Effect of empagliflozin on coronary microvascular function in patients with type 2 diabetes mellitus-A randomized, placebo-controlled cross-over study.

PURPOSE: Results from large scale cardiovascular outcome trials in patients with type 2 diabetes mellitus (DM2) have found that sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular death and hospitalization for heart failure, but the mechanisms behind the beneficial cardiovascular effects are not fully understood. We tested the hypothesis that the SGLT2i, empagliflozin, improves non-endothelial dependent coronary microvascular function, thereby leading to better cardiac function. METHODS: Patients with DM2 followed at the endocrinology outpatient clinic at Bispebjerg University Hospital were included in a double blinded, placebo-controlled cross-over study. Participants were allocated equally to each treatment sequence using simple randomization and treated with empagliflozin 25 mg and placebo for 12 weeks, interrupted by 2 weeks wash-out period. The primary outcome was coronary microvascular function, assessed as coronary flow velocity reserve (CFVR) and measured with transthoracic doppler echocardiography. Echocardiographic parameters of cardiac function were measured, and blood samples were analyzed for a broad panel of cardiovascular biomarkers. RESULTS: Thirteen patients were randomized to each sequence and 10 and 9 completed the study according to protocol, respectively, and were included in the analysis of outcome parameters. We found no improvement in CFVR (change in the empagliflozin period was -0.16 (SD 0.58)). There were no effects on cardiac systolic function or indicators of cardiac filling pressure. Well-known effects of empagliflozin were obtained, such as weight loss and reduction in Hba1c level. Creatinine level increased but remained within normal range. We observed a clear trend of reduction in cardiovascular biomarkers after empagliflozin treatment and increased levels after the placebo period. No serious adverse reactions were reported. CONCLUSIONS: Despite effect on weight-loss, Hba1c and biomarkers, treatment with empagliflozin for 12 weeks did not improve CFVR in patients with DM2.

Effects of ß-hydroxybutyrate on cognition in patients with type 2 diabetes.

OBJECTIVE: Cognitive impairment in type 2 diabetes is associated with cerebral glucose hypometabolism. Providing a glucose substitute such as ketone bodies might restore metabolic balance in glucose-compromised neurones and improve cognitive performance. We aimed to investigate if ß-hydroxybutyrate (ketone body) infusion acutely affects cognitive performance, measured by a neuropsychological test battery, in patients with type 2 diabetes. DESIGN: Randomised, placebo-controlled, double-blind cross-over trial. METHODS: Eighteen patients with type 2 diabetes received i.v. ketone body (ß-hydroxybutyrate) and placebo (saline) infusion in a randomised order on two separate occasions. On both days of examination, blood glucose was clamped at 7.5 mmol/L and a neuropsychological test battery was used to assess global cognitive performance (primary outcome) and specialized cognitive measures of verbal memory, working memory, executive function, psychomotor speed, and sustained attention. RESULTS: During neurocognitive testing, ß-hydroxybutyrate concentrations were 2.4 vs 0.1 mmol/L. Working memory assessed by Wechsler Adult Intelligence Scale letter-number-sequencing significantly improved by 1.6 points (95% CI: 0.7, 2.4; non-adjusted P < 0.001) corresponding to a 17% increase in performance during ketone infusion compared to placebo. There was no change for global cognitive performance or any other cognitive measure after adjusting for multiple comparisons. Blood concentrations of ß-hydroxybutyrate and glycaemic status did not associate with test performance; however, insulin resistance measured by HOMA was related to improved working memory performance during ketone infusion (ß = 4%; 95% CI: 1.1, 7.7; P = 0.012). CONCLUSIONS: Ketone infusion specifically improved working memory performance in patients with type 2 diabetes in the absence of changes in global cognition.

Experimental non-severe hypoglycaemia substantially impairs cognitive function in type 2 diabetes: a randomised crossover trial.

