Comparison of Lactate Dehydrogenase Activity in Hive and Forager Honeybees May Indicate Delayed Onset Muscle Soreness - Preliminary Studies.

Active skeletal muscles produce lactate. H+ is generated during lactate neutralization in the Cori cycle, which leads to muscle acidosis and soreness (the so-called Delayed Onset Muscle Soreness, DOMS) in vertebrates. The aim of the study was to determine the activities/concentrations of compounds involved in the Cori cycle in worker and forager bees. Muscles, fat bodies, and hemolymph from 1- and 14-day-old workers and foragers were collected and assayed for the protein, lactate, glucose, NAD+, and NADH concentrations and lactate dehydrogenase (LDH) activity. Both lactate concentration and LDH activity in the hemolymph, muscles, and fat bodies increased with age. The concentrations of NAD+ and NADH in the tissues decreased with ageing/senescence, whereas protein concentrations increased until day 14 of bee's life and then decreased in foragers. The concentration of glucose decreased in the hemolymph and muscles and increased in the fat bodies. Elevated lactate concentrations in foragers may indicate transition from the aerobic to the anaerobic phase and development of metabolic acidosis that may eventually lead to muscle damage/soreness and shorter lifespan. When analyzing flight dynamics, load mass, and bee behavior, changes in the concentrations of Cori cycle compounds should be taken into account.

Efficacy and safety of dapagliflozin monotherapy in people with Type 2 diabetes: a randomized double-blind placebo-controlled 102-week trial.

AIMS: To assess initial pharmacotherapy of Type 2 diabetes with the sodium-glucose cotransporter-2 inhibitor dapagliflozin. METHODS: This double-blind, placebo-controlled trial, randomly allocated people with Type 2 diabetes aged 18-77 years and inadequate glycaemic control on diet and exercise [HbA1c 53-86 mmol/mol (7.0-10.0%)] to receive placebo (n = 75) or dapagliflozin monotherapy 2.5 mg (n = 65), 5 mg (n = 64) or 10 mg (n = 70) once daily in the morning. After 24 weeks, low-dose double-blind metformin 500 mg/day was added to the placebo group regimen (placebo+low-dose metformin group). Changes in HbA1c level, fasting plasma glucose and body weight, as well as adverse events, were assessed over 102 weeks. RESULTS: Of the 274 participants randomized, 167 completed the study (60.9%). At 102 weeks, significant differences vs placebo+low-dose metformin with dapagliflozin 5 and 10 mg were observed for HbA1c (-5.8 mmol/mol [-0.53%], P = 0.018; and -4.8 mmol/mol [-0.44%], P = 0.048), respectively); and for FPG (-0.69 mmol/L, P = 0.044; and -1.12 mmol/l, P = 0.001, respectively). For body weight, the difference between the dapagliflozin 10-mg group and the placebo+low-dose metformin group was significant (-2.60 kg; P = 0.016). Hypoglycaemic events were uncommon, with rates of 5.3% for placebo+low-dose metformin group and 0-4.6% for the dapagliflozin groups. Genital infections and urinary tract infections were more common in the dapagliflozin groups than in the placebo+low-dose metformin group. CONCLUSIONS: Dapagliflozin as monotherapy in treatment-naïve people with early Type 2 diabetes improved glycaemic control and reduced weight without increasing hypoglycaemia over 102 weeks. Dapagliflozin may provide an alternative initial pharmacotherapy in such people.

Dapagliflozin-induced weight loss affects 24-week glycated haemoglobin and blood pressure levels.

The aim of this study was to investigate the associations between dapagliflozin-mediated reductions in body weight and reductions in glycated haemoglobin (HbA1c) and blood pressure. Data were pooled from seven studies evaluating dapagliflozin 10 mg as monotherapy or combination therapy over 24 weeks. Using linear regression to estimate the contribution of weight loss to HbA1c and blood pressure reductions, the ß-value estimate for HbA1c (%)/kg was 0.028 (p < 0.0001). Weight loss of 2 kg with dapagliflozin contributed to 6% of the total HbA1c reduction. For systolic (SBP) and diastolic blood pressure (DBP), the ß-value (mmHg/kg) estimates were 0.606 (p < 0.0001) and 0.253 (p < 0.0001), respectively. Weight loss of 2 kg contributed to 28% of the overall SBP reduction, and 24% of the overall DBP reduction. In conclusion, dapagliflozin-mediated weight loss may contribute to overall reductions in HbA1c and blood pressure.

Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial.

BACKGROUND: Combining metformin (XR) with dapagliflozin to initiate pharmacotherapy in patients with type 2 diabetes (T2D) and high baseline HbA1c may be advantageous. We conducted two randomised, double-blind, three-arm 24-week trials in treatment-naïve patients to compare dapagliflozin plus metformin, dapagliflozin alone and metformin alone. METHODS: Eligible patients had baseline HbA1c 7.5-12%. Each trial had three arms: dapagliflozin plus metformin, dapagliflozin monotherapy and metformin monotherapy. Dapagliflozin in combination and as monotherapy was dosed at 5 mg (Study 1) and 10 mg (Study 2). Metformin in combination and as monotherapy was titrated to 2000 mg. The primary endpoint was HbA1c change from baseline; secondary endpoints included change in fasting plasma glucose (FPG) and weight. RESULTS: In both trials, combination therapy led to significantly greater reductions in HbA1c compared with either monotherapy: -2.05 for dapagliflozin + metformin, -1.19 for dapagliflozin, and -1.35 for metformin (p < 0.0001) (Study 1); -1.98 for dapagliflozin + metformin, -1.45 for dapagliflozin and -1.44 for metformin (p < 0.0001) (Study 2). Combination therapy was statistically superior to monotherapy in reduction of FPG (p < 0.0001 for both studies); combination therapy was more effective than metformin for weight reduction (p < 0.0001). Dapagliflozin 10 mg was non-inferior to metformin in reducing HbA1c (Study 2). Events suggestive of genital infection were reported in 6.7%, 6.9% and 2.0% (Study 1) and 8.5%, 12.8% and 2.4% (Study 2) of patients in combination, dapagliflozin and metformin groups; events suggestive of urinary tract infection were reported in 7.7%, 7.9% and 7.5% (Study 1) and 7.6%, 11.0% and 4.3% (Study 2) of patients in the respective groups. No major hypoglycaemia was reported. CONCLUSION: In treatment-naïve patients with T2D, dapagliflozin plus metformin was generally well tolerated and effective in reducing HbA1c, FPG and weight. Dapagliflozin-induced glucosuria led to an increase in events suggestive of urinary tract and genital infections.

Irbesartan has no short-term effect on insulin resistance in hypertensive patients with additional cardiometabolic risk factors (i-RESPOND).

AIMS: Intervention studies have shown that angiotensin receptor blockers (ARB) may reduce the incidence of type 2 diabetes mellitus. It is currently unclear whether short-term therapy with ARBs affects metabolic parameters. METHODS: i-RESPOND, a randomised, controlled, multicentre, double-blind study evaluated the effect of 16 weeks of irbesartan vs. hydrochlorothiazide (HCTZ) on insulin resistance as well as on lipid and inflammatory parameters in hypertensive subjects with metabolic syndrome. Patients received irbesartan (150 mg/d; n = 211) or HCTZ (12.5 mg/d; n = 215), titrated to 300 mg/day and 25 mg/day respectively. In a second part of the study (weeks 16-28), patients initially randomised to irbesartan received additional HCTZ and vice versa. RESULTS: At week 16 both irbesartan and HCTZ had no effect on insulin resistance measured by the Matzuda index and beta-cell function. Similarly, in the second part of the study (week 16-28) no differences between irbesartan and HCTZ with respect to glucose metabolism were observed. However, irbesartan induced beneficial changes in high-sensitivity-C-reactive protein (hs-CRP) (irbesartan: -5.5 +/- 5.2%; HCTZ + 19.9 +/- 6.5%, p = 0.0024) and in urinary albumin/creatinine ratio (ACR) (irbesartan: -13%; HCTZ + 9%; p = 0.0041) compared with HCTZ despite a similar decrease in blood pressure in both treatment groups. Irbesartan and HCTZ were well tolerated and adverse events were comparable. CONCLUSION: Irbesartan did not show significant favourable effects on insulin resistance compared with HCTZ in this study; however, may have beneficial effects on inflammation and microalbuminuria in hypertensive patients with metabolic syndrome.

A comparison of the efficacy and safety of irbesartan/HCTZ combination therapy with irbesartan and HCTZ monotherapy in the treatment of moderate hypertension.

