Greetings from snowy Edmonton, where the first two days of Diabetes Canada provided us a warm welcome despite the cold weather. A moving keynote from the highly-respected Dr. Daniel Drucker of the University of Toronto on his remarkable 30 years in incretin biology gave us plenty to think about, from the importance of unbiased basic science research to how we can ensure that innovative new drugs are actually making a difference for patients. We also heard fascinating commentary from lead CANVAS investigator Dr. David Matthews on the complexities of modern clinical trial design and interpretation in an era fraught with “statistical fundamentalism” and sentiments of “p<0.05 or bust.” Read on for all this and more.
The rest of the meeting promises much more thoughtful discussion, and we’ll be back in the coming days with all the details! See our conference preview for a sneak peek of all that’s left to come.
Top Five Highlights
1. Reflecting on his 30 years of work in incretin biology, the great Dr. Daniel Drucker delivered a moving testament to the importance of elucidating drug mechanisms of action, and extending this critical thinking to ensure that improved therapies are truly translating into improvements in patients’ lives. In particular, we appreciated his deep dive on a potential mechanism for cardioprotection in GLP-1 agonists: “If you want to make drugs better, with next-generation versions with even more potent glucose-lowering and even more cardioprotection, then you do need to know how they work to know where to focus attention for innovation.”
2. The esteemed Dr. David Matthews, lead CANVAS investigator, used this SGLT-2 CVOT as a springboard to discuss the complexities of modern clinical trial design and interpretation. He urged caution when comparing across trials with vastly different designs (i.e. CANVAS and EMPA-REG OUTCOME for amputations), and questioned “statistical fundamentalism,” where the question of whether a signal is “real” hinges on the arbitrary threshold of p<0.05 (alluding to EXSCEL’s narrow miss for statistically significant CV superiority).
3. University of Toronto cardiologist Dr. Jacob Udell provided an informative overview of heart failure outcomes in recent diabetes CVOTs, expressing optimism that SGLT-2 inhibitors may one day be indicated for the heart failure population.
4. A fascinating symposium led by educator extraordinaire Ms. Lori Berard and Dr. Michael Vallis, a clinical psychologist specializing in diabetes/obesity, took a deep dive on behavior change strategies to overcome some of the most challenging issues in diabetes care – clinical inertia and fear/reluctance surrounding insulin initiation (a phenomenon they termed “psychological insulin resistance”).
5. Diabetes Canada kicked off with an informative pre-conference workshop designed to support health educators in educating patients on glycemic index.
Top Five Highlights
1. Dr. Drucker Reflects on 30 Years of Incretin Biology Research
Reflecting on his 30 years of work in incretin biology, the great Dr. Daniel Drucker delivered a moving testament to the importance of elucidating drug mechanisms of action, and extending this critical thinking to ensure that improved therapies are truly translating into improvements in patients’ lives. Dr. Drucker’s lecture took a whirlwind tour through the history of the GLP-1 agonist class – from the discovery of the incretin effect, to the isolation of the exendin peptide from Gila monster venom, to the commercialization of GLP-1 agonists, starting with AZ’s Byetta (he knows every product’s approval date by heart), and finally to the demonstration of a cardioprotective benefit for liraglutide (Novo Nordisk’s Victoza) and semaglutide (Novo Nordisk’s once-weekly candidate, expecting FDA approval by year-end). According to Dr. Drucker, the next era of the GLP-1 agonist story will hinge on elucidating the mechanism underlying this cardioprotective effect. While many diabetes thought leaders have emphasized that we shouldn’t wait for a clear understanding of mechanism before prescribing these agents for CV risk reduction (and certainly, regulators and guideline-writing committees need not wait for a crystal clear description of mechanism before recommending a drug that could have powerful benefit), Dr. Drucker pointed to one reason that mechanism matters: “If you want to make drugs better, with next-generation versions with even more potent glucose-lowering and even more cardioprotection, then you do need to know how they work to know where to focus attention for innovation.” To this end, his lab is rigorously investigating potential mechanisms for cardioprotection, and has a leading hypothesis: inflammation. It turns out that the majority of GLP-1 receptors in the immune system are located in intestinal intraepithelial lymphocytes (far from where glucose regulation takes place). While our traditional understanding of GLP-1 receptors in beta cells regulating glucose by stimulating insulin secretion and reducing glucagon secretion is perfectly correct biology, Dr. Drucker illustrated that there is much more to the story. GLP-1 receptors have an entirely different, glucose-unrelated role in the lower gut, where they are responsible for coordinating the anti-inflammatory response. Could this anti-inflammatory action extend to the CV system to combat atherosclerosis? We will certainly have our eyes peeled for updates as this research progresses, and we can’t wait to see what innovations in GLP-1 agonist therapy occur as a result of this mechanistic knowledge (whether or not the anti-inflammation hypothesis turns out to be the prevailing cause of the cardioprotective effect).