AIMS/HYPOTHESIS: Previous studies have demonstrated a relationship between cognitive impairment and hypoglycaemia (<3 mmol/l). This study hypothesised that non-severe insulin-induced hypoglycaemia reduces cognitive function in individuals with type 2 diabetes. METHODS: In this randomised crossover study, 25 participants with type 2 diabetes attended two experimental visits with hyperinsulinaemic glucose clamping: one hypoglycaemic clamp (plasma glucose 3.0 ± 0.2 mmol/l) and one euglycaemic clamp (plasma glucose 6.0 ± 0.2 mmol/l). Participants were eligible if their diabetes was treated with diet or glucose-lowering medications (except sulfonylureas or insulin), age was 35-70 years, BMI was 23-35 kg/m2 and HbA1c was below 75 mmol/mol (9%). Cognitive function was assessed with a neurocognitive test battery measuring verbal memory, executive function, sustained attention and psychomotor speed. From the examined cognitive domains, a global cognition score was constructed estimating global cognition. A measurement for psychomotor speed was selected as the primary outcome. Participants and people assessing the outcomes were blinded to group assignment. RESULTS: Cognitive performance was impaired during hypoglycaemia with a mean score in the primary outcome test, Symbol Digit Modalities Test measuring psychomotor speed, of 48.7 ± 9.8 (hypoglycaemia) vs 56.6 ± 12.0 (euglycaemia); i.e. a change of -7.9 points (95% CI -10.9, -4.9; p < 0.0001). In addition, hypoglycaemia reduced global cognitive score by -0.7 (95% CI -0.9, -0.6; p < 0.0001). A stable glucose plateau was achieved during both experimental visits. For the hypoglycaemic clamp, mean plasma glucose concentration (± SD) during neurocognitive testing was 3.1 (± 0.3) mmol/l. Age, sex, fasting C-peptide, counter-regulatory hormones and the severity of hypoglycaemic symptoms did not influence cognitive function. CONCLUSIONS/INTERPRETATION: Acute non-severe hypoglycaemia (mean plasma glucose 3.1 mmol/l) has a substantial negative impact on cognitive function in individuals with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03014011. FUNDING: The study was supported in part by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp (MSD-MA-NORD-007-01). The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp. Funding was also received from Skibsreder Per Henriksen, R. og hustrus Foundation, The Danish Alzheimer Foundation and Savværksejer Jeppe Juhl og hustrus Foundation.

The effect of DPP-4-protected GLP-1 (7-36) on coronary microvascular function in obese adults.

OBJECTIVE: Glucagon-like-peptide-1 (GLP-1) receptor analogues have been shown to reduce cardiovascular events in patients with type 2 diabetes. However, the mechanism behind is still unknown. The aim of the study was to investigate the effect of intact GLP-1 (7-36) on coronary microcirculation in overweight adults. DESIGN AND METHODS: A double-blinded randomized cross-over study was performed, with 12 overweight participants. Effects of intact GLP-1 (7-36) infusion were compared with a saline infusion on separate days. A DPP-4 inhibitor was administered to block degradation of intact GLP-1 (7-36) to the GLP-1 metabolite (9-36). Coronary microcirculation was assessed by Doppler coronary flow velocity reserve (CFVR) before and after 2 h of infusion. Peripheral endothelial function was assessed by flow mediated dilation (FMD) before and after one hour of infusion. RESULTS: CFVR was 3.77 ±â€¯1.25 during GLP-1 infusion and 3.85 ±â€¯1.32 during saline infusion, endothelial function was 16.3 ±â€¯15.5 % during GLP-1 infusion and 7.85 ±â€¯7.76 % during saline infusion. When adjusting for baseline values no significant differences in CFVR (ΔCFVR 0.38 ±â€¯0.92 vs. ΔCFVR 0.71 ±â€¯1.03, p = 0.43) and no difference in peripheral endothelial function (ΔFMD 7.34 ±â€¯11.5 % vs. ΔFMD -1.25 ±â€¯9.23%, p = 0.14) was found. CONCLUSIONS: We found no effect of intact GLP-1 (7-36), protected from DPP4 mediated degradation on coronary microcirculation in overweight adults.

