Joop D. Lefrandt

Metformin: Taking away the candy for cancer?

Metformin is widely used in the treatment of diabetes mellitus type 2 where it reduces insulin resistance and diabetes-related morbidity and mortality. Population-based studies show that metformin treatment is associated with a dose-dependent reduction in cancer risk. The metformin treatment also increases complete pathological tumour response rates following neoadjuvant chemotherapy for breast cancer, suggesting a potential role as an anti-cancer drug. Diabetes mellitus type 2 is associated with insulin resistance, elevated insulin levels and an increased risk of cancer and cancer-related mortality. This increased risk may be explained by activation of the insulin- and insulin-like growth factor (IGF) signalling pathways and increased signalling through the oestrogen receptor. Reversal of these processes through reduction of insulin resistance by the oral anti-diabetic drug metformin is an attractive anti-cancer strategy. Metformin is an activator of AMP-activated protein kinase (AMPK) which inhibits protein synthesis and gluconeogenesis during cellular stress. The main downstream effect of AMPK activation is the inhibition of mammalian target of rapamycin (mTOR), a downstream effector of growth factor signalling. mTOR is frequently activated in malignant cells and is associated with resistance to anticancer drugs. Furthermore, metformin can induce cell cycle arrest and apoptosis and can reduce growth factor signalling. This review discusses the role of diabetes mellitus type 2 and insulin resistance in carcinogenesis, the preclinical rationale and potential mechanisms of metformins anti-cancer effect and the current and future clinical developments of metformin as a novel anti-cancer drug.

Increased alpha-linolenic acid intake lowers C-reactive protein, but has no effect on markers of atherosclerosis

Objective: To investigate the effects of increased alpha-linolenic acid (ALA)-intake on intima–media thickness (IMT), oxidized low-density lipoprotein (LDL) antibodies, soluble intercellular adhesion molecule-1 (sICAM-1), C-reactive protein (CRP), and interleukins 6 and 10.Design: Randomized double-blind placebo-controlled trial.Subjects: Moderately hypercholesterolaemic men and women (55±10 y) with two other cardiovascular risk factors (n=103).Intervention: Participants were assigned to a margarine enriched with ALA (fatty acid composition 46% LA, 15% ALA) or linoleic acid (LA) (58% LA, 0.3% ALA) for 2 y.Results: Dietary ALA intake was 2.3 en% among ALA users, and 0.4 en% among LA users. The 2-y progression rate of the mean carotid IMT (ALA and LA: +0.05 mm) and femoral IMT (ALA:+0.05 mm; LA:+0.04 mm) was similar, when adjusted for confounding variables. After 1 and 2 y, ALA users had a lower CRP level than LA users (net differences −0.53 and −0.56 mg/l, respectively, P<0.05). No significant effects were observed in oxidized LDL antibodies, and levels of sICAM-1, interleukins 6 and 10.Conclusions: A six-fold increased ALA intake lowers CRP, when compared to a control diet high in LA. The present study found no effects on markers for atherosclerosis.Sponsorship: The Dutch ‘Praeventiefonds’.

The metabolic syndrome in cancer survivors

The metabolic syndrome, as a cluster of cardiovascular risk factors, may represent an important connection between cancer treatment and its common late effect of cardiovascular disease. Insight into the aetiology of the metabolic syndrome after cancer treatment might help to identify and treat cancer survivors with increased cardiovascular risk. In this review, we summarise current knowledge on the prevalence and pathophysiology of the metabolic syndrome in cancer survivors, and discuss current intervention strategies with an emphasis on new developments.

Carotid plaque formation and serum biomarkers

Treatment of carotid artery stenosis by endarterectomy or stenting can significantly reduce stroke risk, but is also associated with surgery related mortality and morbidity. At present it is neither possible to assess whether a carotid plaque will become symptomatic or not, nor to define the time when symptoms will occur. Identification of carotid plaques which confer excess risk of neurologic events is fundamental in the selection of patients for vascular intervention. Molecular processes such as inflammation, lipid accumulation, apoptosis, proteolysis, thrombosis and angiogenesis have shown to be highly related with plaque vulnerability. Serum biomarkers reflecting these processes may distinguish unstable from stable carotid artery stenosis and thus be a powerful tool in the selection of patients for carotid surgery. Until now, no serum biomarker has qualified for regular clinical use in carotid artery disease. However, several biomarkers, especially markers of inflammatory or proteolytic activity seem to be promising in the identification of vulnerable carotid plaques. Therefore, it is anticipated that non-invasive risk assessment in carotid artery disease by determination of serum biomarker levels may play an important future role in clinical practice improving better selection criteria for vascular intervention.

