July 16-18, 2018; Edinburgh, Scotland; Day #1 Highlights – Draft

Greetings from Edinburgh, Scotland, just a two-hour drive from the birth place of Dr. John Macleod, Dr. Banting’s 1923 Nobel prize co-awardee. We’re reporting live from the 10^th World Congress on the Prevention of Diabetes and its Complications (WCPD), where we were pleased to hear from some of the foremost experts in the field today – Drs. Ann Albright (CDC), Profs. Naveed Sattar and John Petrie (University of Glasgow), Prof. David Napier (Cities Changing Diabetes), plus welcoming remarks from Prof. Jaakko Tuomilehto and Mr. Joseph Martin Fitzpatrick, Scottish Minister for Public Health, Sport, and Wellbeing.

See our conference preview for a rundown of all of the talks coming up in the next two days – we’re particularly looking forward to a lecture from Prof. Tuomilehto on the diabetes-dementia link, a session on funding of prevention research, and more.

Top Nine Highlights

1. CDC’s Dr. Ann Albright: “We Absolutely Must Utilize Tech…We’ll Never Get to Scale of Anything Unless We Use Digital”; Data “Pretty Poor” on Virtual DPPs with No Human Coach

CDC’s Dr. Ann Albright brought trademark passion to her discussion of the US’s National Diabetes Prevention Program (NDPP), during which she underscored that “we absolutely must utilize technology – there is no question. We’ll never get to scale of anything unless we use digital.” Not only does technology enable scale, but it also helps people who can’t or won’t travel to a site and the CDC is “all about preference,” she said. She added that the data has been “pretty poor so far” from entirely virtual programs relying on chatbots and/or avatars, since people need human touch. Though she didn’t mention any by name, Lark is one such company, and recently published observational data showing users with obesity/overweight lost 2.4% of bodyweight after ~15 weeks. On the positive side, she pointed to Omada as a successful digital company that materialized from the NDPP. As the biggest DPP provider in the US, Omada has served >150,000 people with prediabetes, though recently announced expansion into type 2 diabetes and hypertension management, leading us to wonder how lucrative prevention was. According to Dr. Albright, DPPs typically cost $400-$500 per year (a maximum of ~$670 total from Medicare), possibly placing Omada’s reimbursement at ~$4o per member per month, though these numbers could be shifted as Omada only gets paid when participants lose weight. We’d love Dr. Albright’s view on this level of reimbursement, and whether she believes it is adequate. She said that some payers are already realizing positive ROI after just one-two years, though we imagine savings will be even greater down the line.  An intervention that can prevent diabetes in large chunks of the population could save huge costs from medications and healthcare utilization – how can we push employers and payers to invest prevention with more gusto, which could draw more players into the field with unique approaches to reach various niches of society. Or – similar to risk corridors – what if DPP providers were allotted greater reimbursement for preventing diabetes in people with more or greater risk factors? From a strategy approach, Dr. Albright expressed curiosity about financial incentives, wondering when they work, for how long, and in whom – her talk followed Prof. Peter Schwarz’s description of an app in which users bet a sum of money that they will take 10,000 steps a day, and pay other app users that sum if they don’t. This app is cost neutral since it shifts money around the users, and currently has ~12,000 users in Germany – however, we have the same questions about target audience and durability of the intervention as Dr. Albright. Conversely, Dr. Albright repeatedly mentioned the supreme importance of each stakeholder not only coming to the table, but also having skin in the game – apart from the obvious higher and better-quality life at stake, financial incentives are one way to get people with prediabetes’ dermal layers involved.

• Dr. Albright shared that >100 insurers/employers have the NDPP as a covered benefit, including Highmark, Anthem a number of Blue Cross Blue Shield plans, Humana, and UnitedHealthcare! Further, >3.4 million public employees and dependents in 18 states have NDPP lifestyle change programs as a covered benefit. At the federal level, Dr. Albright referred to Medicare’s decision to begin covering DPP a “huge victory,” though continued: “Do we love everything they’ve done about the coverage? No. It’s not enough, and you need to meet weight loss and attendance requirements” – we’d add that Medicare still doesn’t cover virtual DPPs outside the context of a few makeups for missed in-person sessions. On the whole, however, she stressed that NDPP is the first ever that CMS is paying for lifestyle intervention to be delivered both inside and outside the healthcare system, and the first time reimbursing something that is administered by trained laypeople. At the other end of federal care, nine states currently have full or partial coverage of DPP through Medicaid authorities, demonstrations, or pilots, and CDC has funded demonstration projects in two states to focus on implementation and uptake (the final demonstration project evaluation report is expected in October of this year). It’s great to see access expand, and CDC fighting tooth and nail to make sure that trend continues. At ADA, Dr. Albright shared that there are ~1,800 recognized DPP providers, and nearly 220,000 individuals had enrolled as of June.

