Chronic liraglutide therapy induces an enhanced endogenous glucagon‐like peptide‐1 secretory response in early type 2 diabetes

Sustained exogenous stimulation of a hormone‐specific receptor can affect endogenous hormonal regulation. In this context, little is known about the impact of chronic treatment with glucagon‐like peptide‐1 (GLP‐1) agonists on the endogenous GLP‐1 response. We therefore evaluated the impact of chronic liraglutide therapy on endogenous GLP‐1 and glucose‐dependent insulinotropic polypeptide (GIP) response to an oral glucose challenge. A total of 51 people with type 2 diabetes of 2.6 ± 1.9 years’ duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with an oral glucose tolerance test (OGTT) every 12 weeks. GLP‐1 and GIP responses were assessed according to their respective area under the curve (AUC) from measurements taken at 0, 30, 60, 90 and 120 minutes during each OGTT. There were no differences in AUC_GIP between the groups. By contrast, although fasting GLP‐1 was unaffected, the liraglutide arm had ~2‐fold higher AUC_{GLP ‐1} at 12 weeks ( P < .001), 24 weeks ( P < .001), 36 weeks ( P = .03) and 48 weeks ( P = .03), as compared with placebo. Thus, chronic liraglutide therapy induces a previously unrecognized, robust and durable enhancement of the endogenous GLP‐1 response, highlighting the need for further study of the long‐term effects of incretin mimetics on L‐cell physiology.     

Comparative effects of liraglutide 3 mg vs structured lifestyle modification on body weight,liver fat and liver function in obese patients with non‐alcoholic fatty liver disease: A pilot randomized trial

We compared the effects of weight loss induced by the glucagon‐like peptide 1‐agonist liraglutide with a structured lifestyle intervention in obese adults with non‐alcoholic fatty liver disease (NAFLD). Obese (body mass index ≥30 kg/m², mean weight 96.0 ± 16.3 kg) non‐diabetic Asian adults, with NAFLD diagnosed by liver fat fraction (LFF) ≥ 5.5% on magnetic resonance imaging without other causes of hepatic steatosis, were randomized to a supervised program of dieting (restriction by 400 kilocalories/d) plus moderate‐intensity aerobic exercise (~200 min/wk; DE group, n = 12), or liraglutide at the 3 mg daily dose approved for weight loss (LI group, n = 12), for 26 weeks. Both DE and LI groups had significant (P < .01) and similar reductions in weight (?3.5 ± 3.3 vs ?3.5 ± 2.1 kg, respectively, P = .72), LFF (?8.9 ± 13.4 vs ?7.2% ± 7.1%, P = .70), serum alanine aminotransferase (?42 ± 46 vs ?34 ± 27 U/L, P = .52) and aspartate aminotransferase (?23 ± 24 vs ?18 ± 15 U/L, P = .53). In this first randomized study comparing the 2 weight‐loss modalities for improving NAFLD, liraglutide was as effective as structured lifestyle modification.     

Investigation of the effect of oral metformin on dipeptidylpeptidase‐4 (DPP‐4) activity in Type 2 diabetes1

Aims Glucagon‐like peptide‐1 (GLP‐1) is an insulinotropic hormone and major component of the enteroinsular axis. Its therapeutic potential in human diabetes is limited by rapid degradation and inactivation by the enzyme dipeptidylpeptidase‐4 (DPP‐4). We investigated the acute effects of metformin with and without food on DPP‐4 activity in Type 2 diabetes. Methods Ten subjects with Type 2 diabetes (6 male/4 female, age 65.8 ± 2.6 years, body mass index 30.0 ± 1.2 kg/m², glycated haemoglobin (HbA_1c) 6.3 ± 0.2%, mean ± sem ) received metformin 1 g orally or placebo together with a standard mixed meal (SMM) in a random crossover design. Six subjects re‐attended fasting and received metformin 1 g without a SMM. Results Following SMM (n = 10), DPP‐4 activity was not suppressed by metformin compared with placebo [area under curve (AUC)_{0–4 h} 1574 ± 4 vs. 1581 ± 8 μmol/ml/min, respectively]. Plasma glucose, insulin and active GLP‐1 were not different. However, DPP‐4 activity was suppressed with metformin following fasting compared with a SMM (n = 6) (AUC_{0–4 h} 1578 ± 4 vs. 1494 ± 9 μmol/min, P < 0.02). Metformin serum levels were significantly lower (P < 0.001) after SMM than fasting (AUC_{0–4 h} 350 ± 66 vs. 457 ± 55 mg/ml/min). Conclusion Metformin inhibits DPP‐4 activity in Type 2 diabetic patients in the fasting state but not when taken with a standard mixed meal. Metformin serum concentrations are lower if the drug is taken with food. These findings should be taken into account in establishing how to maximize efficacy of the drug.     