This prospective, double-blind, parallel-group study randomized patients with moderate hypertension (seated systolic blood pressure (SeSBP) 160-179 mm Hg when seated diastolic blood pressure (SeDBP) <110 mm Hg; or SeDBP 100-109 mm Hg when SeSBP <180 mm Hg) 3:1:1 to treatment with irbesartan 300 mg/hydrochlorothiazide (HCTZ) 25 mg combination therapy (n=328), irbesartan 300 mg monotherapy (n=106) or HCTZ monotherapy 25 mg (n=104). Treatment was initiated at half dose, with forced titration to full dose after two weeks followed by ten further weeks' treatment. The primary efficacy variable was the mean reduction in SeSBP from baseline to week 8. Baseline characteristics were similar between groups, with mean baseline blood pressure approximately 162/98 mm Hg; the mean age was 55 years. At week 8 there was a reduction in SeSBP of 27.1 mm Hg with irbesartan/HCTZ, compared with 22.1 mm Hg with irbesartan monotherapy (P=0.0016) and 15.7 mm Hg with HCTZ (P<0.0001). Both the rate of decline and the total degree of decline achieved were greatest with irbesartan/HCTZ and least with HCTZ. A significantly greater percentage of patients reached a treatment goal of SeSBP <140 mm Hg and SeDBP <90 mm Hg by week 8 with irbesartan/HCTZ (53.4%), compared with irbesartan (40.6%; P=0.0254) and HCTZ (20.2%; P<0.0001) alone. Treatment was well tolerated in all three-treatment groups with a slight increase in adverse events in the combination therapy group. In conclusion, irbesartan/HCTZ (300/25 mg) is well tolerated and achieves rapid and sustained reductions in both systolic blood pressure and diastolic blood pressure in patients with moderate hypertension.

Rationale and design of a study to evaluate management of proteinuria in patients at high risk for vascular events: the IMPROVE trial.

Declining kidney function predicts increasing cardiovascular risk in people with hypertension. Microalbuminuria is a marker for cardiovascular risk and declining kidney function. Agents that block the renin-angiotensin-aldosterone system (RAAS), notably angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), reduce proteinuria and microalbuminuria, lower blood pressure and slow the progression of proteinuric kidney disease. Evidence is accumulating that the combination of an ACE inhibitor and an ARB is the optimal means of RAAS blockade in this setting, slowing the progression of nephropathy independently of blood pressure lowering to a greater degree than can be achieved using maximum approved doses of either agent alone. However, the emerging therapeutic potential of ACE inhibitor/ARB combination therapy in hypertensive kidney disease requires further characterization. The Irbesartan in the Management of PROteinuric patients at high risk for Vascular Events trial aims to determine definitively whether the combination therapy of an ARB, irbesartan and an ACE inhibitor, ramipril, is more effective than ramipril alone in reducing the urinary albumin excretion rate in patients at high cardiovascular risk with hypertension and proteinuria or microalbuminuria.

Treatment of microalbuminuria in hypertensive subjects with elevated cardiovascular risk: results of the IMPROVE trial.

Microalbuminuria independently predicts increased cardiovascular risk in hypertensive patients, especially in those with concomitant diabetes or established cardiovascular disease. Drugs that target the renin-angiotensin-aldosterone system reduce microalbuminuria regardless of diabetic status. The Irbesartan in the Management of PROteinuric patients at high risk for Vascular Events was a multicenter, randomized, double-blind, placebo-controlled paralleled group study in which hypertensive patients with microalbuminuria and increased cardiovascular risk were randomized to 20 weeks treatment with ramipril plus irbesartan or to ramipril plus placebo. Patients discontinued or tapered previous antihypertensive therapy during a 14-day placebo lead-in period. Change in albumin excretion rate from baseline to week 20 was the primary end point. Adjusted week 20 baseline geometric ratios for ramipril plus irbesartan and ramipril plus placebo were not significantly different. Although differences in blood pressure reductions were observed between the two treatments, these changes did not affect microalbuminuria. More patients on dual therapy achieved target blood pressure goals at week 20 than with monotherapy. The incidence of adverse effects and treatment-related adverse effects was similar in both groups. Our results suggest that patients with cardiovascular risk and relatively low albumin excretion rates in early-stage disease may only require monotherapy with renin-angiotensin-aldosterone blocking agents.