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Background Incretin-based therapies are used in the treatment of type 2 diabetes mellitus (T2DM) and obesity. We investigated the changes in arterial stiffness and left ventricular (LV) myocardial deformation after 6-month treatment with the GLP-1 analogue liraglutide in subjects with newly diagnosed T2DM. Methods We randomized 60 patients with newly diagnosed and treatment-naive T2DM to receive either liraglutide (n = 30) or metformin (n = 30) for 6 months. We measured at baseline and after 6-month treatment: (a) carotid-femoral pulse wave velocity (PWV) (b) LV longitudinal strain (GLS), and strain rate (GLSR), peak twisting (pTw), peak twisting velocity (pTwVel) and peak untwisting velocity (pUtwVel) using speckle tracking echocardiography. LV untwisting was calculated as the percentage difference between peak twisting and untwisting at MVO (%dpTw–Utw MVO ), at peak (%dpTw–Utw PEF ) and end of early LV diastolic filling (%dpTw–Utw EDF ) (c) Flow mediated dilatation (FMD) of the brachial artery and percentage difference of FMD (FMD%) (d) malondialdehyde (MDA), protein carbonyls (PCs) and NT-proBNP. Results After 6-months treatment, subjects that received liraglutide presented with a reduced PWV (11.8 ± 2.5 vs. 10.3 ± 3.3 m/s), MDA (0.92 [0.45–2.45] vs. 0.68 [0.43–2.08] nM/L) and NT-proBNP (p < 0.05) in parallel with an increase in GLS (− 15.4 ± 3 vs. − 16.6 ± 2.7), GLSR (0.77 ± 0.2 vs. 0.89 ± 0.2), pUtwVel (− 97 ± 49 vs. − 112 ± 52°, p < 0.05), %dpTw–Utw MVO (31 ± 10 vs. 40 ± 14), %dpTw–Utw PEF (43 ± 19 vs. 53 ± 22) and FMD% (8.9 ± 3 vs. 13.2 ± 6, p < 0.01). There were no statistically significant differences of the measured markers in subjects that received metformin except for an improvement in FMD. In all subjects, PCs levels at baseline were negatively related to the difference of GLS (r = − 0.53) post-treatment and the difference of MDA was associated with the difference of PWV (r = 0.52) (p < 0.05 for all associations) after 6-month treatment. Conclusions Six-month treatment with liraglutide improves arterial stiffness, LV myocardial strain, LV twisting and untwisting and NT-proBNP by reducing oxidative stress in subjects with newly diagnosed T2DM. ClinicalTrials.gov Identifier NCT03010683

To investigate the associations of serum α-Klotho and β-Klotho levels with type 2 diabetes mellitus (T2DM) progression. We evaluated 106 healthy controls and 261 cases of T2DM with or without diabetic complications (range: 45–84years). Serum α-Klotho and β-Klotho levels were analyzed using enzyme-linked immunosorbent assays. Compared to the healthy controls, α-Klotho and β-Klotho levels were significantly lower among patients with T2DM and with or without diabetic complications (P<0.05). Furthermore, α-Klotho levels were lower in the microalbuminuric and macroalbuminuric groups, compared to the normoalbuminuric group. However, β-Klotho levels were only lower in the macroalbuminuric group (P<0.05). Multiple linear regression analyses revealed that α-Klotho and β-Klotho levels were positively correlated with the creatinine clearance rate, and negatively correlated with the urinary albumin to creatinine ratio and randomly sampled serum levels of creatinine, blood urea nitrogen, and blood glucose. Moreover, α-Klotho and β-Klotho levels were positively correlated among patients with T2DM (r=0.693, P<0.001). Serum levels of α-Klotho and β-Klotho are down-regulated in patients with T2DM. Thus, these proteins may participate in the pathological mechanism of diabetes, and the positive correlation of α-Klotho and β-Klotho levels indicates that they might have similar mechanisms in T2DM.

