Effects of dapagliflozin on postprandial lipid metabolism in type 2 diabetes mellitus.

Objectives: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) modulate lipid metabolism and improve cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). The exact cardioprotective mechanism of SGLT2i is unclear. We evaluated the effects of SGLT2i on postprandial lipids, lipoprotein concentrations, glucose and fatty acids. Design: A placebo-controlled randomized, proof-of-concept study. Methods: Fourteen male patients with T2DM on intensive insulin regimen were randomly and double-blind allocated to 12 weeks dapagliflozin (10 mg) or placebo. Postprandial effects were assessed with an 8-h standardized oral fat loading test. Results: Mean glycated A1c did not change by dapagliflozin, but the mean daily insulin dose was significantly reduced. Although dapagliflozin did not affect fasting or postprandial levels of glucose and insulin, it increased the postprandial levels of glucagon. While fasting levels of free fatty acids and beta-hydroxybutyrate (bHBA) were unchanged, dapagliflozin significantly increased the postprandial bHBA response. This was seen in the context of increased postprandial glucagon levels by dapagliflozin, without influencing postprandial insulin or glucose levels. Dapagliflozin did not affect fasting or postprandial plasma cholesterol and triglycerides nor postprandial inflammatory markers. Fasting apolipoprotein B48 was decreased without affecting the postprandial response. Markers of inflammation and vascular function did not change. Conclusion: Treatment with dapagliflozin of patients with T2DM led to a reduction of fasting chylomicron remnants and increased postprandial ketone bodies compared to placebo suggesting enhanced hepatic fatty acid oxidation. The latter may have been caused by decreasing the insulin-glucagon ratio. The beneficial clinical effects seen in the trials using dapagliflozin most likely are not due to effects on postprandial inflammation nor postprandial lipemia.

A placebo-controlled proof-of-concept study of alirocumab on postprandial lipids and vascular elasticity in insulin-treated patients with type 2 diabetes mellitus.

AIM: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD) linked to atherogenic dyslipidaemia and postprandial hyperlipidaemia. Alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, improves CVD risk by reducing the concentration of low-density lipoprotein-cholesterol (LDL-C). However, effects of PCK9 inhibitors on other aspects of diabetic dyslipidaemia, particularly in the postprandial situation, are less clear. MATERIAL AND METHODS: Twelve male patients with T2DM on an intensive insulin regimen completed a 6-week randomized, double-blind, placebo-controlled, proof-of-concept study. Participants received three biweekly dosages of subcutaneous alirocumab (150 mg) or placebo. Before and after the intervention, fasting and postprandial triglyceride (TG) plasma levels, apolipoprotein (apo) B48, lipoprotein composition isolated by ultracentrifugation, vascular function and markers of inflammation were evaluated. RESULTS: Alirocumab treatment reduced fasting plasma TG levels (between group median change -24.7%; P = 0.018) and fasting apoB48 serum levels (-35.9%; P = 0.039) compared with placebo. Alirocumab reduced the plasma TG area under the curve (AUC) (-26.4%; P = 0.006) and apoB48 AUC (-55.7%; P = 0.046), as well as plasma TG incremental AUC (-21.4%; P = 0.04) and apoB48 incremental AUC (-26.8%; P = 0.02). In addition, alirocumab reduced fasting and postprandial TG levels in very low-density lipoprotein (VLDL) and LDL. Alirocumab improved fasting pulse wave velocity, but no changes in postprandial markers of inflammation were observed. CONCLUSIONS: In addition to the well-known LDL-C-reducing effects, 6 weeks of alirocumab treatment lowered both fasting and postprandial plasma TG levels by reducing the TG levels in VLDL and LDL and the concentration of intestinal remnants.

Effect of Vitamin D3 on the Postprandial Lipid Profile in Obese Patients: A Non-Targeted Lipidomics Study.

Abstract: Postprandial lipemia can lead to an accumulation of atherogenic lipoproteins in the circulation associated with systemic low-grade inflammation and an increased risk of cardiovascular disease. Lifestyle and pharmacological treatments are usually prescribed for prevention. Vitamin D3 (cholecalciferol), as an anti-atherogenic agent, is being taken into consideration due to its potential beneficial effects in lipid metabolism and its anti-inflammatory potency. To assess the effects of vitamin D3 in the postprandial lipid profile in obese, vitamin D-deficient women, a non-targeted lipidomics approach using liquid chromatography coupled to a quadrupole time-of flight mass spectrometer was used to identify and quantitate a wide-range of circulating lipid species, including diglycerides, lysophosphatidylcholines, phosphatidylcholines, phosphatidylethanolamines, sphingomyelins and triglycerides. The most important changes were found in plasmatic sphingomyelin levels, which experience a decrease after vitamin D3 intake. Our results suggest a turnover of sphingomyelins, probably due to an increased activity of neutral sphingomyelinases, and, therefore, with implications in the clearance of chylomicrons, LDL and VLDL, decreasing postprandial inflammation and macrophage adherence to endothelia, potentially improving cardiovascular disease risk.

