Bernt Johan von Scholten

Global Changes in Food Supply and the Obesity Epidemic

Purpose of ReviewWe explore how a global shift in the food system caused by global economic growth, increase in available food per capita and in food processing is a driver of the obesity epidemic.Recent FindingsEconomic development in most areas of the world has resulted in increased purchasing power and available per capita food. Supermarkets and a growing fast-food industry have transformed our dietary pattern. Ultra-processed food rich on sugars and saturated fat is now the major source of energy in most countries. The shift in food supply is considered a major driver of the obesity epidemic and the increasing prevalence of accompanying complications, such as type 2 diabetes, cardiovascular disease and cancer. However, the global shift might also have direct effects on the increase in type 2 diabetes, cardiovascular disease and cancer, independently of overweight and obesity.SummaryThe shift in the food supply is a major driver of the obesity epidemic.

Glucagon-like peptide 1 receptor agonist (GLP-1 RA): long-term effect on kidney function in patients with type 2 diabetes

AIMS In a short-term study including 31 patients with type 2 diabetes, glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment was associated with a significant reversible decline in GFR. Twenty-three patients re-initiated GLP-1 RA treatment after the primary study, and the aim was to investigate the long-term effect on kidney function. METHODS We included 30 patients in a one-year extension study, all initially treated with liraglutide for seven weeks. During follow-up 23 were treated with liraglutide and seven untreated. Primary outcome was change in GFR ((51)Cr-EDTA plasma clearance). RESULTS Patients were 61.5 (10.0) years and HbA(1c) 60.1 (13.8) mmol/mol. Baseline GFR was 100.6 (24.9) mL/min/1.73 m(2) and was reduced by 11 (95% CI: 6.6-15.7, p < 0.001) mL/min/1.73 m(2), independent of change in 24-h systolic blood pressure (SBP), weight, UAER or HbA(1c) (p≥0.33). Geometric mean (IQR) of UAER was 25.5 (9.9-50.9) mg/d and was reduced by 27 (95% CI: 5-44; p = 0.020)%, and 24-h SBP was reduced by 8.2 (p = 0.048) mmHg. No changes occurred in untreated patients. CONCLUSIONS Long-term treatment with liraglutide was associated with a reduction in measured GFR similar to the effect during short-term treatment, suggesting a metabolic or haemodynamic reversible effect and not structural changes. Moreover, UAER and 24-h SBP were reduced. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01499108.

The effect of liraglutide on renal function: A randomized clinical trial

Among patients with type 2 diabetes and albuminuria, cardiorenal morbidity and mortality are high despite multifactorial treatment. Short‐term reduction in albuminuria is considered suggestive of long‐term renoprotective effects. We evaluated the renal effects of the glucagon‐like peptide‐1 (GLP‐1) receptor agonist liraglutide on top of multifactorial care, including renin‐angiotensin‐system (RAS)‐inhibition.

Abnormal echocardiography in patients with type 2 diabetes and relation to symptoms and clinical characteristics

Objectives: We aimed to determine the prevalence of echocardiographic abnormalities and their relation to clinical characteristics and cardiac symptoms in a large, contemporary cohort of patients with type 2 diabetes. Results: A total of 1030 patients with type 2 diabetes participated. Echocardiographic abnormalities were present in 513 (49.8%) patients, mainly driven by a high prevalence of diastolic dysfunction 178 (19.4%), left ventricular hypertrophy 213 (21.0%) and left atrial enlargement, 200 (19.6%). The prevalence increased markedly with age from 31.1% in the youngest group (<55 years) to 73.9% in the oldest group (>75 years) (p < 0.001) and was equally distributed among the sexes (p = 0.76). In univariate analyses, electrocardiographic abnormalities, age, body mass index, known coronary heart disease, hypertension, albuminuria, diabetes duration and creatinine were associated with abnormal echocardiography along with dyspnoea and characteristic chest pain (p < 0.05 for all). Neither of the cardiac symptoms nor clinical characteristics had sufficient sensitivity and specificity to accurately identify patients with abnormal echocardiography. Conclusion: Echocardiographic abnormalities are very common in outpatients with type 2 diabetes, but neither cardiac symptoms nor clinical characteristics are effective to identify patients with echocardiographic abnormalities.

The influence of pharmaceutically induced weight changes on estimates of renal function: A patient-level pooled analysis of seven randomised controlled trials of glucose lowering medication

