Overall and inter-individual effect of four different drug classes on soluble urokinase plasminogen activator receptor in type 1 and type 2 diabetes.

AIM: To evaluate the effect of four different drug classes on soluble urokinase plasminogen activator receptor (suPAR), a biomarker active in multiple inflammatory processes and a risk factor for complications, in people with type 1 and type 2 diabetes. METHODS: We conducted post hoc analyses of a randomized, open-label, crossover trial including 26 adults with type 1 and 40 with type 2 diabetes with urinary albumin-creatinine ratio ≥30 and ≤500 mg/g assigned to 4-week treatments with telmisartan 80 mg, empagliflozin 10 mg, linagliptin 5 mg and baricitinib 2 mg, separated by 4-week washouts. Plasma suPAR was measured before and after each treatment. SuPAR change after each treatment was calculated and, for each individual, the best suPAR-reducing drug was identified. Subsequently, the effect of the best individual drug was compared against the mean of the other three drugs. Repeated-measures linear mixed-effects models were employed. RESULTS: The baseline median (interquartile range) plasma suPAR was 3.5 (2.9, 4.3) ng/mL. No overall effect on suPAR levels was observed for any one drug. The individual best-performing drug varied, with baricitinib being selected for 20 participants (30%), followed by empagliflozin for 19 (29%), linagliptin for 16 (24%) and telmisartan for 11 (17%). The individual best-performing drug reduced suPAR by 13.3% (95% confidence interval [CI] 3.7, 22.8; P = 0.007). The difference in suPAR response between the individual best-performing drug and the other three was -19.7% (95% CI -23.1, -16.3; P < 0.001). CONCLUSIONS: We demonstrated no overall effect of 4-week treatment with telmisartan, empagliflozin, linagliptin or baricitinib on suPAR. However, individualization of treatment might significantly reduce suPAR levels.

The importance of addressing multiple risk markers in type 2 diabetes: Results from the LEADER and SUSTAIN 6 trials.

AIMS: To investigate to what extent multiple risk marker improvements confer lower risk of cardiovascular and kidney complications in a contemporary type 2 diabetes population. MATERIALS AND METHODS: Post-hoc analysis of the LEADER (n = 8638; median follow-up 3.8 years) and SUSTAIN 6 (n = 3040; median follow-up 2.1 years) cardiovascular outcome trials. Participants were those with baseline and year-1 assessment of at least one of the parameters of interest; we pooled the liraglutide-/semaglutide- and placebo-treated groups and categorized them by number of risk markers with clinically relevant improvements after 1 year of study participation. We investigated risk of major adverse cardiovascular events (MACE), expanded MACE, cardiovascular death and nephropathy. Predefined clinically relevant changes: body weight loss ≥5%; reductions in: glycated haemoglobin ≥1%, systolic blood pressure ≥5 mmHg and low-density lipoprotein cholesterol ≥0.5 mmol/L; estimated glomerular filtration rate change ≥0 ml/min/1.73 m2 and urinary albumin-to-creatinine ratio change ≥30% of baseline value. Cox regression analysed risk of outcomes adjusted for baseline risk marker levels and treatment group and stratified by trial. RESULTS: Participants with two, three, or four or more improved risk markers versus participants with no risk marker improvement had reduced risk of expanded MACE [hazard ratio (95% confidence interval) 0.80 (0.67-0.96); 0.80 (0.66-0.97); 0.82 (0.66-1.02)], cardiovascular death [0.66 (0.45-0.96), 0.67 (0.45-0.99), 0.60 (0.38-0.94)] and nephropathy [0.71 (0.52-0.97), 0.48 (0.34-0.68), 0.43 (0.29-0.65)]. CONCLUSIONS: In persons with type 2 diabetes, improvements in ≥2 risk markers conferred cardiovascular risk reduction versus none or one improved risk marker. The nephropathy risk decreased with improvement in more risk markers. These findings stress the importance of multifactorial interventions targeting all risk markers.

Non-invasive assessment of temporal changes in myocardial microvascular function in persons with type 2 diabetes and healthy controls.