Effect of a treat-to-target intervention of cardiovascular risk factors on subclinical and clinical atherosclerosis in rheumatoid arthritis: a randomised clinical trial.

BACKGROUND: Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular disease (CVD). No long-term intervention trials on CVD risk factors have been published, and a debate on the efficacy of controlling traditional risk factors in RA is ongoing. We aimed to evaluate a treat-to-target approach versus usual care regarding traditional CVD risk factors in patients with RA. METHODS: In this open-label, randomised controlled trial, patients with RA aged <70 years without prior CVD or diabetes mellitus were randomised 1:1 to either a treat-to-target approach or usual care of traditional CVD risk factors. The primary outcome was defined as change in carotid intima media thickness (cIMT) over 5 years, and the secondary outcome was a composite of first occurrence of fatal and non-fatal cardiovascular events. RESULTS: A total of 320 patients (mean age 52.4 years; 69.7% female) with RA underwent randomisation and 219 patients (68.4%) completed 5 years of follow-up. The mean cIMT progression was significantly reduced in the treat-to-target group compared with usual care (0.023 [95% CI 0.011 to 0.036] mm vs 0.045 [95% CI 0.030 to 0.059] mm; p=0.028). Cardiovascular events occurred in 2 (1.3%) of the patients in the treat-to-target group vs 7 (4.7%) in those receiving usual care (p=0.048 by log-rank test). CONCLUSION: This study provides evidence on the benefit of a treat-to-target approach of traditional CVD risk factors for primary prevention in patients with well-treated RA. TRIAL REGISTRATION NUMBER: NTR3873.

Increased NEFA levels reduce blood Mg2+ in hypertriacylglycerolaemic states via direct binding of NEFA to Mg2.

AIMS/HYPOTHESIS: The blood triacylglycerol level is one of the main determinants of blood Mg2+ concentration in individuals with type 2 diabetes. Hypomagnesaemia (blood Mg2+ concentration <0.7 mmol/l) has serious consequences as it increases the risk of developing type 2 diabetes and accelerates progression of the disease. This study aimed to determine the mechanism by which triacylglycerol levels affect blood Mg2+ concentrations. METHODS: Using samples from 285 overweight individuals (BMI >27 kg/m2) who participated in the 300-Obesity study (an observational cross-sectional cohort study, as part of the Human Functional Genetics Projects), we investigated the association between serum Mg2+ with laboratory variables, including an extensive lipid profile. In a separate set of studies, hyperlipidaemia was induced in mice and in healthy humans via an oral lipid load, and blood Mg2+, triacylglycerol and NEFA concentrations were measured using colourimetric assays. In vitro, NEFAs harvested from albumin were added in increasing concentrations to several Mg2+-containing solutions to study the direct interaction between Mg2+ and NEFAs. RESULTS: In the cohort of overweight individuals, serum Mg2+ levels were inversely correlated with triacylglycerols incorporated in large VLDL particles (r = -0.159, p ≤ 0.01). After lipid loading, we observed a postprandial increase in plasma triacylglycerol and NEFA levels and a reciprocal reduction in blood Mg2+ concentration both in mice (Δ plasma Mg2+ -0.31 mmol/l at 4 h post oral gavage) and in healthy humans (Δ plasma Mg2+ -0.07 mmol/l at 6 h post lipid intake). Further, in vitro experiments revealed that the decrease in plasma Mg2+ may be explained by direct binding of Mg2+ to NEFAs. Moreover, Mg2+ was found to bind to albumin in a NEFA-dependent manner, evidenced by the fact that Mg2+ did not bind to fatty-acid-free albumin. The NEFA-dependent reduction in the free Mg2+ concentration was not affected by the presence of physiological concentrations of other cations. CONCLUSIONS/INTERPRETATION: This study shows that elevated NEFA and triacylglycerol levels directly reduce blood Mg2+ levels, in part explaining the high prevalence of hypomagnesaemia in metabolic disorders. We show that blood NEFA level affects the free Mg2+ concentration, and therefore, our data challenge how the fractional excretion of Mg2+ is calculated and interpreted in the clinic.

Dyslipidemias in clinical practice.

Most dyslipidemic conditions have been linked to an increased risk of cardiovascular disease. Over the past few years major advances have been made regarding the genetic and metabolic basis of dyslipidemias. Detailed characterization of the genetic basis of familial lipid disorders and knowledge concerning the effects of environmental factors on the expression of dyslipidemias have increased substantially, contributing to a better diagnosis in individual patients. In addition to these developments, therapeutic options to lower cholesterol levels in clinical practice have expanded even further in patients with familial hypercholesterolemia and in subjects with cardiovascular disease. Finally, promising upcoming therapeutic lipid lowering strategies will be reviewed. All these advances will be discussed in relation to current clinical practice with special focus on common lipid disorders including familial dyslipidemias.