• We were excited to learn that the CDC has had fruitful discussions with a former Proctor & Gamble employee, the one “responsible for Swiffer and Mr. Clean.” She noted that he has really intriguing ideas, including a model about how to get lifestyle coaches deployed all over the place to reach millions of people. We’re delighted to hear that Dr. Albright and co. are treating issues of enrollment and scale through the lens of business – she even said, “we need to be with those guys more,” referring to smart industry thinkers. We couldn’t agree more! She’s even thinking through the realm of marketing, discussing how she could reframe the DPP– which only takes ~24 hours of total time – as a single day, when speaking to someone who wasn’t sure about the year-long commitment. “If you could spend one day to save your life, what would you do?” CDC is also partnered with Google to change the Health Card that pops up when people search “type 2 diabetes.” Currently, the card includes some information on prediabetes, but Dr. Albright believes it can be optimized to connect users to resources and increase participation in the CDC’s diabetes risk test.

• Dr. Albright provided some details on the NDPP Operations Center, which she introduced at ADA as similar to emergency operations centers that are established for infectious disease outbreaks. While details were still somewhat scant, it sounds like the Center will primarily consist of infrastructure to sustain operations, as well as to sustain expansion of the team (and draw people in). “There will be screens, so we’ll know what’s going on in Georgia, in Kentucky, in New York, and Chicago. The data has to be dynamic. It’ll take a while to set up.”  Real-time data should allow for more sophisticated analyses, not to mention more targeted and timely resource deployment.

2. Dr. Naveed Sattar Expresses Cautiously Optimistic Mindset on the Prevention of CV Complications in High Income Countries, Stresses Downside: Increased Lifespan Means More Comorbidities

Dr. Naveed Sattar attributed significant decreases in the prevalence of heart attack and stroke to better risk management and earlier diagnosis for patients with diabetes but was careful to note that the increased lifespan conferred by this care presents new challenges. Pointing to continually decreasing rates of heart attack and stroke in higher-income countries, Dr. Sattar made his top-line conclusion clear: The population with type 2 diabetes is gradually winning the battle against severe CV complications; in fact, the rates of decline of these diseases are greater in people with type 2 diabetes than in the general population (although both are decreasing), contributing to an increase in the average lifespan of people with diabetes so that it is slowly approaching that of those without diabetes. Furthermore, screening for serious microvascular complications such as retinopathy and nephropathy has become common-practice, helping to lower progression rates of both in higher income countries. However, Dr. Sattar was cautious in his optimism; both high glucose levels as well as high blood pressure and altered lipid levels contribute to CV risk in patients with type 2 diabetes. The risk factors for the latter two have significantly improved in the past 20-30 years alongside decreasing smoking rates, advances in blood pressure medications, and increased statin uptake, yet there has been less progress in glycemic control. Moreover, a longer average lifespan, while certainly an overwhelming victory for the population with diabetes, unfortunately confers a higher risk of other co-morbidities, simply because people are living longer; in the same time period in which heart attack and stroke have decreased in those with type 2 diabetes, peripheral arterial disease and heart failure have become relatively more common outcomes in diabetes. Combined with a consistently rising prevalence of type 2 diabetes, Dr. Sattar conveyed that there is still much left to be done in the fight against CV disease complications. Nonetheless, between reductions in risks and earlier diagnoses, it is clear that progress is being made. The way we see it, as new drug classes with potential renal and CV outcome benefits as well as better ways to improve other risk factors are discovered, outcomes only should improve, and for that we are thankful.

• Dr. Sattar offered commentary on two studies, EMPA-REG OUTCOME and DiRECT. On the former, he pointed to his recent publication on cardiorenal complications in type 2 diabetes, noting that most were “surprised” empagliflozin seemed to exert protection through volume reduction, rather than an atherosclerosis-related mechanism, as per a post hoc of the CVOT presented by Dr. David Fitchett at AHA 2017. Our sense from thought leaders, though, is that this mechanism is consistent with the very early separation of outcomes curves seen in SGLT-2 CVOTs: Volume effects would be consistent with an early benefit that appears to be maintained but other theories for benefit are also being examined. In contrast, GLP-1 agonists are thought to offer benefit mainly through anti-atherosclerotic effects, consistent with the more slow-and-steady, gradual separation of curves observed in those CVOTs. On DiRECT, the NHS-focused calorie restriction trial that led to 46% diabetes remission, Dr. Sattar suggested that “we could potentially do lifestyle better and offer a menu of options to our patients.” We were already fairly impressed by the intervention as it was delivered – especially in that it was administered by usual care providers (mostly nurses with a day worth of training) – s0 we’re all ears for future thoughts from Dr. Sattar.