BACKGROUND: Cardiac Rubidium-82 (82 Rb) positron emission tomography/computed tomography (PET/CT) provides a measure of the myocardial blood flow and the myocardial flow reserve, which reflects the function of both large epicardial arteries and the myocardial microcirculation. Knowledge on changes in the myocardial microvascular function over time is lacking. METHODS: In this cohort study, we recruited 60 persons with type 2 diabetes and 30 non-diabetic controls, in 2013; all free of overt cardiovascular disease. All underwent a cardiac 82 Rb PET/CT scan. In 2019, all survivors (n = 82) were invited for a repeated cardiac 82 Rb PET/CT scan using the same protocol, and 29 with type 2 diabetes and 19 controls participated. RESULTS: Median duration between visits was 6.2 years (IQR: 6.1-6.3). In the total cohort, the mean age was 66.4 years (SD: 9.3) and 33% were females. The myocardial flow reserve was lower in persons with type 2 diabetes compared to controls (p = 0.002) but there was no temporal change in the myocardial flow reserve in participants with type 2 diabetes: mean change: -0.22 (95% CI: -0.47 to 0.02) nor in controls: -0.12 (-0.49 to 0.25) or when comparing type 2 diabetes to controls: mean difference: -0.10 (95% CI: -0.52 to 0.31). The temporal reduction in stress-induced myocardial blood flow did not differ within the groups but was more pronounced in type 2 diabetes compared to controls: mean difference: -0.30 (95% CI: -0.55 to -0.04). CONCLUSION: The myocardial microvascular function was impaired in persons with type 2 diabetes compared to controls but did not change significantly in either of the groups when evaluated over 6 years.

Liraglutide reduces cardiac adipose tissue in type 2 diabetes: A secondary analysis of the LIRAFLAME randomized placebo-controlled trial.

AIM: To test the hypothesis that treatment with liraglutide can reduce cardiac adipose tissue. MATERIALS AND METHODS: LIRAFLAME is a randomized placebo-controlled, double-blind, parallel clinical study. Participants with type 2 diabetes were randomized to treatment with liraglutide 1.8 mg/d or placebo for 26 weeks. Computed tomography was performed at baseline and at end of treatment to evaluate the cardiac adipose tissue volume, quantified automatically. We report the results of a secondary endpoint evaluating changes in cardiac adipose tissue. RESULTS: A total of 102 participants were randomly assigned to liraglutide (n = 51) or placebo (n = 51). At baseline, the mean (SD) cardiac adipose tissue volume was comparable between the liraglutide and the placebo group (232.6 [112.8] vs. 227.0 [103.2] mL; P = 0.80). The mean change in body weight was -3.7 (-4.8, -2.6) kg in the liraglutide and -0.18 (-0.76, 0.40) kg in the placebo group. From baseline to end of treatment the mean cardiac adipose tissue change was -11.5 (95% confidence interval -17.6, -5.4) mL in the liraglutide (P < 0.001) and -0.01 (-5.3, 5.3) mL in the placebo (P = 1.00) groups. The reduction in cardiac adipose tissue was significantly greater in the liraglutide compared to the placebo group (mean difference -11.4 [-19.4, -3.3] mL; P = 0.006), but significance was lost after adjustment for changes in body mass index (P = 0.46). CONCLUSION: Treatment with liraglutide for 26 weeks was associated with a reduction in cardiac adipose tissue compared to placebo. The reduction was not independent of weight loss, suggesting that this is not a drug-specific effect.

Relation of cardiac adipose tissue to coronary calcification and myocardial microvascular function in type 1 and type 2 diabetes.

BACKGROUND: Cardiac adipose tissue may have local paracrine effects on epicardial arteries and the underlying myocardium, promoting calcification and affecting myocardial microcirculation. We explored whether the total amount of cardiac adipose tissue was associated with coronary artery calcium score (CAC) and myocardial flow reserve in persons with type 1 or type 2 diabetes and healthy controls. METHODS: We studied three groups: (1) 30 controls, (2) 60 persons with type 1 diabetes and (3) 60 persons with type 2 diabetes. The three groups were matched for sex and age. The three groups derived from retrospective analysis of two clinical studies. All underwent cardiac 82Rb positron emission tomography/computed tomography (PET/CT) scanning. Cardiac adipose tissue volume (the sum of epicardial and pericardial fat), CAC, and myocardial flow reserve (ratio of pharmacological stress flow and rest flow) were evaluated using semiautomatic software. We applied linear regression to assess the association between cardiac adipose tissue, CAC and myocardial flow reserve. RESULTS: Mean (SD) cardiac adipose tissue volume was 99 (61) mL in the control group, 106 (78) mL in the type 1 diabetes group and 228 (97) mL in the type 2 diabetes group. Cardiac adipose tissue was positively associated with body mass index in all three groups (p ≤ 0.02). In the controls, cardiac adipose tissue was positively associated with CAC score (p = 0.008) and negatively associated with myocardial flow reserve (p = 0.005). However, cardiac adipose tissue was not associated with CAC or myocardial flow reserve in the groups including persons with type 1 or type 2 diabetes (p ≥ 0.50). CONCLUSIONS: In contrast to what was found in healthy controls, we could not establish a relation between cardiac adipose tissue and coronary calcification or myocardial microvascular function in person with type 1 or type 2 diabetes. The role of cardiac adipose tissue in cardiovascular disease in diabetes remains unclear.