- Dr. Drucker underscored the importance of unbiased basic research, urging the diabetes community to “step up our game” in terms of quality and reproducibility of science. As it relates to incretins, Dr. Drucker pointed out that the most notorious recent example of “bad science” was the controversy over a potential pancreatitis signal in the GLP-1 agonist class. While the matter has mostly been put to bed (as signaled by the utter lack of concern over pancreatitis expressed during last month’s FDA Advisory Committee meeting to discuss the approval of semaglutide), we note that once these safety worries arise, they often linger in the real world and negatively impact prescription habits. For instance, we heard from panelists at the FDA Advisory Committee meeting to discuss Victoza’s CV indication that the agency should consider removing the drug’s black box warning for medullary thyroid cancer, because as Dr. Judith Fradkin put it, “we’re telling people this drug may cause cancer based on animal studies, and that may put off its use by people who could benefit – we should think about the negative effect this language could have on use.” We so appreciate this discussion recognizing how flawed science can manifest in real-world patient outcomes, and for much more on this, we recommend Dr. Drucker’s recent review in Cell Metabolism, “Never Waste a Good Crisis: Confronting Reproducibility in Translational Research.”
- Given the variety of glucose-lowering therapies now available (some of which Dr. Drucker played a role in discovering!) are people with diabetes doing as well as they could be? Dr. Drucker’s answer was a resounding “no.” Reflecting on the troubling gap in outcomes between RCTs and real-world trials, as well as the sharply reduced adherence to therapies for diabetes vs. oncology, he surmised that the diabetes community hasn’t managed to impart the seriousness and urgency of this disease to patients or society as a whole. He charged everyone in the standing-room-only lecture hall with the responsibility to make change to this end, noting that “there’s no point in developing and prescribing new medications if their benefits aren’t being realized.” Dr. Drucker’s extensive insights on diabetes certainly seem to span this gap, from animal models in a lab to patients in the real world.
2. Dr. Matthews on the Downside of “Statistical Fundamentalism” in Clinical Trials
The esteemed Dr. David Matthews, lead CANVAS investigator, used this SGLT-2 CVOT as a springboard to discuss the complexities of modern clinical trial design and interpretation. Presented for the first time at ADA 2017, CANVAS found a 14% risk reduction for three-point MACE (non-fatal MI, non-fatal stroke, or CV death) with J&J’s canagliflozin (Invokana) vs. placebo, on par with the results seen in EMPA-REG OUTCOME for Lilly/BI’s empagliflozin (Jardiance), but also found a nearly two-fold risk for lower-extremity amputations with canagliflozin, which hasn’t been seen for empagliflozin. Dr. Matthews underscored that CANVAS and EMPA-REG OUTCOME involved different baseline study populations, different trial duration, and a different process for event adjudication. On one hand, this heterogeneity lends greater credence to the notion of a cardioprotective class effect for SGLT-2 inhibitors, since significant risk reduction for MACE was duplicated in these two distinct trials. However, as for whether the amputation signal could be a class effect, the distinctions between CANVAS and EMPA-REG OUTCOME (especially in terms of how systematically amputation events were captured) makes this an unanswerable question. This is one reason we’d love to see an “all-brand” outcomes trial including all SGLT-2 inhibitors head-to-head (as well as GLP-1 agonists, for that matter!). While funding such a large-scale trial may be far off, another actionable option is to foster more standardization between CVOTs, particularly when it comes to event collection and adjudication. Moreover, we see an immense role that real-world evidence could play in understanding amputation risk with SGLT-2 inhibitors.
- Dr. Matthews questioned “statistical fundamentalism,” where the question of whether a signal is “real” hinges on the arbitrary threshold of p<0.05. We note that this all-or-none, “p<0.05 or bust” mentality has important consequences for everything from regulatory decisions to treatment guidelines to drug formulary positioning – an issue the diabetes world was forced to confront at EASD 2017 with the EXSCEL CVOT, in which AZ’s Bydureon (exenatide once-weekly) missed superiority on three-point MACE by a razor-thin margin (HR=0.91, 95% CI: 0.83-1.00, p=0.06 for superiority). This near-miss means that Bydureon is unlikely to receive a label update to reflect CV benefits, and it leaves lingering questions about how the product will be positioned in future diabetes guidelines and drug formularies especially in comparison to other GLP-1 agonists with positive CVOT data, but on the basis of much differently-designed clinical trials. In fact, immediately following the EXSCEL full results presentation at EASD, Dr. Drucker asked in a separate symposium, “If one p-value is 0.49 and another is 0.51, do we worship the first drug over the second?” In a similar vein, Dr. Matthews cast doubt on the implacably rigid idea of “spending alpha” – the notion that in situations with a hierarchy of primary and secondary endpoints, nothing can be considered truly statistically significant if an earlier analysis failed to achieve significance. That is, according to this very rigid methodology, no significant secondary outcomes can be taken as “real” if the primary outcome was not significant. We agree with Dr. Matthews that the field must agree upon better ways to analyze and interpret key outcomes data, or better yet, to collect said data in standard fashion in the first place.