• According to Dr. Sattar, the most significant risk factor for complications is age of onset of diabetes, regardless of whether it is type 1 or type 2. With an average diagnosis age of 14 for patients with type 1 diabetes, compared to 50-60 years old for type 2 diabetes, the former are at much greater lifetime risk for long-term complications, mortality, and heart failure. However, according to Dr. Sattar, more of this risk may reduce through the earlier introduction of statin therapies and blood pressure medications, which are often overlooked in early care; indeed, there aren’t any professional guidelines, to our knowledge, on lipid management in type 1 diabetes, especially in younger adults, stemming from a relative dearth of RCT evidence in this area.

• An important caveat to Dr. Sattar’s talk is that all of the data showing improvement in complications was taken from high-income countries. In lower and middle-income countries, access to medical care and even the most basic drugs is lacking. Also, as onset of diabetes is often younger, there is a faster progression, and it goes undiagnosed for longer. Together, these factors result in significantly higher rates of mortality; for example, in Mexico, mortality rates of those age 35-74 with diabetes are over double the rate of higher-income countries from over 40 years ago, when human insulin was a novel therapy. While there certainly is reason to celebrate recent innovation in diabetes therapies, access remains extremely exclusive, almost entirely reserved for wealthier nations. Even in the US, only 4% and 7% of patients are on SGLT-2 inhibitors or GLP-1 agonists, respectively. As such, we agree with Dr. Sattar that the biggest problem around the world is extending therapies, new and old, to all patients with diabetes.

3. SGLT-2 Inhibitors and GLP-1 Agonists Display Promise of Renal Protection, and Metformin May Also Have Previously Unrecognised Renal Benefits, According to Drs. Wilding & Petrie

SGLT-2 expert Dr. John Wilding and clinical trial guru Prof. John Petrie (involved in both LEADER and REMOVAL) offered insights on the effects of SGLT-2s, GLP-1s, and metformin on the kidney. Both took a highly evidenced-based approach, drawing on secondary outcomes from major completed CVOTs. This talk could hardly have come at a more appropriate time, on the very same day that J&J announced CREDENCE, the renal outcomes trial for Invokana, was stopped early for efficacy – nearly a year ahead of its expected completion date.

• Dr. Wilding asserted that CVOT data suggesting renal protection from SGLT-2s is promising but not conclusive – though, hours later, his opinion might have been slightly different. He acknowledged that the designs and population characteristics of EMPA-REG OUTCOME, CANVAS, and DECLARE were not appropriate to definitively demonstrate renal protection, but he considered the secondary outcomes promising nonetheless. EMPA-REG OUTCOME reported a 39% risk reduction for incident or worsening nephropathy (HR=0.61, 95% CI: 0.53-0.70) with empagliflozin, and CANVAS found a similar 40% reduction on a composite renal endpoint of 40% reduction in eGFR, ESRD, or renal death (HR=0.60, 95% CI: 0.47-0.77). Because these trials did not include renal function in any primary endpoint and weren’t enriched for kidney disease, though, they can’t support a claim for renal protection. However, almost concurrently with Dr. Wilding’s talk, J&J announced that CREDENCE – the renal outcomes trial for Invokana, enrolling those with type 2 and eGFR ≥30 ml/min/1.73 m² and <90 ml/min/1.73 m² – was stopped early because it had met its primary endpoint, a composite of doubling of serum creatinine, ESRD, and CV or renal death. While no numbers have been released, it’s hard to overstate how much stronger the SGLT-2 class’ claim to renal-protection just became. Dapa-CKD and EMPA-KIDNEY are ongoing and yet-to-begin, respectively, but these results bode extremely well for those trials.

  • In attempting to explain renal protection, Dr. Wilding suggested that SGLT-2s’ mechanism of action may very well positively affect the kidney, by means of (i) increasing sodium concentration in urine to constrict the afferent arteriole, (ii) decreasing oxygen consumption, and/or (iii) reducing inflammation through pathways associated with SGLT-2 inhibitors. Very excitingly, Dr. Wilding sees no reason that any of these mechanisms should not also work for patients with type 1 diabetes (perhaps even people without diabetes?), which is certainly exciting and would “push him off of the fence” as to whether SGLT-2s should be taken by patients with type 1 diabetes. Patients with type 1 have been excluded from Dapa-CKD and CREDENCE (and likely will be from EMPA-KIDNEY) and we don’t expect a dedicated trial in type 1, but we’re very encouraged to hear this from Dr. Wilding given the near complete lack of treatment for CKD. Down the line, we wonder what role real-world, observational studies might play in establishing a renal benefit for type 1?