Long-Term Cardiovascular Mortality in Patients With Differentiated Thyroid Carcinoma: An Observational Study

PURPOSE The primary aim was to study the risk of cardiovascular mortality in patients with differentiated thyroid carcinoma (DTC). Secondary aims were to evaluate all-cause mortality and explore the relation between thyroid-stimulating hormone (TSH; also known as thyrotropin) level and these outcome parameters. PATIENTS AND METHODS Subjects from two cohorts were retrospectively compared by Cox regression analyses; 524 patients with DTC and 1,572 sex- and age-matched controls from a large population-based study in the same geographic region. RESULTS Mean age plus or minus standard deviation was 49 ± 14 years. Median follow-up was 8.5 years (interquartile range [IQR], 4.1 to 15.9 years) for patients with DTC and 10.5 years (IQR, 9.9 to 10.9 years) for controls. One hundred patients with DTC (19.1%) died, 22 (4.2%) as a result of cardiovascular disease, 39 (7.4%) as a result of DTC, and 39 (7.4%) as a result of other/unknown causes. Eighty-five controls (5.4%) died, 24 (1.5%) as a result of cardiovascular disease and 61 (3.9%) as a result of other/unknown causes. Patients with DTC had an increased risk of cardiovascular and all-cause mortality (hazard ratios [HRs], 3.35 [95% CI, 1.66 to 6.74] and 4.40 [95% CI, 3.15 to 6.14], respectively, adjusted for age, sex, and cardiovascular risk factors). Within the DTC group, TSH level was predictive for cardiovascular mortality; the adjusted HR was 3.08 (95% CI, 1.32 to 7.21) for each 10-fold decrease in geometric mean TSH level. CONCLUSION The risk of cardiovascular and all-cause mortality is increased in patients with DTC, independent of age, sex, and cardiovascular risk factors. A lower TSH level is associated with increased cardiovascular mortality, supporting the current European Thyroid Association and the American Thyroid Association guidelines of tempering TSH suppression in patients with low risk of cancer recurrence. Furthermore, patients with DTC may benefit from assessment and treatment of cardiovascular risk factors.

Accumulation of Advanced Glycation End Products and Chronic Complications in ESRD Treated by Dialysis

Cardiovascular and connective tissue disorders are very common in patients with end-stage renal disease (ESRD), and the accumulation of advanced glycation end products (AGEs) is significantly increased in these patients. Accumulation of AGEs is believed to have a role in tissue protein aging and the pathogenesis of such age-related diseases as diabetes and ESRD. AGEs accumulate in patients with ESRD as a result of nonenzymatic glycation, oxidative stress, and diminished clearance of AGE precursors. Some AGEs show characteristic brown pigmentation and fluorescence, form protein-protein cross-links, and may ligate with AGE-specific receptors, inducing oxidative stress and cytokine production. This review focuses on the clinical relevance of AGE accumulation in patients with ESRD treated by dialysis for the development of long-term complications. The formation and accumulation of AGEs in patients with ESRD are discussed, as well as the relationship between AGE accumulation and such major complications of ESRD as cardiovascular and connective tissue disorders.

Skin Autofluorescence as a Measure of Advanced Glycation End Products Deposition Is Elevated in Peripheral Artery Disease

Objective—Evidence for an important role of advanced glycation end products (AGEs) in the development of atherosclerosis and cardiovascular disease beyond diabetes mellitus and renal disease is growing. Skin autofluorescence (SAF) is a validated noninvasive measure of tissue AGEs. We hypothesized that SAF is elevated in peripheral artery disease (PAD). Methods and Results—A case–control study was performed in 492 patients with PAD and 164 controls, matched for age (mean 66±10 years) and presence of diabetes mellitus. Cardiovascular risk factors and comorbidity (coronary artery disease, cerebrovascular disease, abdominal aortic aneurysm) were assessed. SAF was measured with the AGE Reader. SAF was higher in patients compared with controls: geometric mean 2.77 (95% confidence interval [CI], 2.71–2.83) versus 2.44 (95% CI, 2.35–2.53) arbitrary units, P=0.4×10−8. In logistic regression, the adjusted odds ratio for the presence of PAD was 2.47 (95% CI, 1.66–3.69) per 1 unit increase of SAF. PAD patients with cardiovascular comorbidity had a higher SAF compared with those without: geometric mean 2.93 (95% CI, 2.85–3.02) versus 2.63 (95% CI, 2.55–2.71) arbitrary units, P=0.4×10−6, also after correction for confounders. Regression analysis showed that age, smoking, diabetes mellitus, chronic kidney disease, and a history of cerebrovascular disease or abdominal aortic aneurysm were independently associated with SAF in the patients with PAD. Conclusion—Accumulation of tissue AGEs is increased in patients with PAD, independent of cardiovascular risk factors and comorbidity, although these conditions are associated with a further increase. These findings underscore the importance of AGEs in PAD, irrespective of the presence of diabetes mellitus and renal insufficiency.

