Our team is in-air, heading back to the Northern hemisphere after a trip across the equator to Buenos Aires, Argentina for the fourth CODHy Latin America. In our full report, we bring you our insights and takeaways from the meeting’s litany of interesting and, as the conference name promises, controversial presentations on the most pressing issues in diabetes and obesity care. Given the current era of positive CVOTs, several of this year’s sessions were dedicated to an exploration of the benefits of newer anti-diabetes agents such as the SGLT-2 inhibitor and GLP-1 agonist classes and how to balance this with the very real issues of their high cost and low accessibility, particularly in middle and low income countries. The agenda also featured plenty of commentary on a number of hot topics ranging from the costs and benefits of new basal insulins, the rise of biosimilar insulins, and the pros and cons of initial combination therapy from the outset of diabetes diagnosis. Tension was perhaps strongest on the topic of the future of sulfonylureas – an inexpensive and hugely popular therapy in Latin America, but one associated with deep concerns over hypoglycemia and potential cardiovascular risk (to say nothing of weight gain and edema). Read on for full comprehensive coverage of this always thought-provoking meeting.
Detailed Discussion and Commentary
Therapy in the Treatment of Type 2 Diabetes
The Present and Future of Drug Therapy
Ralph DeFronzo, MD (University of Texas Health Science Center, San Antonio, TX)
Dr. Ralph DeFronzo kicked off the meeting with a strong endorsement for the preferential use of GLP-1 agonists, TZD pioglitazone, and SGLT-2 inhibitors as first-line therapy in type 2 diabetes. He largely pointed to recent positive cardiovascular outcomes trial (CVOT) data for agents in these classes to make his point and argued that, given the massive investment from industry to conduct these long, expensive, and rigorous trials, we need to change our approach to type 2 diabetes treatment when they’re positive (we agree, but for a different reason – not that industry has spent a lot, but due to the data showing CV and kidney protection). In particular, he underscored that GLP-1 agonists are able to produce sustained reductions in A1c over a number of years and highlighted data suggesting that GLP-1 agonist liraglutide (Novo Nordisk’s Victoza) is able to return beta cells to normal function. In sum, Dr. DeFronzo persuasively argued, “You tell me why a drug that lowers A1c, causes weight loss, is safe, and causes normal beta cell function should not be first line therapy.” He further highlighted the impressive LEADER and SUSTAIN 6 trial results demonstrating a cardioprotective benefit for liraglutide and Novo Nordisk’s semaglutide, respectively, noting, “if you didn’t already think the drug did enough, it now prevents you from having CV events.” Similarly, Dr. DeFronzo highlighted the positive CVOT results for SGLT-2 inhibitors (specifically from EMPA-REG OUTCOME for Lilly/BI’s Jardiance [empagliflozin]) and for pioglitazone (from IRIS and from a secondary endpoint in PROACTIVE) in support of their use as first-line options as well. On the other hand, he suggested that the positive evidence of CV benefit for metformin from UKPDS is weak at best, given the small number (n=342) of patients in the analysis. Furthermore, he suggested that sulfonylureas are certainly not cardioprotective and could possibly actually cause CV harm – we’ve long heard they cause beta cell burnout, though not from anyone that has been willing to go on record. In light of demonstrated positive benefits for other drug classes, just to drive the point home, Dr. DeFronzo characterized the use of older drugs like metformin and sulfonylureas as “archaic.” Dr. DeFronzo acknowledged, however, that cost may be a barrier to GLP-1 agonist, SGLT-2 inhibitor, and pioglitazone therapy – that said, he compellingly pointed out that “if you’re dead, no drug is going to help you.” Dead is one thing – but in our view, alive and costing the system hundreds of thousands of dollars a year is another, and the far more challenging thing to think about from a systems perspective.
- Dr. DeFronzo offered a number of positive comments related to upcoming SGLT-2 inhibitor and GLP-1 agonist-based therapies in the pipeline. On the SGLT-2 inhibitor front, he was particularly optimistic about Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin, suggesting that the candidate could produce better results than standalone SGLT-2 inhibitors and that he has long considered the decision to develop SGLT-2-selective inhibitors a mistake. He also highlighted the potential of J&J’s canagliflozin and phentermine co-administration therapy for obesity and expressed his interest in a potential SGLT-2 inhibitor/pioglitazone combination. On the GLP-1 agonist front, he highlighted novel administration methods in the form of Intarcia’s implantable ITCA 650 (exenatide mini-pump) and Novo Nordisk’s oral semaglutide. He also expressed excitement over GLP-1 agonist/basal insulin fixed-ratio combinations (Novo Nordisk’s Xultophy [insulin degludec/liraglutide] in particular) and polyagonists in development such as GLP-1/GIP and GLP-1/glucagon dual agonists. Whew! This talk was anything but boring.
Digital Care of the Patient with Diabetes
Itamar Raz, MD (Hadassah Hebrew University Hospital, Jersualem, Israel)
The esteemed Dr. Itamar Raz, one of CODHy Latin America’s organizers, compellingly discussed the present and future role of digital medicine in promoting personalized diabetes care. He began the presentation by contrasting the constant decision-making that diabetes management requires with the brief amount of time people with diabetes actually spend with their physicians, emphasizing that the majority of diabetes management is self-management. Mobile health technologies, Dr. Raz noted, offer patients a more streamlined, effective, and adherence-friendly avenue for diabetes self-management. Today’s mobile health apps can collect and analyze data on everything from a patient’s daily activity levels to their nutritional habits to their blood glucose levels, providing them with insights and decision support that are getting smarter and more sophisticated by the day. This digital form of diabetes management promotes engagement and requires less effort for self-management for individuals, and, according to Dr. Raz, if expanded to the level of the clinic and wider healthcare network, could eventually foster greater consistency and information flow as patients move between their different providers or even be used as a tool to identify and ameliorate high level disparities in diabetes care between different regions or demographic groups. With a nod to the global plausibility of this notion of the ‘virtual diabetes clinic,’ Dr. Raz pointed out that smartphones will be used by 70-90% of the world’s population by the year 2020. He envisions that mobile app-based health services will eventually be used at every stage of diabetes care, starting at prevention strategies for at-risk individuals all the way to decision support for complex treatment regimens for individuals with insulin pumps or multiple daily injections.
Novel Insulin Analogs
Ultra Long Acting Basal Insulin – Does Benefit Outweigh Cost?
