Excellence in Diabetes 2013

February 7-9, 2013; Istanbul, Turkey Day #1 Highlights – Draft

Executive Highlights

The second day of Excellence in Diabetes (EiD) 2013 continued to keep us very busy with many notable discussions on type 2 diabetes and obesity. We bring you abbreviated coverage from day #2 of this notable conference and supplemental coverage of yesterday – and we will still send you a more detailed report early next week. We salute, again, Dr. David Matthews and his extraordinary planning team. These bullets below are snap-shots of our (many) favorite presentations today, while in our “Detailed Discussion and Commentary” section are reports in our more traditional conference style from notable talks given yesterday that we could not write up in time to publish in our Day 1 report (which you can read at https://closeconcerns.box.com/s/k1re77kqvyhmq4plmiem).

  • We had the special opportunity to experience the clinical decision making processes of Dr. Melanie Davies (University of Leicester, Leicester, UK) and Dr. David Matthews (Oxford Centre for Diabetes, Oxford, UK) as they discussed what medications they would prescribe a type 2 diabetes case study including when they would begin insulin. Notably, Dr. Davies described how NICE guides for a sulfonylurea to generally be used as a second line therapy and physicians should initiate NPH insulin in their patients needing insulin therapy unless they are particularly at risk for hypoglycemia. Both of these guidelines elicited critical comments from the United States-based physicians, Dr. Harold Lebovitz (State University of New York, New York City, NY) and Dr. Julio Rosenstock (Dallas Diabetes and Endocrine Center, Dallas, TX) who questioned if this is in the best interest of patients. From a patient perspective, we are worried due to all the negative side effects that we hear about related to SFUs – we hope that patients are guided toward using the “best” SFU since we understand there is quite a difference across the board in the tolerability profiles of agents in this now-generic class. In response, Dr. Davies, Dr. Matthews, and Dr. Amanda Adler (Addenbrooke Hospital, Cambridge, UK) described how with proper justification it is not difficult for a physician to prescribe alternatives to the NICE guidelines. We wonder how often that happens and we are excited for the day when more patients can get much better generics; DPP-4 inhibitors, as a reminder, will be generic around 2022 and will provide a much easier option for many patients to take, in our view.
  • Dr. Adler continued this discussion in her presentation on how NICE and other payors decide which therapies to cover. She reminded the audience that when NICE is deciding whether it should pay for a new diabetes drug it must not only compare it against other anti-diabetics but also cancer, Alzheimer’s Disease, etc. drugs that it might not be able to afford if it covers the new diabetes medicine. We would love to see a comparison of how much NICE advocates spending on various patients in each therapeutic area. Dr. Adler then walked the audience through NICE’s decision to not recommend insulin detemir or glargine over NPH insulin for most patients since NPH insulin is a “good drug” and detemir and glargine are, according to Dr. Adler, not that much better. When she was questioned on the validity of this statement considering that physicians are often more comfortable with analog insulins, she stated that this discrepancy is because the “industry’s marketing is more powerful than the drugs are superior.” Wow. Given the stability and hypoglycemia profiles associated with NPH for many patients, we found this very disappointing to hear. Dr. Adler described NICE’s decision torecommend against using dapagliflozin as “completely preliminary” and explained that it was partly due to the lack of trials comparing dapagliflozin to active comparators. She concluded by reminding attendees from countries with private payors that their health plans back home use decisions making processes similar to NICE’s.
  • Dr. Massimo Riccaboni (IMT School for Advanced Studies, Lucca, Italy) presented a fascinating argument on why pharma is seeing a trend toward having fewer new molecular entities approved each year. He concluded that incentives for investors are decreasing due to low success rates for approvals (partly due to companies’ high-risk/high-reward strategy), higher R&D cost, longer R&D and approval times (thus shortening effective patent life), parallel development of similar drugs, and increased generic competition. He therefore urged companies to put more stock in incremental innovation. We’ll be thinking about this perspective and be back with more on it; for a start, we would also point out that the bar is thankfully higher today for new medications and though this makes it harder work to commercialize a better drug, it’s good news for patients that therapies today are much better than in decades past. That said, we also would like to see therapies developed successfully and commercialized successfully – without that, they will never be marketed and will never go generic and will never reach patients who would otherwise have no other way to access.
