAT, and LAT. GLP‐1 analogs may have significant roles in combating metabolic, obesity‐associated diseases via reductions of key AT depot volumes.
To systematically investigate all relevant evidence on the association between high-density lipoprotein cholesterol (HDL-C) and multiple myeloma (MM).
We searched PubMed and Cochrane library ...databases (up to 20 September 2022) for studies with evidence on HDL-C in patients with MM. A qualitative synthesis of published prospective and retrospective studies for the role of HDL-C and other lipid profile parameters in MM was performed. Additionally, a meta-analysis on HDL-C mean differences (MD) between MM cases and controls was performed.
Fourteen studies (3 prospective, 11 retrospective) including 895 MM patients were eligible for this systematic review. Ten studies compared HDL-C levels in MM patients with healthy controls. In these 10 studies (n = 17,213), pooled analyses showed that MM patients had significantly lower HDL-C levels compared to healthy controls (MD: −13.07 mg/dl, 95% CI: −17.83, −8.32, p < 0.00001). Regarding secondary endpoints, total cholesterol (TC) (MD: −22.19 mg/dl, 95% CI: −39.08, −5.30) and apolipoprotein A-I (apoA-I) (−40.20 mg/dl, 95% CI: −55.00, −25.39) demonstrated significant decreases, while differences in low-density lipoprotein cholesterol (LDL-C) (MD: −11.33 mg/dl, 95% CI: −36.95, 14.30) and triglycerides (MD: 9.93 mg/dl, 95% CI: −3.40, 23.26) were not shown to be significant.
HDL-C, as well as TC and apoA-I, levels are significantly decreased in MM. Hence, lipid profile parameters should be taken into account when assessing such patients.
•Low high-density lipoprotein cholesterol (HDL-C) levels represent an important feature in multiple myeloma (MM).•Patients with MM have lower HDL-C, total cholesterol, and apolipoprotein A-I levels compared with healthy controls.•Lipid profile parameters should be taken into account when assessing MM patients.
Abstract The focus of this review is on the role of apolipoprotein C-II (apoC-II) in lipoprotein metabolism and the potential effects on the risk of cardiovascular disease (CVD). We searched ...PubMed/Scopus for articles regarding apoC-II and its role in lipoprotein metabolism and the risk of CVD. Apolipoprotein C-II is a constituent of chylomicrons, very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein (HDL). Apolipoprotein C-II contains 3 amphipathic α -helices. The lipid-binding domain of apoC-II is located in the N-terminal, whereas the C-terminal helix of apoC-II is responsible for the interaction with lipoprotein lipase (LPL). At intermediate concentrations (approximately 4 mg/dL) and in normolipidemic subjects, apoC-II activates LPL. In contrast, both an excess and a deficiency of apoC-II are associated with reduced LPL activity and hypertriglyceridemia. Furthermore, excess apoC-II has been associated with increased triglyceride-rich particles and alterations in HDL particle distribution, factors that may increase the risk of CVD. However, there is not enough current evidence to clarify whether increased apoC-II causes hypertriglyceridemia or is an epiphenomenon reflecting hypertriglyceridemia. A number of pharmaceutical interventions, including statins, fibrates, ezetimibe, nicotinic acid, and orlistat, have been shown to reduce the increased apoC-II concentrations. An excess of apoC-II is associated with increased triglyceride-rich particles and alterations in HDL particle distribution. However, prospective trials are needed to assess if apoC-II is a CVD marker or a risk factor in high-risk patients.
The use of anticancer drugs is beneficial for patients with malignancies but is frequently associated with the occurrence of electrolyte disorders, which can be hazardous and in many cases fatal. The ...review presents the electrolyte abnormalities that can occur with the use of anticancer drugs and provides the related mechanisms. Platinum-containing anticancer drugs induce hypomagnesemia, hypokalemia and hypocalcemia. Moreover, platinum-containing drugs are associated with hyponatremia, especially when combined with large volumes of hypotonic fluids aiming to prevent nephrotoxicity. Alkylating agents have been linked with the occurrence of hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) and Fanconi’s syndrome (hypophosphatemia, aminoaciduria, hypouricemia and/or glucosuria). Vinca alkaloids are associated with hyponatremia due to SIADH. Epidermal growth factor receptor monoclonal antibody inhibitors induce hypomagnesemia, hypokalemia and hypocalcemia. Other, monoclonal antibodies, such as cixutumumab, cause hyponatremia due to SIADH. Tyrosine kinase inhibitors are linked to hyponatremia and hypophosphatemia. Mammalian target of rapamycin inhibitors induce hyponatremia (due to aldosterone resistance), hypokalemia and hypophosphatemia. Other drugs such as immunomodulators or methotrexate have been also associated with hyponatremia. The administration of estrogens at high doses, streptozocin, azacitidine and suramin may induce hypophosphatemia. Finally, the drug-related tumor lysis syndrome is associated with hyperphosphatemia, hyperkalemia and hypocalcemia. The prevention of electrolyte derangements may lead to reduction of adverse events during the administration of anticancer drugs.
Decreased serum sodium concentration is a rather frequent electrolyte disorder in the elderly population because of the presence of factors contributing to increased antidiuretic hormone, the ...frequent prescription of drugs associated with hyponatremia and also because of other mechanisms such as the "tea and toast" syndrome. The aim of this review is to present certain challenges in the evaluation and treatment of hyponatremia in the elderly population and provide practical solutions. Hyponatremia in elderly subjects is mainly caused by drugs (more frequently thiazides and antidepressants), the syndrome of inappropriate antidiuretic hormone secretion (SIAD) or endocrinopathies; however, hyponatremia is multifactorial in a significant proportion of patients. Special attention is needed in the elderly population to exclude endocrinopathies as a cause of hyponatremia before establishing the diagnosis of SIAD, which then requires a stepped diagnostic approach to reveal its underlying cause. The treatment of hyponatremia depends on the type of hyponatremia. Special attention is also needed to correct serum sodium levels at the appropriate rate, especially in chronic hyponatremia, in order to avoid the osmotic demyelination syndrome. In conclusion, both the evaluation and the treatment of hyponatremia pose many challenges in the elderly population.
SGLT2 inhibitors: are they safe? Filippas-Ntekouan, Sebastian; Filippatos, Theodosios D.; Elisaf, Moses S.
Postgraduate medicine,
01/2018, Letnik:
130, Številka:
1
Journal Article
Recenzirano
Sodium-glucose linked transporter type 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs with positive cardiovascular and kidney effects. The aim of this review is to present the ...safety issues associated with SGLT2 inhibitors. Urogenital infections are the most frequently encountered adverse events, although tend to be mild to moderate and are easily manageable with standard treatment. Although no increased acute kidney injury risk was evident in the major trials, the mechanism of action of these drugs requires caution when they are administered in patients with extracellular volume depletion or with drugs affecting renal hemodynamics. Canagliflozin raised the risk of amputations and the rate of fractures in the CANVAS trial, although more data are necessary before drawing definite conclusions. The risk of euglycemic diabetic ketoacidosis seems to be minimal when the drugs are prescribed properly. Regarding other adverse events, SGLT2 inhibitors do not increase the risk of hypoglycemia even when co-administered with insulin, but a decrease in the dose of sulphonylureas may be needed. The available data do not point to a causative role of SGLT2 inhibitors on malignancy risk, however, these drugs should be used with caution in patients with known hematuria or history of bladder cancer. SGLT2 inhibitors seem to be safe and effective in the treatment of diabetes but more studies are required to assess their long-term safety.
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.
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