BACKGROUND Estimation of kidney function (eGFR) is essential in monitoring of patients with kidney disease. Estimates of kidney function based on serum creatinine are derived from cross-sectional studies. If body weight (BW) changes, this might affect creatinine and eGFR. The Cockcroft-Gault (CG) equation includes creatinine and BW, whereas the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations only include creatinine. METHODS Data were pooled from the six LEAD (Liraglutide Effect and Action in Diabetes) trials and the LIRA-DPP4 trial. The trials were conducted in patients with type 2 diabetes and of 26weeks duration. We investigated changes in eGFR for patients treated with liraglutide, and for patients treated with glucose-lowering medications with less weight-reducing effects (insulin glargine, glimepiride, exenatide and rosiglitazone). RESULTS We included 5100 patients (liraglutide n=3173, comparator n=1927). Mean (SD) CKD-EPI eGFR was 81.2 (20.6) ml/min/1.73m(2) for liraglutide and 81.6 (20.3) ml/min/1.73m(2) for comparator. For liraglutide, BW changed -1.9 (95% CI (-2.0; -1.8)) kg, for comparator BW changed 0.2 (95% CI (0.03; 0.3)) kg. Using regression modelling, a 10% BW decrease yielded no change in creatinine, MDRD eGFR or CKD-EPI eGFR for both liraglutide and comparator, but was associated with a 10.2% (-11.3%; -9.1%) decrease in CG eGFR for liraglutide, and a 10.6% (-12.0%; -9.1%) decrease for comparator. CONCLUSIONS A liraglutide-induced weight reduction of 1.9kg was not associated with change in creatinine. Accordingly, there was no change in weight-independent estimates of GFR, whereas weight-dependent estimates were changed. The MDRD and CKD-EPI equations can be used in patients experiencing pharmaceutically induced weight reductions.

Pleiotropic effects of liraglutide treatment on renal risk factors in type 2 diabetes: Individual effects of treatment

AIMS/HYPOTHESIS Management of diabetic nephropathy includes reduction of albuminuria, blood pressure and weight. The GLP-1 receptor agonist liraglutide may possess these pleiotropic effects in addition to the glucose lowering effect. We aimed to elucidate the individual liraglutide treatment response by determining if high responders (highest reduction) in each risk factor also had high response in other renal risk factors (cross-dependency). METHODS Open-label study: 31 type 2 diabetics treated with liraglutide for 7weeks. After 3weeks washout 23 re-started treatment and were followed for 1year. HbA1c, weight, systolic blood pressure (SBP), urinary albumin excretion rate (UAER) and mGFR (51Cr-EDTA) were evaluated. Changes in high (Q4) vs. low responders (Q1-Q3) were compared for each renal risk factor. The effects of treatment/off treatment/re-treatment (off-on/off-on effect) were evaluated to account for random effects. RESULTS After 7weeks HbA1c was reduced 6(95% CI: 3;9)mmol/mol, weight 2.5(1.8;3.2)kg, SBP 4(-1;9)mmHg, UAER 30(12;44)% and mGFR 11(7;14)ml/min per 1.73m2. mGFR high responders had a significant reduction in weight compared to low responders (4.3 vs. 1.9kg; p=0.002). SBP high responders had a tendency of a higher reduction in UAER compared to low responders (47 vs. 23%, p=0.14). No cross-dependency was observed in any of the other renal risk factors (p≥0.16). Treatment response did not differ after 7weeks and 1year (p≥0.12). CONCLUSIONS/INTERPRETATION Liraglutide possesses pleiotropic effects on renal risk factors. On patient level, effect on the individual risk factor cannot be anticipated based on response in other risk factors. Response when re-starting treatment did not differ, indicating that our primary findings were not random.

Epicardial, pericardial and total cardiac fat and cardiovascular disease in type 2 diabetic patients with elevated urinary albumin excretion rate:

Background We evaluated the association of cardiac adipose tissue including epicardial adipose tissue and pericardial adipose tissue with incident cardiovascular disease and mortality, coronary artery calcium, carotid intima media thickness and inflammatory markers. Design A prospective study of 200 patients with type 2 diabetes and elevated urinary albumin excretion rate (UAER). Methods Cardiac adipose tissue was measured from baseline echocardiography. The composite endpoint comprised incident cardiovascular disease and all-cause mortality. Coronary artery calcium, carotid intima media thickness and inflammatory markers were measured at baseline. Cardiac adipose tissue was investigated as continuous and binary variable. Analyses were performed unadjusted (model 1), and adjusted for age, sex (model 2), body mass index, low-density lipoprotein cholesterol, smoking, glycated haemoglobin, and systolic blood pressure (model 3). Results Patients were followed-up after 6.1 years for non-fatal cardiovascular disease (n = 29) or mortality (n = 23). Cardiac adipose tissue (p = 0.049) and epicardial adipose tissue (p = 0.029) were associated with cardiovascular disease and mortality in model 1. When split by the median, patients with high cardiac adipose tissue had a higher risk of cardiovascular disease and mortality than patients with low cardiac adipose tissue in unadjusted (hazard ratio 1.9, confidence interval: 1.1; 3.4, p = 0.027) and adjusted (hazard ratio 2.0, confidence interval: 1.1; 3.7, p = 0.017) models. Cardiac adipose tissue (p =  0.033) was associated with baseline coronary artery calcium (model 1) and interleukin-8 (models 1–3, all p < 0.039). Conclusions In type 2 diabetes patients without coronary artery disease, high cardiac adipose tissue levels were associated with increased risk of incident cardiovascular disease or all-cause mortality even after accounting for traditional cardiovascular disease risk factors. High cardiac adipose tissue amounts were associated with subclinical atherosclerosis (coronary artery calcium) and with the pro-atherogenic inflammatory marker interleukin-8.

