Role of the sympathetic nervous system in cardiometabolic control: implications for targeted multiorgan neuromodulation approaches.

Sympathetic overdrive plays a key role in the perturbation of cardiometabolic homeostasis. Diet-induced and exercise-induced weight loss remains a key strategy to combat metabolic disorders, but is often difficult to achieve. Current pharmacological approaches result in variable responses in different patient cohorts and long-term efficacy may be limited by medication intolerance and nonadherence. A clinical need exists for complementary therapies to curb the burden of cardiometabolic diseases. One such approach may include interventional sympathetic neuromodulation of organs relevant to cardiometabolic control. The experience from catheter-based renal denervation studies clearly demonstrates the feasibility, safety and efficacy of such an approach. In analogy, denervation of the common hepatic artery is now feasible in humans and may prove to be similarly useful in modulating sympathetic overdrive directed towards the liver, pancreas and duodenum. Such a targeted multiorgan neuromodulation strategy may beneficially influence multiple aspects of the cardiometabolic disease continuum offering a holistic approach.

Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes: a randomised, placebo-controlled clinical trial.

AIMS/HYPOTHESIS: This multicentre randomised double-blind placebo-controlled clinical trial assessed the efficacy and safety of a methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib, in individuals with obesity (BMI ≥30 kg/m2) and type 2 diabetes (HbA1c 53-97 mmol/mol [7-11%] and fasting glucose <15.6 mmol/l). METHODS: Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8 mg beloranib s.c. twice weekly for 26 weeks. Participants, investigators and the sponsor were blinded to group assignment. The primary endpoint was the change in weight from baseline to week 26. The trial was terminated early when beloranib development was stopped because of an imbalance of venous thromboembolism events in beloranib-treated individuals vs placebo that became evident during late-stage development of the drug. RESULTS: In total, 153 participants were randomised, 51 to placebo, 52 to 1.2 mg beloranib and 50 to 1.8 mg beloranib. In participants who completed week 26, the least squares mean ± SE weight change (baseline 111 kg) was -3.1 ± 1.2% with placebo (n = 22) vs -13.5 ± 1.1% and -12.7 ± 1.3% with 1.2 and 1.8 mg beloranib, respectively (n = 25; n = 19; p < 0.0001). The change in HbA1c (baseline 67 mmol/mol [8.3%]) was -6.6 ± 2.2 mmol/mol (-0.6 ± 0.2%) with placebo vs -21.9 ± 2.2 mmol/mol (-2.0 ± 0.2%) or -21.9 ± 3.3 mmol/mol (-2.0 ± 0.3%) with 1.2 or 1.8 mg beloranib (p < 0.0001), respectively. The most common beloranib adverse events were sleep related. One beloranib-treated participant experienced a non-fatal pulmonary embolism. CONCLUSIONS/INTERPRETATION: MetAP2 inhibitors represent a novel mechanism for producing meaningful weight loss and improvement in HbA1c. TRIAL REGISTRATION: ClinicalTrials.gov NCT02324491 FUNDING: The study was funded by Zafgen, Inc.

Impact of an integrated diabetes service involving specialist outreach and primary health care on risk factors for micro- and macrovascular diabetes complications in remote Indigenous communities in Australia.

OBJECTIVE: To determine the impact of an integrated diabetes service involving specialist outreach and primary health care teams on risk factors for micro- and macrovascular diabetes complications in three remote Indigenous Australian communities over a 12-month period. DESIGN: Quantitative, retrospective evaluation. SETTING: Primary health care clinics in remote Indigenous communities in Australia. PARTICIPANTS: One-hundred-and-twenty-four adults (including 123 Indigenous Australians; 76.6% female) with diabetes living in remote communities. MAIN OUTCOME MEASURES: Glycosylated haemoglobin, lipid profile, estimated glomerular filtration rate, urinary albumin : creatinine ratio and blood pressure. RESULTS: Diabetes prevalence in the three communities was high, at 32.8%. A total of 124 patients reviewed by the outreach service had a median consultation rate of 1.0 by an endocrinologist and 0.9 by a diabetes nurse educator over the 12-month period. Diabetes care plans were made in collaboration with local primary health care services, which also provided patients with diabetes care between outreach team visits. A significant reduction was seen in median (interquartile range) glycosylated haemoglobin from baseline to 12 months. Median (interquartile range) total cholesterol was also reduced. The number of patients prescribed glucagon-like peptide-1 analogues and dipeptidyl peptidase-4 inhibitors increased over the 12 months and an increase in the number of patients prescribed insulin trended towards statistical significance. CONCLUSION: A collaborative health care approach to deliver diabetes care to remote Indigenous Australian communities was associated with an improvement in glycosylated haemoglobin and total cholesterol, both important risk factors, respectively, for micro- and macrovascular diabetes complications.