Effect of liraglutide on body weight and microvascular function in non-diabetic overweight women with coronary microvascular dysfunction.

BACKGROUND: Coronary microvascular dysfunction (CMD) is associated with adverse cardiovascular outcomes and CMD is a hallmark of type 2 diabetes. Liraglutide improves cardiovascular prognosis through partly unknown mechanisms. We hypothesized that treatment with liraglutide improves CMD and symptoms through weight loss, in non-diabetic overweight patients with angina and no obstructive coronary artery disease (CAD). METHODS: We included 33 non-diabetic overweight women (BMI > 25) with CMD (Coronary flow velocity reserve (CFVR) ≤2.5), angina symptoms and no obstructive CAD, in an open-label proof-of-concept study. The protocol included a control period of 5 weeks followed by an intervention period with liraglutide aiming at 3 mg daily for 12 weeks. Participants were investigated before and after the control period and again 1-2 weeks after last liraglutide dose. Primary outcomes were change in CFVR and change in angina symptoms measured by the Seattle Angina Questionnaire (SAQ) in the intervention period compared with the control period. (clinicaltrials.gov, NCT02602600, and ethically approved). RESULTS: Twenty-nine participants completed the study. Liraglutide treatment led to a significant weight loss (mean 6.03 kg (95%CI: 5.22;6.84)) and decrease in systolic blood pressure (mean 10.95 mm Hg (95%CI: 4.60;17.30)). Baseline median CFVR was 2.30 (IQR 1.91;2.51) and remained unchanged after liraglutide treatment (mean change 0.07 (95%CI: -0.07;0.21)). There were no effects on symptoms measured by SAQ or parameters of left ventricular systolic as well as diastolic function. CONCLUSIONS: Treatment with liraglutide led to significant weight loss and lowering of blood pressure with no concomitant symptoms alleviation during treatment and no improvement in coronary microvascular function.

Video consultations as add-on to standard care among patients with type 2 diabetes not responding to standard regimens: a randomized controlled trial.

OBJECTIVE: To examine whether video consultations preceded by measurements of blood glucose, weight and blood pressure as add-on to standard care could contribute to achieving and maintaining good diabetes control among patients with poorly regulated type 2 diabetes (T2D). DESIGN: Randomized controlled trial. METHODS: 165 patients with T2D were randomized 1:1 to telemedicine intervention as add-on to clinic-based care or control (clinic-based care). The intervention consisted of monthly video conferences with a nurse via a tablet computer and lasted for 32 weeks. Regularly self-monitored measurements of blood sugar, blood pressure and weight were uploaded and visible to patient and nurse. Both groups were followed up six months after the end of the intervention period. PRIMARY ENDPOINT: HbA1c after eight months. RESULTS: Video conferences preceded by uploads of measurements as add-on to clinic-based care led to a significant reduction of HbA1c compared to that in standard care (0.69% vs 0.18%, P = 0.022). However, at six-month follow-up, the inter-group difference in HbA1c-reduction was no longer significant. Non-completers had higher HbA1c levels at baseline and a lower degree of education. CONCLUSION: Video consultations preceded by uploading relevant measurements can lead to clinically and statistically significant improvements in glycemic control among patients who have not responded to standard regimens. However, continuing effort and attention are essential as the effect does not persist when intervention ends. Furthermore, future studies should focus on differentiation as the most vulnerable patients are at greater risk of non-adherence.

Effect of the glucagon-like peptide-1 analogue liraglutide on coronary microvascular function in patients with type 2 diabetes - a randomized, single-blinded, cross-over pilot study.

