Liraglutide treatment for the prevention of glucose tolerance deterioration in women with prior gestational diabetes mellitus: A 52-week randomized controlled clinical trial.

AIM: We investigated the effect of 52-week treatment with liraglutide, a glucagon-like peptide 1 receptor agonist, on glucose tolerance and incretin effect in women with previous gestational diabetes mellitus (pGDM). MATERIALS AND METHODS: Women with overweight/obesity and pGDM were randomized to once daily subcutaneous liraglutide 1.8 mg or placebo for 52 weeks. Participants underwent oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion at baseline and at 52 weeks, and an additional OGTT after the drug wash-out. RESULTS: In total, 104 women [age: mean ± SD, 38 ± 5 years; fasting plasma glucose (FPG): 5.5 ± 0.4 mmol/L; glycated haemoglobin (HbA1c): 33 ± 4 mmol/mol, bodyweight: 88.2 ± 14.8 kg, body mass index: 31.1 ± 4.3 kg/m2 ] were assigned to liraglutide (n = 49) or placebo (n = 55). Estimated treatment difference (ETD) for area under curve during OGTT was -173 (95% confidence interval -250 to -97) mmol/L × min, p < .0001, but after wash-out the difference disappeared [ETD 58 (-30 to 146) mmol/L × min, p = .536]. Liraglutide reduced FPG [ETD -0.2 (-0.4 to -0.1) mmol/L, p = .018], HbA1c [-2.2 (-3.5 to -0.8) mmol/mol, p = .018] and bodyweight [-3.9 (-6.2 to -1.6) kg, p = .012]. No change in the incretin effect was observed. The number of women with prediabetes was reduced from 64% to 10% with liraglutide vs. 50% with placebo [adjusted odds ratio 0.10 (0.03-0.32), p = .002]. CONCLUSIONS: Treatment with liraglutide for 52 weeks improved glucose tolerance, FPG, HbA1c and bodyweight in women with overweight/obesity and pGDM. Progression to prediabetes while on drug was markedly reduced, but after a 1-week drug wash-out, the effect was lost.

Metabolic effects of 1-week binge drinking and fast food intake during Roskilde Festival in young healthy male adults.

AIMS/HYPOTHESIS: Metabolic effects of intermittent unhealthy lifestyle in young adults are poorly studied. We investigated the gluco-metabolic and hepatic effects of participation in Roskilde Festival (1 week of binge drinking and junk food consumption) in young, healthy males. METHODS: Fourteen festival participants (FP) were studied before, during and after 1 week's participation in Roskilde Festival. Fourteen matched controls (CTRL) who did not participate in Roskilde Festival or change their lifestyle in other ways were investigated along a similar timeline. RESULTS: The FP group consumed more alcohol compared to their standard living conditions (2.0 ± 3.9 vs 16.3 ± 8.3 units/day, P < 0.001). CTRLs did not change their alcohol consumption. AUC for glucose during OGTT did not change in either group. C-peptide responses increased in the FP group (206 ± 24 vs 236 ± 17 min × nmol/L, P = 0.052) and the Matsuda index of insulin sensitivity decreased (6.2 ± 2.4 vs 4.7 ± 1.4, P = 0.054). AUC for glucagon during oral glucose tolerance test (OGTT) increased in the FP group (1037 ± 90 vs 1562 ± 195 min × pmol/L, P = 0.003) together with fasting fibroblast growth factor 21 (FGF21) (62 ± 30 vs 132 ± 72 pmol/L, P < 0.001), growth differentiation factor 15 (GDF5) (276 ± 78 vs 330 ± 83 pg/mL, P = 0.009) and aspartate aminotransferase (AST) levels (37.6 ± 6.8 vs 42.4 ± 11 U/L, P = 0.043). Four participants (29%) developed ultrasound-detectable steatosis and a mean strain elastography-assessed liver stiffness increased (P = 0.026) in the FP group. CONCLUSIONS/INTERPRETATION: Participation in Roskilde Festival did not affect oral glucose tolerance but was associated with a reduction in insulin sensitivity, increases in glucagon, FGF21, GDF15 and AST and lead to increased liver stiffness and, in 29% of the participants, ultrasound-detectable hepatic steatosis.