Pleiotropic effects of liraglutide in patients with type 2 diabetes and moderate renal impairment: Individual effects of treatment.

Liraglutide has pleiotropic effects favouring cardiovascular and renal risks. We investigated individual responses to liraglutide in six cardio-renal risk factors to examine whether responses in one risk factor are associated with changes in other risk factors (cross-dependency). We performed secondary analysis of the LIRA-RENAL trial (n = 279) in type 2 diabetes. HbA1c, body weight, systolic blood pressure (SBP), low density lipoprotein (LDL)-cholesterol, urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were measured at baseline and after 26 weeks of liraglutide/placebo treatment: "Good responders" had a change within the best quartile. In the liraglutide-treated group, good HbA1c responders showed similar changes in other risk factors analysed to low responders (P ≥ 0.17). Good body weight responders had a larger reduction in HbA1c than low body weight responders (-1.6 ± 0.94 vs. -1.0 ± 0.82%; P = 0.003), but similar changes in the other risk factors (P ≥ 0.11). Good and low responders in SBP, UACR, LDL-cholesterol or eGFR showed similar changes in other risk factors (P ≥ 0.07). Treatment response to liraglutide is largely individual; aside from an association between body weight and HbA1c reduction, there are no obvious cross-dependencies in risk factor response.

Toe-brachial index as a predictor of cardiovascular disease and all-cause mortality in people with type 2 diabetes and microalbuminuria.

AIMS/HYPOTHESIS: The study aimed to evaluate toe-brachial index (TBI) and ankle-brachial index (ABI) as determinants of incident cardiovascular disease (CVD) and all-cause mortality in people with type 2 diabetes and microalbuminuria. METHODS: This was a prospective study including 200 participants. Unadjusted and adjusted (traditional risk factors and additional inclusion of N-terminal pro-brain natriuretic peptide [NT-proBNP] and coronary artery calcification) Cox regression models were performed. C statistics and relative integrated discrimination improvement (rIDI) evaluated risk prediction improvement. RESULTS: Median follow-up was 6.1 years; 40 CVD events and 26 deaths were recorded. Lower TBI was associated with increased risk of CVD (HR per 1 SD decrease: 1.55 [95% CI 1.38, 1.68]) and all-cause mortality (1.41 [1.22, 1.60]) unadjusted and after adjustment for traditional risk factors (CVD 1.50 [1.27, 1.65] and all-cause mortality 1.37 [1.01, 1.60]). Lower ABI was a determinant of CVD (1.49 [1.32, 1.61]) and all-cause mortality (1.37 [1.09, 1.57]) unadjusted and after adjustment for traditional risk factors (CVD 1.44 [1.23, 1.59] and all-cause mortality 1.39 [1.07, 1.60]). After additional adjustment for NT-proBNP and coronary artery calcification, lower TBI remained a determinant of CVD (p = 0.023). When TBI was added to traditional risk factors, the AUC increased significantly for CVD, by 0.063 (95% CI 0.012, 0.115) from 0.743 (p = 0.016), but not for all-cause mortality; adding ABI did not improve the AUC significantly. The rIDI for TBI was 46.7% (p < 0.001) for CVD and 46.0% (p = 0.002) for all-cause mortality; for ABI, the rIDI was 51.8% (p = 0.004) for CVD and 53.6% (p = 0.031) for all-cause mortality. CONCLUSIONS/INTERPRETATION: Reduced TBI and ABI were associated with increased risk of CVD and all-cause mortality, independent of traditional risk factors in type 2 diabetes, and improved prognostic accuracy.

Symmetric and asymmetric dimethylarginine as risk markers of cardiovascular disease, all-cause mortality and deterioration in kidney function in persons with type 2 diabetes and microalbuminuria.