BACKGROUND: Impaired coronary microcirculation is associated with a poor prognosis in patients with type 2 diabetes. In the absence of stenosis of major coronary arteries, coronary flow reserve (CFR) reflects coronary microcirculation. Studies have shown beneficial effects of glucagon-like peptide-1 (GLP-1) on the cardiovascular system. The aim of the study was to explore the short-term effect of GLP-1 treatment on coronary microcirculation estimated by CFR in patients with type 2 diabetes. METHODS: Patients with type 2 diabetes and no history of coronary artery disease were treated with either the GLP-1 analogue liraglutide or received no treatment for 10 weeks, in a randomized, single-blinded, cross-over setup with a 2 weeks wash-out period. The effect of liraglutide on coronary microcirculation was evaluated using non-invasive trans-thoracic Doppler-flow echocardiography during dipyridamole induced stress. Peripheral microvascular endothelial function was assessed by Endo-PAT2000®. Interventions were compared by two-sample t-test after ensuring no carry over effect. RESULTS: A total of 24 patients were included. Twenty patients completed the study (15 male; mean age 57 ± 9; mean BMI 33.1 ± 4.4, mean baseline CFR 2.35 ± 0.45). There was a small increase in CFR following liraglutide treatment (change 0.18, CI95% [-0.01; 0.36], p = 0.06) but no difference in effect in comparison with no treatment (difference between treatment allocation 0.16, CI95% [-0.08; 0.40], p = 0.18). Liraglutide significantly reduced glycated haemoglobin (HbA1c) (-10.1 mmol/mol CI95% [-13.9; -6.4], p = 0.01), systolic blood pressure (-10 mmHg CI95% [-17; -3], p = 0.01) and weight (-1.9 kg CI95% [-3.6; -0.2], p = 0.03) compared to no treatment. There was no effect on peripheral microvascular endothelial function after either intervention. CONCLUSIONS: In this short-term treatment study, 10 weeks of liraglutide treatment had no significant effect on neither coronary nor peripheral microvascular function in patients with type 2 diabetes. Further long-term studies, preferably in patients with more impaired microvascular function and using a higher dosage of GLP-1 analogues, are needed to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01931982 .

Denmark's comparative position regarding health status, healthcare provision, self-management and social support: Diabetes Attitudes, Wishes and Needs second study (DAWN2).

AIMS: The aim of this study was to benchmark the Danish sample of the second Diabetes, Attitudes, Wishes and Needs (DAWN2) study with the global average in order to determine Denmark's comparative position for health status, healthcare provision, self-management and social support from the perspective of people with diabetes, family members of people with diabetes and healthcare professionals. METHODS: A total of 502 Danish people with diabetes (PWD), 122 adult family members of people with diabetes (FM) and 283 healthcare professionals (HCPs) participated in the study. Data on healthcare provision and physical and psychosocial wellbeing were collected from the 17 participating countries. RESULTS: Psychological wellbeing was higher among Danish PWD; conversely, self-management behaviour of PWD ranked below the global average. A substantial gap was found in the perceptions of PWD and HCPs regarding the extent to which healthcare provision was deemed person-centred. The gap was found to be larger, however, when looking at the global data. Danish FM reported higher education participation and satisfaction rates as well as lower distress than the global average, but there appears to be an untapped potential when it comes to converting education participation of FM into social support for PWD. CONCLUSIONS: Our findings suggest that PWD in Denmark rank above the global average on measures of psychological wellbeing, despite psychological wellbeing being under-prioritised by HCP. However, there is room for improvement when it comes to self-management behaviours. Special attention is needed to address this issue without compromising the psychological wellbeing of the PWD.

Effects of telemedicine in the treatment of patients with type 2 diabetes--a study protocol.