One Year's Treatment with the Glucagon-Like Peptide 1 Receptor Agonist Liraglutide Decreases Hepatic Fat Content in Women with Nonalcoholic Fatty Liver Disease and Prior Gestational Diabetes Mellitus in a Randomized, Placebo-Controlled Trial.

Prior gestational diabetes mellitus (pGDM) is associated with increased risk of nonalcoholic fatty liver disease (NAFLD). Treatment with glucagon-like peptide 1 (GLP-1) receptor agonists has shown beneficial effects in NAFLD patients. We evaluated the effect of the GLP-1 analogue liraglutide on NAFLD features in women with pGDM. Eighty-two overweight/obese, nondiabetic women with pGDM were included. We performed abdominal ultrasound, transient elastography with controlled attenuation parameter (CAP), and blood sampling at baseline and after 1 year. Thirty-seven women were randomized to liraglutide (1.8 mg once-daily) and 45 to placebo. Based on the ultrasound scan, 18 women (22%) had ultrasound-verified NAFLD at baseline and of these, 10 (56%) received liraglutide treatment. After 1 year, eight participants no longer had steatosis, four in each treatment group. The number of participants who developed NAFLD was similar in the two treatment groups; five in the liraglutide group and six in the placebo group (p = 0.74). Compared to placebo, liraglutide reduced the CAP-assessed intrahepatic fat content (-28 (-44;-11) vs. 2 (-13;18) dB/m, p < 0.01) and body weight (-4.7 (-6.4;-2.9) vs. -1.4 (-3;0.3) kg, p < 0.01). One-year's liraglutide treatment had no effect on the presence of ultrasound-diagnosed NAFLD in overweight/obese nondiabetic women with pGDM, but reduced body weight and steatosis assessed by transient elastography with CAP.

Normal insulin sensitivity, glucose tolerance, gut incretin and pancreatic hormone responses in adults with atopic dermatitis.

AIM: To examine whether adults with mild to moderate atopic dermatitis (AD) had reduced insulin sensitivity and/or exhibited other gluco-metabolic disturbances compared with carefully matched healthy controls. MATERIALS AND METHODS: Sixteen adult, non-obese, non-diabetic patients with mild to moderate AD and 16 gender-, age- and body mass index (BMI)-matched healthy controls underwent a hyperinsulinaemic euglycaemic clamp (insulin infusion rate: 40 mU/m2 /minute) and an oral glucose tolerance test (OGTT) with frequent blood sampling for gut and pancreatic hormones. RESULTS: The two groups were similar in age (33 ± 3 vs. 33 ± 3 years, mean ± standard error of the mean [SEM]), gender (56% women), BMI (24.5 ± 0.7 vs. 24.4 ± 0.7 kg/m2 ), physical activity level, fasting plasma glucose and HbA1c. Patients with AD had a mean Eczema Area and Severity Index score of 8.5 ± 1.0 (moderate disease) and a mean AD duration of 28 ± 3 years. During the OGTT, circulating glucose, insulin, C-peptide, glucagon and glucose-dependent insulinotropic polypeptide, respectively, were similar in the two groups, except glucagon-like peptide-1, which was higher in patients with AD. The clamp showed no differences in insulin sensitivity between groups (M-value 9.2 ± 0.6 vs. 9.8 ± 0.8, P = .541, 95% CI -1.51; 2.60), or circulating insulin, C-peptide and glucagon levels. CONCLUSIONS: Using OGTT and the hyperinsulinaemic euglycaemic clamp technique, we found no difference in insulin sensitivity or other gluco-metabolic characteristics between patients with mild to moderate AD and matched healthy controls, suggesting that the inflammatory skin disease AD has little or no influence on glucose metabolism.