Aims/hypothesisVascular changes in individuals with type 2 diabetes mellitus majorly contribute to the development of cardiovascular disease. Increased cardiorespiratory fitness (CRF) has been associated with improvements in vascular health. Although CRF tends to improve with exercise training, there remains a portion of participants with little or no improvement. Given the importance of vascular function in individuals with type 2 diabetes, we assessed whether individuals who failed to improve CRF following a 1 year exercise intervention also failed to improve arterial stiffness and structural indices.MethodsIndividuals with type 2 diabetes with no major micro- and macrovascular complications and aged between 30 and 75 years old (n = 63) participated in a three-arm, 1 year, randomised controlled exercise intervention in Lisbon, Portugal. The study involved a non-exercise control group, a moderate continuous training combined with resistance training (RT) group and a high-intensity interval training with RT group. Allocation of participants into the intervention and control groups was done using a computer-generated list of random numbers. An improvement in CRF was defined as a change in V̇O2peak ≥5%. Vascular stiffness and structural indices were measured using ultrasound imaging and applanation tonometry. Generalised estimating equations were used to compare changes in vascular measures across individuals in the control group (n = 22) and those in the exercise groups who either had improved CRF (CRF responders; n = 14) or whose CRF did not improve (CRF non-responders; n = 27) following 1 year of exercise training.ResultsCompared with the control group, exercisers, with and without improvements in CRF, had decreased carotid intima–media thickness (IMT) (CRF responders: β = −2.84 [95% CI −5.63, −0.04]; CRF non-responders: β = −5.89 [95% CI −9.38, −2.40]) and lower-limb pulse wave velocity (PWV) (CRF responders: β = −0.14 [95% CI −0.25, −0.03]; CRF non-responders: β = −0.14 [95% CI −0.25, −0.03]), the latter being an indicator of peripheral arterial stiffness. Only CRF responders had decreased PWV of the upper limb compared with control participants (β = −0.12 [95% CI −0.23, −0.01]). As for central stiffness, CRF non-responders had increased aortic PWV compared with CRF responders (β = 0.19 [95% CI 0.07, 0.31]), whereas only the CRF non-responders had altered carotid distensibility coefficient compared with the control group (β = 0.00 [95% CI 3.01 × 10−5, 0.00]). No interaction effects between the CRF responders and non-responders vs control group were found for the remaining stiffness or haemodynamic indices (p>0.05).Conclusions/interpretationRegardless of improvements in CRF, individuals with type 2 diabetes had significant improvements in carotid IMT and lower-limb arterial stiffness following a 1 year exercise intervention. Thus, a lack of improvement in CRF following exercise in people with type 2 diabetes does not necessarily entail a lack of improvement in vascular health.Trial registrationClinicalTrials.gov NCT03144505FundingThis work was supported by fellowships from the Portuguese Foundation for Science and Technology. This work is also financed by a national grant through the Fundação para a Ciência e Tecnologia (FCT), within the unit I&D 472.

OBJECTIVE:--The Treating to New Targets study showed that intensive lipid-lowering therapy with atorvastatin 80 mg/day provides significant clinical benefit beyond that afforded by atorvastatin 10 mg/day in patients with stable coronary heart disease (CHD). The objective of our study was to investigate whether similar benefits of high-dose intensive atorvastatin therapy can be achieved in patients with CHD and diabetes. RESEARCH DESIGN AND METHODS--A total of 1,501 patients with diabetes and CHD, with LDL cholesterol levels of <130 mg/dl, were randomized to double-blind therapy with either atorvastatin 10 (n = 753) or 80 (n = 748) mg/day. Patients were followed for a median of 4.9 years. The primary end point was the time to first major cardiovascular event, defined as death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke. RESULTS:--End-of-treatment mean LDL cholesterol levels were 98.6 mg/dl with atorvastatin 10 mg and 77.0 mg/dl with atorvastatin 80 mg. A primary event occurred in 135 patients (17.9%) receiving atorvastatin 10 mg, compared with 103 patients (13.8%) receiving atorvastatin 80 mg (hazard ratio 0.75 [95% CI 0.58-0.97], P = 0.026). Significant differences between the groups in favor of atorvastatin 80 mg were also observed for time to cerebrovascular event (0.69 [0.48-0.98], P = 0.037) and any cardiovascular event (0.85 [0.73-1.00], P = 0.044). There were no significant differences between the treatment groups in the rates of treatment-related adverse events and persistent elevations in liver enzymes. CONCLUSIONS:--Among patients with clinically evident CHD and diabetes, intensive therapy with atorvastatin 80 mg significantly reduced the rate of major cardiovascular events by 25% compared with atorvastatin 10 mg.

OBJECTIVE: Physical fitness is inversely related to mortality in the general population and in subjects with type 2 diabetes. Here, we present data concerning the relationship between changes in physical fitness and modifiable cardiovascular risk factors in subjects with type 2 diabetes from the Italian Diabetes and Exercise Study. RESEARCH DESIGN AND METHODS: Sedentary patients with type 2 diabetes (n = 606) were enrolled in 22 outpatient diabetes clinics and randomized to twice-a-week supervised aerobic and resistance training plus exercise counseling versus counseling alone for 12 months. Baseline to end-of-study changes in cardiorespiratory fitness, strength, and flexibility, as assessed by VO2max estimation, a 5–8 maximal repetition test, and a hip/trunk flexibility test, respectively, were calculated in the whole cohort, and multiple regression analyses were applied to assess the relationship with cardiovascular risk factors. RESULTS: Changes in VO2max, upper and lower body strength, and flexibility were significantly associated with the variation in the volume of physical activity, HbA1c, BMI, waist circumference, high-sensitivity C-reactive protein (hs-CRP), coronary heart disease (CHD) risk score, and inversely, HDL cholesterol. Changes in fitness predicted improvements in HbA1c, waist circumference, HDL cholesterol, hs-CRP, and CHD risk score, independent of study arm, BMI, and in case of strength, also waist circumference. CONCLUSIONS: Physical activity/exercise-induced increases in fitness, particularly muscular, predict improvements in cardiovascular risk factors in subjects with type 2 diabetes independently of weight loss, thus indicating the need for targeting fitness in these individuals, particularly in subjects who struggle to lose weight.

