We are en route back to San Francisco following five days of learning at IDF’s World Diabetes Congress in Melbourne, Australia. The Melbourne Exhibition and Convention Centre served as a terrific home to the meeting, and we are grateful for the health-focused hospitality of the conference organizers e.g., distribution of wholesome lunches and hosting of daily walks and runs, making attendees feel guilty for taking escalators, etc..
The final day of the World Diabetes Congress was a half-day, featuring about five hours of insightful discussion on topics ranging from lessons that obesity advocates can learn from the fight against tobacco to a session on the SAVOR and EXAMINE DPP-4 inhibitor cardiovascular outcomes trials. During the latter session, Dr. Itamar Raz (Hadassah Medical Center, Jerusalem, Israel) forthrightly acknowledged that the results of SAVOR may very well herald a DPP-4 inhibitor class effect on heart failure and suggested that providers may either want to monitor patients on Onglyza (saxagliptin) who are at high risk for heart failure (especially during the first few months of treatment) or avoid the use of saxagliptin in these patients altogether. Since SAVOR showed a significant increase in hospitalization for heart failure in the treatment arm while EXAMINE did not (it showed a non-significant trend), Dr. Raz (along with some other KOLs who spoke at IDF) expressed hope that Merck’s TECOS CVOT on Januvia (sitagliptin) will shed light on whether increased risk of heart failure is an overall class effect of DPP-4 inhibitors. Continuing the day’s theme of drug safety, Dr. Harold Lebovitz (State University of New York Health Science Center, Brooklyn, NY) gave a presentation in which he at one point argued that TZDs have become the victim of a regulatory environment in which entire drug classes are shot down by data on rare events drawn from hypothesis-generating, non-randomized trials. He feels that the TZD class is highly useful, especially at lower doses that may shield patients from the class’ non-CV side effects. He also argued that diabetes drugs must receive a fair and comprehensive risk/benefit evaluation that draws from the most rigorous data available – hopefully the availability of hard CVOT data in the future will help minimize data scares based on less rigorous trials.
During the session on lessons from anti-tobacco efforts, we were struck by the interconnectedness of the tobacco and junk food industries. Indeed, at the time that the big tobacco company Philip Morris owned Kraft Foods (as well as Miller Brewing), its Chairman Mr. Hamish Maxwell is quoted as having characterized smoking, drinking, and “dietary hazards” as “little causes” that receive the public’s attention only because the world is “generally more peaceful and affluent than ever before.” Though we think that there are many qualities to the fight against obesity that make it distinct from tobacco control efforts (e.g., people must eat for survival, while one does not need to smoke), we think obesity advocates can learn important lessons from tobacco, including that one must be patient in order to see the positive impact of public health efforts.
Top FIVE Highlights
1. Co-lead investigator of BMS/AZ’s SAVOR trial (for Onglyza [saxagliptin]) Dr. Itamar Raz (Hadassah Medical Center, Jerusalem, Israel) joined the growing list of KOLs acknowledging that DPP-4 inhibitors might have a class effect on heart failure. During Q&A, Dr. Raz suggested that providers should either try to avoid the use of saxagliptin in patients at high risk for heart failure or more closely monitor high-risk patients taking the drug. In particular, he is concerned about the first few months of treatment (the time in which the greatest risk was seen in SAVOR – please see AHA 2013 Days #1-2 for results of the detailed heart failure analysis). Although we have heard suggestions to the same effect from multiple speakers at IDF and other recent conferences, we found it notable to hear the idea from Dr. Raz, since he was so intimately involved in SAVOR. Dr. Raz noted that pooling the results of SAVOR and EXAMINE (which evaluated Takeda’s Nesina [alogliptin]) indicates a statistically significant 24% increased risk for hospitalization for heart failure. He also cited the results of the VIVIDD study on Novartis’ Galvus (vildagliptin), which found a change in end-systolic ejection volumes in the treatment arm (although no significant impact on cardiovascular outcomes). Interestingly, Dr. Raz also stated his belief that saxagliptin does not have a direct effect on the myocardium, suggesting that the effect may be mediated through other, currently undetermined factors.
2. During the same symposium’s Q&A session, Dr. Raz emphasized that the results of TECOS, Merck’s CVOT for its DPP-4 inhibitor Januvia (sitagliptin), will be key in evaluating the potential DPP-4 inhibitor class effect on heart failure. We would agree, as the mixed data seen so far is not enough in the minds of many KOLs to alter prescribing recommendations for DPP-4 inhibitors on a large scale, especially given their otherwise favorable safety profile. As background, TECOS’ data readout is expected in late 2014. The CAROLINA and CARMELINA CVOTs for BI/Lilly’s Tradjenta (linagliptin) will also provide additional clarity to the issue, although the planned primary completion dates of those two studies lie farther in the future, in 2018.