Philip Home, DM, DPhil (Newcastle University, Newcastle Upon Tyne, UK) and Baruch Itzhak, MD (Clalit Health Services, Haifa, Israel)
In an engaging debate, both Dr. Baruch Itzhak and Professor Philip Home presented compelling arguments related to the cost-effectiveness of next-generation ultra-long-acting basal insulins. Dr. Itzhak argued that these new insulins – such as Novo Nordisk’s Tresiba (insulin degludec) and Sanofi’s Toujeo (U300 insulin glargine) justify their higher cost as they boast a more ideal profile of action for a basal insulin, with a long duration of action and flat action profile without any sort of peak. Dr. Itzhak highlighted that both of these insulins produce less hypoglycemia than older basal insulin glargine (Sanofi’s Lantus). He considered this one of the most important features of these new products, citing that hypoglycemia remains one of the main obstacles for healthcare providers toward effective insulin treatment. Furthermore, he emphasized the various direct and indirect economic costs of severe hypoglycemia and pointed to estimates that severe hypoglycemia resulted in over $600 million spent on emergency department visits and hospitalizations over a five-year period in the US. We actually think the cost of this is far, far higher, according to Truven, which is now owned by IBM Watson (need more be said?) Professor Philip Home readily agreed that hypoglycemia is immensely important to people with diabetes and to the healthcare professionals who work with them. He also similarly agreed that hypoglycemia reduction is the main advantages of next-generation basal insulin. Besides hypoglycemia reduction, he suggested that next-generation basals and even Lantus offer little advantage over NPH in terms of (i) better improvement in acute hyperglycemia symptoms; (ii) improvement in long-term hyperglycemia-related outcomes; (iii) body weight management; and (iv) insulin dosage and convenience of administration. Even when considering hypoglycemia, Professor Home suggested that hypoglycemia is not necessarily a major issue for type 2 diabetes (citing data suggesting that less than 18% of patients experienced hypoglycemia over a four-year period – we were a bit surprised to hear something that sounded so dismissive about what is effectively millions of patients globally though we need to check in with Professor Home to make sure we are interpreting this correctly!), and thus, from a population perspective, the gain in quality of life may not justify the added cost of next-generation insulins. More specifically, Professor Philip Home cited meta-analyses of the benefits of Tresiba to conclude that, in the UK, Tresiba would only be cost-effective if it is priced at a less than $20/month premium compared to Lantus. (We are reminded of Dr. Irl Hirsch’s comment about meta-analyses several years ago “There are lies, damn lies, and meta-analyses!”) Professor Home shared that Novo Nordisk evidently found such cost-benefit analyses convincing and thus slashed the cost of Tresiba in the UK by 35% in July 2016, making Tresiba only 12% more expensive than Lantus there and thus cost-effective. (We aren’t sure if “thus cost-effective” is correct; perhaps “thus, possible to sell” may be, but we are speculating.) That said, he emphasized that if the cost of Tresiba in the UK were just 6% higher than current levels, the cost advantage would be wiped out – this comparison becomes even more challenging when evaluating the cost-effectiveness of Tresiba vs. biosimilar insulin glargine. While the cost-effectiveness argument in the overall type 2 diabetes population is weaker, Professor Home suggested that greater cost-benefit may be possible in specific populations of people with type 2 diabetes, such as those with recurrent hypoglycemia, those with hypoglycemia unawareness and severe hypoglycemia, or those engaged in high-risk jobs or other activities.
- Our take: We certainly agree that those with low residual insulin production, possibly on multiple daily injection, and at higher risk of hypoglycemia (people with type 1 diabetes included) could benefit immensely from these next-generation products. For those with less progressive type 2 diabetes, we’re hoping that newer non-insulin agents (GLP-1 agonists, SGLT-2 inhibitors, etc.) will be able to delay or even prevent the need for insulin initiation altogether – although, of course, that would not solve Professor Home’s cost issues. Overall, we continue to believe that next-generation insulins are an important advance for the diabetes field and a tool that we’re glad to see added to the armamentarium, though of course they won’t be right for everyone and it will be important to identify which patients stand to benefit the most from these agents and ensure their accessibility for these patients.
Questions and Answers
Q: Is there a study comparing the pharmacoeconomic benefits of Tresiba and Toujeo? Is there any difference in hypoglycemia?
Dr. Itzhak: I’m not familiar with any study comparing those two. In real life, both of them are good. I’m not aware of any comparison of cost-effectiveness.
Professor Home: I’ve seen nothing published on this either. That said, it would’ve be difficult to do a network analysis because both have been comprehensively compared to Lantus.
Editor’s note: a new n=1,590 patient head to head study of degludec vs glargine comparing the number of blood-glucose confirmed hypoglycemic events between weeks 16 and 52 came out recently – see more here.
Dr. Itamar Raz: Philip, you did a great job of showing us how, in the UK, you were able to drive down the price of Tresiba. But I think that many other countries wouldn’t be able to achieve the same outcome with Novo Nordisk. Also, separately, when we looked at NPH vs. Lantus, the gap in hypoglycemia rates was higher and more justified than the difference between Lantus and ultra-long-acting basal insulins. In my country, we use Lantus as a tool to persuade family physicians to start insulin. They’re worried about hypoglycemia and when they hear that hypoglycemia is reduced tremendously, the use of insulin increases tremendously. There’s also the psychological part. If I had to treat patients with NPH today vs. Lantus, I would feel very bad about it. I agree with you that this can be the best insulin in special cases where hypoglycemia is an issue.
Professor Home: In a cost-effectiveness analysis, we don’t introduce the psychological aspect for the physician, but we do consider the patient perspective and there could be an improvement in fear of hypoglycemia with these new products. There’s a fair amount of data that quality of life is correlated to hypoglycemia and fear, but the data is heavily compounded as those who are ill tend to get more hypoglycemia and the decrease in quality of life could also be due to the illness. Your point about these products encouraging earlier insulin initiation is quite interesting – if as a result, you improve glucose control earlier and get better outcomes, that would be a positive on the cost-effectiveness. I’ve never seen people do these calculations, but if you can get A1c to 6.5%, virtually anything is cost-effective. If you can get to that level earlier, it’s highly cost-effective.