“Supranormal” Cardiac Function in Athletes Related to Better Arterial and Endothelial Function

Objective: Athlete's heart is associated with left ventricular (LV) hypertrophy (LVH), and “supranormal” cardiac function, suggesting that this is a physiological process. Hypertrophy alone cannot explain increase in cardiac function, therefore, other mechanisms, such as better ventriculo‐arterial coupling might be involved. Methods: We studied 60 male (21 ± 3 years) subjects: 27 endurance athletes, and a control group of 33 age‐matched sedentary subjects. We assessed global systolic and diastolic LV function, short‐ and long‐axis myocardial velocities, arterial structure and function and ventriculo‐arterial coupling, endothelial function by flow‐mediated dilatation, and amino‐terminal pro‐brain natriuretic peptide (NT‐proBNP) and biological markers of myocardial fibrosis and of oxidative stress. Results: Athletes had “supranormal” LV longitudinal function (12.4 ± 1.0 vs 10.1 ± 1.4 cm/s for longitudinal systolic velocity, and 17.4 ± 2.6 vs 15.1 ± 2.4 cm/s for longitudinal early diastolic velocity, both P < 0.01), whereas ejection fraction and short‐axis function were similar to controls. Meanwhile, they had better endothelial function (16.7 ± 7.0 vs 13.3 ± 5.3%, P < 0.05) and lower arterial stiffness (pulse wave velocity 7.1 ± 0.6 vs 8.8 ± 1.1 m/s, P = 0.0001), related to lower oxidative stress (0.259 ± 0.71 vs 0.428 ± 0.88 nmol/mL, P = 0.0001), with improved ventriculo‐arterial coupling (37.1 ± 21.5 vs 15.5 ± 13.4 mmHg.m/s³× 10³, P = 0.0001). NT‐proBNP and markers of myocardial fibrosis were not different from controls. LV longitudinal function was directly related to ventriculo‐arterial coupling, and inversely related to arterial stiffness and to oxidative stress. Conclusions: “Supranormal” cardiac function in athletes is due to better endothelial and arterial function, related to lower oxidative stress, with optimized ventriculo‐arterial coupling; athlete's heart is purely a physiological phenomenon, associated with “supranormal” cardiac function, and there are no markers of myocardial fibrosis. (Echocardiography 2010;27:659‐667)     

Improved glycaemic control with minimal hypoglycaemia and no weight change with the once‐daily human glucagon‐like peptide‐1 analogue liraglutide as add‐on to sulphonylurea in Japanese patients with type 2 diabetes

Aim: Sulphonylureas (SUs) are often used as first‐line treatments for type 2 diabetes in Japan, hence it is important to study new antidiabetic drugs in combination with SUs in Japanese patients. Methods: The efficacy and safety of the once‐daily human glucagon‐like peptide‐1 (GLP‐1) analogue liraglutide were compared in 264 Japanese subjects [mean body mass index (BMI) 24.9 kg/m²; mean glycated haemoglobin (HBA1c) 8.4%] randomized and exposed to receive liraglutide 0.6 mg/day (n = 88), 0.9 mg/day (n = 88) or placebo (n = 88) each added to SU monotherapy (glibenclamide, glicazide or glimeprimide) in a 24‐week, double‐blind, parallel‐group trial. Results: The mean change in HBA1c from baseline to week 24 (LOCF) was ?1.56 (s.d. 0.84) and ?1.46 (s.d. 0.95) with liraglutide 0.9 and 0.6 mg respectively, and ?0.40 (s.d. 0.93) with placebo. HBA1c decreased in the placebo group from 8.45 to 8.06%, while liraglutide reduced HBA1c from 8.60 to 7.14%, and from 8.23 to 6.67% at the 0.6 and 0.9 mg doses respectively. Mean HBA1c at week 24 of the two liraglutide groups were significantly lower than the placebo group (p < 0.0001 for both). More subjects reached HBA1c < 7.0% with liraglutide (0.6 mg: 46.5%; 0.9 mg: 71.3%) vs. placebo (14.8%). Fasting plasma glucose (FPG) levels were significantly improved with liraglutide (difference ?1.47 mmol/l and ?1.80 mmol/l with 0.6 and 0.9 mg vs. placebo; p < 0.0001). Overall safety was similar between treatments: no major hypoglycaemic episodes were reported, while 84/77/38 minor hypoglycaemic episodes occurred in the 0.6 mg/0.9 mg and placebo treatment groups (all in combination with SU), reflecting lower ambient glucose levels. No relevant change in mean body weight occurred in subjects receiving liraglutide (0.6 mg: 0.06 kg; 0.9 mg: ?0.37 kg), while mean body weight decreased in subjects receiving placebo (?1.12 kg). Conclusions: The addition of liraglutide to SU treatment for 24 weeks dose‐dependently improved glycaemic control vs. SU monotherapy, without causing major hypoglycaemia or weight gain or loss.     