  • During the session on diabetes care “from head to toe” Dr. Robert Ratner (CSMO, ADA, Alexandria, VA) presented on current best practices for kidney care – we found it surprising that he characterized diabetic nephropathy as one of the success stories for diabetes. While great strides have certainly been made in identifying the diabetic etiology behind kidney disease and in improving treatment options, the lack of a disease- modifying agent for chronic kidney disease (CKD) does not make this a major success story in our view, nor do the very large number of patients on dialysis. Furthermore, most oral antidiabetic agents are unsafe or must be used with caution in patients with CKD, highlighting a significant unmet need for a patient population whose disease progression depends on proper glycemic control.
  • The majority of the afternoon was dedicated to presenting on the Oxford Health Alliance’s Community Interventions for Health study (which was funded in part by Novo Nordisk and in part by PepsiCo). In presentations featuring short video-clip interviews with Sir John Bell, KOLs, and the study’s investigators Dr. Matthews and Dr. Denise Steven (MATRIX Public Health Solutions, New Haven, CT) described how CIH has initiated and tracked the impact culturally relevant, low dose, broad scope community interventions in China, India, and Mexico. Dr. Pamela Dyson (CEO, Oxford Health Alliance, Oxford, UK) presented results of the main outcomes, showing that after the 18-month community-level intervention, major risk factors for developing non-communicable diseases (physical activity, fruit and vegetable intake, BMI) were significantly better in the intervention group compared to the control group. We were impressed with the comprehensiveness of this initiative and are excited to bring you more details in the future – particularly fascinating were the evaluations of the process and methodology provided by Dr. Stevens, which provided insights into factors influencing the impact of the interventions.
  • During J&J’s corporate symposium on the kidney as a therapeutic target for type 2 diabetes, Dr. Julio Rosenstock (Dallas Diabetes and Endocrine Center, Dallas, TX) provided a comprehensive overview of canagliflozin, dapagliflozin, and empagliflozin’s clinical results. He was particularly excited about the idea of using SGLT-2 inhibitors in patients who have already failed multiple oral agents and do not want to initiateinjectable therapy (either a GLP-1 agonist or insulin), and he is also curious to see how SGLT-2 inhibitors in combination with insulin will do head-to-head with a GLP-1 agonist as an add on to insulin. We also will be very eager to see what fixed-dose combinations can be developed – that is, of course, assuming we will see approvals in the US.
  • Dr. John Buse (University of North Carolina School of Medicine, Chapel Hill, NC) and Dr. Michael Lincoff (Cleveland Clinic, Cleveland, OH) rewarded the ~40 attendees who stayed for the last of the 11-hour day’s sessions with a detailed description of cardiovascular risk in- and cardiovascular treatments for people with type 2 diabetes. Soberingly, Dr Buse urged the audience to treat their type 2 diabetes patients as if they will have a hard attack tomorrow since many will one day. Dr. Lincoff then detailed the different medications available and in development that could help reduce this risk. As one of Alecardio’s (aleglitazar’s first cardiovascular outcomes trial) primary investigators, he informed the audience that aleglitazar is one of the first diabetes drugs for which cardiovascular superiority might be established pre-approval but that if the drug fails to achieve this it likely marks the end of PPAR agonists.
  • In the day’s keynote lecture, Dr. Silvio Inzucchi (Yale University, New Haven, CT), lead author of the 2012 ADA/EASD position statement, led us through a detailed explanation of the statement, providing guidance on how to individualize targets and treatment regimens.

Detailed Discussion and Commentary

Interrogate the Expert

DR. ROBERT RATNER ON INDIVIDUALIZING TREATMENT

Dr. Robert Ratner, MD (CSMO, ADA, Alexandria, VA)

Dr. Robert Ratner discussed his views on how the current approach to developing guidelines could be improved to actually promote patient-centered care. The role of guidelines is to help physicians identify what the appropriate thing to do is where uncertainty exists, but current diabetes guidelines offer only limited clarity for how to best practice patient-centered care. Dr. Ratner noted that there is a lack of high quality evidence on which to base patient-centered guidelines even though tens of thousands of randomized controlled trials (RCTs) are published in a year. This suggests that current RCTs do not optimally address appropriate questions for personalizing medicine and that study design or data analysis methods must be modified identify which treatments work for which individuals. Dr. Ratner proposed that using adaptive study designs or recursive partitioning could accomplish these goals (details and examples below) of predicting best responders and worst responders. Dr. Ratner’s talk was followed by an engaging Q&A session, that included discussion of if MACE or even A1c should be sole primary outcome measures, the many shortcomings of randomized controlled trials, and frustrations with pharmaceutical companies running most clinical trials.