Women with prior gestational diabetes mellitus and prediabetes are characterised by a decreased incretin effect.

AIMS/HYPOTHESIS: We investigated whether a reduced incretin effect, as observed in patients with type 2 diabetes, can be detected in high-risk individuals, such as women with prior gestational diabetes mellitus (pGDM). METHODS: In this cross-sectional study, 102 women without diabetes with pGDM and 15 control participants without pGDM and with normal glucose tolerance (NGT) underwent a 4 h 75 g OGTT and an isoglycaemic i.v. glucose infusion (IIGI). Women with pGDM were classified as having NGT or prediabetes (impaired fasting glucose and/or impaired glucose tolerance). Insulin sensitivity was assessed using the Matsuda index and HOMA2-IR and the incretin effect was calculated from insulin responses during the study (100% × [AUCinsulin,OGTT - AUCinsulin,IIGI]/AUCinsulin,OGTT). RESULTS: Sixty-three of the 102 women with pGDM (62%) had prediabetes (median [interquartile range]: age, 38.3 [6.5] years; BMI, 32.1 [5.8] kg/m2) and 39 women (38%) had NGT (age, 39.5 [5.6] years; BMI, 31.0 [6.7] kg/m2). Control participants (n = 15) were not significantly different from the pGDM group with regards to age (39.2 [7.4] years) and BMI (28.8 [9.2] kg/m2). Compared with women with NGT and control participants, women with prediabetes had lower insulin sensitivity, as measured by the Matsuda index (3.0 [2.4] vs 5.0 [2.6] vs 1.5 [1.8], respectively; p < 0.001). The incretin effect was 55.3% [27.8], 73.8% [19.0] and 76.7% [24.6] in women with prediabetes, women with normal glucose tolerance and control participants, respectively (p < 0.01). CONCLUSION/INTERPRETATION: Prediabetes was highly prevalent in women with pGDM, and alterations in the incretin effect were detected in this group before the development of type 2 diabetes. TRIAL REGISTRATION: clinicaltrialsregister.eu 2012-001371-37-DK.

Nonalcoholic Fatty Liver Disease Is Prevalent in Women With Prior Gestational Diabetes Mellitus and Independently Associated With Insulin Resistance and Waist Circumference.

OBJECTIVE: Type 2 diabetes increases the risk of nonalcoholic fatty liver disease (NAFLD), which is a potentially reversible condition but is also associated with progressive fibrosis and cirrhosis. Women with prior gestational diabetes mellitus (pGDM) have a higher risk for NAFLD. RESEARCH DESIGN AND METHODS: One hundred women without diabetes who had pGDM (median [interquartile range]: age 38.6 [6.4] years; BMI 31.0 [6.2] kg/m2) and 11 healthy control subjects without NAFLD (age 37.9 [7.8] years; BMI 28.1 [0.8] kg/m2) underwent a 75-g oral glucose tolerance test (OGTT), DXA whole-body scan, and ultrasonic evaluation of hepatic steatosis. RESULTS: Twenty-four (24%) women with pGDM had NAFLD on the basis of the ultrasound scan. None had cirrhosis. Women with NAFLD had a higher BMI (P = 0.0002) and waist circumference (P = 0.0003), increased insulin resistance (P = 0.0004), and delayed suppression of glucagon after the OGTT (P < 0.0001), but NAFLD was not associated with the degree of glucose intolerance (P = 0.2196). Visceral fat mass differed among the three groups, with the NAFLD group having the highest amount of fat and the control subjects the lowest (P = 0.0003). By logistic regression analysis, insulin resistance (P = 0.0057) and waist circumference (P = 0.0109) were independently associated with NAFLD. CONCLUSIONS: NAFLD was prevalent in this cohort of relatively young and nonseverely obese women with pGDM who are considered healthy apart from their increased risk for diabetes. Insulin resistance and a larger waist circumference were independently associated with the presence of NAFLD, whereas glucose intolerance was not.