The once‐daily human glucagon‐like peptide‐1 analog,liraglutide, improves β‐cell function in Japanese patients with type 2 diabetes

Aims/Introduction: β‐cell function was evaluated by homeostasis model assessment of β‐cell function (HOMA‐B) index, proinsulin:insulin and proinsulin:C‐peptide ratios in adult, Japanese type 2 diabetes patients receiving liraglutide. Materials and Methods: Data from two randomized, controlled clinical trials (A and B) including 664 Japanese type 2 diabetes patients (mean values: glycated hemoglobin [HbA_1c] 8.61–9.32%; body mass index [BMI] 24.4–25.3 kg/m²) were analyzed. In two 24‐week trials, patients received liraglutide 0.9 mg (n = 268) or glibenclamide 2.5 mg (n = 132; trial A), or liraglutide 0.6, 0.9 mg (n = 176) or placebo (n = 88) added to previous sulfonylurea therapy (trial B). Results: Liraglutide was associated with improved glycemic control vs sulfonylurea monotherapy or placebo. In liraglutide‐treated groups in trials A and B, area under the curve (AUC) _{insulin 0–3 h} was improved (P < 0.001 for all) and the AUC_{insulin 0–3 h}:AUC_{glucose 0–3 h} ratio was increased (estimated treatment difference [liraglutide–comparator] 0.058 [0.036, 0.079]). HOMA‐B significantly increased with liraglutide relative to comparator in trial B (P < 0.05), but not in trial A. The reduction in fasting proinsulin:insulin ratio was 50% greater than in comparator groups. Conclusions: In Japanese type 2 diabetes patients, liraglutide was associated with effective glycemic control, restoration of prandial insulin response and indications of improved β‐cell function. This trial was registered with Clinicaltrials.gov (trial A: no. NCT00393718/JapicCTI‐060328 and trial B: no. NCT00395746/JapicCTI‐060324). (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00193.x, 2012)     

Effect of continuous exenatide infusion on cardiac function and peri‐operative glucose control in patients undergoing cardiac surgery: A single‐blind,randomized controlled trial

We performed a randomized controlled trial with the glucagon‐like peptide‐1 (GLP‐1) receptor agonist exenatide as add‐on to standard peri‐operative insulin therapy in patients undergoing elective cardiac surgery. The aims of the study were to intensify peri‐operative glucose control while minimizing the risk of hypoglycaemia and to evaluate the suggested cardioprotective effects of GLP‐1‐based treatments. A total of 38 patients with decreased left ventricular systolic function (ejection fraction ≤50%) scheduled for elective coronary artery bypass grafting (CABG) were randomized to receive either exenatide or placebo in a continuous 72‐hour intravenous (i.v.) infusion on top of standard peri‐operative insulin therapy. While no significant difference in postoperative echocardiographic variables was found between the groups, participants receiving exenatide showed improved peri‐operative glucose control as compared with the placebo group (average glycaemia 6.4 ± 0.5 vs 7.3 ± 0.8 mmol/L; P < .001; percentage of time in target range of 4.5–6.5 mmol/L 54.8% ± 14.5% vs 38.6% ± 14.4%; P = .001; percentage of time above target range 39.7% ± 13.9% vs 52.8% ± 15.2%; P = .009) without an increased risk of hypoglycaemia (glycaemia <3.3 mmol/L: 0.10 ± 0.32 vs 0.21 ± 0.42 episodes per participant; P = .586). Continuous administration of i.v. exenatide in patients undergoing elective CABG could provide a safe option for intensifying the peri‐operative glucose management of such patients.     