We aimed to determine the prevalence of arterial stiffness in young adults with youth-onset type 2 diabetes who previously participated in the TODAY clinical trial and whether arterial stiffness is influenced by their prior diabetes treatment assignment or glycemic control. We measured arterial stiffness by femoral, radial, and foot pulse wave velocity (PWV), augmentation index (AIx), and brachial distensibility (BrachD) in 453 TODAY participants (age 20.8 ± 2.5 years, diabetes duration 7.6 ± 1.5 years, 36.4% male, BMI 36.7 ± 8.2 kg/m2) at a mean of 7.6 years post-randomization. Increased arterial stiffness in TODAY youth was defined compared with data from lean controls. We assessed whether glycemic control over time or diabetes treatment in TODAY was associated with arterial stiffness. Arterial stiffness was identified in up to 50% of TODAY participants. Prior diabetes treatment assignment was not associated with higher arterial stiffness. Glycemic control over time was associated with PWV radial and foot only. Age, race-ethnicity, sex, higher blood pressure and BMI were also associated with higher arterial stiffness. Nearly half of TODAY youth have increased arterial stiffness. Targeting blood pressure and perhaps obesity and glycemic control may positively impact arterial health in adolescents with type 2 diabetes. Trial registration: ClinicalTrials.govNCT00081328.

Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Although several important studies have been performed in hypertensive type 2 diabetic patients, it is not known whether lowering blood pressure in normotensive (BP <140/90mm Hg) patients offers any beneficial results on vascular complications. The current study evaluated the effect of intensive versus moderate diastolic blood pressure (DBP) control on diabetic vascular complications in 480 normotensive type 2 diabetic patients. The current study was a prospective, randomized controlled trial in normotensive type 2 diabetic subjects. The subjects were randomized to intensive (10mm Hg below the baseline DBP) versus moderate (80 to 89mm Hg) DBP control. Patients in the moderate therapy group were given placebo, while the patients randomized to intensive therapy received either nisoldipine or enalapril in a blinded manner as the initial antihypertensive medication. The primary end point evaluated was the change in creatinine clearance with the secondary endpoints consisting of change in urinary albumin excretion, progression of retinopathy and neuropathy and the incidence of cardiovascular disease. The mean follow-up was 5.3 years. Mean BP in the intensive group was 128 ± 0.8/75 ± 0.3mm Hg versus 137 ± 0.7/81 ± 0.3mm Hg in the moderate group, P < 0.0001. Although no difference was demonstrated in creatinine clearance (P = 0.43), a lower percentage of patients in the intensive group progressed from normoalbuminuria to microalbuminuria (P = 0.012) and microalbuminuria to overt albuminuria (P = 0.028). The intensive BP control group also demonstrated less progression of diabetic retinopathy (P = 0.019) and a lower incidence of strokes (P = 0.03). The results were the same whether enalapril or nisoldipine was used as the initial antihypertensive agent. Over a five-year follow-up period, intensive (∼128/75mm Hg) BP control in normotensive type 2 diabetic patients: (1) slowed the progression to incipient and overt diabetic nephropathy; (2) decreased the progression of diabetic retinopathy; and (3) diminished the incidence of stroke.