  • Dr. Ratner lamented that clinical guidelines are largely informed by expert opinion rather than grade A evidence based on randomized controlled trials (RCTs). He discussed results from a study (Tricoci et al., JAMA 2009) demonstrating that the vast majority of evidence informing the AHA/ACC’s clinical guidelines for heart disease was grade C (“expert opinion”), and only a very small proportion of the guideline was informed by grade A evidence. Even after a conscientious effort to produce more grade A evidence through RCTs, there was only a minimal improvement in the quality of evidence informing the guidelines between the two updates in 2001 and 2006.
  • A paradox exists, Dr. Ratner remarked, whereby the scientific community is conducting an enormous number of clinical trials (e.g., 18,000 RCTs were published in 2011) yet every meta- analysis always comes to the same conclusion that the available evidence is limited or of poor quality. This then suggests that current trials are not designed to answer the right questions. Dr. Ratner stated that many RCTs are driven by the need to meet safety and efficacy requirements for regulatory development, but few actually answer the questions of how to best use medications and what the best treatment is. Even comparative effectiveness trials, such as the highly anticipated GRADE trial (which aims to compare comparative effectiveness of the five drug classes listed as second line drugs in the 2012 ADA/EASD position statement), only provide data on mean responsiveness and do not actually provide clinicians with actionable information on what works best for whom. This was the first overt criticism of GRADE that we had heard.
  • Dr. Ratner proposed that several new study designs and analytical strategies are now available to accomplish just this goal. One method would be to use an adaptive design whereby, rather than having a strict drug assignment, one can prospectively define the characteristics of people going into a particular arm (one example that comes to mind for us is Novo Nordisk’s liraglutide-Detemir Study where non-responders to liraglutide were then subsequently randomized to liraglutide plus placebo or liraglutide plus detemir).
  • Another method would be to use recursive partitioning as an analytical technique. This technique can identify baseline characteristics that predict responsiveness. As an example, Dr. Ratner cited data from a study that attempted to identify which patients failing basal insulin therapy would respond best to the intensification to basal-bolus therapy. By employing recursive partitioning, the study found that of patients whose A1c was <8.8% and whose daily insulin requirement was less than 0.5 U/kg/day, 86% achieved an A1c <7% after addition of bolus therapy. In contrast, for those whose A1cs were >8.8% and had a daily basal insulin requirement of >83 units, 0% achieved an A1c of <7% after adding bolus therapy.
  • Beyond identifying “best responders” this technique can also identify the population suffering the most harm so that physicians avoid prescribing a medication to someone with such characteristics if possible. In liraglutide’s LEAD trial, “triple responders,” defined as those reaching an A1c of <7% with no weight gain or hypoglycemia, were most common in patients who had a baseline A1c of <8.5%, had started the trial on monotherapy or lifestyle only, and had a <5 years duration of diabetes (74% were tripleresponders). In contrast, for those with a baseline A1c of >8.5%, the triple response rate was only 19%, and this dropped to 14% in the population with both baseline A1c >8.5% and two or more therapies pre-existing therapies upon entry into the study. Furthermore, the study identified the population with the highest rate of vomiting and nausea as white women (25% of women vs. 16% of men and 27% of white patients vs. 14% of non-white women).

Questions and Answers

Ele Ferrannini (University of Pisa School of Medicine, Pisa, Italy): So much in terms of money and time are spent on clinical trials. Would you say that the era of guidelines is coming to an end almost inevitably? Firstly, because there are so many drugs becoming available for diabetes. If you were to analyze every combination in every sequence, it would be unsustainable. This is a radical criticism of the randomized controlled trial way of assessing efficacy and the benefit:risk ratio. On the other hand, you have something called clinical judgment – thinking about how this particular patient would respond to what we have on our minds. The question is whether this is ever going to be feasible with what you call level A evidence or even level B evidence. Do you think this is going to be possible given the plethora of approaches we have available?