• Prof. Petrie drew on CVOT data to demonstrate renal protection from GLP-1s, but focused on recent data that suggest metformin may have previously-unrecognized renal benefits. Leading with LEADER (pun intended), Prof. Petrie cited a 22% reduction on a composite nephropathy outcome of macroalbuminuria, doubling of serum creatinine, ESRD, and renal death with liraglutide vs. placebo (HR = 0.78, 95% CI: 0.67-0.92). He also noted clinical data demonstrating a 36% reduction of renal complications with semaglutide in SUSTAIN 6 (onset of persistent macroalbuminuria, doubling of serum creatinine, need for renal replacement therapy, and renal death) and overall positive trends, including a nominally significant effect with exenatide LAR in EXSCEL on new-onset macroalbuminuria; even lixisenatide, his “least favorite GLP-1,” trended in a positive direction in reducing progression of micro albuminuria. Altogether, these positive results, even if they are only secondary, further support the licensed use of Victoza and Trulicity in those with severe renal impairment (down to 15 ml/min/1.73 m²), without dose adjustments; based on these results, Prof. Petrie expressed confidence that there is renal efficacy, not just safety, in the GLP-1 class, and that this may be based on reduced low-grade inflammation.

  • Prof. Petrie took the opportunity to draw together recent data on the renal effects of metformin: these provide new insights despite the therapy's long tenure as a first-line therapy for type 2 diabetes. The most definitive results, Prof. Petrie says, come from REMOVAL, a study he led in type 1 that demonstrated a treatment difference on eGFR of 4.00 mL/min/1.73 m² with metformin vs. placebo after 36 months (95% CI: 2.19-5.81, p<0.0001). Prof. Petrie indicated that he initially had concerns that this decrease might be an artefact of weight loss or other factors, but now offered results from a new post-hoc of REMOVAL identifying a statistically significant improvement in eGFR over three years based on central measurements of plasma cystatin C rather than site-measured creatinine. Taken with recently-published epidemiological data from Scotland and also from rat models including of adenine-induced chronic kidney disease (Neven et al, April 2018, Pubmed ID 29716795), these results signal intriguing potential for the renal protective properties of metformin, though Prof. Petrie acknowledged that this remains far from conclusive at this stage.

4. Now 16 Cities Changing Diabetes Partner Cities, Expected to Be “Well Over 25” Next Year; Perspectives from Leicester and Mexico City

UCL’s Prof. David Napier shared that there are now 16 partner cities in Cities Changing Diabetes, and he expects that’ll be “well over 25” by next year. Since the excellent Cities Changing Diabetes Summit last October in Houston, the number of partner cities has doubled (!): Mérida (Mexico), Buenos Aires (Argentina; the first and only South American participant), Leicester (UK), Beirut (Lebanon), Koriyama (Japan), Hangzhou, Beijing, and Xiamen (all in China) have all come on board, joining Vancouver (Canada), Houston (US), Mexico City (Mexico), Copenhagen (Denmark), Johannesburg (South Africa), Rome (Italy), Tianjin, and Shanghai (both in China). Between these 16 cities, the Novo Nordisk-funded program now touches ~100 million lives! Australia is now the only (inhabitable) continent not boasting a partner city, though in terms of diabetes burden, we’d especially love to see involvement from cities in India and Northern/Central Africa. Prof. Napier’s talk comprised a high-level overview of Cities Changing Diabetes, reviewing the free tools (Rule of Halves, Diabetes Vulnerability Assessment, and Urban Diabetes Risk Assessment) available on the CCD website. For the Diabetes Vulnerability Assessment, personnel have now conducted at least 740 two-hour interviews of people with diabetes, zeroing in on needs, priorities, and barriers to care, and they are now beginning to “unpack the data.” Citing a dearth of research in the social and cultural domains of diabetogenesis, Prof. Napier explained that this initiative aims to “bring lived experience to the level of evidence.” In Q&A, he asserted that changes have to be brought to the level of advocacy and political action – we look forward to following this thread as Cities Changing Diabetes progresses and grows. 

• One of the new partner cities, Leicester (UK), has adopted three key areas of focus for Cities Changing Diabetes: (i) risk identification and lifestyle education in community settings; (ii) increasing awareness and use of the existing built environment; and (iii) evaluation of current or planned school-based lifestyle programs. We were especially excited to hear that Leicester’s plan places an emphasis on workplace wellness – a potentially effective measure in diabetes prevention. Leicester’s ability to focus on more specific areas of diabetes prevention, such as workplace wellness, is a testament to its relatively strong built environment (13 parks, 31 outdoor gyms, and broad political support for fitness initiatives). Given this great infrastructure, many of the initiatives that the Leicester Diabetes Center is undertaking as part of Cities Changing Diabetes involve the promotion of events such as the Leicester Let’s Ride festival (which the LDC plans to link to Team Novo Nordisk) and advertisement of established tools such as the Leicester Diabetes Risk Score – an online assessment for risk of diabetes recognized by Diabetes UK. Leicester East Parliament Member Mr. Keith Vaz has type 2 diabetes and is a “fantastic advocate,” so Cities Changing Diabetes personnel are eager to pursue policy change with his support.