INTRODUCTION: Despite rehabilitation programmes offered to all patients with newly diagnosed type 2 diabetes in Denmark, a number of patients either never accomplish good diabetes regulation or the regulation deteriorates with time. Therefore, new approaches are needed. The aim of the present study is to examine whether telemedicine conferences with a nurse can contribute to achieving good diabetes control among patients with poorly regulated type 2 diabetes. MATERIAL AND METHODS: A total of 165 patients with type 2 diabetes who have formerly undergone a rehabilitation programme are randomized to either telemedicine intervention or usual care. The intervention lasts for 32 weeks and consists of monthly videoconferences with a nurse from a health-care centre as an add-on to usual care. Blood sugar, blood pressure and weight are regularly self-monitored and measurements are automatically transferred to a database. Glycaemic control (HbA1c level) is examined at baseline, 16 weeks, 32 weeks and 58 weeks (six months post intervention). Blood pressure, weight, waist/hip ratio, quality of life, physical activity, lipids, creatinine and haemoglobin are examined at baseline and after 32 weeks. CONCLUSION: The study will examine whether telemedicine technology can contribute to achieving good diabetes regulation. FUNDING: The City of Copenhagen and the Prevention Fund of the Capital Region of Denmark funded the project. Also "Smedemester Niels Hansen og Hustru Johanne F. Frederiksens Legat" has supported the study. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT01688778.

[The prevalence of type 2-diabetes in ethnic minorities]. / Type 2-diabetes hos etniske minoriteter.

In general, type 2 diabetes is more common among immigrants than among the inhabitants with a Western background. The higher prevalence among ethnic minorities is probably due to a complex correlation between genetic factors, diet, exercise, linguistic and cultural obstacles, low birthweight and high catch up weight as well as socio-economic factors. Ethnic minorities are heterogeneous, and individual initiatives within the different groups are needed. The evidence regarding the effect of initiatives targeted at ethnic minorities in Denmark is sparse. In future, clinically controlled studies in this field should be carried out.

Additive effects of glucagon-like peptide 1 and pioglitazone in patients with type 2 diabetes.

OBJECTIVE: To evaluate the effect of combination therapy with pioglitazone and glucagon-like peptide (GLP)-1 in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Eight patients with type 2 diabetes (BMI 32.7 +/- 1.3 kg/m(2) and fasting plasma glucose 13.5 +/- 1.2 mmol/l) underwent four different treatment regimens in random order: saline therapy, monotherapy with continuous subcutaneous infusion of GLP-1 (4.8 pmol x kg(-1) x min(-1)), monotherapy with pioglitazone (30-mg tablet of Actos), and combination therapy with GLP-1 and pioglitazone. The observation period was 48 h. End points were plasma levels of glucose, insulin, glucagon, free fatty acids (FFAs), and sensation of appetite. RESULTS: Fasting plasma glucose decreased from 13.5 +/- 1.2 mmol/l (saline) to 11.7 +/- 1.2 (GLP-1) and 11.5 +/- 1.2 (pioglitazone) and further decreased to 9.9 +/- 1.0 (combination) (P < 0.001). Eight-hour mean plasma glucose levels were reduced from 13.7 +/- 1.1 mmol/l (saline) to 10.6 +/- 1.0 (GLP-1) and 12.0 +/- 1.2 (pioglitazone) and were further reduced to 9.5 +/- 0.8 (combination) (P < 0.0001). Insulin levels increased during monotherapy with GLP-1 compared with monotherapy with pioglitazone (P < 0.01). Glucagon levels were reduced in GLP-1 and combination therapy compared with saline and monotherapy with pioglitazone (P < 0.01). FFAs during breakfast (area under the curve, 0-3 h) were reduced in combination therapy compared with saline (P = 0.03). Sensation of appetite was reduced during monotherapy with GLP-1 and combination therapy (P < 0.05). CONCLUSIONS: GLP-1 and pioglitazone show an additive glucose-lowering effect. A combination of the two agents may, therefore, be a valuable therapeutic approach for the treatment of type 2 diabetes.

Postprandial glycemic control with biphasic insulin aspart in patients with type 1 diabetes.