Biosimilar in Insulin Therapy
Paolo Pozzilli, MD (Campus Bio-Medico University of Rome, Rome, Italy) and Guillermo González Gálvez, MD (Universidad de Guadalajara, Guadalajara, Mexico)
A highly engaging debate on biosimilar insulin therapy between Drs. Paolo Pozzilli (pro biosimilar) and Guillermo González Gálvez (anti biosimilar) underscored the dual great optimism and continued anxiety many in the diabetes field feel on the topic. Dr. Pozzilli positioned the introduction of biosimilar insulins as a net positive for the field, suggesting that the increased competition and “liberalization of the market” can drive down prices for the originator insulin products as well. With their lower cost, biosimilars may reduce the cost of treating diabetes, expand accessibility to insulin, and expand the number of options available to patients with diabetes. Dr. Pozzilli acknowledged that immunogenicity with biosimilars are a potential concern, but emphasized that the clinical data for Lilly/BI’s biosimilar insulin glargine Basaglar in particular has been very reassuring. Overall, Dr. Pozzilli advocated for the diabetes field to embrace biosimilars and called for standardization of global regulatory requirements for biosimilars to simplify their development process. Dr. Gálvez similarly emphasized the need for a high regulatory bar for biosimilars, particularly in his home country of Mexico, but advocated for caution with biosimilars for now. Like others we’ve heard on the conference circuit, Dr. Gálvez underscored that biosimilars are not generics and that the manufacturing process is both extremely complicated and maintained as a proprietary secret within the industry even after patent expiry for biologics. Thus, he suggested that it’s difficult to have a high degree of confidence that biosimilar insulins are truly identical to the originator insulins. Overall, Dr. Gálvez felt that the ~15% discounts we’ve seen with biosimilars like Basaglar relative to Lantus aren’t worth the risks associated with switching someone from Lantus when we have a wealth of clinical experience with and evidence for Lantus. Dr. Gálvez’s view is evidently fairly common in the Latin American region – at the end of the debate, the majority of audience members voted against the use of biosimilars (an outcome that surprised Dr. Pozzilli and was contrary to his usual experience with biosimilar debates at other conferences). It’s clear that concerns about the safety and quality assurance of biosimilars persist in the global diabetes field and appear especially poignant in those that may have had experiences with poor quality biosimilars. Thus, in our view, it’s doubly important to make sure that all biosimilars that reach the market are thoroughly vetted and safe – of course, this might mean that biosimilars will never be able to be offered at the discounts of 80% that we see in generics given the higher development costs, but even a 15% discount is tremendously helpful for some. We also agree with comments from Dr. Pozzilli and Professor Philip Home in Q&A that patients who are doing well on Lantus should not be forcibly switched to a biosimilar version.
- To further make his argument, Dr. Gálvez pointed to Mexico’s own experience with a biosimilar insulin glargine, Bonglixan. The biosimilar from Landsteiner Scientific, was licensed in Mexico as a “biogeneric” prior to the creation of more rigorous regulations for biosimilars. As it is much lower cost than Lantus, physicians in the public sector only have access to Bonglixan (rather than Lantus) for their patients and, according to Dr. Gálvez, physicians anecdotally reported lower efficacy (requiring a higher dose of insulin), with more reports of hypoglycemia and one case of allergy. He implied that one of the main reasons the company decided to launch Bonglixan was the relatively lax regulatory process, and thus the ability to have a relatively inexpensive development program. Now that Mexico would retroactively like to see clinical data that meets their new, higher regulatory bar, the company is apparently thinking of withdrawing from the market. We expect that these quality concerns do not necessarily apply to Lilly/BI’s Basaglar. Given Lilly’s long experience in the insulin field, there is a greater degree of confidence in the company’s biosimilar – indeed panelists made comments to this effect in Q&A.
Questions and Answers
Dr. Pozzilli: I’d like to defend the “yes” position. I’m surprised honestly that, in this part of the world, the majority here have voted for “no.” I’m surprised because I’ve attended a number of similar debates at other meetings and the consensus is usually in favor of biosimilars. I’m surprised because honestly the issue of cost is an important one and we cannot really forget about it, particularly in a country like Argentina. I’m surprised to hear so many concerns about manufacturing issues – we’re not bioengineers, we’re physicians, so let’s leave the manufacturing to the bioengineers. Any problems with the product will be checked by regulatory agencies. According to the clinical data with Basaglar, we haven’t seen any difference from Lantus in terms of its profile. Evidence-based medicine should drive decisions, not gut feeling.
That said, of course I raise the issue of immunogenicity. I’ve published a lot on insulin antibodies and of course the issue is still there – who knows what happens when you switch from one insulin to another? Who is going to decide when to switch? It is just cost-savings that dictate when you should switch? But generally speaking, we should favor the introduction of these new insulins at this time.
Dr. Gálvez: I think many people voted for “no” because most of us are in private practice and, in private practice, all patients need to pay out of pocket. So for this little of a discount – 15% - I don’t want to expose my patients to a copy of the original when we have all of this experience and evidence with the original. We also know that the majority of regulatory agencies in our countries are focused on trying to pay nearly nothing for every medication, so we’re not confident that these new biosimilar insulins are regulated well here. It’s a risk to expose a lot of patients to the products that I have mentioned. When we use one of these not very well-studied insulins in Mexico, we have a lot of problems and we have to respond to those problems.
Dr. Pozzilli: The per day cost of glargine Lantus today in Italy is approximately 0.42 Euro cents. It was nearly a double figure last year, while Basaglar stands approximately at 0.40 cents per day. The arrival of a competitor drove down drastically the cost of the originator with huge cost savings for the payer.
Dr. Baruch Itzhak: The government in South American doesn’t take into consideration the poorer outcomes associated with use of biosimilars other than Basaglar. Similarly, they don’t take into account the hypoglycemia benefits of ultra-long-acting insulins. What about the cost of hospitalizations due to hypoglycemia though?
Dr. Gálvez: The problem in some countries like Mexico is that regulatory agencies don’t take into account that point of producing more hypoglycemia. They evaluate the cost of the product – on the basis of that, they make a decision on whether to reimburse the product or not.
Dr. Shlomo Vinker: It’s important to note when insulin manufacturers produce insulin biosimilars. For example, Lilly knows how to produce insulin – they’re well-qualified and we shouldn’t be concerned about safety. I’m not sure about the manufacturers in China and India.