Dr. Robert Ratner: I completely agree with you. I firmly believe that the regulatory requirements have to change. To ask the question “what is the response to therapy vs. placebo?” for a chronic disease makes no sense to me. We do not use placebos in diabetes. It might make sense in prostate cancer where watchful waiting is a valid alternative, however, it does not for diabetes. I think that these comparisons have to be against reasonable alternatives. By using reasonable alternatives we can begin to determine those treatments that work best. The decision tree for what you choose to prescribe needs to be based on science. The question is how valid and deep is the science there.

Dr. Ferrannini: If you go to these two extreme groups – the responders and the non- responders – is there anything in the phenotype that can guide you to make decisions for the average person?

Dr. Ratner: I am frequently asked whether there is any value in measuring the C-peptide response in people with type 2 diabetes, and I had always said no because I did not know what you could do clinically with that information. However, now it might be that you can insert that data into a decision tree like this. However, if the data is not able to impact your clinical decision making, then that information may help answer an interesting pathological question but it is not clinically relevant. Interestingly enough, when we tried using C-peptide in some of these decisions trees, they fell out as being insignificant. You want to know to the best of your ability what the signals are that are clinically available that might predict the probability of achieving your goal.

Dr. Ferrannini: Along these lines, don’t you think that understanding the mechanism of action of the drugs would help? If there is some evidence that insulin can give the beta cell a moment of rest while sulfonylureas cannot or might be harmful to the health of the beta cell, and we had all this information for the marketed drugs as well as their most frequent combinations, it could help us make these decisions.

Dr. Ratner: Absolutely, I completely agree with you. The basic science should be the underpinnings of the design of clinical trials. In the GRADE study, you have “here are the available drugs – lets throw them in”. More information is not being factored in, such as the question of hypoglycemia in the glargine arm or if the patients are overweight. These global trials become unfocused and unreasonable.

Dr. Ferrannini: Much information can be gained by looking at the extremes – those that did not respond at all and those who responded brilliantly – and by seeing what the phenotypes were. What you have shown us is still a stochastic or statistical approach that will give you a probability. That is better than what has been done before, but it is still an average response isn’t it?

Dr. Ratner: I would not say that it is an average response – it is a probability. We are playing the odds. I suppose that if I were a gambler, I would much rather go to the gaming table knowing what the odds are than guessing what the odds are. And hopefully, if we can provide you with some of the odds, then the clinical decision that you and your patient make will be more successful.

Dr. Ferrannini: We just had a beautiful debate about what is it that you want to achieve by screening for type 2 diabetes. Don’t you think that the time is right for including something else in the outcome other than A1c? For example, adherence is an objective measure of what will happen in real life.

Dr. Ratner: Absolutely, I could not agree more and that is why I hope that the regulatory environment will change. I think that using A1c as an isolated marker of success is a horrible mistake. If you give enough insulin often enough to a patient, you can get their A1c down. The hypoglycemia might be unacceptable, but that is not what is accounted for. One of the difficulties of composite outcomes is how do you weight them? How important is A1c compared to hypoglycemia? These questions can be argued and are a legitimate discussion. This is just one example of expanding that outcome to something beyond glucose.

Dr. Ferrannini: The ACCORD, ADVANCE, and VADT trials have been so confusing to at least most of us. There have been many problems. One thing is that the outcome that was chosen – MACE – was essentially chosen by the cardiologists. So unless you drop dead, you do not count. MACE is a very hard outcome. Linking together stroke and MI [myocardial infarction] is to an extent questionable. If you think as we heard previously this morning that the most prevalent cardiac problems in patients with type 2 diabetes are heart failure and atrial fibrillation, then they never are part of the cardiovascular outcome or endpoint. Those outcomes are more difficult to ascertain as you have to do a differential diagnosis, but if you are diabetic and you develop atrial fibrillation, it is very likely to be a cardiovascular outcome for you. We also know that we need to be publishing the results of the trials we conduct. Yet the trend that we are seeing in recent years is that the pharmaceutical-company driven trials are rather reticent to publishing much data from their files.

