The ADA Presidents Oral Session: Tuesday 13th June
medwireNews: The ADA Presidents Oral Session closed the 2017 American Diabetes Association 77th Scientific Sessions.
Chair of the Meeting Planning Committee Maureen Gannon (Vanderbilt University Medical Center, Nashville, Tennessee, USA) said: “The eight oral presentations in this session were selected by the Planning Committee as the best of the submitted abstracts. Each year, this session provides a deep appreciation for the depth and the breadth of high-quality research being done under the leadership of the ADA.”
Oral basal insulin success in type 2 diabetes
One of the highlights of this session was data from an 8-week feasibility study of oral basal insulin in people with type 2 diabetes, presented by Leona Plum-Mörschel (Profil, Neuss, Germany). The trial included 50 participants who were randomly assigned in a double-dummy design to receive once-daily oral insulin 338 plus placebo injection or once-daily insulin glargine injection plus oral placebo.
During the study, fasting plasma glucose fell by a similar degree with both treatments, from around 175 to 129 mg/dL with oral insulin 338 and from around 165 to 121 mg/dL with insulin glargine. A similar pattern was seen with glycated hemoglobin (HbA1c), falling from 8.1% and 8.2% to 7.3% and 7.1% with oral insulin 338 and insulin glargine, respectively.
In addition, there were no severe hypoglycemic events and overall hypoglycemia rates were similar between the two groups.
Plum-Mörschel concluded: “After almost 100 years of oral insulin research, this trial demonstrates for the first time that an oral basal insulin safely can improve glycemic control in patients with type 2 diabetes.”
Speaking at a press conference, study co-author, Karsten Wassermann (Novo Nordisk A/S, Copenhagen, Denmark) said: “While these data are highly encouraging, there is a need to optimize the tablet to further increase the insulin bioavailability.”
Indeed, this particular formulation had a bioavailability of around 2%. Its production has now been discontinued because the overall investments needed to produce the quantities required for wide public use are not commercially viable, Wasserman explained. He added that improvement of technologies involved in the product’s development is the focus of ongoing research.
Human glucagon receptor antibody cuts insulin needs in type 2 diabetes
Another novel treatment presented during this session was REMD-477, a human glucagon receptor antibody. Jeremy Pettus, from the University of California, in San Diego, USA, explained that REMD-477 blocks glucagon receptor signaling and reduces hepatic glucose output. Its efficacy was tested in a double-blind, placebo-controlled trial among 21 patients with type 1 diabetes.
The patients received 70 mg of REMD-477 or placebo on day 2 of a 5-day inpatient observation period and were then followed up for a further 8 weeks.
Pettus reported that, by day 4, there was a significant 26% drop in daily insulin requirement in the patients who received REMD-477 compared with those who received placebo, which he described as clinically meaningful.
This difference in insulin requirements remained at day 19 and was accompanied by a significant 31 mg/dL lower mean glucose level in the REMD-477 group compared with the placebo group, and a 15% increase in time in target glucose range.
Pettus told reporters: “Our study strongly supports the long-held theory that blocking glucagon may have a significant clinical impact on care for people with type 1 diabetes by improving glucose levels and lowering insulin doses.”
“We expected that the drug [REMD-477] would have an effect, yet the degree to which the drug reduced the need for insulin and improved patients’ blood sugar levels without increasing hypoglycemia events was a surprise.”
He said that the next steps will be to conduct a repeated dosing study, look at the effects of blocking glucagon on hypoglycemia, and investigate whether there is any restoration of beta-cell function.
CVD-REAL: CVD benefits of SGLT-2 inhibitors independent of pre-existing CVD
Moving on to dealing with the complications associated with diabetes, Matthew Cavender (University of North Carolina School of Medicine, Chapel Hill USA) presented new data from the CVD-REAL study.
CVD-REAL is an observational study of 306,156 patients with type 2 diabetes from six countries, investigating the impact of sodium glucose cotransporter-2 (SGLT-2) inhibitors on heart failure and death.
Initial data, presented at the 2017 American College of Cardiology Conference, showed that initiation of an SGLT-2 inhibitor was associated with a significant reduction in death and heart failure compared with initiation of other glucose-lowering drugs.