Skin Autofluorescence Is Associated With 5-Year Mortality and Cardiovascular Events in Patients With Peripheral Artery Disease

Objective—Advanced glycation end products play a pivotal role in atherosclerosis. Recently, we showed that tissue advanced glycation end products deposition, noninvasively assessed by skin autofluorescence (SAF), is increased in patients with peripheral artery disease. The aim of the present study was to establish whether SAF is associated with all-cause mortality and with fatal or nonfatal major adverse cardiovascular events (MACE) in patients with peripheral artery disease. Approach and Results—We performed a single-center prospective cohort study of 252 patients with peripheral artery disease (mean age, 66±11 years), recruited from the outpatient clinic (October 2007 to June 2008) who were followed until June 2013. SAF was measured with the AGE Reader. The primary end point was all-cause mortality, and the secondary end point was fatal or nonfatal MACE, defined as cardiovascular death and nonfatal myocardial infarction or stroke. During a median follow-up of 5.1 (interquartile range, 5.0–5.3) years, 62 (25%) patients died. Fatal or nonfatal MACE occurred in 62 (25%) patients. A higher SAF was associated with increased risk for all-cause mortality (hazard ratio per unit increase, 2.01; 95% confidence interval, 1.40–2.88; P=0.0002) and fatal or nonfatal MACE (hazard ratio, 1.82; 95% confidence interval, 1.28–2.60; P=0.001), also after adjustment for cardiovascular risk factors and the use of lipid-lowering drugs (hazard ratio, 1.63; 95% confidence interval, 1.13–2.34; P=0.009 and hazard ratio, 1.50; 95% confidence interval, 1.04–2.17; P=0.03, for all-cause mortality and fatal and nonfatal MACE, respectively). Conclusions—SAF as a measure of advanced glycation end products deposition is independently associated with all-cause mortality and fatal or nonfatal MACE in patients with peripheral artery disease after a 5-year follow-up.

Skin Autofluorescence, a Non-Invasive Marker for AGE Accumulation, Is Associated with the Degree of Atherosclerosis

Introduction Advanced glycation endproducts (AGEs) may be involved in the development of atherosclerosis, beyond diabetes and renal disease. Skin autofluorescence (AF) is a non-invasive marker for AGEs. We examined whether skin AF is increased in (subclinical) atherosclerosis and associated with the degree of atherosclerosis independent of diabetes and renal function. Methods A cross-sectional study of 223 patients referred for primary (n = 163) or secondary (n = 60) prevention between 2006 and 2012 was performed. Skin AF was measured using the AGE-Reader. Ultrasonography was used to assess plaques in carotid and femoral arteries and computed tomography for the calculation of the coronary artery calcium score (CACS; in primary prevention only). Primary prevention patients were divided into a group with subclinical atherosclerosis defined as >1 plaque or CACS>100 (n = 67; age 53 year [interquartile range 48–56]; 49% male) and without (controls; 96; 43 [38–51]; 55%). Secondary prevention were patients with peripheral arterial disease (60; 64 [58–70]; 73%). Results Skin AF was higher in subclinical and clinical atherosclerosis compared with controls (skin AF 2.11 [interquartile range 1.83–2.46] and 2.71 [2.15–3.27] vs. 1.87 [1.68–2.12] respectively; P = 0.005 and <0.001). In a multivariate analysis, the association of skin AF with the atherosclerosis categories was independent of age, sex, diabetes, presence of the metabolic syndrome, Framingham Risk Score, and renal function. Skin AF correlated with most cardiovascular risk factors, Framingham risk score, and IMT and CACS. Conclusions Skin AF is increased in documented subclinical and clinical atherosclerosis, independent of known risk factors such as diabetes and renal disease. These data suggest that AGEs may be associated with the burden of atherosclerosis and warrant a prospective study to investigate its clinical usability as a risk assessment tool for primary prevention.

Dermal factors influencing measurement of skin autofluorescence.

BACKGROUND Skin autofluorescence (SAF) is a noninvasive marker of accumulation of advanced glycation end products. It predicts cardiovascular complications and mortality in diabetes and renal failure. We assessed the influence of potential common confounders in SAF measurement, by determining the effects of endogenous and exogenous local dermal changes by body creams, hyperemia, vasoconstriction, and hydration. METHODS SAF was measured before and after local administration of body lotion, day cream, sunscreen, or self-browning cream and after attempts to remove these effects with alcohol swabs and washing. SAF was measured before and during three hyperemia maneuvers: vasoconstriction and on a dry and wet skin. RESULTS The body lotion increased SAF by 18%. Day cream, sunscreen, and self-browning cream gave an increase of >100%. Except for body lotion, subsequent cleaning with alcohol swabs and washing with soap did not return SAF to baseline values. The effect of self-browning cream persisted for 2 weeks and that of sunscreen for 4 days. Hyperemia caused by a hot bath, capsicum cream, or postocclusive reactive hyperemia gave a decrease in SAF of, respectively, 18%, 22%, and 2.3%. Vasoconstriction caused by immersing the arm in cold water gave a 10% increase. Hydration state did not influence SAF. CONCLUSIONS Measurement of SAF is strongly affected by several skin creams. This effect was often not fully corrected by alcohol swabs and washing with soap and may persist for many days. Marked hyperemia and vasoconstriction also influence SAF. We advise avoiding these potential error sources.