Liraglutide,a once‐daily human GLP‐1 analogue,added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD‐1 SU)

Aim To compare the effects of combining liraglutide (0.6, 1.2 or 1.8 mg/day) or rosiglitazone 4 mg/day (all n ≥ 228) or placebo (n = 114) with glimepiride (2–4 mg/day) on glycaemic control, body weight and safety in Type 2 diabetes. Methods In total, 1041 adults (mean ± sd ), age 56 ± 10 years, weight 82 ± 17 kg and glycated haemoglobin (HbA_1c) 8.4 ± 1.0% at 116 sites in 21 countries were stratified based on previous oral glucose‐lowering mono : combination therapies (30 : 70%) to participate in a five‐arm, 26‐week, double‐dummy, randomized study. Results Liraglutide (1.2 or 1.8 mg) produced greater reductions in HbA_1c from baseline, (?1.1%, baseline 8.5%) compared with placebo (+0.2%, P < 0.0001, baseline 8.4%) or rosiglitazone (?0.4%, P < 0.0001, baseline 8.4%) when added to glimepiride. Liraglutide 0.6 mg was less effective (?0.6%, baseline 8.4%). Fasting plasma glucose decreased by week 2, with a 1.6 mmol/l decrease from baseline at week 26 with liraglutide 1.2 mg (baseline 9.8 mmol/l) or 1.8 mg (baseline 9.7 mmol/l) compared with a 0.9 mmol/l increase (placebo, P < 0.0001, baseline 9.5 mmol/l) or 1.0 mmol/l decrease (rosiglitazone, P < 0.006, baseline 9.9 mmol/l). Decreases in postprandial plasma glucose from baseline were greater with liraglutide 1.2 or 1.8 mg [?2.5 to ?2.7 mmol/l (baseline 12.9 mmol/l for both)] compared with placebo (?0.4 mmol/l, P < 0.0001, baseline 12.7 mmol/l) or rosiglitazone (?1.8 mmol/l, P < 0.05, baseline 13.0 mmol/l). Changes in body weight with liraglutide 1.8 mg (?0.2 kg, baseline 83.0 kg), 1.2 mg (+0.3 kg, baseline 80.0 kg) or placebo (?0.1 kg, baseline 81.9 kg) were less than with rosiglitazone (+2.1 kg, P < 0.0001, baseline 80.6 kg). Main adverse events for all treatments were minor hypoglycaemia (< 10%), nausea (< 11%), vomiting (< 5%) and diarrhoea (< 8%). Conclusions Liraglutide added to glimepiride was well tolerated and provided improved glycaemic control and favourable weight profile.     

The Effects of Glibenclamide,a KATP Channel Blocker,on the Warm‐Up Phenomenon

Background: The warm‐up phenomenon observed after the second of two sequential exercise tests is characterized by an increased time to ischemia and ischemic threshold, and the latter is related to ischemic preconditioning. Previous studies have demonstrated that a single dose of glibenclamide, a cardiac ATP‐sensitive K (K_ATP) channel blocker, prevents ischemic preconditioning. This study aimed to investigate the effects of chronic treatment with glibenclamide during two sequential exercise tests. Methods: Forty patients with angina pectoris were divided into three groups: 20 nondiabetics (NDM), 10 patients with diabetes in treatment with glibenclamide (DMG) and 10 diabetic patients with other treatments (DMO). All patients underwent two consecutive exercise tests. Results: Heart rate and rate‐pressure product at 1.0 mm ST‐segment depression significantly increased during the second exercise test in NDM group (121.3 ± 16.5 vs 127.3 ± 15.3 beats/min, P < 0.001, and 216.7 + 43.1 vs 232.1 ± 43.0 beats·min^?1·mmHg·10², P < 0.001), and in DMO group (114.1 ± 19.6 vs 119.6 ± 18.1 beats/min, P = 0.001, and 199.8 ± 36.6 vs 222.2 ± 29.2 beats·min^?1·mmHg·10², P = 0.019), but it did not change in patients in DMG group (130.7 ± 14.5 vs 132.1 ±14.7 beats/min, P = ns, and 251.7 ± 47.2 vs 250.3 ± 42.8 beats·min^?1·mmHg·10², P = ns). In the three groups, NDM, DMO, and DMG, the time to 1.0 mm ST‐segment depression during the second exercise test was greater than during the first (225.0 ± 112.5 vs 267.0 ± 122.3 seconds, P = 0.006; 187.5 ± 54.0 vs 226.5 ± 74.6 seconds, P = 0.029 and 150.0 ± 78.7 vs 186.0 ± 81.9 seconds, P < 0.001). Conclusion: The chronic use of glibenclamide may have mediated the loss of preconditioning benefits in the warm‐up phenomenon, probably through its KATP channel‐blocker activity, but without acting upon the tolerance to exercise.     