3. Diabetes Drugs in Heart Failure: Insights from Recent CVOTs + Hope for SGLT-2 Inhibitors
University of Toronto cardiologist Dr. Jacob Udell provided an informative overview of heart failure outcomes in recent diabetes CVOTs, expressing measured optimism that SGLT-2 inhibitors may one day be indicated for the heart failure population. In this era of the CVOT, several outcomes trials have shown risk reduction for heart failure hospitalization. This has been most impressive for SGLT-2 agents: EMPA-REG OUTCOME for Lilly/BI’s Jardiance (empagliflozin) found a 35% risk reduction for this outcome (HR = 0.65, 95% CI:0.50-0.85, p=0.002), while CANVAS for J&J’s Invokana (canagliflozin) found a 33% risk reduction (HR=0.67, 95% CI: 0.52-0.87). Dr. Udell also highlighted that the LEADER trial of Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) trended toward a 13% risk reduction for hospitalization for heart failure, but this finding did not reach statistical significance (HR=0.87, 95% CI: 0.73-1.05, p=0.14). Notably, there was no suggestion of heart failure benefit in SUSTAIN 6 for Novo Nordisk’s semaglutide or EXSCEL for AZ’s Bydureon (exenatide once-weekly), though we note that SUSTAIN 6 was a much smaller, pre-approval trial, and EXSCEL’s pragmatic study design may have dampened any potential heart failure signal. Still, as Dr. Naveed Sattar pointed out at ESC 2017, GLP-1 agonists are unlikely to be investigated toward a heart failure indication, while studies have already been launched to evaluate SGLT-2 inhibitors (Lilly/BI’s empagliflozin and AZ’s dapagliflozin) in people with chronic heart failure, with and without diabetes. There is certainly hope building among thought leaders that SGLT-2 therapies could have profound implications in prevent heart failure. According to Dr. Udell, the fact that heart failure is being investigated in these large-scale outcomes trials on the basis of secondary CVOT endpoints alone (without prior heart failure-specific phase 2 trials) represents a major vote of confidence. He suggested that he might have explored phase 2 dose-ranging studies first to unravel how SGLT-2 inhibitors interact with concomitant medications that people take for heart failure (like Novartis’ Entresto). Questions about primary vs. secondary prevention remain. AZ’s DAPA-HF trial for Farxiga (dapagliflozin) is expected to complete in December 2019, followed by the EMPEROR studies for Jardiance in June 2020.
- The mechanism underlying risk reduction for heart failure in these CVOTs remains unclear, but Dr. Udell offered some speculation around weight loss. He is the lead author of a 2015 meta-analysis assessing the effect of a variety of glucose-lowering drugs (including DPP-4 inhibitors, PPAR agonists, and basal insulin) on heart failure. The study revealed that for every 1 kg (2.2 lbs) of weight gain associated with glucose-lowering drugs or strategies, the relative increase in heart failure risk grew by 7% (p=0.022).
- In an earlier session, renowned cardiologist Dr. David Fitchett discussed unmet need in heart failure care and made a compelling case for new heart failure therapies. He revealed that heart failure is the most common reason for hospital admission in the US. We can only imagine the massive cost-savings to the healthcare system if SGLT-2 inhibitors could eventually be prescribed as dedicated heart failure therapies in their own right.