Dr. Gálvez: It’s important to note that Lilly needs this kind of insulin to complete their insulin product lineup. The other companies from China and India are producing these biosimilars because we want to sell large amounts of insulin around the world – they don’t care about efficacy or safety. We don’t get have Basaglar in Mexico, but if Basaglar enters Mexico at a 30%-40% discount relative to Lantus, then it could be very important in Mexico. On the other hand, if it enters Mexico with a cost very similar to the original, we probably wouldn’t prescribe it very much, especially in private practice.
Dr. Pozzilli: The very first insulin was produced by Lilly. At the end of the day, when you want to buy something for yourself, the quality of the product is related to the quality of the firm that produces the product. We know that the quality is not the same when we buy bad copies of something (shoes, watches, etc.) – psychologically speaking, we know we save more money but don’t expect the same quality. On the other hand, when you have a producer with a good history of selling and producing the product, like Lilly, we should feel very confident and we’ll save money for our patients and our health service.
Dr. Vinker: In a separate question, should we keep patients on the same insulin or should we switch them back and forth depending on what’s available, etc.?
Dr. Pozzilli: In Italy, we have a strong authority that checks doctors’ behavior regularly. You can’t just switch a patient from one insulin to another – you need to justify it and have a good reason. Most doctors will probably say we want to save money by switching, which is acceptable.
Dr. Vinker: To clarify, I mean will the biosimilars be interchangeable? For example, in generics, you can get a different brand of metformin every month. It’s not the same with insulin, right?
Dr. Pozzilli: Of course.
Dr. Home: I think we need to be very clear about the difference between substitution and interchangeability. Even substitution – where the doctor switches a patient from one basal insulin to another long-term – can be problematic. Even those on insulin who have a love-hate relationship with their current insulin tend to destabilize when you switch across what should be identical products. Interchangeability – where the pharmacist substitutes a different insulin without physician input – is really a dangerous issue. It happens in some poorer countries due to availability and it causes a lot of issues.
Anti-Diabetic Agents: Preferred Second Line Therapy in America vs. The Rest of the World
Debate: Sulfonylureas vs. DPP-4 Inhibitors
Pablo Aschner, MD (Javeriana University School of Medicine, Bogotá, Colombia) & Philip Home, DM, DPhil (Newcastle University, Newcastle Upon Tyne, UK)
Dr. Pablo Aschner kicked off this debate session on sulfonylureas versus DPP-4 inhibitors with an extremely unenthusiastic defense of sulfonylureas, prefacing his talk by remarking that the main virtue of sulfonylureas is their wide accessibility in Latin America, where they are one of the only affordable options available to most patients. Keenly aware of the SU’s reputation for increasing the risk of cardiovascular events, Dr. Aschner defended the cardiovascular neutrality of newer SUs such as glimepiride and gliclazide – though conceded that these, like older SUs, still carry the risk of hypoglycemia – this seems like an extremely contradictory position to us, given the connection between severe hypoglycemia and cardiovascular events. This is something that patients should be counseled about from the very initiation of SU therapy, he argued, so they aren’t tempted to abandon therapy entirely if they experience this side effect – the negative impact of hypoglycemia goes far beyond quality of life and fear of future hypoglycemia, in our view, though those are incredibly important and should not be so easily dismissed either. Overall, Dr. Aschner clearly views sulfonylureas as a last resort when no other options are available, though he acknowledged that he would “maybe defend the use of sulfonylureas sometimes” under the following circumstances in Latin America: (i) as an alternative to metformin when other drug classes are unavailable (presumably, these patients would be unable to take metformin for some reason); (ii) as an initial combination with metformin when other classes are unavailable and A1c exceeds 9%; (iii) and as an add-on to metformin when other classes are unavailable. His message came across loud and clear that SUs are not the ideal therapeutic option, but may be the only option in many parts of the world. In response, the great Professor Philip Home offered a heated defense of DPP-4 inhibitors and their superiority over sulfonylureas. Indeed, in Professor Home’s own words, the “clinical preferability of DPP-4 inhibitors is clear,” and he reviewed a wealth of evidence to support that this class, unlike SUs, does not contribute to hypoglycemia or weight gain. The neutral CVOT results from SAVOR, EXAMINE, and TECOS also provide a reassuring sign that DPP-4 inhibitors are free from the cardiovascular risk associated with SUs (particularly older ones such as glibenclamide, which is strongly discouraged in most international guidelines, even those with a positive bent toward SUs). Though cost of therapy is indeed an important factor in an individual’s diabetes care, we find the economic argument for SUs inadequate and unconvincing given the increased overall healthcare costs associated with increased hypoglycemia. We look forward to a future where each patient can receive what is truly the optimal therapy in purely clinical terms, and for therapy to be looked at as an investment, not a cost.
Debate: GLP-1 Agonists vs. SGLT-2 Inhibitors
Naim Sedadeh, MD (Rambam Health Care Campus, Haifa, Israel) & Leon Litwak, MD (Hospital Italiano, Buenos Aires Argentina)
A second debate session pitted GLP-1 agonists against SGLT-2 inhibitors, though what followed is best characterized as a dialogue rather than a debate, with both speakers agreeing that both of these newer diabetes medications are clinically superior to the majority of other available diabetes therapies. Indeed, both GLP-1 agonists and SGLT-2 inhibitors, in addition to their glucose lowering effects, promote weight loss and potential cardioprotection (as demonstrated by the LEADER and SUSTAIN-6 trials for the GLP-1 agonists liraglutide and semaglutide and the EMPA-REG OUTCOME trial for the SGLT-2 inhibitor empagliflozin). The two drug classes have been compared head-to-head only once, in the DURATION-8 study comparing dapagliflozin and exenatide once-weekly dual therapy with either monotherapy. Unsurprisingly, the combination treatment was superior to either monotherapy alone, but there were no significant differences in weight reduction, A1c, or fasting plasma glucose between the dapagliflozin and exenatide monotherapy arms – that said, a more potent GLP-1 agonist like once-weekly semaglutide will likely have greater A1c efficacy and a greater effect on weight than SGLT-2 inhibitors (and has already demonstrated superiority to exenatide once-weekly in a head-to-head study). Speaking in favor of GLP-1 agonists, Dr. Naim Sedadeh summarized the recently-published results of Lorenzi et al.’s meta-analysis comparing RCT data for GLP-1 agonists and SGLT-2 inhibitors (versus placebo or other OADs such as DPP-4 inhibitors). In this study, GLP-1 agonists produced a mean A1c reduction of 0.7-1.7%, versus only 0.4-1.0% for SGLT-2 inhibitors. Furthermore, GLP-1 agonists were associated with a stronger reduction in fasting plasma glucose (in terms of hypoglycemia, weight reduction, cardiovascular benefits, and clinical restrictions, the analysis deemed the two drug classes equal). On the SGLT-2 inhibitor side, Dr. Leon Litwak countered that SGLT-2 inhibitors, as oral agents, are easier to use and less expensive than GLP-1 agonists, and may be more adherence-friendly because they do not involve injections or titration. Ultimately, both classes offer substantial benefits and the choice of therapy should come down to individual patient characteristics, in our view. Of course, we certainly view the co-administration of the two as a very promising combination as well!