BACKGROUND: To evaluate symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) as risk markers of cardiovascular disease, all-cause mortality and deterioration in renal function in a well characterised type 2 diabetic population with microalbuminuria and without symptoms of coronary artery disease. METHODS: 200 participants followed for 6.1 years. SDMA and ADMA were measured at baseline. Endpoints included (1) composite cardiovascular endpoint (n = 40); (2) all-cause mortality (n = 26); and (3) decline in eGFR of >30% (n = 42). Cox models were unadjusted and adjusted for traditional risk factors (sex, age, systolic blood pressure, LDL-cholesterol, smoking, HbA1c, creatinine and urinary albumin excretion rate). To assess if SDMA or ADMA improved risk prediction beyond traditional risk factors we calculated c statistics and relative integrated discrimination improvement (rIDI). C statistic (area under the curve) quantifies the model's improved ability to discriminate events from non-events. rIDI quantifies the increase in separation of events and non-events on a relative scale. RESULTS: Higher SDMA was associated with increased risk of all three endpoints (unadjusted: p ≤ 0.001; adjusted: p ≤ 0.02). Higher ADMA was associated with all-cause mortality (unadjusted: p = 0.002; adjusted: p = 0.006), but not cardiovascular disease or decline in eGFR (p ≥ 0.29).The c statistic was not significant for any of the endpoints for either SDMA or ADMA (p ≥ 0.10). The rIDI for SDMA was 15.0% (p = 0.081) for the cardiovascular endpoint, 52.5% (p = 0.025) for all-cause mortality and 48.8% (p = 0.007) for decline in eGFR; for ADMA the rIDI was 49.1% (p = 0.017) for all-cause mortality. CONCLUSION: In persons with type 2 diabetes and microalbuminuria higher SDMA was associated with incident cardiovascular disease, all-cause mortality and deterioration in renal function. Higher ADMA was associated with all-cause mortality. SDMA and ADMA significantly improved risk prediction for all-cause mortality, and SDMA for deterioration in renal function beyond traditional risk factors.

Optimization of Albuminuria-Lowering Treatment in Diabetes by Crossover Rotation to Four Different Drug Classes: A Randomized Crossover Trial.

OBJECTIVE: Renin-angiotensin system (RAS) inhibitors decrease the urinary albumin to creatinine ratio (UACR) but are ineffective in up to 40% of patients. We hypothesized that rotation through different drug classes overcomes RAS inhibitor resistance and tested this in a randomized crossover trial. RESEARCH DESIGN AND METHODS: We assigned 26 adults with type 1 diabetes and 37 with type 2 diabetes and UACR between 30 and 500 mg/g and estimated glomerular filtration rate >45 mL/min/1.73 m2 to 4-week treatment periods with telmisartan 80 mg, empagliflozin 10 mg, linagliptin 5 mg, and baricitinib 2 mg in random order, separated by 4-week washout periods. Each participant was then re-exposed for 4 weeks to the drug that induced that individual's largest UACR reduction. Primary outcome was the difference in UACR response to the best-performing drug during the confirmation period versus UACR response to the other three drugs. RESULTS: There was substantial variation in the best-performing drug. Telmisartan was best performing for 33 participants (52%), empagliflozin and linagliptin in 11 (17%), and baricitinib in 8 participants (13%). The individuals' best-performing drug changed UACR from baseline during the first and confirmatory exposures by a mean of -39.6% (95% CI -44.8, -33.8; P < 0.001) and -22.4% (95% CI -29.7, -12.5; P < 0.001), respectively. The Pearson correlation for first versus confirmatory exposure was 0.39 (P = 0.017). The mean change in UACR with the other three drugs was +1.6% (95% CI -4.3%, 8.0%; P = 0.593 versus baseline; difference versus individuals' best-performing drug at confirmation, 30.9% [95% CI 18.0, 45.3]; P < 0.001). CONCLUSIONS: We demonstrated a large and reproducible variation in participants' responses to different UACR-lowering drug classes. These data support systematic rotation through different drug classes to overcome therapy resistance to RAS inhibition.

Effect of liraglutide on expression of inflammatory genes in type 2 diabetes.