The effect of a glucagon-like peptide-1 receptor agonist on glucose tolerance in women with previous gestational diabetes mellitus: protocol for an investigator-initiated, randomised, placebo-controlled, double-blinded, parallel intervention trial.

INTRODUCTION: Pregnancy is associated with decreased insulin sensitivity, which is usually overcome by a compensatory increase in insulin secretion. Some pregnant women are not able to increase their insulin secretion sufficiently, and consequently develop gestational diabetes mellitus (GDM). The disease normally disappears after delivery. Nevertheless, women with previous GDM have a high risk of developing type 2 diabetes (T2D) later in life. We aim to investigate the early development of T2D in women with previous GDM and to evaluate whether treatment with the glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, may modify their risk of developing T2D. METHODS AND ANALYSES: 100 women with previous GDM will be randomised to either liraglutide or placebo treatment for 1 year (blinded) with an open-label extension for another 4 years. Additionally, 15 women without previous GDM will constitute a baseline control group. Women will be tested with an oral glucose tolerance test (primary endpoint: area under the curve for plasma glucose) and an isoglycaemic intravenous glucose infusion at baseline, after 1 year and after 5 years. Additional evaluations include a glucagon test, dual-energy X-ray absorptiometry, imaging of the liver (ultrasound elastography and fibroscanning), an ad libitum meal for food intake evaluation and questionnaires related to appetite, quality of life and alcohol consumption habits. ETHICS AND DISSEMINATION: The protocol has been approved by the Danish Medicines Agency, the Scientific-Ethical Committee of the Capital Region of Denmark, and the Danish Data Protection Agency and will be carried out under the surveillance and guidance of the GCP unit at Copenhagen University Hospital Bispebjerg in compliance with the ICH-GCP guidelines and in accordance with the Helsinki Declaration. Positive, negative and inconclusive results will be published at scientific conferences and as one or more scientific manuscripts in peer-reviewed journals. REGISTRATIONS: The trial is registered at https://eudract.ema.europa.eu (2012-001371-37) and http://www.clinicaltrials.gov (NCT01795248).

Minimally invasive aortic valve replacement: late conversion to full sternotomy doubles operative time.

In this descriptive prospective study, we evaluate the outcomes of surgery in 98 patients who were scheduled to undergo minimally invasive aortic valve replacement. These patients were compared with a group of 50 patients who underwent scheduled aortic valve replacement through a full sternotomy. The 30-day mortality rate for the 98 patients was zero, although 14 of the 98 mini-sternotomies had to be converted to complete sternotomies intraoperatively due to technical problems. Such conversion doubled the operative time over that of the planned full sternotomies. In the group of patients whose operations were completed as mini-sternotomies, 4 died later of noncardiac causes. The aortic cross-clamp and perfusion times were significantly different across all groups (P < 0.001), with the intended full-sternotomy group having the shortest times. In conclusion, the mini-aortic valve replacement is an excellent operation in selected patients, but its true advantages over conventional aortic valve replacement (other than a smaller scar) await evaluation by means of randomized clinical trial. The "extended mini-aortic valve replacement" operation, on the other hand, is a risky procedure that should be avoided by better preoperative evaluation of patients. In any event, the decision to extend a mini-sternotomy to a full sternotomy should be made early in the course of operation, before cardiopulmonary bypass is instituted.

Minimally invasive aortic valve replacement reduces atelectasis in cardiac intensive care.