Heart Failure in Type 2 Diabetes: Should We Avoid or Recommend Treatment?
DPP-4 Inhibitors and GLP-1 and Heart Failure
Patricio Lopez-Jaramillo, MD (Fundación Oftalmológica de Santander, Bucaramanga, Colombia)
Dr. Patricio Lopez-Jaramillo argued that the neutral cardiovascular outcome trial (CVOT) results for DPP-4 inhibitors to date do not support their use in diabetes treatment from a cost-benefit perspective. Dr. Lopez-Jaramillo emphasized that three main criteria must be met to justify a drug’s use in treatment: (i) it must be more effective than current options; (ii) it must be safer; and (iii) it must offer a better cost-benefit ratio. On the efficacy point, he argued that we should primarily consider the impact of drugs on macrovascular complications, specifically in terms of cardiovascular outcomes. Regarding DPP-4 inhibitors, he noted that trials to date and meta-analyses of multiple trials have indicated that the class is neutral in terms of overall cardiovascular safety – he suggested that this was disappointing, as he’d like to see decreased cardiovascular risk if he intervenes with a therapy. Turning to GLP-1 agonists, Dr. Lopez-Jaramillo similarly argued that meta-analyses to date have not indicated a cardiovascular benefit for the class as a whole, though he conceded that the LEADER and SUSTAIN 6 results for Novo Nordisk’s liraglutide and semaglutide were impressive and that he could support the inclusion of those two specific agents in the diabetes treatment guidance. Overall, however, Dr. Lopez-Jaramillo argued that it would be difficult to convince a poor health system – like many in the countries in Latin America – to invest in expensive incretin-based therapies when “there is no evidence of benefit.” While we certainly agree that cardiovascular outcomes are very important and lowering cardiovascular risk is one of the main goals of diabetes therapy, we wouldn’t be so quick to dismiss drugs with neutral CVOT results as not providing any benefit at all. The long-term microvascular benefit offered by these agents’ A1c efficacy coupled with their day-to-day benefits on quality of life (in the form of reduced hypoglycemia, increased glycemic variability, and general safety/tolerability) more than justifies their use in patients for whom they are appropriate in our view – and that’s to say nothing of the cardiovascular and renal benefits that were demonstrated in both LEADER and SUSTAIN 6. While prevention of macrovascular complications is important, they are not the only complications associated with diabetes and we believe it’s important to impress this message upon health systems and other payers. As well, of course, more time may result in cardioprotection that may not be seen earlier on in all trials – some trials were simply powered for cardio-neutrality, given the high cost of getting to market.
SGLT-2/PIO and Heart Failure
Luc Van Gaal, MD (Antwerp University Hospital, Antwerp, Belgium)
Dr. Luc Van Gaal provided a comprehensive overview of the knowledge to date regarding the relationship between heart failure and type 2 diabetes, as well as the impact of TZD pioglitazone and SGLT-2 inhibitors on heart failure. He ultimately suggested that the co-administration of pioglitazone and an SGLT-2 inhibitor has potential. That said, he emphasized that we will likely never get a clear answer to the cardiovascular impact of SGLT-2 inhibitor and pioglitazone co-administration from current CVOTs. He pointed out that there were only a few hundred patients in EMPA-REG OUTCOME that were on both pioglitazone and empagliflozin, yielding too small a number of events for analysis. The ongoing DECLARE and CANVAS trials for AZ’s Farxiga (dapagliflozin) and J&J’s Invokana (canagliflozin), respectively, specifically listed pioglitazone therapy as an exclusion criterion. That said, Dr. Van Gaal shared that small studies have found that positive effects for each standalone drug (A1c, weight, and blood pressure reductions) were sustained when administered together with no increase in adverse events. Overall, the combination certainly seems very promising for patients who prefer oral therapy – that said, we’ve found the benefits of GLP-1 agonist and SGLT-2 inhibitor co-administration compelling as well.
Preferred Anti Diabetes Therapies for Cardiovascular Diseases
Itamar Raz, MD (Hadassah Hebrew University Hospital, Jersualem, Israel)
Based on the positive results from recent diabetes CVOTs, Dr. Itamar Raz offered specific recommendations on the most appropriate patient populations for GLP-1 agonists, SGLT-2 inhibitors, and other second-line treatment options. Overall, Dr. Raz maintained that metformin should still be considered first-line therapy in type 2 diabetes and that GLP-1 agonists, SGLT-2 inhibitors, TZD pioglitazone, and DPP-4 inhibitors could all variously be considered for second-line therapy in different kinds of patients. Dr. Raz particularly drew on sub-group analyses from the LEADER trial for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) and from the EMPA-REG OUTCOME trial for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) to make his point. He noted that in LEADER, liraglutide demonstrated a much more compelling effect in those with a BMI over 30 kg/m2, those with eGFR below 60 ml/min/1.72 m2, and those with established cardiovascular disease (as opposed to merely exhibiting cardiovascular risk factors). As such, Dr. Raz preferentially recommended GLP-1 agonists as second-line therapy in patients with obesity, previous history of stroke, established cardiovascular disease or multiple CV risk factors, and/or renal failure. On the flip side, in EMPA-REG OUTCOME, the greatest benefit for empagliflozin was seen in those with a BMI less than 30 kg/m2 and with eGFR between 60 and 90 ml/min/1.72 m2 (EMPA-REG OUTCOME only enrolled patients with established cardiovascular disease). Dr. Raz recommended the use of SGLT-2 inhibitors in patients with established cardiovascular disease with BMI less than 30 kg/m2 and eGFR greater than 60 ml/min/1.72 m2. That said, he pointed out that the point estimate of the hazard ratio for stroke in EMPA-REG OUTCOME was above 1.0 – though the finding was not statistically significant – which led him to recommend caution regarding SGLT-2 inhibitor use in patients with a previous history of stroke. For patients with previous stroke, in addition to GLP-1 agonists, Dr. Raz suggested the use of TZD pioglitazone on the basis of the IRIS trial, which demonstrated cardiovascular benefits in paitents with such a history (albeit these patients had insulin resistance but not type 2 diabetes). Finally, in a brief mention, Dr. Raz relegated DPP-4 inhibitors to elderly patients, presumably due to their extremely benign safety and tolerability profile. We very much appreciated Dr. Raz’s clear and helpful advice for clinical decision-making in an era in which we’re fortunate to have multiple drug classes with demonstrated CV safety or even benefits. It appears that while multiple drugs may boast cardioprotection, some may be more appropriate for certain patients’ cardiovascular characteristics than others and identifying these subgroups is key to truly individualized diabetes therapy.