4. How to Overcome “Psychological Insulin Resistance”
A fascinating symposium led by educator extraordinaire Ms. Lori Berard and Dr. Michael Vallis, a clinical psychologist specializing in diabetes/obesity, took a deep dive on behavior change strategies to overcome one of the most challenging issues in diabetes care: clinical inertia. In particular, the duo focused on the feelings of fear and reluctance that for many patients surround the initiation of insulin therapy – a phenomenon they termed “psychological insulin resistance.” To help patients overcome this, Dr. Vallis introduced the concept of motivational communication, a technique that helps patients reason their way to the conclusion that they need to change their behavior in order to achieve their personal health goals – a strategy that runs completely counter to the traditional model of persuading patients to make such changes. This technique is less about motivating patients, but rather assessing their motivations – what’s keeping them from behavior change, and what would compel them to make changes? In the context of insulin initiation, common barriers include fear of hypoglycemia, apprehension toward weight gain, aversion to needles and injections, and the belief that insulin therapy is too complicated – or worse, that insulin therapy causes complications like blindness or amputation (often based on the experience of a person they know who experienced these complications while on insulin). Dr. Vallis and Ms. Berard emphasized that discussion of these barriers should come at the very beginning of the conversation about beginning insulin therapy. Listening to the patient and demonstrating that you understand their concerns is crucial groundwork that will make them more receptive when you invite them to reconsider these beliefs with new information. (To this end Dr. Vallis joked that diabetes educators are more like “diabetes negotiators.”) As a helpful tip, Dr. Vallis and Ms. Berard underscored that mediating this mindset shift around insulin therapy is most effective when diabetes treatment goals are explained in “patient language” rather than “HCP language” – that is, it’s more impactful to frame improved diabetes control as having more energy to spend time with family than achievement of an A1c target. We appreciated this incredibly actionable advice, and would certainly like to see greater use of motivational communication strategies in diabetes care, where patients are especially susceptible to shame, blame, and scolding rather than shared understanding with their providers.
5. Tailoring Diabetes Nutrition Guidelines to Glycemic Index
Diabetes Canada kicked off with an informative pre-conference workshop designed to support health educators in educating patients on glycemic index. As a testament to the high interest in nutrition education as part of diabetes management, this session was standing room only! Nutrition expert Dr. Shannan Grant (Mount Saint Vincent University, Halifax, Nova Scotia) demystified glycemic index, describing it as a simple scale that ranks carbohydrate-containing foods by the extent to which they raise blood sugar (measured from 0-100, with 100 corresponding to pure glucose). Due to the impaired glucose tolerance that characterizes diabetes, in general, the lower glycemic index the better when it comes to adopting a diabetes-friendly diet. Beyond limiting post-prandial glucose spikes, a low glycemic index diet can have a beneficial impact on A1c: according to the evidence reviewed, replacing only 60% of one’s daily carbohydrates with low GI options is enough to improve glycemic control. To this end, in partnership with Diabetes Canada, she and her colleagues are pioneering an educational curriculum on how to incorporate knowledge of glycemic index into diabetes self-management education. We were very lucky to see a preview of these materials and be involved with the activities Dr. Grant and her colleague, Ms. Rebecca Noseworthy (Clinical Research Project Manager, Hospital for Sick Children, Ontario, Canada) designed to stimulate feedback and usage of the materials during the workshop. The program helpfully parses common foods according to the traffic light method: green (go/“choose most often”), yellow (caution/“choose less often”), and red (stop/“choose least often”), corresponding to low (<55), medium (56-69), and high (>70) glycemic index across. Very low carb foods like meat or vegetables don’t have a glycemic index. It quickly became apparent that a food’s glycemic index can be rather counterintuitive, and not always aligned with to how “healthy” the food is perceived to be – this underscores the need for greater education on this topic. For fruits, apples, pears, berries, oranges, mangoes, and grapefruit have a low glycemic index (despite all being “sweet”), whereas grapes, kiwi, pineapple, and figs are medium, and watermelon is high. For grains, Dr. Grant recommended sourdough bread, barley, and steel cut oats as low glycemic index options, as opposed to medium glycemic index pita brain, couscous, and whole wheat bread, and high glycemic index pretzels, naan, and white bread. As for starches, low glycemic index options include sweet potato, followed by medium glycemic index beets and parsnips, and high glycemic index white rice. Dr. Grant emphasized that adding even one lower glycemic index choice per meal can go a long way toward obtaining glycemic targets.
- We were particularly interested to learn just how flexible glycemic index can be for the same foods under different conditions. For instance, pasta cooked “al dente” has a low glycemic index, whereas soft, overcooked pasta has an extremely high glycemic index. Even potatoes eaten cold vs. hot, or potatoes that are baked or roasted vs. boiled can have a lower glycemic index. Similarly, bananas rise in glycemic index as they ripen, from low glycemic index in green, unripe form and high glycemic index as they turn brown. We continue to be amazed at all that’s left to learn in nutrition science. Certainly, increased patient education around glycemic index and the factors that can influence it could greatly benefit people with diabetes as they look to refine their dietary choices.
-- by Abigail Dove, Payal Marathe, and Kelly Close