• Because of its massive population and high prevalence of diabetes, Mexico City is adopting a digital and community wellness approach to its Cities Changing Diabetes initiative. Partnering institutions in Mexico City began by conducting a qualitative diabetes vulnerability assessment, ultimately creating a quantitative model that considers socioeconomic status, education, access to health services, BMI, physical activity, diet, and family history. Currently, the program is investigating the relationship between diabetes and the urban environment in Mexico City using geographic information science (GIS) data, audits of public places, and self-report questionnaires. With the quantitative model and built environment data in hand, Cities Changing Diabetes in Mexico City is planning on developing and testing a mobile app to improve food choices and physical activity levels among residents in 2019. Given the size of the population and ubiquity of diabetes in Mexico, we see CCD Mexico’s adaptation of a digital platform as very wise, and hope its development can serve as a learning lab for apps in other cities (though cultural factors may differ).

5. Cambridge’s Prof. Nick Wareham Makes Strong Case for Population Approaches to Diabetes Prevention

University of Cambridge’s Prof. Nick Wareham made a very compelling case for population-level interventions in addition to individual lifestyle intervention, and explained how the implementation of the two approaches differs. One reason individual interventions can’t stand on their own, said Prof. Wareham, is that the gap between efficacy (RCT) and effectiveness (real-world) for prevention interventions can be very large. He pointed to the VA MOVE! weight loss program, widely regarded as a success. In the program, people who simply participated had a 20% risk reduction for diabetes; those who participated in an intense and sustained manner had a 33% risk reduction for diabetes. These numbers sound great, but they sound “completely ineffective” at a population level when one considers that out of 1,800,000 eligible people, only ~238,000 (13%) participated, and just ~19,000 (1%) did so in an intense and sustained way. Another pitfall with individual interventions is the required screening actually creates additional burden for the system. Prof. Wareham demonstrated this phenomenon with an example: In the UK, there are 3 million people eligible for the English NDPP. Say 50% are interested, so 1.5 million people are screened using the QRisk prediction algorithm for CVD. ~607,000 people exceed the risk score threshold of 5.6, and 129,000 of them have A1cs between 6.0%-6.5%. Those 129,000 can take part in the NDPP program, which Prof. Wareham calls a good number. ~50,000 (37%) of those people follow through and enroll in the DPP. Prof. Wareham pointed out two externalities from the screening process: (i) In performing the A1c test, you just found ~30,000 people who already had diabetes; and (ii) The ~80,000 people who qualified but did not enroll in the DPP have been told they are at risk and now want extra follow-up with their doctor. After all is said and done, the program could feasibly prevent ~2,500-4,400 cases of diabetes 10 years later – Prof. Wareham said it’s “not a population-level solution to save money, but it does have a place in the broader strategy to treat diabetes.”

• Prof. Wareham hates being asked “if you were a politician, what one policy would you implement,” because (i) there’s not one population-level intervention (e.g., soda tax) that could make a difference, rather an array of interventions; and (ii) There’s not enough evidence to act with 100% certainty in selecting a policy. “If we persist in thinking that we need evidence to act, we’ll never do anything, and we’ll be paralyzed.” Instead of following the traditional route of science, with observational evidence preceding intervention development, then feasibility/pilot trial, then an RCT, then evidence synthesis, and finally policy/action, public health strategies must instead jump directly from observational evidence to policy development, and then policy action. After the policy has been implemented, it can be evaluated (perhaps in a natural experiment), and evidence synthesis can feed back into policy iteration. The one caveat he gave when describing the design of interventions for public health was to ensure that they don’t exacerbate inequalities, which is possible when they require agency on the end user’s part. For example, front-of-the-pack nutrition labeling requires an individual to read and know basic nutrition science; on the opposite end of the spectrum, low-agency interventions like fortifying flour with folic acid don’t require conscious thought from the end user and would therefore not be expected to exacerbate inequity. So, once a population-level, low-agency intervention has been selected, Prof. Wareham suggested not asking “what works,” rather “what are you prepared to do?” What is the government willing to do? “Look at a range of different risk factors and opportunities, and decide where you have enough political capital to change policy.”   

• The population-level approach makes sense from a cost-effectiveness perspective, according to 2011 NICE Public Health Guidance. Targeted, individual interventions yielding 1 kg (~2.2 lb) weight loss would be cost-effective at the £20,000/QALY threshold if the intervention cost < £100 per person. If weight loss was 3-4 kg (~6.6-8.8 lb), the intervention would be cost savings. At the same time, a population-level intervention that achieved a 0.25 kg (~0.6 lb) leftward weight shift would be cost-effective at the same £20,000/QALY threshold if the cost per person was just £10.

• “If we think prevention will reduce spend on diabetes, we’re fooling ourselves. It might possibly to do that in the long-term, but probably overcome by changes in demography, but certainly won’t do that in the short term.”