Felix Escaño, MD (Centro Escaño, Santo Domingo, Dominican Republic)
Dr. Felix Escaño emphasized the need for intensive provider education on new insulin therapies, especially in Latin American countries and especially among general practitioners. He noted that insulin therapy is often delayed due to provider and patient fears about hypoglycemia, weight gain, and needles. While new generation insulins – such as Novo Nordisk’s Tresiba (insulin degludec) and Sanofi’s Toujeo (U300 insulin glargine) – are able to mitigate some of these downsides, Dr. Escaño suggested that many physicians do not learn about these advanced agents in a timely manner. Furthermore, he noted that some new insulins are offered in highly concentrated forms that could lead to dosing mistakes if providers and patients do not receive proper education on their use. Finally, Dr. Escaño underscored the confusion caused by the 40+ biosimilar insulins that are available or will soon be available in the Latin American markets, ranging from options from relatively established manufacturers like Lilly (biosimilar insulin glargine Basaglar) to those from various relatively small Indian manufacturers, etc. Dr. Escaño shared that, in his experience, primary care and other unspecialized doctors are especially bewildered by the sheer number of biosimilar insulins that are or will soon be available. Given the even greater proliferation of biosimilar insulins in Latin American countries (due to less strict regulatory requirements compared to the US), it’s arguably even more important to offer clear education and guidelines on the use of these products for physicians in these countries – see our coverage of Dr. Guillermo Gálvez opposing viewpoint on the use of biosimilars above for more.
Fernando Javier Lavalle Gonzalez, MD (Autonomous University of Nuevo León, Nuevo Leon, Mexico)
Dr. Fernando Javier Lavalle Gonzalez discussed the role of TZD pioglitazone in the diabetes armamentarium, particularly suggesting that it may be useful in younger patients. To support his point, Dr. Gonzalez pointed to data on the impact of TZDs on insulin sensitivity and beta cell function. He also noted that in studies, TZDs including pioglitazone have shown the greatest durability of effect over a number of years. Further, pioglitazone likely boasts cardioprotective benefits, based on the PROACTIVE and IRIS studies. Thus, given that younger patients with type 2 diabetes will likely need long-term treatment over many, many years, he suggested that the combination of insulin sensitizing, durability of effect, and cardioprotection could make pioglitazone a particularly good option. Of course, pioglitazone and TZDs in general are associated a several significant downsides as well, including increased risk of heart failure and bone fractures. We hope that these adverse effects can be mitigated with careful dosing and monitoring, however, given the significant upside that has emerged for this agent, not to mention its low-cost generic status.
Isaac Sinay, MD (Instituto Cardiovascular de Buenos Aires, Buenos Aires, Argentina)
Dr. Isaac Sinay provided an overview of the cardiovascular data for SGLT-2 inhibitors to date, from the EMPA-REG OUTCOME trial of Lilly/BI’s Jardiance (empagliflozin) and from meta-analyses of the class as a whole. Ultimately, he concluded that the evidence to date supports use of SGLT-2 inhibitors in patients with diabetes and cardiovascular disease. That said, he emphasized that the level of evidence is a modest Level B and only supports a “reasonable indication” (Class 2a), as it’s on the basis of only a single prospective, randomized, controlled trial. In order to support a recommendation (Class 1) for their use with a high level of evidence (Level A), the additional ongoing CVOTs for the class will need to support the conclusions of EMPA-REG OUTCOME.
Combination Therapy in Diabetes
Debate: Initial Combination Therapy in Type 2 Diabetes
Philip Home, DM, DPhil (Newcastle University, Newcastle Upon Tyne, UK) & Ralph DeFronzo, MD (University of Texas Health Science Center, San Antonio, TX)
This very lively debate session pitted two very notable speakers, Professor Philip Home and Dr. Ralph DeFronzo, against one another on the issue of combination therapy as an initial therapy for newly-onset type 2 diabetes.
- Professor Home noted the clear superiority of eventually moving to a combination approach that targets multiple mechanisms in the pathophysiology of diabetes, but stressed that this is not his preferred methodology for initial therapy. “If you want to start with initial combination therapy, you are outside of most major clinical guidelines,” Professor Home argued, “Do you wish to practice otherwise than the suggested global expertise?” Indeed, most major diabetes algorithms – from the ADA, EASD, Canadian Diabetes Association, ALAD (Latin American Diabetes Association), and IDF, to name a few – recommend initial monotherapy. Professor Home advised that this is good practice because of the clinical principle of exposing patients to as few therapies and interventions as it is necessary to achieve good health targets, noting the side effect and cost burden of multiple medications in cases when “one would do the job.”