Cardiac Functional Reserve is Diminished in Growth Hormone‐Deficient Adults

Various studies have shown that patients with severe growth hormone deficiency (GHD) have diverse changes in left ventricular (LV) size or performance but so far there is no direct indication of cardiac reserve ability to maintain the circulation during peak exercise. We tested the hypothesis that patients with severe GHD have reduced cardiac reserve function compared with healthy controls. Eighteen patients with severe GHD were studied and compared with 18 age‐, sex‐, and body mass index (BMI)‐matched healthy controls. Peak cardiac power and cardiorespiratory fitness were investigated using noninvasive hemodynamic measurements during maximal cardiopulmonary exercise testing. Compared with matched controls, the cardiac power of GHD patients during exercise to volitional exhaustion was significantly reduced by 15% (mean ± SD: 4.4 ± 1.0 watts (W) vs. 5.2 ± 1.0 W, P= 0.02), despite attaining similar aerobic exercise peaks (VO_{2 max}, GHD: 2390 ± 822 mL/min vs. controls: 2461 ± 872 mL/min, P= 0.80) and similar peak respiratory exchange ratios. The lower peak cardiac power could not be accounted for by peripheral alterations because both groups reached similar peak exercise systemic vascular resistances. Patients with GHD also had lower cardiac chronotropic reserve (peak heart rate: 154 ± 21 bpm vs. 174 ± 11 bpm, P= 0.001) and a lower cardiac pressure‐generating capacity (systolic blood pressure [SBP] 160 ± 25 mmHg vs. 200 ± 15 mmHg, P < 0.0001). Using this robust noninvasive method of assessing functional cardiac pumping capacity we have for the first time shown that patients with severe GHD have a significantly impaired cardiac functional reserve associated with chronotropic incompetence and impaired pressure‐generating capacity.     

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

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

Nateglinide combination therapy with basal insulin and metformin in patients with Type 2 diabetes

Aims To compare the effect of adding nateglinide or placebo on postprandial glucose excursions (PPGEs), glycated haemoglobin (HbA_1c), diurnal glucose profiles and hypoglycaemia in patients with Type 2 diabetes treated with the combination of basal insulin and metformin. Research design and methods This was an investigator‐initiated, double‐blind, randomized, parallel‐group, study in five centres. Patients with Type 2 diabetes (n = 88, age 56.0 ± 0.9 years, duration of diabetes 9.4 ± 0.5 years, HbA_1c 7.8 ± 0.1%, body mass index 32.4 ± 0.5 kg/m²) treated with basal insulin and metformin entered a 24‐week period, during which basal insulin was titrated to optimize glucose control. Thereafter, the patients were randomized to receive either nateglinide (120 mg three times daily) or placebo before their main meals for 24 weeks. Results During the optimization period, HbA_1c decreased by ?0.3 ± 0.1 and ?0.4 ± 0.2% (NS) and insulin doses increased by 10.0 IU (2.0–32.0) [0.09 IU/kg (0.02–0.34)] and 10.0 IU (0.0–19.0) [0.11 IU/kg (0.0–0.25)] (NS) in the nateglinide and placebo groups. Mean postprandial glucose during weeks 20–24 averaged 9.0 ± 0.3 and 10.0 ± 0.3 mmol/l in the nateglinide and placebo groups (P = 0.025) and mean PPGE averaged 2.4 ± 0.2 and 3.1 ± 0.2 mmol/l, respectively (P = 0.019). At 24 weeks as compared with 0 weeks, mean HbA_1c had decreased by 0.41 ± 0.12% in the nateglinide group and by 0.04 ± 0.12% in the placebo group (P = 0.023). The frequency of confirmed, symptomatic hypoglycaemia was 7.7 episodes/patient‐year vs. 4.7 episodes/patient‐year in the nateglinide and placebo groups (P = 0.031). Conclusions Addition of a short‐acting insulin secretagogue at main meals improves postprandial hyperglycaemia during combination therapy with basal insulin and metformin, but increases the frequency of hypolycaemia.     

The once‐daily human GLP‐1 analogue liraglutide impacts appetite and energy intake in patients with type 2 diabetes after short‐term treatment

The aim was to investigate effects of liraglutide on appetite and energy intake in a randomized, placebo‐controlled, double‐blind, crossover study. Eighteen subjects with type 2 diabetes were assigned to treatment with once‐daily subcutaneous liraglutide (increasing by weekly 0.6 mg increments) or placebo for 3 weeks. Appetite ratings were assessed using visual analogue scales during a 5‐h meal test. Energy and macronutrient intake during the subsequent ad libitum lunch were also measured. After 3 weeks, mean postprandial and minimum hunger ratings were significantly lower with liraglutide 1.8 mg than placebo (p < 0.01), and the mean overall appetite score was significantly higher (p = 0.05), indicating reduced appetite. Liraglutide was associated with higher maximum fullness ratings (p = 0.001) and lower minimum ratings of prospective food consumption (p = 0.01). Mean estimated energy intake was 18% lower for liraglutide than placebo [estimated ratio 0.82 (95% CI 0.73;0.94); p = 0.004], but no significant differences in macronutrient distribution were noted. Findings suggest that reduced appetite and energy intake may contribute to liraglutide‐induced weight loss.     