Effects of liraglutide on cardiovascular risk biomarkers in patients with type 2 diabetes and albuminuria: A sub‐analysis of a randomized, placebo‐controlled, double‐blind, crossover trial

We assessed the effects of liraglutide treatment on five cardiovascular risk biomarkers, reflecting different pathophysiology: tumour necrosis factor (TNF)‐α; soluble urokinase plasminogen activator receptor (suPAR); mid‐regional pro‐adrenomedullin (MR‐proADM); mid‐regional pro‐atrial natriuretic peptide (MR‐proANP); and copeptin, in people with type 2 diabetes with albuminuria. In a randomized, double‐blind, placebo‐controlled, crossover trial we enrolled people with type 2 diabetes and persistent albuminuria (urinary albumin‐to‐creatinine ratio [UACR] >30 mg/g) and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. Participants received liraglutide (1.8 mg/d) and matched placebo for 12 weeks, in random order. The primary endpoint was change in albuminuria; this was a prespecified sub‐study. A total of 32 participants were randomized, of whom 27 completed the study. TNF‐α level was 12% (95% confidence interval [CI] 3; 20) lower after liraglutide treatment compared with placebo (P = .012); MR‐proADM level was 4% (95% CI 0; 8) lower after liraglutide treatment compared with placebo (P = .038), and MR‐proANP level was 13% (95% CI 4; 21) lower after liraglutide treatment compared with placebo (P = .006). In the present study, we showed anti‐inflammatory effects of liraglutide treatment, reflected in reductions in levels of TNF‐α and MR‐proADM, while the reduction in MR‐proANP levels may represent a clinically relevant benefit with regard to heart failure.

Cardiac Autonomic Function Is Associated With the Coronary Microcirculatory Function in Patients With Type 2 Diabetes.

Cardiac autonomic dysfunction and cardiac microvascular dysfunction are diabetic complications associated with increased mortality, but the association between these has been difficult to assess. We applied new and sensitive methods to assess this in patients with type 2 diabetes mellitus (T2DM). In a cross-sectional design, coronary flow reserve (CFR) assessed by cardiac 82Rb-positron emission tomography/computed tomography, cardiac autonomic reflex tests, and heart rate variability indices were performed in 55 patients with T2DM, without cardiovascular disease, and in 28 control subjects. Cardiac 123I-metaiodobenzylguanidine scintigraphy was conducted in a subgroup of 29 patients and 14 control subjects and evaluated as the late heart-to-mediastinum ratio and washout rate. Impaired function of all the cardiac autonomic measures (except the washout rate) was associated with reduced CFR. A heart rate variability index, reflecting sympathetic and parasympathetic function (low-frequency power), and the late heart-to-mediastinum ratio, reflecting the function of adrenergic receptors and sympathetic activity, were positively correlated with CFR after adjustment for age and heart rate. The late heart-to- mediastinum ratio remained correlated with CFR after further adjustment. In patients with T2DM without cardiovascular disease, we demonstrate an independent association between cardiac autonomic function and CFR. We suggest that a reduced cardiac autonomic function and damage to the adrenergic receptors may contribute to the development of cardiac microvascular dysfunction.

Trimethylamine N-oxide (TMAO) as a New Potential Therapeutic Target for Insulin Resistance and Cancer

BACKGROUND The intake of animal products in food has been associated with both the development of insulin resistance and gastrointestinal cancers (GIC). Through the digestion of animal protein and other constituents of animal products, the commensal bacteria in the gut (the gut microbiota) forms metabolites that can contribute to the development of both insulin resistance and cancer. Trimethylamine-N-Oxide (TMAO) is such a molecule and has recently drawn a lot of attention as it may be a risk factor for - and a link between - the gut microbiota and cardiovascular and renal disease. Further, TMAO is anticipated to have significance as a biomarker of - or even an independent risk factor for - other undesirable conditions, including insulin resistance and GIC. TMAO originates from a precursor, trimethylamine (TMA) that is a metabolite of various precursors; mainly choline and carnitine from ingested foods. METHODS We review the literature on TMAO as a shared risk factor and/or pathway between insulin resistance and GIC risk and take the reader through the literature of interventions that could reduce formation of TMAO and thereby the risk of insulin resistance and GIC. The purpose of the work is to generate a hypothesis to be tested in preclinical and clinical studies. RESULTS TMAO seems to be associated with both insulin resistance and GIC risk and also with atherosclerotic cardiovascular disease. One shared pathway is the formation of N-Nitroso compounds, a group of metabolites that can cause DNA-damage and epigenetic changes. Levels of TMAO can be reduced by limiting the dietary intake of certain foods, most importantly animal products. Further, certain drugs, namely Meldonium and 3,3-dimethyl- 1-butanol, may inhibit the formation of TMAO by inhibiting bacterial enzymes. CONCLUSIONS The TMAO pathway and its metabolites are possibly involved in the development of two major health problems: insulin resistance and cancer. Within these pathways novel therapeutic targets may be identified. Further research is needed in order to verify existing or develop new pharmacological agents that modify these pathways and reduce the risk of insulin resistance and GIC.