- Unsurprisingly, Dr. Ralph DeFronzo followed with a vehement defense of initial combination therapy, noting at the start of his talk that his rationale for this comes from clinical evidence and not blind reliance on guidelines, which over the passage of time are often revealed to be incorrect. He characterized the current paradigm as a “treat to fail” approach, whereby therapy is intensified only after patients inevitably fail to reach target on initial monotherapy, therefore creating many years of undue glycemic burden – exacerbating beta cell loss and increasing the risk of developing diabetes complications. Dr. DeFronzo made a compelling case for treating the pathophysiological basis of diabetes through “the DeFronzo method,” a triple combination of diabetes drugs (metformin, TZD pioglitazone, and twice-daily GLP-1 agonist exenatide) that together target the “ominous octet” with the primary goal of preserving beta cell function. He drew upon interim three-year data – first presented at EASD 2015 – from a trial evaluating his signature triple therapy (metformin+pioglitazone+exenatide) vs. conventional therapy (metformin followed by sequential addition of glipizide and insulin glargine) in drug-naïve patients with newly diagnosed type 2 diabetes (n=155, baseline A1c=8.6%). The average A1c at 36 months was 6.7% in the conventional group and a striking 5.8% in the triple therapy group (p<0.0001). Additionally, triple therapy led to a 3.1 kg weight loss (vs. a 3.7 kg weight gain with the conventional approach) and significant improvements in insulin sensitivity and beta cell function. In terms of adverse events, rates of edema and GI side effects were higher with triple therapy, but hypoglycemia was significantly lower. We’ve been duly impressed with these results for some time now and we look forward to the full publication of these results. We certainly hope this study will continue to spark a broader conversation about the current approach to type 2 diabetes treatment, as it certainly challenges the existing guidelines. Any paradigm shift toward early, aggressive combination therapy would require buy-in from payers to support patients in access to multiple drugs – an uphill battle as current coverage policies heavily favor the typical approach of monotherapy followed by combinations. That said, if future follow-on studies confirm Dr. DeFronzo’s findings on the superiority of an initial combination therapy approach, perhaps an update to the treatment guidelines is in order. Whether it is by Dr. DeFronzo’s triple therapy approach of another strategy, we would surely like to see an improvement in the level of care the typical patient receives upon initial diagnosis.
Debate: GLP-1 Agonist vs. Prandial Insulin After Basal
Ralph DeFronzo, MD (University of Texas Health Science Center, San Antonio, TX) & María del Rosario Archevaleta Granell, MD (Universidad Autónoma de Guadalajara, Guadalajara, Mexico)
Without leaving his place at the podium, Dr. Ralph DeFronzo returned for a second debate, this time centered on the merits of GLP-1 agonists versus prandial insulin as an add-on to intensify basal insulin therapy. Unsurprisingly, given Dr. DeFronzo’s famed triple therapy of metformin/pioglitazone/exenatide, he argued in favor of the GLP-1 agonists, while Dr. María del Rosario Archevaleta Granell defended prandial insulin. Dr. DeFronzo opened with a criticism of insulin’s biggest downsides – weight gain, hypoglycemia (the cause of significant morbidity, mortality, cognitive dysfunction, and reduced quality of life), and, perhaps most importantly, lack of patient friendliness. Indeed, prandial insulin therapy requires multiple injections per day, not to mention frequent glucose monitoring and the difficulty of titration and dose adjustment. GLP-1 agonists, by contrast, come in the form of a once-daily or once-weekly injection and are free from the risk of hypoglycemia. Furthermore, they promote a multitude of beneficial effects that insulin does not: weight loss, decreased blood pressure and fasting plasma triglycerides, decreased insulin resistance, reduction in the risk of cardiovascular death (at least for liraglutide and semaglutide), and, most notably for Dr. DeFronzo, preserving beta cell function and thereby correcting the basic pathophysiological defects of diabetes. He concluded his presentation with a rhetorical question: why would you opt for a drug (insulin) that causes hypoglycemia and weight gain, does nothing to correct the basic pathophysiological defects of diabetes, and usually fails to achieve the desired level of glycemic control due to lack of user friendliness? Dr. Rosario Archevaleta countered with an acknowledgement that a GLP-1 agonist would be her preferred choice of therapy in an ideal world, but in reality uses prandial insulin because it is vastly more affordable – particularly in her home country of Mexico, where GLP-1 agonists are even less accessible than they are in the United States. Earlier in the debate Dr. DeFronzo anticipated the cost argument for prandial insulin by saying “better alive than dead” – that is, even if GLP-1 agonists are expensive they can be lifesaving. Dr. Rosario Archevaleta responded to this directly, ending her presentation on a provocative note: “better alive than dead, but you also need a roof over your head.” This is a difficult issue – we continue to hope for a future where each patient can receive what is truly the optimal therapy in purely clinical terms, but as things currently stand (especially in developing countries), cost remains the primary driver of therapy choice. That is too bad given the much higher costs downstream of macrovascular and microvascular complications.
- According to Dr. DeFronzo’s calculations, the cost of insulin therapy is actually greater than or equal to the cost of GLP-1 agonists when considered holistically. He noted that – at least in the United States – insulin is as expensive as a GLP-1 agonist when also accounting for the cost of insulin test strips, and a single overnight hospital visit for insulin-induced hypoglycemia could pay for several years of GLP-1 agonist therapy. We would be curious to know whether this is also the case elsewhere around the world. If cost, as Dr. Rosario Archevaleta suggested, is truly the only reason clinicians consider choosing insulin over GLP-1 agonists, these hidden insulin-related expenses need more attention and we hope data on this might compel health systems to reimburse safer medications that may cost more upfront but are less likely to induce severe hypoglycemia.
Bariatric and Metabolic Surgery 2016/2017
Only for Obese People – No
Philip Home, DM, DPhil (Newcastle University, Newcastle Upon Tyne, UK)
Professor Home argued for a cardiovascular risk and complications-centric model in the consideration of metabolic surgery for individual patients. He emphasized that metabolic surgery is not a cosmetic procedure; it has been demonstrated to produce “dramatic” improvements on metabolic co-morbidities such as reduction of fatty liver and remission of diabetes. He also pointed out that those with diabetes and fatty liver face a substantially elevated risk for cardiovascular disease and thus, if metabolic surgery is able to improve the prognosis for these two conditions, it should be viewed as a tool to reduce cardiovascular risk. He further noted that many people with type 2 diabetes and fatty liver do not have obesity by the widely accepted standard of BMI ≥30, such as many Asian patients. Further, patients with BMI <35 (a commonly accepted BMI-based threshold for metabolic surgery) respond just as well to metabolic surgery as those with BMI ≥35. Thus, these patients could still stand to substantially benefit from metabolic surgery, but they might not meet BMI-centric criteria for the surgery. As an alternative to BMI-based recommendations for metabolic surgery, Professor Home expressed support for the complications-based model codified at WCITT2D in 2015 and adopted by the ADA and many other professional societies. We certainly agree that BMI by itself is insufficient to recommend metabolic surgery and are glad to see continued global standardization of guidelines on metabolic surgery. Of course, the “holy grail” so to speak would be medications or devices that can mimic the effects of bariatric surgery in a less invasive manner – Fractyl is working on such a concept for type 2 diabetes and fatty liver disease and there is a robust NAFLD/NASH competitive landscape, though no pharmacotherapies are currently indicated for this area of very high unmet need.
