The American Diabetes Association (ADA) has held their 78th Scientific Sessions this year from June 22-26 in Orlando, Florida, US. The latest research findings, new technology and treatment that could improve the health and well-being of diabetic patients were shared in the meeting, together with some of the discussions that drive the field forward. This year, a lot of focus was on the importance of cardiovascular disease (CVD) risk in patients with diabetes, as these individuals are known to have a higher CV risk than those without diabetes.1 Acknowledging that, a debate on the value of cardiovascular outcomes trials (CVOTs) in diabetes sparked some thoughts on how antihyperglycemic treatments should be investigated in the future. The draft for the ADA and European Association for the Study of Diabetes (EASD) consensus report on hyperglycemia management in type 2 diabetes was also unveiled during the scientific sessions, sculpturing the pathways for better management in these patients.
Leading the fight against diabetes
With the ability to cause serious complications including blindness, lower limb amputation, kidney failure, and heart problem,2 diabetes has become a major global health threat with an estimate of 425 million adults aged between 20-79 years diagnosed with the disease.3 If the trend is allowed to continue, the number of patients would reach 629 million by 2045, a striking figure that cannot be overlooked.3
Carrying the mission to lead the fight against the deadly consequences of diabetes and fight for those affected by diabetes, the ADA invited diabetes professionals from all over the world to gather in Orlando, Florida, US, for sharing and to learn about the latest breakthrough in this fight.
Diabetes medications and improvement in CV outcomes
Patients with type 2 diabetes are more susceptible to CVD than the normal population, which are also the leading cause of death in these patients.1,4 In the past 80 years, the treatment goals for diabetic patients experienced a rapid transformation from preventing imminent mortality (severe hyperglycemia leading to a diabetic coma) to alleviating symptoms, and to achieve long-term glycemic control with the intention of preventing diabetic complications.5
Upon realizing the importance of diabetes medications to improve CV outcomes, the U.S. Food and Administration (FDA) released a recommendation on the clinical trials of drug treatments for type 2 diabetes to better assess the CV safety of these new therapies.5 Ever since, antihyperglycemic drug trials that assess CV events, better known as CV outcomes trials (CVOTs), have become an integral part of the drug approval process.5
The debate on CVOTs: To stay or to change
To date, there are many CVOTs on the various classes of drugs including dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonist (GLP-1 RA), sodium-glucose linked transporter type 2 (SGLT-2) inhibitors, basal insulin analog, and α-glucosidase inhibitor.6 These trials were deemed extremely valuable – not only do they confirm the CV safety of the medications, but also identify the CV benefits (for example SGLT-2 inhibitors and GLP-1 receptor agonist), which Dr. Steven P. Marso, Medical Director of Cardiovascular Services at HCA Midwest Health, described these evidence as “landmark findings” that would not be discovered prior to the FDA guidance update in 2008.7
However, throughout the process of obtaining the valuable knowledge, an enormous amount of resources were spent as the trials would typically require a large number of patients, investigators, and centers across multiple countries.4 “The reality is, when the FDA and the European Medicines Agency flipped the switch in 2008, it increased the scope of the development programs by about 70-fold, now requiring about 15,000 patient-years of exposure to establish at a minimum CV safety and to get ultimate approval of these medications for use in the clinical space,” said Dr. Darren McGuire, Professor in the Department of Internal Medicine at the University of Texas Southwestern Medical Center and Director of the Parkland Hospital and Health System Outpatient Cardiology Clinics, at the 78th ADA Scientific Sessions, who felt there are more cost-effective ways to conduct the trials.7
Finding a balance in conducting CVOTs
The idea proposed by Dr. McGuire was not to abandon the present strategies of doing CVOTs entirely, but to fine-tune the study designs so that more informative results and values can be obtained from the trials.7 Dr. McGuire mentioned one of the tactics to make CVOTs more cost-effective is to modify the primary outcomes by including heart failure outcome in the composite of CV outcomes, or as a co-primary outcome along with atherosclerotic vascular disease outcome analyzed at a similar priority.7 Expanding the composite outcome can increase the event rates, which lead to a shorter trial duration, given the outcomes are appropriately selected.4