Pharmacokinetic and pharmacodynamic properties of taspoglutide,a once‐weekly,human GLP‐1 analogue,after single‐dose administration in patients with Type 2 diabetes

Aims The study objectives were to evaluate the pharmacokinetic and pharmacodynamic properties, as well as safety and tolerability, of single doses of taspoglutide, a human glucagon‐like peptide‐1 (GLP‐1) analogue. Methods In a double‐blind, placebo‐controlled study, 48 patients with Type 2 diabetes [mean age 56 ± 7 years; mean body mass index (BMI) 30.4 ± 3.0 kg/m²] inadequately controlled with metformin (≤ 2 g/day) were enrolled in three sequential cohorts; 12 patients in each cohort were randomized to a single subcutaneous injection of taspoglutide (1, 8 or 30 mg) and four received placebo. Results Plasma concentrations peaked within 24 h after injection and were sustained for ≥ 14 days with all doses. In comparison with placebo, the 8‐ and 30‐mg doses of taspoglutide significantly reduced glycaemic parameters, including 24‐h blood glucose and 5‐h postprandial glucose areas under the curve (AUCs), for up to 14 days with the 30‐mg dose (P < 0.001). The most common adverse events, primarily gastrointestinal in nature, were dose‐dependent and transient. Conclusions A single dose of taspoglutide significantly improved glycaemic parameters in Type 2 diabetes patients for up to 14 days. The formulation was well tolerated and appears suitable for weekly administration.     

Clinical Efficacy of Phosphodiesterase‐5 Inhibitor Tadalafil in Eisenmenger Syndrome—A Randomized,Placebo‐controlled,Double‐blind Crossover Study

Objectives. In a randomized double‐blind crossover trial, we compared the efficacy of phosphodiesterase‐5 (PDE‐5) inhibitor tadalafil with placebo in patients of Eisenmenger Syndrome (ES). The primary end point was the change in 6‐minute walk test distance (6 MWD). Secondary end points were the effect of the drug on systemic oxygen saturation (SO₂), pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), effective pulmonary blood flow (EPBF), and World Health Organization (WHO) functional class. Background. ES is a disorder with limited treatment options. Uncontrolled studies have shown PDE‐5 inhibitors to be beneficial in patients of ES. Methods. Twenty‐eight symptomatic adult patients of ES with weight ≥30 kg in WHO class II and III were enrolled. Patients were given 40 mg of tadalafil or matching placebo for 6 weeks followed by crossover to the other drug after a washout period of 2 weeks. Assessment of WHO class, exercise capacity by 6 MWD, and various hemodynamic parameters by cardiac catheterization was done at baseline, after 6 weeks and at the end of the study. Results. All patients completed the study. There was significant increase in 6 MWD following drug administration compared with baseline (404.18 ± 69.54 m vs. 357.75 ± 73.25 m, P < .001). Compared with placebo, tadalafil produced significant decrease in PVR (?7.32 ± 1.58, P < .001), resulting in significant increase in EPBF (0.12 ± 0.05, P= .03), SO₂ % (1.72 ± 0.58, P= .007), and WHO functional class (1.96 ± 0.18 vs. 2.14 ± 0.44, P= .025), with no significant change in SVR (P= NS). Conclusion. In this first short‐term placebo‐controlled trial of tadalafil in patients of ES, the drug was well tolerated and significantly improved exercise capacity, functional class, SO₂, and pulmonary hemodynamics. http://www.clinicaltrial.gov/ct2/show/NCT01200732?term=NCT01200732&rank=1     

Liraglutide,a once‐daily human GLP‐1 analogue,improves pancreatic B‐cell function and arginine‐stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus

Aims To assess the effect of liraglutide, a once‐daily human glucagon‐like peptide‐1 analogue on pancreatic B‐cell function. Methods Patients with Type 2 diabetes (n = 39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First‐ and second‐phase insulin release were measured by means of the insulin‐modified frequently sampled intravenous glucose tolerance test. Arginine‐stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/l). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin‐modified frequently sampled intravenous glucose tolerance test. Results The two highest doses of liraglutide (1.25 and 1.9 mg/day) significantly increased first‐phase insulin secretion by 118 and 103%, respectively (P < 0.05). Second‐phase insulin secretion was significantly increased only in the 1.25 mg/day group vs. placebo. Arginine‐stimulated insulin secretion increased significantly at the two highest dose levels vs. placebo by 114 and 94%, respectively (P < 0.05). There was no significant treatment effect on glucose effectiveness or insulin sensitivity. Conclusions Fourteen weeks of treatment with liraglutide showed improvements in first‐ and second‐phase insulin secretion, together with improvements in arginine‐stimulated insulin secretion during hyperglycaemia.     