6. Diabetes is an Operable Disease, According to Dr. Francesco Rubino

In an emphatic defense of gastric bypass surgery, Dr. Francesco Rubino presented data on an eclectic set of outcomes, ranging from remission and prevention to cost-effectiveness and safety, in an attempt to make the case that diabetes is effectively treated by gastric bypass. While reviews of gastric bypass as a viable therapy for diabetes have historically been mixed, particularly with respect to long-term complications and hospitalization, Dr. Rubino sought to demonstrate its validity and prolonged effectiveness not only for preventing diabetes, but also for causing remission. On the second, Dr. Rubino compared a large cohort study of patients with type 2 diabetes under medical management only in which rates of partial (A1c£6.5% for at least one year without ongoing pharmacologic therapy), complete (A1c£6.0% under the same guidelines), and prolonged remission were 2.8%, 0.24%, and 0.04%, respectively, to a more recent, observational study (n=1156) that demonstrated remission rates of 75% at 2 years, 62% at 6 years, and 51% at 12 years with gastric bypass. While these results seem extremely positive, it is important to note that the pharmacologic stipulation in the definition of remission inherently excludes many patients that are likely managing their diabetes very well, but may be taking insulin, metformin, or even an anti-hypertensive. However, it is also important to note that these results are not surprising, as a comparable 51% rate of remission five years after surgery was also demonstrated in the Swedish Obese Subjects (SOS) study, another large, observational study on gastric bypass in people with diabetes. With respect to prevention, Dr. Rubino presented a matched cohort study (n=4334) which demonstrated an 80% reduction (HR=0.20, 95% CI: 0.13-0.30) in the development of type 2 diabetes over the course of seven years post-operation in patients who were obese but did not have diabetes. Dr. Rubino touched on many other positive studies demonstrating strong efficacy in terms of fatal CV events, total CV events, and survival 15+ years after surgery, as well as the superiority of bypass surgery compared to intensive lifestyle management for A1c and medication need after three years. However, poignantly missing from his presentation, in our opinion, was a more in-depth analysis of the long-term costs and known complications of gastric bypass surgery – though this could stem more from a lack of data than anything else; one slide in the presentation did demonstrate over $5,000 in savings four years post-operation compared to controls. While this is certainly a win for patients in the short-term, these results are not consistent with the 15-year follow-up for the SOS study that showed total healthcare costs were higher for the euglycemic and prediabetes subgroups compared to the conventional treatment group, although no difference in cost was found for the diabetes group compared to the conventional treatment group; much of the increase in cost was attributed to inpatient care, suggesting high rates of follow-up surgery and inpatient surgery complications, neither of which Dr. Rubino addressed in the long-term in his presentation.

That being said, all of these studies have demonstrated at least some upside to bariatric surgery for those with or at risk for type 2 diabetes. Accordingly, metabolic surgery has been included as a treatment option for obese patients with type 2 diabetes in the ADA Standards of Care since 2017. It was this statement (and that of the Diabetes Surgery Summit) which Dr. Rubino used as evidence that diabetes is an operable condition, although he believes that the surgery could be extended to patients that are not obese given the comparable reductions in A1c in obese and non-obese groups in the STAMPEDE trial. While we acknowledge the efficacy of the surgery, we altogether believe that the decision to go ahead with it must be made in careful consideration with the healthcare provider due to the its cost and potential for long-term side effects; moreover, in any conversation about bariatric surgery, we think it’s important to remember that this will never be a population-level solution to diabetes or obesity.

• In response to common criticisms that the effect of gastric bypass is entirely dependent on the weight change caused by the surgery, Dr. Rubino pointed out that GI surgery is not so different from other weight-independent diabetes therapies. For example, Dr. Rubino pointed to exercise, intracranial leptin, and insulin (which often confers weight gain) as having positive, weight-independent effects on diabetes; even decreased caloric intake, which everyone would at first associate solely with weight loss, improves insulin sensitivity overnight before any weight is lost. Moreover, many of these therapies operate similarly to metabolic surgery by altering gut hormones, bile acids, the microbiome, or nutrient sensing. The difficulty now, as identified by Dr. Rubino, is identifying exactly which of these effects (or which combination) holds the most therapeutic promise.

• Renowned metabolism expert Dr. Sadaf Farooqi stressed the role that biology plays in feeding and diabetes, referencing Rhythm Pharmaceutical’s setmelanotide as a drug that may “finally help” those with biological predispositions to obesity. In her talk on the genetics of diabetes, Dr. Farooqi, who discovered the first genetic defects linked to obesity, referenced phase 2 data on Rhythm’s setmelanotide as evidence that it may be the first therapy with the potential to significantly decrease weight gain in those with genetic conditions associated with obesity such as leptin and pro-opiomelanocortin (POMC) receptor deficiency. Rhythm is moving closer to obtaining indications for POMC and leptin receptor deficiencies, as they have recently completed pivotal enrollment (n=10) for phase 3 trials in each condition; the company recently gave an update on their clinical trial results and announced a Proposed Public Offering to fund phase 3 trials and a subsequent NDA filing for setmelanotide.