Dr. Ratner: So many of our trials are being driven by regulatory requirements. The important questions that we and our patients really want to know become ancillary questions, and that is a problem. I am concerned that diabetes has become largely a cardiovascular disease. It is an interesting conundrum we have come into. When we were coming into training, we had entire wards full of people who were on dialysis, who were blind, or who were amputees. We do not see that as much anymore. Amputations, blindness, and renal failure due to diabetes are going down in terms of incidence rates. What has happened is that the diabetes prevalence is going up so rapidly that the cardiologists are now seeing so many people with diabetes and cardiovascular disease. If you look, the incidence rate of cardiovascular deaths in diabetes is going down. The problem is that the number of people with diabetes is going up and have been completely captured by the cardiologists. It goes back to the question: what is your goal for therapy? If the goal for therapy is to prevent mortality, then we are 100% failures; I do not think that is a reasonable goal for therapy. If you ask your patients with diabetes what is their greatest fear with diabetes, very few will express concern about having a heart attack. Those on insulin will often mention gaining weight. Those who had older family members with diabetes will often express fear about going blind or losing a leg. We are dealing with a chronic disease. We are looking at living with a disease for 30, 40, 50 years, and I think that the outcomes have to consider that longevity.

Dr. Julio Rosenstock (Dallas Diabetes and Endocrine Center, Dallas, TX): I think that we both agree that randomized controlled trials – that are meant to be the panacea of information for guidance and so on – have tremendous limitations. They avoid a lot of the people that commonly use the treatment. They are very hard to reproduce and generalize from. They are not long enough. You cannot talk about adherence because all of the resources are there to ensure participants take their medication. Why can’t we develop trials where we test people over a certain period of time and test them against other therapies? The more I look at trials, the more respect I have for regulators. I think that the FDA and EMA are right. We have a lot of drugs now and new ones have to provide the added value, which is what the FDA is going for.

Dr. Harold Lebovitz (State University of New York, New York City, NY): I think we are really stuck with the fact that type 2 diabetes is not a single disease. There are a number of genes involved in determining whether a person gets with type 2 diabetes and what the course of their disease will be. We have very little data on these differences, but there is no doubt that there are these differences. So I think that we really need not only better data methods, but we need to consider the differences in our populations. Until we start to look at populations, we are not going to understand this. The regulators say that if you do not have this percentage of Caucasians and this percentage of African Americans, then you do not have a valid trial. The other problem we have is that a lot of our clinical trials are designed by pharmaceutical companies and their goal is to satisfy the regulators instead of the questions we were asking when we designed our own trials. Many of these trials really do not answer significant clinical endpoints.

Dr. Ratner: I would emphasize the fact that with 18,000 randomized controlled trials published a year, we still do not have many more answers. I think that means that we are not asking the right questions.

Diabetes Prevention Parallel Session: High Risk Groups

WEIGHT LOSS AGENTS: FROM PILLS TO PEPTIDES

Luc Van Gaal, MD, PhD (Antwerp University Hospital, Antwerp, Belgium)

Dr. Luc Van Gaal detailed the different obesity pharmacotherapies currently available and in development with an over-arching focus on the need for drugs that consistently produce >10% weight loss in the average person. Beginning with pills, Dr. Van Gaal reviewed the phase 3 results for Vivus’ Qsymia (phentermine/topiramate), Arena/Eisai’s Belviq (topiramate), and Orexigen’s Contrave (naltrexone/bupropion). He characterized all three as having good-but-limited efficacy and distinguished Qsymia for breaking the mean 10% weight loss mark in one of its phase 3 trials, EQUIP (though it did not quite repeat this efficacy milestone in CONQUER/SEQUEL when patients had a lower baseline BMI). In discussing future drug candidates, Dr. Van Gaal highlighted the need for therapies that produce greater than 10% weight loss. He began with a brief comment on how SGLT-2 inhibitors could produce weight loss of ~12 kg/year (~26 lbs/year) by increasing the excretion of glucose through the urine; however animal models experienced compensatory hunger that thwarted this weight loss. Dr. Van Gaal, dedicated the remainder of his lecture to discussing the clinical results for GLP-1 agonists as anti-obesity medications, concluding that while these candidates are associated with good weight loss, they will not likely provide greater than 10% weight loss. He briefly remarked that pramlintide/metreleptin could be a more promising weight loss approach, as it has the potential to achieve the 10% benchmark – pramlintide may be able to sensitize the body to metreleptin, or vice versa (he hypothesizes the former), resulting in a synergistic effect. We note, however, that Amylin and Takeda had a phase 3 metreleptin/pramlintide candidate until it was discontinued in 2011 following a “commercial reassessment” – no details were provided on the decision, and we’re curious whether it was insufficient efficacy, regulatory concerns, safety signals, or some combination, that prompted them to drop the candidate.