Combination of the insulin sensitizer, pioglitazone, and the long-acting GLP-1 human analog, liraglutide, exerts potent synergistic glucose-lowering efficacy in severely diabetic ZDF rats

Objective: Severe insulin resistance and impaired pancreatic β‐cell function are pathophysiological contributors to type 2 diabetes, and ideally, antihyperglycaemic strategies should address both. Research Design and Methods: Therapeutic benefits of combining the long‐acting human glucagon‐like peptide‐1 (GLP‐1) analog, liraglutide (0.4 mg/kg/day), with insulin sensitizer, pioglitazone (10 mg/kg/day), were assessed in severely diabetic Zucker diabetic fatty rats for 42 days. Impact on glycaemic control was assessed by glycated haemoglobin (HbA_1C) at day 28 and by oral glucose tolerance test at day 42. Results: Liraglutide and pioglitazone synergistically improved glycaemic control as reflected by a marked decrease in HbA_1C (liraglutide + pioglitazone: 4.8 ± 0.3%; liraglutide: 8.8 ± 0.6%; pioglitazone: 7.9 ± 0.4%; vehicle: 9.7 ± 0.3%) and improved oral glucose tolerance at day 42 (area under the curve; liraglutide + pioglitazone: 4244 ± 445 mmol/l × min; liraglutide: 7164 ± 187 mmol/l × min; pioglitazone: 7430 ± 446 mmol/l × min; vehicle: 8093 ± 139 mmol/l × min). A 24‐h plasma glucose profile at day 38 was significantly decreased only in the liraglutide + pioglitazone group. In addition, 24‐h insulin profile was significantly elevated only in the liraglutide + pioglitazone group. Liraglutide significantly decreased food intake alone and in combination with pioglitazone, while pioglitazone alone increased cumulated food intake. As a result, rats on liraglutide alone gained significantly less weight than vehicle‐treated rats, whereas rats on pioglitazone alone gained significantly more body weight than vehicle‐treated rats. However, combination therapy with liraglutide and pioglitazone caused the largest weight gain, probably reflecting marked improvement of energy balance because of reduction of glucosuria. Conclusions: Combination therapy with insulinotropic GLP‐1 agonist liraglutide and insulin sensitizer, pioglitazone, improves glycaemic control above and beyond what would be expected from additive effects of the two antidiabetic agents.     

Septal Dyskinesia and Global Left Ventricular Dysfunction in Pediatric Wolff‐Parkinson‐White Syndrome with Septal Accessory Pathway

LV Dysfunction in WPW Syndrome. Introduction: Echocardiographic studies have shown that some patients with Wolff‐Parkinson‐White (WPW) syndrome have myocardial dyskinesia in the segments precociously activated by an accessory pathway (AP). The aim of the present study was to determine the extent to which the AP contributes to global left ventricular (LV) dysfunction. Methods: Electrophysiological and echocardiographic data from 62 children with WPW (age at diagnosis = 5.9 ± 4.2 years) were retrospectively analyzed. Results: The left ventricular ejection fraction (LVEF) of patients with septal APs (53 ± 11%) was significantly lower than that of patients with right (62 ± 5%) or left (61 ± 4%) APs (P = 0.001). Compared to patients with normal septal motion (n = 56), patients with septal dyskinesia (n = 6) had a reduced LVEF (61 ± 4% and 42 ± 5%, respectively) and an increased LV end diastolic dimension (P < 0.001 for both comparisons). Multivariate analysis identified septal dyskinesia as the only significant risk factor for reduced LVEF. All 6 patients with septal dyskinesia had right septal APs, and a preexcited QRS duration that was longer than that of patients with normal septal motion (140 ± 18 ms and 113 ± 32 ms, respectively; P = 0.045). After RFA there were improvements in both intraventricular dyssynchrony (septal‐to‐posterior wall motion delay, from 154 ± 91 ms to 33 ± 17 ms) and interventricular septal thinning (from 3.0 ± 0.5 mm to 5.3 ± 2.6 mm), and a significant increase in LVEF (from 42 ± 5% to 67 ± 8%; P = 0.001). Conclusion: The dyskinetic segment activated by a right septal AP in WPW syndrome may lead to ventricular dilation and dysfunction. RFA produced mechanical resynchronization, reverse remodeling, and improvements in LV function. (J Cardiovasc Electrophysiol, Vol. 21, pp. 290–295, March 2010)     