7. Association Between Pioglitazone and Macular Edema; Unmet Needs, Possible Pharma Targets for Diabetes Eye Care

In a wide-ranging talk on diabetes eye health, Queen’s University Belfast’s Prof. Noemi Lois reminded attendees that pioglitazone (TZD) should be avoided “if at all possible” due to its propensity to cause macular edema (DME). She showed an edema-ridden retinal image from a 63-year-old woman with type 2 diabetes. Weeks later, the edema had subsided, even though Prof. Lois claimed that she didn’t touch the eye – she simply recommended that the woman stop taking pioglitazone. In Q&A, she clarified that pioglitazone shouldn’t be paused in all cases, but if it is used, providers should make sure the ophthalmologist knows about it. At her clinic, some patients have been added to the anti-VEGF list and began receiving injections, even though pioglitazone cessation would’ve stopped the DME at much lower cost and with no risk of side effects. Of course, the DME risk-boosting properties of pioglitazone were first presented at EASD 2013, but session moderator Prof. John Petrie even pointed out that it was a valuable discussion to have, since it’s a perspective that non-eye specialists may not have at top of mind.

• Prof. Lois described two urgent needs from an eye health perspective: (i) there is no available treatment for retinal ischemia (none of the treatments improve retinal perfusion); and (ii) there is no treatment to prevent or treat retinal scarring – in fact, current treatments may make it worse by disbalancing VEGF/CTFG/TGFβ ratios.

• Prof. Lois is very optimistic about the LENS (Lowering Events in Non-proliferative retinopathy in Scotland) study, which is evaluating the efficacy of PPAR-α agonist fenofibrate in preventing retinopathy over three years. Both FIELD and ACCORD showed benefits of the cholesterol-lowering, generic fenofibrate on retinopathy, but LENS will specifically study the indication. Notably, Singapore and Australia have already indicated fenofibrate for diabetes-related retinopathy. Said Prof. Lois, “I think it’s cheap and safe, and old studies support its use, so I think LENS will be very strong.”

• According to Prof. Lois, DME is a result of excess fluid leakage, but also an impairment in the pumping (removal) of fluid, a fact that receives less attention than she feels it deserves. Fluid removal in the eye is impaired by two potential mechanisms in diabetes. First, choroidopathy (damage to the vascular layer of the eye) could lead to excess fluid leakage, and the retinal pigment epithelium (which normally pumps fluid out) either wouldn’t be able to keep up or could also be damaged. Second, Muller cells (neural cells in the retina) are known to swell in the context of retinopathy, leading to DME. “These are both potential targets for new therapies,” she claimed.

8. Prof. Peter Schwarz’s Six Enablers/Trends in Diabetes Prevention

University of Dresden’s Prof. Peter Schwarz provided an overview of the prevention landscape, giving his two cents on where the field could and should head. See the below bullets for the six possible enablers/trends. In his plenary lecture, he also urged attendees to think at scale (interventions that could affect 1,000,000), learn from the field’s mistakes (an interesting philosophy, counter to that of scaling successful pilots), and share ideas, information, and knowledge.

• Prevention could become more physiological. After posing the question of what protects people from diabetes as the “secret to success,” Prof. Schwarz advanced the slide deck to four words written in large text: “Visceral fat! Liver fat!” Indeed, in the German TULIP trial, a high liver fat content was one predictor of non-response to lifestyle intervention. Prof. Schwarz noted that this phenomenon can’t be explained fully, but it is a “sexy, new strategy” for defining responders and non-responders. That could save cost, but what can be done to prevent diabetes in people who already have significant liver fat depots?

• CGM as a tool for identifying people at high risk of diabetes. “Not everyone with high fasting glucose or postprandial glucose are at risk of developing diabetes.” Perhaps investigators could use CGM to monitor glucose in a number of individuals with prediabetes, hopefully detecting correlations between glycemic patterns and progression to diabetes (or response to lifestyle intervention).

• Prevention could become less drug-driven. Prof. Schwarz cited Lipska et al.’s 2016 analysis of diabetes drugs’ impacts on A1c and severe hypoglycemia, claiming that “using drugs to lower glucose is not always a benefit – so using drugs to prevent diabetes is not an option in the long term.” We’d point out first that this study was retrospectively looking at drugs in diabetes, not prevention – at this point, there are no drugs approved for use in prediabetes in the US (nor even any FDA pathway), so our understanding of the preventive effects of medications are still elementary – of course metformin lowered three-year type 2 diabetes risk by 31% vs. placebo in the DPP trial. Second, there’s a lot to unpack with the Lipska et al. analysis, which makes some controversial claims about the cost-effectiveness of “newer” drug classes – see our full analysis here.