Anti-inflammatory effects of glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment in T2D may contribute to the cardiovascular benefits observed with GLP-1 RAs in outcome studies. We investigated if the GLP-1 RA liraglutide exerts anti-inflammatory effects through modulation of inflammatory gene expression in peripheral blood mononuclear cells (PBMCs). From 54 participants of a double-blinded trial where individuals with type 2 diabetes (T2D) were randomized to liraglutide (1.8 mg/day) or placebo for 26 weeks, a sub-study was performed in which PBMCs were extracted from fresh blood at study start and at end-of-treatment. The expression of selected inflammatory genes in PBMCs were measured by quantitative real-time polymerase chain reaction (PCR). Moreover, the expression of the GLP-1 receptor (GLP1R) was examined in a subset (n = 40) of the PBMC samples. The human monocytic cell line THP-1 was used for in vitro GLP-1 exposure experiments. The expression of tumor necrosis factor-α (TNFA) (p = 0.004) and interleukin-1ß (IL1B) was downregulated (p = 0.046) in the liraglutide-treated group (n = 31), and unchanged in the placebo group (n = 21, p ≥ 0.11), with no significant differences between the two groups (p ≥ 0.67). The expression of interferon-γ (IFNG) and cluster of differentiation 163 (CD163) were upregulated in both groups (p ≤ 0.006) with no differences between groups (p ≥ 0.47). C-C Motif Chemokine Ligand 5 (CCL5) was upregulated in the liraglutide-treated group (p = 0.002) and unchanged in the placebo group (p = 0.14), with no significant difference between groups (p = 0.36). Intercellular adhesion molecule 1 (ICAM1) was unchanged in both groups (p ≥ 0.43). GLP1R expression in the PBMCs was undetectable. In vitro experiments showed no effect of GLP-1 treatment on inflammatory gene expression in THP-1 cells. GLP1R expression in THP-1 cells was not detectable. In summary, we observed a discrete modulatory effect of liraglutide on the expression of inflammatory genes in PBMCs. The lack of evidence for GLP1R expression in PBMCs and THP-1 cells suggests that possible effects of liraglutide on the PBMCs' gene expression are most likely indirect. Further investigations are needed to establish the anti-inflammatory potential of GLP-1 RAs.

Targeting epicardial adipose tissue with exercise, diet, bariatric surgery or pharmaceutical interventions: A systematic review and meta-analysis.

Epicardial adipose tissue (EAT) and pericardial adipose tissue (PAT) are metabolically active fat depots implicated in cardiovascular disease, and EAT has potential as a novel cardiac risk factor, suitable as a target for interventions. The objective of this systematic review and meta-analysis was to investigate the evidence whether EAT and PAT volume can be reduced by weight-loss interventions (exercise, diet, bariatric surgery or pharmaceutical interventions). A systematic literature search identified 34 studies that were included in the qualitative synthesis (exercise, n = 10, diet, n = 5, bariatric surgery, n = 9 and pharmaceutical interventions, n = 10). Of the 34 studies, 10 reported sufficient data to be included in the meta-analysis. The meta-analysis was only conducted for changes in EAT volume, since only few controlled studies reported changes in PAT (n = 3) or total cardiac adipose tissue volume (n = 1). A significant pooled effect size (ES) for reduction in EAT volume was observed following weight-loss interventions as compared with control interventions (ES = -0.89, 95% CI: -1.23 to -0.55, P < 0.001). When comparing the effect of exercise training versus control on EAT volume reduction, there was a significant pooled ES favouring exercise training (ES: -1.11, 95% CI: -1.57 to -0.65, P < 0.001). Similarly, the ES of pharmaceutical versus control interventions on EAT volume reduction was significant, favouring pharmaceutical interventions (ES: -0.79, 95% CI: -1.37 to -0.21, P < 0.0072). In conclusion, this systematic review and meta-analysis provides evidence that exercise, diet, bariatric surgery and pharmaceutical interventions can reduce cardiac adipose tissue volume.

Effect of 26 Weeks of Liraglutide Treatment on Coronary Artery Inflammation in Type 2 Diabetes Quantified by [64Cu]Cu-DOTATATE PET/CT: Results from the LIRAFLAME Trial.