Another strategy that received a lot of attention was to conduct trials in a creative way such as the use of factorial or adaptive trial designs, superiority trials, and real-world data collected using electronic medical record system.4,8 These study designs not only allow an innovative way to assess CV outcomes, but also open up the possibility to assess some of the older therapies such as metformin which remains unknown with respect to its incremental benefit on CVD.7
Revisiting the updated standards of medical care in diabetes
Switching the focus on diabetes from bench to bedside, the standards of care for diabetes by the ADA was revised and made available to the public in January 2018, providing a comprehensive overview of patient-centered management in diabetes.9
The updated guideline made a major change to the algorithm for the pharmacologic treatment of patients with type 2 diabetes.9 While metformin along with lifestyle management is still the preferred initial treatment, new evidence has been incorporated into the algorithm to better manage patients with established atherosclerotic CVD (ASCVD) (Figure 1).9
In cases where other pharmacological agents are needed, the guideline stressed the decision to be guided by considerations on a combination of factor including efficacy, hypoglycemia risk, history of ASCVD, impact on weight, potential side-effects, impact on the kidneys, delivery method, cost, and patient preferences.9 The guideline summarized the drug-specific and patient factors that are relevant to the choice of medication, with a selection of important factors presented in Table 1 (For the full table, please refer to the ADA 2018 standard of care for diabetes).9
The 2018 ADA/EASD consensus report
As more evidence has been discovered with the CVOTs, the ADA/EASD committee decided to update their basic framework for treating type 2 diabetes, which would be their third collaboration after the initial statement in 2012 and revision in 2015.10
The new consensus statement made its first appearance during the ADA Scientific Sessions, allowing the attendees to get a glimpse on the ADA/EASD committee’s stance.11 The consensus statement shifted the treatment framework towards a patient-centered approach, by emphasizing the importance of considering patient’s comorbidities, particularly CVD or high CV risk, when selecting medications for these patients.11
Treatment algorithm will also be separated to address patients with ASCVD and those with heart failure, based on an initial assessment of CV status for determining the treatment approach.12 In patients whom ASCVD predominates, GLP-1 RA, followed by SGLT-2 inhibitors, is recommended.12 Whereas in patients whom heart failure predominates, SGLT-2 inhibitor is recommended (GLP-1 RA is recommended as an alternative option).12
“What’s new since 2015 is we recommend that these comorbidities be considered first and foremost, because they do influence the choice of a particular glucose-lowering medication…The presence of CVD is a compelling indication for the selection of certain glucose-lowering drugs,” said Dr. Debroah J. Wexler, Associate Professor of Medicine at Harvard Medical School, Associate Clinical Chief of the Massachusetts General Hospital Diabetes Unit, and Co-Clinical Director of the MGH Diabetes Center, in response to the updated consensus statement.
Meanwhile, for patients without ASCVD or heart failure, individual needs and preferences (i.e., undesirable effects such as weight gain and hypoglycemia) will be the next priority for consideration.11
Feedback to the consensus statement
One of the purposes to reveal the consensus statement was to allow different parties including diabetes care providers, clinical researchers, patient groups, payers, regulators, and all other stakeholders to make comments before a finalized report would be released at the EASD Annual Meeting in Berlin, Germany.11
The feedbacks towards the consensus statement were generally positive. Dr. Silvio E. Inzucchi, MD of Yale University School of Medicine, New Haven, Connecticut, said, “the committee did a spectacular job in synthesizing the information, and also pointing out where evidence was lacking. I think the approach of determining whether someone has CVD as an initial decision node makes sense.”12
Reflecting from the meeting and moving on
Apart from the fierce debate on the value of CVOTs and the informative guideline updates, the ADA 78th Scientific Sessions also brought out a lot of research findings and new insight to drive diabetes out from our daily life. At this very moment, diabetes professionals can reflect on the topics that have been discussed during the meeting and patiently wait for this year’s EASD Annual Meeting, where the finalized consensus statement would be published along with more new research findings that will make a difference to the life of diabetic patients.