During the ADA Presidents oral session, Cavender extended these findings to show that the reduction was independent of pre-existing cardiovascular disease (CVD) or SGLT-2 inhibitor type, which varied by country.
He reported that patients with prior CVD had a 53% lower risk for CVD when their diabetes was treated with SGLT-2 inhibitors compared with other oral glucose-lowering drugs. The risk reduction was 46% in patients without prior CVD.
Similar reductions were observed for heart failure, at 31% and 55%, respectively, and the composite of heart failure and death, at 41% and 48%, respectively.
“This study offers further evidence regarding the potential of SGLT-2 inhibitors to improve outcomes in patients with diabetes,” Cavender told the press.
He added: “While our results are striking in their similarity to a prior randomized study evaluating the benefit of SGLT-2 inhibitors in patients with diabetes and known cardiovascular disease, these results go one step further to show that SGLT-2 inhibition may benefit all patients with diabetes, regardless of whether they have known cardiovascular disease.”
Cavender concluded: “These findings suggest that use of SGLT-2 inhibitors may provide the opportunity to reduce the incidence of heart failure among patients with diabetes.”
Cognitive behavioral therapy and exercise improve diabetes-related depression
Another complication that is gaining recognition in patients with diabetes is depression. In this session, Mary de Groot (Indian University School of Medicine, Indianapolis, USA) reported her findings from Program ACTIVE II: A comparative effectiveness trial to treat major depression in type 2 diabetes.
De Groot explained that depression is twice as common in people with diabetes than in the general population and one in four people with diabetes will have depression in their lifetime. In addition, depression in diabetes has been linked to decreased blood glucose control and adherence to medication; increased complications, medical costs, and functional disability; and premature mortality.
The Program ACTIVE II study showed that cognitive behavioral therapy, exercise, and a combination of the two increased the likelihood for being depression-free five- to sixfold compared with usual care. All three interventions were also associated with reduced diabetes distress, while counseling plus exercise and exercise alone improved overall and diabetes-specific quality of life.
In addition, participants assigned to the exercise group with a starting HbA1c level of 7.0% or higher had a clinically meaningful 0.7% reduction in their HbA1c levels at the end of the exercise intervention, compared with those receiving usual care.
In a statement to the press, de Groot said: “Our study is the first to demonstrate that exercise guided by a personal trainer and performed by participants in their communities is effective in treating both depression and diabetes, even after accounting for changes in diabetes medications.”
“Exercise is also effective in managing blood sugar control in [these] people.”
She also said that the study demonstrates that it is possible to extend access to depression care in both rural and urban areas.
Diabetes genetics, the brain, and key preclinical findings
Also presenting data during the Presidents session were Chelsea Kasper (University of Washington, Seattle, USA), Weier Qi (Joslin Diabetes Center, Boston, Massachusetts, USA), Hidetoshi Kitajima (University of Oxford, UK), and Peng Zhou (Harvard Medical School, Boston, Massachusetts, USA).
Kasper talked about the control of glucose counterregulation by the hypothalamic ventromedial nucleus (VMN), concluding that activation of VMN nitric oxide synthase 1 (NOS1) neurons is sufficient to induce robust, reversible hyperglycemia, and this involves a suppression of insulin secretion, and an increased glucagon secretion characteristic of counterregulatory responses to hyperglycemia.
She added that VMNNOS1 activation is associated with secondary behaviors such as the fear response.
“Ultimately we hope that delineating the underlying neurocircuitary will inform our understanding of both the adverse health consequences of hypoglycemia and how these regulatory responses may become ineffective in patients with diabetes,” Kasper said.
Qi reported that pyruvate kinase M2 (PKM2) is a novel protective factor identified in patients with long-duration type 1 diabetes. She said that PKM2 prevents accumulation of toxic metabolites and prevents kidney fibrosis induced by diabetes, and could therefore represent a novel therapeutic target for the treatment of diabetes.
Kitajima reported his team’s use of discovery and fine-mapping of type 2 diabetes susceptibility loci to show strong evidence of heterogeneity in allelic effects between individuals with different ancestry.
Finally, Zhou presented his findings from studies in mice showing that palmitic acid esters of hydroxy stearic acid can reduce hepatic glucose production in a way that appears to be mediated by cyclic adenosine monophosphate pathway protein receptors.
By Laura Cowen
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