  • In August 2011, Amylin and Takeda announced that they had discontinued the development of their pramlintide/metreleptin candidate following a commercial reassessment. While no specifics were provided, Amylin and Takeda were jointly working on co-formulating pramlintide and metreleptin such that it would require less than four separate injections per day. In the commercial reassessment, the companies took into consideration “a revised development plan”, as well as “evolving dynamics with the obesity therapeutic area.” For more details on Amylin and Takeda’s decision, please see our August 24, 2011 Closer Look at http://www.closeconcerns.com/knowledgebase/r/6c49be28.
  • We share Dr. Van Gaal’s desire for weight loss pharmacotherapies that produce more than 10% weight loss, however, we note that Qsymia, Belviq, and Contrave are known to have efficacy well above 10% weight loss in certain responders. Thus, we point out that healthcare providers (guided by the labels’ stopping rules) could ultimately place each of their patients on mini “trials” to determine if they are a responder on one of these three drugs. Though further research is needed on how to optimize this process, such responder targeting could result in many people achieving >10% weight loss even if the individual drug does not have >10% weight loss in the average person.

Sessions On: Treating Diabetes – Cutting Edge

BARIATRIC SURGERY: HOW THE GUT TALKS TO THE BRAIN

Carel le Roux, MD, PhD (University of Gothenberg, Gothenberg, Sweden)

There was small drop in attendance as the first day of the conference drew to a close with Dr. Carel le Roux’s engaging and informative presentation on bariatric surgery and type 2 diabetes. He noted the glycemic improvements (and sometime diabetes remission) associated with bariatric surgery, but quickly drew the audience’s focus to what he believes is bariatric surgery’s most impressive effect – reducing inflammation and thereby kidney disease. Dr. le Roux explained that many obese people with type 2 diabetes come in for bariatric surgery with C-reactive protein (a marker for inflammation) levels around 8 g/ml and achieve a CRP ~2 g/ml following surgery. According to Dr. le Roux, these patients also tend to have a significant reduction in urine markers of renal inflammation; he noted that further research is still needed to better understand the nuances of this dramatic change, including its consistency and predictability. Dr. le Roux pointed out the common misconception that bariatric surgery results in weight maintenance by permanently reducing the amount of food consumed. Countering this, he presented data showing that roughly one year following their operation, people actually consume nearly the same volume they did beforehand. The difference is in the types of food they are eating. One of the most common side-effects of bariatric surgery, he said, is the “I don’t like burgers anymore syndrome.” Thus, his patients can eat the same amount of food they did before surgery without gaining weight.

  • Dr. le Roux later exclaimed that it is “rubbish” to call bariatric surgery a treatment for obesity, because even the 25% weight loss associated with the surgery does not bring all people to a healthy weight. (We were a little surprised he was so emphatic, considering that bariatric surgery is consistently associated with far greater weight loss than either lifestyle modification or obesity medications.) Notably, however, he pointed out that it is bariatric surgery’s weight maintenance that is remarkable. Presumably also important is the point that many people have diabetes that goes into remission or pre-diabetes that reverts to normoglycemia for at least some period.
  • Looking to the future during Q&A, Dr. le Roux remarked that we may eventually be able to mimic the effects of bariatric surgery using devices and drugs. We have heard this over time from such US leaders as Dr. Lee Kaplan (MGH) and Dr. David Cummings (University of Washington) and look forward to hearing early progress on this front.

Questions and Answers

Q: What do you think we will be doing in bariatric surgery in 10-15 years?

A: I think that surgery is giving us a blueprint that we can try to mimic through devices, pharmacotherapy, and most likely a combination of these two. I also think that the surgeries can be improved. We just need to work out what does what.

-- by Hannah Deming, Jessica Dong, and Kelly Close