Background: Quantification of coronary artery inflammation and atherosclerosis remains a challenge in high-risk individuals. In this study we sought to investigate if the glucagon like peptide-1 receptor agonist liraglutide has a direct anti-inflammatory effect in the coronary arteries using positron emission tomography (PET) with a radioactive tracer targeting activated macrophages in the vessel-wall. Methods: Thirty randomly selected participants with type 2 diabetes from the placebo-controlled trial LIRAFLAME were enrolled in this sub-study. Participants were, prior to enrollment in this sub-study, randomized to either treatment with daily liraglutide (n=15) or placebo (n=15). Both groups underwent a combined [64Cu]Cu-DOTATATE positron emission tomography and computed tomography scan of the heart at baseline and after 26 weeks of treatment. Coronary artery uptake of [64Cu]Cu-DOTATATE were measured as maximum standardized uptake values (SUVmax); and means of the maximum values (mSUVmax), both values were calculated at the level of each participant and each individual coronary-segment. Results: SUVmax and mSUVmax values decreased significantly in the liraglutide group both at the participant level (SUVmax: p=0.013; mSUVmax: p=0.004) and at the coronary-segment level (SUVmax: p=0.001; mSUVmax: p<0.0001). No change was observed in the placebo group neither at the participant level (SUVmax: p=0.69; mSUVmax: p=0.67) or at the coronary-segment level (SUVmax: p=0.49; mSUVmax: p=0.30). When comparing the mean change in uptake values between the two groups at both the participant level (SUVmax: p=0.076; mSUVmax: p=0.077) and the coronary segment level (SUVmax: p=0.13; mSUVmax: p=0.11) a borderline significant difference was observed. Baseline SUVmax [64Cu]Cu-DOTATATE uptake values showed a weak positive correlation with the inflammatory biomarker high-sensitivity c-reactive protein (τ =0.26, p=0.045). Conclusion: Liraglutide treatment for 26-weeks caused a significant reduction in [64Cu]Cu-DOTATATE uptake in the coronary arteries whereas this was not seen in the placebo treated group. In addition, [64Cu]Cu-DOTATATE PET/CT as a marker of coronary inflammation correlated with the systemic inflammation marker hs-CRP.

Effect of Liraglutide on Arterial Inflammation Assessed as [18F]FDG Uptake in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: The mechanism behind the cardiovascular protection observed with human GLP-1 RA (glucagon-like peptide-1 receptor agonists) in type 2 diabetes is unknown. We hypothesized that treatment with the GLP-1 RA liraglutide had a positive effect on vascular inflammation. METHODS: LIRAFLAME (Effect of liraglutide on vascular inflammation in type-2 diabetes: A randomized, placebocontrolled, double-blind, parallel clinical PET/CT trial) was a double-blind, randomized controlled trial performed at a single university hospital clinic in Denmark. Patients with type 2 diabetes were via computer-generated randomization list assigned (1:1) liraglutide up to 1.8 mg or placebo once daily for 26 weeks. The primary end point was change in vascular inflammation over 26 weeks assessed by [18F]-fluorodeoxyglucose positron emission tomography/computed tomography. Analyses were based on intention-to-treat. Key secondary outcomes included change in other indices of atherosclerosis. RESULTS: Between October 26, 2017, and August 16, 2019, 147 patients were screened and 102 were randomly assigned to liraglutide (n=51) or placebo (n=51) and 99 (97%) completed the trial. Change in the [18F]-fluorodeoxyglucose positron emission tomography measure of vascular inflammation (active-segment target-to-background ratio) did not differ between treatment groups: change from baseline to 26 weeks was -0.04 (95% CI, -0.17 to 0.08) in the liraglutide group compared with -0.09 (-0.19 to 0.01) in the placebo group (mean difference, 0.05 [95% CI, -0.11 to 0.21], P=0.53). Secondary analyses restricted to [18F]-fluorodeoxyglucose positron emission tomography of the carotid arteries as well as other indices of atherosclerosis confirmed the primary result. We performed an explorative analysis of interaction between treatment group and history of cardiovascular disease (P=0.052). CONCLUSIONS: In this low to moderate risk population with type 2 diabetes, liraglutide did not change vascular inflammation assessed as [18F]-fluorodeoxyglucose uptake compared with placebo. An explorative analysis indicated a possible effect in persons with history of cardiovascular disease, in line with current guidelines where liraglutide is recommended to patients with history of cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03449654.

Effect of Liraglutide on Vascular Inflammation Evaluated by [64Cu]DOTATATE.