3. During his overview of past and future perspectives on type 2 diabetes therapies, Dr. Harold Lebovitz (State University of New York Health Science Center, Brooklyn, NY) came to the defense of the TZD class, arguing that they have been subjected to an unfair risk/benefit analysis in recent years. He noted that the cardiovascular safety concerns that doomed GSK’s Avandia (rosiglitazone) were drawn from meta-analyses, while the more rigorous RECORD and BARI-2D randomized control trials showed no evidence of an increase in CVD risk. In Dr. Lebovitz’s mind, TZDs are some of the most effective agents available, due to their ability to reduce insulin resistance, preserve beta cells, and reduce liver fat. Most trials that have raised safety concerns with TZDs (such as bone fractures and congestive heart failure) used the highest doses of either rosiglitazone or Takeda’s Actos (pioglitazone); Dr. Lebovitz theorized that more moderate doses of the drugs could yield more attractive risk/benefit profiles – we would love to see trials testing a combination of low-dose TZD with other drugs. Speaking more generally about the current scientific and regulatory climate, Dr. Lebovitz lamented that nowadays, drugs are being taken off the market due to very rare adverse events seen in non-randomized control trials. Dr. Lebovitz believes that drugs, instead, must be comprehensively analyzed in terms of their overall risk/benefit profile, and studies other than RCTs can only be seen as hypothesis generating. We drew many parallels between Dr. Lebovitz’s presentation and the recent controversy over incretins and pancreatic safety (please see our Pancreatitis Primer for a timeline of major events) – Dr. Lebovitz over the years, of course, has had significant commentary on various safety scares. While the many ongoing CVOTs for type 2 diabetes drugs should help to improve the quality of drug safety data, we see they may still not be enough to rigorously assess extremely rare events like pancreatic cancer. As such, we hope that Dr. Lebovitz’s healthy dose of big-picture perspective urging people to take a comprehensive approach to risk/benefit profiles is applied in future cases such as these..
4. Dr. Mike Daube (Curtin University, Bentley, Australia) pointedly quoted former Chairman of Philip Morris (the company that used to own both Miller Brewing and Kraft Foods) during his presentation on what obesity advocates can learn from tobacco control efforts – back when Mr. Maxwell ran Philip Morris, he made this provocative statement: “Many of the threats to us arise from concerns, which have lost touch with common sense and reality. People and politicians do need causes and in a world that is generally more peaceful and affluent than ever before, there is a shortage of big causes. That is why we hear so much about little causes like smoking, drinking, and dietary hazards.” Today, to think of smoking as a “little cause” would seem preposterous, and we hope that dietary concerns will be raised to the same national stage as a key public health concern of the times. Dr. Daube’s main recommendation was that those working in the obesity field must unite behind a common message and set of policy requests. Downheartedly, he described a meeting with Australia’s Minister of Health and leaders in the anti-obesity field, in which the advocates spent the majority of the allotted time competing against one another (e.g., arguing that healthy food access is more important than physical activity programs), leaving the Minister at a loss on how to move forward. We think it is an important challenge for advocates to simplify and distill the multifactorial nature of obesity into a set of clear (and well supported within the medical and public health communities) policy proposals on which politicians can take action.
5. Dr. Simon Heller (University of Sheffield, Sheffield, UK) highlighted the difficulties of using clinical trials to identify clinically meaningful treatments for hypoglycemia. Notably, he remarked that while observational studies do have their limitations, they may also provide some benefits that cannot be achieved with randomized controlled trials. According to Dr. Heller, observational trials often show much higher rates of hypoglycemia and reflect real-life clinical experiences better than randomized controlled trials– a benefit that HCPs should consider when assessing data on hypoglycemia treatments. The biggest issues with clinical trials and assessment of hypoglycemia, Dr. Heller noted, are the multiple definitions of hypoglycemia, the differences in reporting hypoglycemia, and the selection of populations with a very low hypoglycemia event rate. Regarding this last point, Dr. Heller urged researchers to investigate hypoglycemia treatments in the highest risk groups since, often, clinical trials tend to select populations that have too low of a hypoglycemic event rate and are, therefore, not clinically representative. Big picture, Dr. Heller explained that without investigating a group of clinically representative patients, it is difficult to develop reimbursement strategies for various treatments. Although clinical trials are typically seen as the golden standard for producing evidence, Dr. Heller’s presentation reminds us that research without clinical applicability is meaningless.
--by Adam Brown, Hannah Deming, Hannah Martin, Manu Venkat, and Kelly Close