• Prevention could better address the needs of the patients. Prof. Schwarz claimed that quality of life drives adherence, and the peer group is more influential than providers for patient lifestyle. Technology can help give options and meet patients where they are, and social media can help connect peers.

• Prevention could be much more specific. Europeans walk 2,700 steps per day. People are inactive 23.4 hours per day. Yet, walking 10,000 steps per day helps to prevent any disease, and 1,000 additional steps per day reduces blood glucose more than metformin. Prof. Schwarz sees all of these claims as motivation to boost activity. He also cited a study showing that diet coke confers an even higher type 2 diabetes risk than regular coke, since it alters the microbiome. Reaching consensus around what is truly healthy in the lifestyle domain, and disseminating that information, will be key. 

• Prevention could be much more individualized. Prof. Schwarz is energized by the idea of assessment and risk-stratification – in a world where there are 100+ unique interventions available, an algorithm could look at an individual’s morbidity, preference, and readiness to change lifestyles, and tell which intervention would be optimal. “This would not cost a cent more, but it could boost cost-effectiveness and efficacy.”

9. Prof. Andrew Morris’ Eight Barriers to Big Data Use in Healthcare

Health Data Research’s Prof. Andrew Morris advocated strongly for greater the convergence of care and research via big data, but pointed to eight barriers preventing the rise of efficient, learning health systems that “collect data once and use it often.”

(i) Skills. There is a dramatic shortage in data scientists. Across industries, the EU alone needs 346,000 data scientists by 2020, and even today, 77% of such positions are unfilled. Considering the economy for big data in healthcare is expected to scale from $14 billion in 2017 to over $60 billion by 2025, we suspect that many of the data vacancies will be in the realm of healthcare.

(ii) Scale. Prof. Morris described the interoperability to combine data from different systems and sources today as “at times really clunky.” He showed the below visual, illustrating the correlation between systolic blood pressure and mortality in 5,000, then 50,000, then 500,000 people, to demonstrate the importance of leveraging large data sets to pick up on signals (the 5,000-person chart on the right is from the landmark Framingham Heart Study).

(iii) e-Infrastructure. In order to support big data science, health systems will need to think “cloud first” to support it. He noted that computing is mostly at the terabyte (10¹²) level today, but will soon hit the petabyte (10¹⁵) level, and eventually the exabyte (10¹⁸) level.

(iv) Digital maturity. There needs to be a significant investment digital investment from heath systems (e.g., EMRs) to ensure that data are routinely collected and transmitted in real-time.

(v) Interdisciplinarity. “How do we get folks breathing the same air?” He pointed out that at some of the very best centers and health systems in the US – Stanford, Geisinger, and Duke, specifically – people from various academic backgrounds are co-creating.

(vi) Data quality. Prof. Morris told of how he examined the ways in which metformin was prescribed in Scotland – due to a lack of standardization in script-writing, he discovered that there were 5,720 variants in how providers prescribed metformin (for example, different ways of writing “taken twice daily”). Clearly, this impedes research and tracking, so Prof. Morris suggested it is a “duty” to look at standards and how they’re being implemented at the point of care.” We’d add that standardization should go beyond borders to enable data from all over the world to talk and easily fit together.

(vii) International partnership. “If we collaborate we can demonstrate real benefit to patients.” He quoted a 2011 Wall Street Journal article entitled, “The New Einsteins Will be Scientists Who Share.”

(viii) Trust. “This is the biggest of them all!” Data security and privacy are at the top of mind in many industries, perhaps healthcare most of all. Prof. Morris urged leadership in defining trust and sharing in benefits (i.e., if data is successfully monetized or leads to a discovery, then the health system/society may deserve some of the return).

• >250,000 UK citizens are waiting for “unreported” medical images – deep learning has tremendous potential to mitigate this contributor to delay in the system. Prof. Morris pointed to three recent articles detailing the potential of deep learning: Dermatologist-level classification of skin cancer with deep neural networks (Nature 2017), a genetic analysis of the proteome at scale (Nature 2018; identified 1,927 associations between plasma proteome levels and the genome), and the construction of an algorithm that classifies images for macular degeneration and diabetic retinopathy (Cell 2018). This last

• Prof. Morris provided examples of stratifying care by phenotype in Scotland, which was only possible to the SCI Diabetes – the national informatics system to support care and research, which has captured high-level phenotype data from >95% of patients since 2007. Based on these data, researchers have found that retinopathy screening in low-risk type 2s may only be needed once every two years (an example of distributing resources in a more efficient way), that TZDs may be associated with central fractures (dogma was that they were only associated with peripheral fractures), and that a gene (ATM) is associated with glycemic response to metformin.

-- by Brian Levine, Peter Rentzepis, Ann Carracher, and Kelly Close