Short‐Term Effect of Atorvastatin on Endothelial Function in Healthy Offspring of Parents with Type 2 Diabetes Mellitus

Endothelial function is impaired in healthy subjects at risk of type 2 diabetes mellitus (DM). We investigated whether endothelial dysfunction can be normalized by statin therapy in this potentially predisposed population. Flow‐mediated dilation (FMD) was measured in 56 first‐degree relatives (FDRs) (normotensive, normal glucose tolerance) and 20 age‐, sex‐, and BMI‐matched controls with no family history of DM. Other measurements included insulin resistance index using the homeostasis model of insulin resistance (HOMA_IR), plasma lipids, and markers of inflammation. The FDRs were then randomized and treated with atorvastatin (80 mg) or placebo daily in a 4‐week double‐blind, placebo‐controlled trial. The FDRs had significantly impaired FMD (4.4 ± 8.1% vs. 13.0 ± 4.2%; P < 0.001), higher HOMA_IR (1.72 ± 1.45 vs. 1.25 ± 0.43; P= 0.002), and elevated levels of plasma markers of inflammation—highly sensitive C‐reactive protein (hsCRP) (2.6 ± 3.8 mg/L vs. 0.7 ± 1.0 mg/L; P= 0.06), interleukin (IL)‐6 (0.07 ± 0.13 ng/mL vs. 0.03 ± 0.01 ng/mL; P < 0.001), and soluble intercellular adhesion molecule (sICAM) (267.7 ± 30.7 ng/mL vs. 238.2 ± 20.4 ng/mL; P < 0.001). FMD improved in the atorvastatin‐treated subjects when compared with the placebo‐treated subjects (atorvastatin, from 3.7 ± 8.5% to 9.8 ± 7.3%; placebo, from 3.9 ± 5.6% to 4.7 ± 4.2%; P= 0.001). There were also reductions in the levels of IL‐6 (0.08 ± 0.02 ng/mL vs. 0.04 ± 0.01 ng/mL; P < 0.001) and hsCRP (3.0 ± 3.9 mg/L vs. 1.0 ± 1.3 mg/L; P= 0.006). Our study suggests that treatment with atorvastatin may improve endothelial function and decrease levels of inflammatory markers in FDRs of type 2 DM patients.     

Dipeptidyl‐peptidase IV inhibitor is effective in patients with type 2 diabetes with high serum eicosapentaenoic acid concentrations

Aims/Introduction: Eicosapentaenoic acid (EPA) stimulates glucagon‐like peptide‐1 (GLP‐1) secretion in mice. We investigated the relationship between serum EPA concentrations and the efficacy of dipeptidyl‐peptidase IV (DPP‐4) inhibitor in patients with type 2 diabetes. Materials and Methods: Serum EPA concentrations were measured in 62 consecutive patients with type 2 diabetes who were newly given DPP‐4 inhibitor as a monotherapy or as an add‐on therapy to oral hypoglycemic agents. The dosage of oral hypoglycemic agents was maintained during the observation period. After 24 weeks of treatment with DPP‐4 inhibitor, we evaluated the relationships between a decrease in hemoglobin A1c from baseline and serum EPA concentrations, as well as age, sex, body mass index (BMI), hemoglobin A1c at baseline and usage of antidiabetic concomitant drugs. Results: Hemoglobin A1c was significantly decreased from 8.1 ± 1.1% to 7.2 ± 1.0% by DPP‐4 inhibitor. A decrease in hemoglobin A1c correlated with BMI (r = ?0.396, P = 0.0013), age (r = 0.275, P = 0.0032), hemoglobin A1c at baseline (r = 0.490, P < 0.0001) and log EPA (r = 0.285, P = 0.0246). Multiple regression analysis showed that BMI (β = ?0.419, P = 0.0002), hemoglobin A1c at baseline (β = 0.579, P < 0.0001) and log EPA (β = 0.220, P = 0.0228) were independent determinants of decrease in hemoglobin A1c. Conclusions: DPP‐4 inhibitor is effective in patients with type 2 diabetes with high serum EPA concentrations. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00220.x , 2012)