We sought to investigate the ability of biphasic insulin aspart 30 (BIAsp 30) to control postprandial hyperglycemia and hyperlipidemia in a meal-test comparison with biphasic human insulin 30 (BHI 30). In this randomised crossover trial, 50 patients with type 1 diabetes (mean age, 35.7 +/- 9.4 years; body mass index [BMI], 24.0 +/- 2.6 kg/m(2); HbA(1c), 8.6% +/- 1.1%) were studied on 3 separate days, where the following treatments were given in random order: BIAsp 30 injected immediately before a standard breakfast, BHI 30 injected 30 minutes before breakfast (BHI 30(t=-30)), and BHI 30 injected immediately before breakfast (BHI 30(t=0)). The dose was 0.40 U/kg for all 3 treatments. BIAsp 30 reduced the area under the baseline adjusted 4-hour postprandial serum glucose curve (AUC(0-4h)) by 23% compared with BHI 30(t=0) (P <.0001) and by 9% compared with BHI 30(t=-30) (P =.013). Maximum serum glucose concentration (C(max)) was lower for BIAsp 30 compared with BHI 30(t=0) (14.0 +/- 2.4 v 16.5 +/- 2.8 mmol/L, P <.0001), and time to maximal serum glucose concentration (t(max)) was approximately 20 minutes shorter for BIAsp 30, irrespective of timing of BHI 30 injection (P <.0001). There were no significant differences among the 3 treatments with respect to postprandial levels of free fatty acids or triglycerides. The pharmacokinetic results were consistent with the above observations, ie, significantly larger insulin AUC(0-4h), higher C(max) and shorter t(max) were observed for BIAsp 30 compared with BHI 30, irrespective of timing of BHI 30 injection. We conclude that postprandial glycemic control was more effective with BIAsp 30 than with BHI 30, irrespective of timing of BHI 30 injection.

Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study.

BACKGROUND: Glucagon-like peptide 1 (GLP-1) has been proposed as a treatment for type 2 diabetes. We have investigated the long-term effects of continuous administration of this peptide hormone in a 6-week pilot study. METHODS: 20 patients with type 2 diabetes were alternately assigned continuous subcutaneous infusion of GLP-1 (n=10) or saline (n=10) for 6 weeks. Before (week 0) and at weeks 1 and 6, they underwent beta-cell function tests (hyperglycaemic clamps), 8 h profiles of plasma glucose, insulin, C-peptide, glucagon, and free fatty acids, and appetite and side-effect ratings on 100 mm visual analogue scales; at weeks 0 and 6 they also underwent dexascanning, measurement of insulin sensitivity (hyperinsulinaemic euglycaemic clamps), haemoglobin A(1c), and fructosamine. The primary endpoints were haemoglobin A(1c) concentration, 8-h profile of glucose concentration in plasma, and beta-cell function (defined as the first-phase response to glucose and the maximum insulin secretory capacity of the cell). Analyses were per protocol. FINDINGS: One patient assigned saline was excluded because no veins were accessible. In the remaining nine patients in that group, no significant changes were observed except an increase in fructosamine concentration (p=0.0004). In the GLP-1 group, fasting and 8 h mean plasma glucose decreased by 4.3 mmol/L and 5.5 mmol/L (p<0.0001). Haemoglobin A(1c) decreased by 1.3% (p=0.003) and fructosamine fell to normal values (p=0.0002). Fasting and 8 h mean concentrations of free fatty acids decreased by 30% and 23% (p=0.0005 and 0.01, respectively). Gastric emptying was inhibited, bodyweight decreased by 1.9 kg, and appetite was reduced. Both insulin sensitivity and beta-cell function improved (p=0.003 and p=0.003, respectively). No important side-effects were seen. INTERPRETATION: GLP-1 could be a new treatment for type 2 diabetes, though further investigation of the long-term effects of GLP-1 is needed.