OBJECTIVE: Respiratory failure is a major complication after cardiac surgery. The purpose was to evaluate the impact of minimally invasive aortic valve replacement (mini AVR) on the occurrence of left lower lobe atelectasis (LLLA) in the cardiac intensive care unit (ICU). PATIENTS AND METHODS: 98 patients were scheduled to undergo mini AVR. 14 of these patients were converted to a full sternotomy due to technical problems. These patients were compared to a group of 50 patients having planned AVR through a full sternotomy. The incidence of LLLA was evaluated on the first postoperative chest X-ray in the cardiac ICU. RESULTS: In the group having completed mini AVR 20/84 (24%) had a partial LLLA while in the group having extension to a full sternotomy 9/14 (64%) had LLLA lobe (P<0.005). In the group of 50 patients who had AVR through a full sternotomy, 27 patients (54%) had LLLA in the ICU which is also significantly higher (P<0.008) than the percentage of atelectasis in the mini AVR group. CONCLUSIONS: Patients who had mini AVR had a significantly lower incidence of LLLA in the cardiac ICU than patients who had AVR through a full sternotomy.

[Aortic homograft implantation in severe endocarditis]. / Aortahomograftoperationer ved svaer endokarditis.

INTRODUCTION: Severe endocarditis of the native aortic valve or a prosthetic valve with destruction of the cusps, paravalvular abscess formation and/or fistulas caused by aggressive bacteria has a mortality of almost 100% without surgery. The objective was to evaluate the results of treatment with an aortic homograft in combination with antibiotics. MATERIALS AND METHODS: 24 patients with either aortic prosthetic valve endocarditis (n = 16) or severe aortic endocarditis (n = 8) were operated with implantation of an aortic homograft at a Danish university hospital from 1997-2006. Staphylococcus species were the most common pathogens followed by streptococcus. Intravenous antibiotic therapy was started before surgery and continued for 4-6 weeks. The patients were followed-up for (1/2)-10 years (mean 5 years). RESULTS: 3 patients with prosthetic valve endocarditis died within the first 24 hours from heart failure. 2 of these patients required in addition implantation of mitral valve prostheses. 5 patients died 1-7 years after the operation from non-cardiac causes. Within the follow-up period no patients had relapse of endocarditis, and only one episode of recurrence endocarditis in an intravenous drug abuser was registered after 4 years. CONCLUSION: An aortic homograft in combination with intravenous antibiotics is an excellent treatment of severe endocarditis in the aortic valve or an aortic valve prosthesis.

[Total remission of hemiparesis after operation in acute aortic dissection]. / Fuldstaendig remission af hemiparese efter operation for akut proksimal aortadissektion.

Cerebral ischaemia might not preclude operation in acute aortic dissection. A 37-year-old male with an acute proximal aortic dissection (type A) and coma and hemiparesis caused by involvement of the arch vessels and secondary brain malperfusion underwent emergency surgical repair with replacement of the ascending aorta in profound circulatory arrest. The patient recovered fully and was asymptomatic and in good health two years after the operation.

Outcome of aortic homograft implantation in 24 cases of severe infective endocarditis.

The objective of the study was to evaluate the results of treatment of severe aortic endocarditis with an aortic homograft (an aortic valve and root from a donor) in combination with antibiotic therapy. 24 patients with either aortic prosthetic valve endocarditis (n=16) or severe aortic native valve endocarditis (n=8) with destruction of 1 or more cusps, paravalvular abscess formation and/or cardiac fistulas caused by aggressive bacteria, underwent surgery in 1997-2006. Staphylococcal species were the most common pathogens followed by streptococci. Intravenous antibiotic therapy was started before surgery and continued for at least 4-6 weeks. Three patients with prosthetic valve endocarditis died within the first 24 h after surgery from heart failure. Two of these patients required an additional implantation of a mitral valve prosthesis. Five patients died from non-cardiac causes within 1-7 y of surgery. Within the follow-up period no patients had relapse of endocarditis, and only 1 episode of recurrent endocarditis in an intravenous drug abuser was registered. In conclusion, an aortic homograft in combination with intravenous antibiotics is an excellent option for treatment of severe aortic endocarditis.