Progression of subclinical atherosclerosis in subjects with rheumatoid arthritis and the metabolic syndrome.

BACKGROUND AND AIMS: Rheumatoid arthritis (RA) has been associated with an increased risk of atherosclerosis. We aimed to evaluate the progression of carotid intima media thickness (cIMT) in RA patients subject to a cardiovascular treat-to-target intervention. In addition, the presence of the metabolic syndrome (MetS) on cIMT outcomes was evaluated. METHODS: We performed a cohort analysis of FRANCIS, in which RA patients ≤70 years without CVD or diabetes mellitus were randomized for either a treat-to-target intervention or usual care concerning CVD risk factors. MetS was scored at baseline. RESULTS: Three-year data was available in 212 well-controlled RA patients. The treat-to-target intervention resulted in a lower cIMT progression over three years compared to the usual care. However, there was no difference in cIMT at three years between groups. MetS was present in 40.1% of RA patients. Baseline cIMT was significantly higher in RA patients with MetS compared to those without (0.619 (0.112) versus 0.557 (0.104) mm; p < 0.001). After three years, cIMT progression was comparable (0.043 (0.071) versus 0.043 (0.072) mm; p = 0.96). In RA patients with MetS, the presence of plaques increased over three years from 12.9% to 23.5% (p = 0.01). The type of intervention had no effect on cIMT progression in RA patients with MetS. However, in subjects without MetS, treat-to-target resulted in a lower progression. CONCLUSIONS: RA patients with MetS showed an increased CVD risk profile based on both a higher prevalence of CVD risk factors and structural vascular changes. A treat-to-target approach of CVD risk factors reduced cIMT progression only in RA patients without MetS.

Evidence for increased chylomicron remnants in rheumatoid arthritis.

BACKGROUND: Levels of apolipoprotein (apo) B48 may be increased in conditions associated with systemic inflammation and increased cardiovascular disease (CVD) risk such as rheumatoid arthritis (RA). We aimed to evaluate apo B48 levels in patients with RA in relation to subclinical atherosclerosis. METHODS: Patients with RA (without CVD) and controls without RA but with high CVD risk (based on the presence of diabetes mellitus or a history of CVD) and healthy controls were included in this cross-sectional study. Carotid intima-media thickness (cIMT) was measured as a surrogate for vascular damage. RESULTS: In total, 312 patients with RA, 65 controls with high CVD risk and 36 healthy controls were included. Patients with RA had the highest mean apo B48 (10.00 ± 6.65 mg/L) compared to controls with high CVD risk and healthy controls (8.37 ± 5.16 and 5.22 ± 2.46, P < .001). Triglycerides levels were comparable with controls. In RA, apo B48 correlated positively with triglycerides (r = .645; P < .001) but not with cIMT. However, in RA subjects not using lipid or blood pressure lowering medication, a weak correlation was found with cIMT (r = .157; P = .014). RA patients in the highest apo B48 tertile were more often rheumatoid factor positive and anti-CCP positive compared to the lowest tertile. CONCLUSION: Rheumatoid arthritis patients have higher levels of apo B48 compared to controls with high CVD risk and healthy controls, with normal levels of triglycerides. This accumulation of atherogenic chylomicron remnants may contribute to the elevated CVD risk in RA patients.

Interventions in type 2 diabetes mellitus and cardiovascular mortality-An overview of clinical trials.

Diabetes mellitus type 2 (T2DM) has been associated with an increased cardiovascular risk. Improving glycaemia or other traditional cardiovascular risk factors may reduce cardiovascular risk in patients with T2DM. However, single risk intervention in T2DM has not provided convincing evidence in the reduction of cardiovascular risk. The aim of this paper is to provide an overview of clinical trials involving reduction of cardiovascular outcomes in patients with T2DM. Trials with glucose lowering therapies have shown conflicting results. Intensive therapy to reduce glycaemia has shown some benefit on composite cardiovascular endpoints but these benefits take a longer period to emerge. Recent studies with empagliflozin and glucagon-like peptide-1 (GLP-1) agonists show promising results, but the mechanisms are most likely not mediated by improved glycaemia, given the relatively rapid effects. Both LDL-cholesterol and blood pressure reduction have been proven by large meta-analysis to reduce both cardiovascular events and mortality in all patients with T2DM. Treatment of microalbuminuria and anti-platelet therapy have only been proven in diabetic patients with increased cardiovascular risk. Classical lifestyle interventions have been disappointing with respect to cardiovascular outcome, possibly due to limited weight reduction. So far, the strongest evidence lies on bariatric surgery and a multifactorial intervention to reduce mortality and cardiovascular events in the long term.