Aims/hypothesis Endothelial dysfunction is important in the development of vascular complications in diabetes. Patients with type 2 diabetes have increased production of the vasoconstrictor and pro-inflammatory peptide, endothelin-1. Short-term intra-arterial administration of endothelin antagonists improves endothelium-dependent vasodilatation in patients with type 2 diabetes. We tested the hypothesis that oral administration of the dual endothelin receptor antagonist, bosentan, improves peripheral endothelial function in patients with type 2 diabetes and microalbuminuria. Methods This placebo-controlled and double-blind study was performed on 46 patients with type 2 diabetes and microalbuminuria (urine albumin/creatinine ratio >3 mg/mmol) at a medical university department. Patients were randomised to bosentan, 125 mg two times per day ( n  = 28), or placebo ( n  = 28) for 4 weeks. The computer-generated randomisation code was kept in sealed envelopes. Patients and people doing examinations or assessing outcomes were blinded. The primary endpoint was change in microvascular endothelium-dependent vasodilatation, based on change in digital reactive hyperaemia index. The secondary endpoint was change in brachial artery flow-mediated vasodilatation. Results Reactive hyperaemia index increased from 1.73 ± 0.43 (mean ± SD) at baseline to 2.08 ± 0.59 at follow-up ( p  < 0.05) in the bosentan group ( n  = 22), but did not change in the placebo group (1.84 ± 0.49 to 1.87 ± 0.47; n  = 24). The change in reactive hyperaemia index from baseline was greater in the bosentan group than in the placebo group ( p  < 0.05). Nitroglycerine-induced digital hyperaemia was not affected. Brachial artery flow-mediated vasodilatation and blood pressure did not change during treatment. Conclusions/interpretation Oral treatment of 4 weeks duration with the dual endothelin receptor antagonist, bosentan, improves peripheral endothelial function in patients with type 2 diabetes and microalbuminuria. Trial Registration: ClinicalTrial.gov NCT01357109; Karolinska Clinical Trial Registration Identifier CT20090017 (see www.kctr.se ) Funding: Research Council of Sweden, Swedish Heart and Lung Foundation, Novo Nordisk Foundation, Karolinska Institutet/Stockholm County Council Strategic Cardiovascular Programme, Gustav V and Queen Victoria Foundation, the Family Erling Persson Foundation, Actelion Pharmaceuticals and Actelion Research Award.

Cardiovascular autonomic neuropathy (CAN) predicts clinical diabetic nephropathy (DN). We investigated the relationship between DN structural lesions and CAN. Sixty three Pima Indians with type 2 diabetes underwent kidney biopsies following a 6-year clinical trial testing the renoprotective efficacy of losartan vs. placebo. CAN was assessed a median 9.2years later. CAN variables included expiration/inspiration ratio (E/I), standard deviation of the normal R-R interval (sdNN), and low and high frequency signal power and their ratio (LF, HF, LF/HF); lower values reflect more severe neuropathy. Associations of CAN with renal structural variables were assessed by linear regression adjusted for age, sex, diabetes duration, blood pressure, HbA1c, glomerular filtration rate, and treatment assignment during the trial. Global glomerular sclerosis was negatively associated with sdNN (partial r=−0.35, p=0.01) and LF (r=−0.32, p=0.02); glomerular basement membrane width was negatively associated with all measures of CAN except for LF/HF (r=−0.28 to −0.42, p<0.05); filtration surface density was positively associated with sdNN, LF, and HF (r=0.31 to 0.38, p<0.05); and cortical interstitial fractional volume was negatively associated with HF (r=−0.27, p=0.04). CAN associates with DN lesions.

Eighty percent of premature mortality from cardiovascular disease occurs in low- and middle-income countries. Hypertension, diabetes, and smoking are the top risk factors causing this disease burden. The study aimed to test the hypothesis that utilizing community health workers (CHWs) to manage hypertension, diabetes and smoking in an integrated manner would lead to improved control of these conditions. This was a 2-year cluster (n = 12) randomized controlled trial of 3,556 adults (35 to 70 years of age) in a single town in India, who were screened at home for hypertension, diabetes, and smoking. Of these adults, 1,242 (35%) had at least 1 risk factor (hypertension = 650, diabetes = 317, smoking = 500) and were enrolled in the study. The intervention group had behavioral change communication through regular home visits from community health workers. The control group received usual care in the community. The primary outcomes were changes in systolic blood pressure, fasting blood glucose, and average number of cigarettes/bidis smoked daily among individuals with respective risk factors. The mean ± SD change in systolic blood pressure at 2 years was -12.2 ± 19.5 mm Hg in the intervention group as compared with -6.4 ± 26.1 mm Hg in the control group, resulting in an adjusted difference of -8.9 mm Hg (95% confidence interval [CI]: -3.5 to -14.4 mm Hg; p = 0.001). The change in fasting blood glucose was -43.0 ± 83.5 mg/dl in the intervention group and -16.3 ± 77.2 mg/dl in the control group, leading to an adjusted difference of -21.3 mg/dl (95% CI: 18.4 to -61 mg/dl; p = 0.29). The change in mean number of cigarettes/bidis smoked was nonsignificant at +0.2 cigarettes/bidis (95% CI: 5.6 to -5.2 cigarettes/bidis; p = 0.93). A population-based strategy of integrated risk factor management through community health workers led to improved systolic blood pressure in hypertension, an inconclusive effect on fasting blood glucose in diabetes, and no demonstrable effect on smoking. (Study of a Community-Based Approach to Control Cardiovascular Risk Factors in India [SEHAT]; NCT02115711).