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18th January 2021
The monoclonal antibody bimagrumab binds to and blocks the activity of the activin type II receptor (ActRII), promoting skeletal muscle hypertrophy and reducing body fat mass. Given this potential action, researchers from Pennington Biomedical Research Centre, Louisiana State University, in the US, hypothesised that the drug might represent a beneficial approach to the management of obese, type 2 diabetic patients. They recruited type 2 diabetes aged between 18 and 75 years with a glycated haemoglobin (HbA1C) of 6.5 to 10%, a body mass index (BMI) of 28 to 40 and a weight of between 65 and 140kg. All patients were prescribed either metformin (as mono-therapy), dipeptidyl peptidase 4 (DPP4) inhibitors, (again as mono-therapy) or a combination of both drugs, although a small number were not prescribed any diabetic medicines. These treatments were permitted because of their weight neutral effect. Eligible participants were randomised 1:1 to either Bimagrumab (10mg/kg to a maximum of 1200mg in 5% dextrose) or placebo (5% dextrose) via 30-minute intravenous infusion every 4 weeks for a total of 48 weeks and both clinicians and patients were blinded to allocation. The primary endpoint was a change from baseline to week 48 in total fat mass (FM) which was measured by dual energy X-ray absorptiometry. Secondary endpoints included change in diabetic status (HbA1C), body weight, BMI and both HOMA2 and the Matsuda index which are measures of insulin sensitivity.
A total of 75 patients were randomised to either bimagrumab (37) or placebo (38). The mean age of those assigned to bimagrumab was 60.7 years (62.2% female). At week 48, total FM decreased by a mean of 7.49 kg in the bimagrumab group vs 0.18 kg in the placebo group (p < 0.01). Similarly, there were significant reductions in BMI (2.19 vs 0.28, p < 0.001), body weight (5.90 kg vs 0.79 (p < 0.01) and HbA1C levels (0.76 vs 0.04, p < 0.05). Interestingly, the bimagrumab group also saw a significant increase in lean muscle mass compared to the placebo group (1.70 kg vs 0.4 kg, p < 0.001). However, there were no significant changes to either measure of insulin sensitivity or in use of anti-diabetic medication. Commenting on their findings, the authors noted that treatment with bimagrumab led to a small increase in lean muscle mass which is a beneficial effect given that muscle loss is typically observed when type 2 diabetes adopt a low-calorie diet.
They concluded that inhibition of ActRII may provide a novel pathway for the management of excess body fat and metabolic disturbances as seen in type 2 diabetics.
Heymsfield SB et al. Effect of Bimagrumab vs placebo on body fat mass among adults with type 2 diabetes and obesity. A phase 2 randomised clinical trial. JAMA Netw Open 2021
23rd October 2020
Patients with type 2 diabetes have also been shown to have an increased the risk of cognitive impairment and dementia. Achievement of good glycaemic control is associated with a reduction in the risk of many of adverse health outcomes and this can be attained through weight loss, but the evidence for an improvement in cognitive impairment is currently mixed. In this study, researchers from several centres in the US have reported on the results from the Action for Health in Diabetes (look AHEAD) study which suggests that it is glycaemic control, rather than weight reduction, which has the greatest impact on cognitive functioning. The look AHEAD study is a single blind, randomised trial that recruited 5145 individuals during 2001 to 2004 with a BMI >25kg/m2, a HbA1c < 11%, triglycerides < 600mg/dl and a systolic/diastolic blood pressure < 160/100 mmHg. Participants were randomised to either an intensive lifestyle intervention (ILI) or a diabetes support and education (DSE) control group and the interventions continued until 2012, which was an average of 9.9 years. For the cognitive assessment arm, 1089 participants from the original study were recruited at year 8 or 9 of follow-up and undertook 2 or 3 cognitive assessments, that evaluated verbal learning, memory, speed of processing, executive function and global cognitive functioning.
There was an equal number of participants from the ILI and DSE groups; the mean age of both samples was 58 years, and 42% of both groups was male and roughly 10% had pre-existing cardiovascular disease. Improvements in blood sugar control was associated with greater improvements in cognitive scores for most measures. In contrast, the association between improvements in weight loss and cognitive scores was less clear and depended to some extent, on the cognitive measure.
The authors were unable to account for these findings and concluded that any improvements in cognitive function were largely dependent on baseline levels of adiposity and cardiovascular disease history.
Carmichael OT et al. Long-term change in physiological markers and cognitive performance in type 2 diabetes: the look AHEAD trial. J Clin Endrocrinol Metab 2020; doi:10.1210/clinem/dgaa591