Quantification of vascular inflammation before and after treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may help reveal mechanistic pathways underlying the cardiovascular benefits of these drugs. We assessed change in vascular inflammation in the carotid arteries over 26 weeks by copper-64-labeled [1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid]-D-Phe1, Tyr3-octreotate ([64Cu]DOTATATE) PET in 30 participants included in a substudy of a double-blind trial where persons with type 2 diabetes (T2D) were randomized to liraglutide (n = 15) or placebo (n = 15) for 26 weeks. Mean age (SD) was 66.4 (7.2) years, HbA1c 56.4 (9.2) mmol/mol and BMI 28.9 (4.6) kg/m2. Weight and HbA1c were significantly reduced by liraglutide vs. placebo (p ≤ 0.01). The [64Cu]DOTATATE uptake (mean standardized uptake values) was significantly reduced in the liraglutide-treated group (-0.11 [95% confidence interval -0.19 to -0.03], p = 0.01) and not changed significantly in the placebo group (-0.07 [-0.14 to 0.01], p = 0.08). The mean difference between groups did not reach significance (-0.04 [-0.15 to 0.07], p = 0.44). In conclusion, [64Cu]DOTATATE uptake was reduced in persons with T2D treated with liraglutide. However, the reduction compared to placebo did not reach statistical significance, perhaps due to limited power. A reduction in vascular inflammation with liraglutide could help explain the cardiovascular protection observed with GLP-1 RAs in outcome studies but warrants further and larger studies.

Ceramides and phospholipids are downregulated with liraglutide treatment: results from the LiraFlame randomized controlled trial.

INTRODUCTION: Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can reduce risk of cardiovascular disease (CVD) in persons living with type 2 diabetes, however the mechanisms explaining this cardiovascular benefit are still debated. We investigated changes in the plasma lipidome following treatment with the GLP-1 RA liraglutide. RESEARCH DESIGN AND METHODS: In a double-blind placebo-controlled trial, we randomized 102 persons with type 2 diabetes to liraglutide or placebo for 26 weeks. Fasting blood plasma was collected at baseline and at end-of-treatment. The lipidome was measured using liquid-chromatography-coupled mass-spectrometry as a secondary end point in the study. Treatment response of each lipid was tested with lipid-specific linear mixed-effect models comparing liraglutide with placebo. Bonferroni p<7.1e-03 was employed. The independence of the findings from clinical covariates was evaluated with adjustment for body mass index, HbA1c, fasting status, lipid-lowering treatment and change in lipid-lowering treatment during the trial. RESULTS: In total, 260 lipids were identified covering 11 lipid families. We observed significant decreases following liraglutide treatment compared with placebo in 21 lipids (p<7.1e-03) from the following lipid families: ceramides, hexocyl-ceramides, phosphatidylcholines, phosphatidylethanolamines and triglycerides. We confirmed these findings in adjusted models (p≤0.01). In the liraglutide-treated group, the individual lipids were reduced in the range of 14%-61% from baseline level, compared with 19% decrease to 27% increase from baseline level in the placebo group. CONCLUSIONS: Compared with placebo, liraglutide treatment led to a significant downregulation in ceramides, phospholipids and triglycerides, which all are linked to higher risk of CVD. These findings were independent of relevant clinical covariates. Our findings are hypothesis generating and shed light on the biological mechanisms underlying the cardiovascular benefits observed with GLP-1 RAs in outcome studies, and further strengthen the evidence base for recommending GLP-1 RAs to prevent CVD in type 2 diabetes. TRIAL REGISTRATION NUMBER: NCT03449654.

The Association Between Cardiovascular Autonomic Function and Changes in Kidney and Myocardial Function in Type 2 Diabetes and Healthy Controls.

Background: The mechanisms linking cardiovascular autonomic neuropathy, diabetic kidney disease and cardiovascular mortality in type 2 diabetes are widely unknown. We investigated the relationship between baseline cardiovascular autonomic function and changes in kidney and myocardial function over six years in patients with type 2 diabetes and healthy controls. Methods: Post-hoc analysis of a cohort study in 24 patients with type 2 diabetes and 18 healthy controls. Baseline determinants were cardiovascular autonomic reflex tests (heart rate response to: standing (30:15); deep breathing (E:I); and the Valsalva test) and time- and frequency-domain heart rate variability indices. Outcomes were changes in estimated glomerular filtration rate (eGFR), albuminuria, myocardial flow reserve (MFR) measured by cardiac 82Rb Positron emission tomography computed tomography (PET/CT), and coronary artery calcium score (CACS). Results: Mean age at inclusion was 61 ± 10 years and 36% were female. Mean follow up time was 6 ± 0 years. A lower response in heart rate to the Valsalva test (corresponding to weaker autonomic function) was associated with a larger decline in eGFR (p=0.04), but not significantly after adjustment for sex, baseline age, smoking status, systolic blood pressure, heart rate, HbA1c, body mass index and baseline eGFR (p=0.12). A higher baseline response in heart rate to standing (30:15) was associated with a larger decline in myocardial flow reserve in the unadjusted analysis (p=0.02) and after adjustment (p=0.02). A higher response in heart rate to the Valsalva maneuver was associated with a larger increase in CACS (p = 0.02), but the association became insignificant after adjustment (p = 0.16). Conclusion: A lower response in heart rate to the Valsalva test was associated with a larger decline in kidney function, indicating that autonomic dysfunction may predict future loss of kidney function. However, we did not find any association between lower values in cardiovascular autonomic function at baseline and a worsening in albuminuria, myocardial function, or atherosclerotic burden.

Cardiac Autonomic Function Is Associated With Myocardial Flow Reserve in Type 1 Diabetes.

The link between cardiac autonomic neuropathy and risk of cardiovascular disease is highlighted as an area in which research is needed. This study was undertaken to evaluate the association between measures of cardiac autonomic function and cardiac vascular function in type 1 diabetes using new and sensitive methods. This was a cross-sectional study in patients with type 1 diabetes, stratified by normoalbuminuria (n = 30) and macroalbuminuria (n = 30), and in healthy control subjects (n = 30). Cardiac autonomic function was evaluated using heart rate variability (HRV) indices, cardiovascular autonomic reflex tests (CARTs), and cardiac 123I-metaiodobenzylguanidine (MIBG) imaging. Cardiac vascular function was assessed as myocardial flow reserve (MFR) measured by cardiac 82Rb-positron emission tomography/computed tomography. The measures of cardiac autonomic function (except low frequency-to-high frequency ratio and the Valsalva test ratio) were positively correlated to MFR in unadjusted analysis. All the HRV indices lost significance after adjustment for age and heart rate. After further adjustment for relevant cardiovascular risk factors, the late heart-to-mediastinum ratio directly measuring the function of adrenergic receptors and sympathetic integrity (from the MIBG scintigraphy) and the 30-to-15 ratio (a CART), remained positively associated with MFR (P ≤ 0.04). Cardiac autonomic dysfunction, including loss of cardiac sympathetic integrity in type 1 diabetes, is associated with and may contribute to impaired myocardial blood flow regulation.

Myocardial flow reserve assessed by cardiac 82Rb positron emission tomography/computed tomography is associated with albumin excretion in patients with Type 1 diabetes.

AIMS: To evaluate myocardial flow reserve (MFR) and coronary artery calcium (CAC) in persons with Type 1 diabetes with or without albuminuria and in non-diabetic controls. MFR reflects the function of large epicardial arteries and myocardial microcirculation. CAC represents structural aspects of atherosclerosis. In addition, we evaluated the association of MFR and CAC with retinopathy, another microvascular complication. METHODS AND RESULTS: Cross-sectional study in Type 1 diabetes, stratified by normoalbuminuria (NORMO; n = 30) and macroalbuminuria (MACRO; n = 30), and in non-diabetic controls (n = 30). MFR (pharmacological stress flow/rest flow) was evaluated by cardiac 82Rb positron emission tomography/computed tomography. MFR was similar in patients with NORMO and controls (3.1 ± 0.79 vs. 3.0 ± 0.79; P = 0.74). Patients with MACRO had lower (impaired) MFR when compared with NORMO (2.1 ± 0.92 vs. 3.1 ± 0.79; P < 0.0001). The CAC score [median (interquartile range)] was higher in NORMO when compared with controls [72 (22-247) vs. 0 (0-81), P = 0.03], and comparable between MACRO and NORMO. MFR was comparable in patients with diabetes and simplex or no retinopathy (n = 24 and n = 12, 2.8 ± 0.84 vs. 3.3 ± 0.77, P = 0.11), but lower in proliferative (n = 24) compared with simplex retinopathy (2.1 ± 0.97 vs. 2.8 ± 0.84, P = 0.02). The CAC score was comparable between groups of retinopathy. CONCLUSION: Myocardial microvascular function was comparable in non-diabetic controls and patients with Type 1 diabetes and NORMO; but impaired in the presence of microvascular complications (MACRO and proliferative retinopathy). Coronary calcification was elevated in diabetes, however, not explained by albuminuria.

Global Changes in Food Supply and the Obesity Epidemic.

PURPOSE OF REVIEW: We 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 FINDINGS: Economic 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. The shift in the food supply is a major driver of the obesity epidemic.