Modern Aspects of Pharmacotherapy for Obesity
Luc Van Gaal, MD (Antwerp University Hospital, Antwerp, Belgium)
Dr. Luc Van Gaal provided a thorough overview of the pharmacological treatment of obesity, surmising that this comes down to “giving the right drug to the right patient at the right moment by the right HCP.” Dr. Van Gaal reviewed the clinical data for the major obesity drugs, noting that, despite different biological targets, each drug’s efficacy plateaus at ~8%-10% weight loss. Of course, even 5% weight loss can produce enormous benefits (improvements in adipose tissue, liver and muscle insulin sensitivity, and beta cell function, translating to a significant reduction in type 2 diabetes and heart disease risk and significant improvements in quality of life), but many patients and providers seeking to treat obesity via medical means would like to see weight loss greater than the 10% that current drugs can provide. Circumventing this apparent clinical impasse, according to Dr. Van Gaal, comes down to the notion of prescribing obesity drugs “at the right moment.” He recommends encouraging patients to undertake a very low calorie diet and a behavior modification program to achieve the maximum possible amount of lifestyle-induced weight loss (approximately 7%) first, before adding an obesity drug to induce an extra push. In his experience this method typically produces 12%-14% weight loss, significantly better than the 8%-10% weight loss expected with the simultaneous initiation of drugs and behavior modification. Nevertheless, for patients trying to lose even more significant amounts of weight, pharmacotherapy remains insufficient. For this reason, Dr. Van Gaal concluded with a look to the future of obesity pharmacology, which he characterized as a “search to break the 10% weight loss target.” In monotherapy he anticipates the development of oxyntomodulin (GLP-1/glucagon dual agonists), PYY analogs, and implantable and/or oral semaglutide. The real future of obesity pharmacotherapy, however, will likely be a combination approach that targets multiple mechanisms in obesity’s pathophysiology. The obesity drug competitive landscape includes several novel drug classes, (including MC4R agonists, MetAP2 inhibitors, PYY, and long-acting amylin analogues to name a few) and Dr. Van Gaal forecasted the eventual development of dual therapies such as the combination of GLP-1 agonists with MC4R agonists, amylin, PYY, and glucagon, and even triple therapy of GLP-1/GIP/glucagon – Dr. Richard DiMarchi has done tremendous work on this front and we expect to see more on this in the future now that Dr. DiMarchi is backed by the resources of Novo Nordisk (not to mention Novo Nordisk’s clear commitment to expanding the obesity market). This is a future we very much look forward to, especially given the scarcity of options in obesity care and the stigma surrounding this challenging disease. Of course, the obesity market outside Novo Nordisk’s Saxenda is still struggling and we continue to believe that tremendous room for great patient and provider education about obesity as a disease exists and that this groundwork must be laid in order to encourage acceptance and uptake of obesity pharmacotherapies.
Ricardo Cohen, MD (Hospital Oswaldo Cruz, São Paulo, Brazil)
Dr. Ricardo Cohen closed this obesity-focused session with a discussion of the merits of bariatric surgery as a treatment for obesity and comorbid type 2 diabetes. Aware of his status as perhaps the only surgeon in attendance at CODHy, he prefaced his presentation by stating that instead of posing medical versus surgical approaches to obesity care against each other we should view the two as companion rather than competing options in the care of this difficult disease. Dr. Cohen’s core argument was that obesity should be treated using the “cancer model” – that is, care from an interdisciplinary team and continued follow-up to support patients through potential relapsing and remitting. Bariatric surgery, according to Dr. Cohen is one facet of this multidisciplinary care model – alongside medication, nutrition counseling, and lifestyle modification programs. Bariatric surgery is an invasive and often costly measure, and certainly not something to be undertaken without an awareness of the lifelong management it requires. That said, for patients who have struggled to lose weight with diet, exercise, and pharmacotherapy alone, bariatric surgery can have dramatic benefits. According to the Swedish Obese Subjects (SOS) study, bariatric surgery produced improvements in (i) all-cause mortality; (ii) reduced CV events (both fatal and non-fatal); (iii) cancer mortality; and (iv) microvascular complications over a 10 year follow-up. Furthermore, the STAMPEDE study (three year results published in March 2014; five year results presented at ACC in April 2016) compellingly demonstrated that gastric bypass and sleeve procedures were more effective than medical treatment of diabetes in managing A1c and BMI, including BMIs under 35 kg/m2. We continue to view bariatric surgery with cautious optimism. As Dr. Cohen convincingly demonstrated, it is certainly effective for obesity and diabetes management over the short term, but we remain curious to learn more about the long-term durability of these effects, as well as the scalability of surgery as a population level solution to the growing obesity epidemic.
Prevention of Type 2 Diabetes
Prevention of Type 2 Diabetes: Did We Fail?
Noël Barengo, MD, PhD (Florida International University, Miami, FL)
Esteemed prevention expert Dr. Noël Barengo provided an overview of successes in worldwide diabetes prevention efforts. He began with a description of the two dominant philosophies on prevention: the population approach, aimed at lowering the disease risk of the population as a whole, and the high-risk approach, which targets resources toward identifying and treating individuals at high risk of disease. Dr. Barengo pointed to Finland and Cameroon as the “current state of the art” in terms of population-level strategies; these are the only countries with large scale, nationally-sponsored diabetes prevention programs – FIN-D2D and the Cameroon National Diabetes Prevention Program, respectively. A Fin himself, Dr. Barengo took a deep dive on Finland’s program, which involves a combination of public awareness campaigns, frequent diabetes risk screenings, and wide availability of behavior change programs for at-risk individuals (in Finland, these are based on the framework of Dr. Jaakko Tuomilehto’s Finnish Diabetes Prevention Study (FIN DPS), which demonstrated a 58% reduction in diabetes risk with intensive lifestyle intervention). Dr. Barengo noted that Finland is now one of the few countries in which obesity and type 2 diabetes rates are leveling and even decreasing, and the growing media coverage of the burden of diabetes and obesity has made this a core issue on the Finnish political agenda. Although it is impossible to attribute these improvements exclusively to the FIN-D2D program, it certainly speaks to the potency of a population-wide approach to prevention. On the high-risk prevention strategy front, Dr. Barengo pointed to the success – and, importantly cost-effectiveness – of the United States’ DPP (now reimbursed by Medicaid!) and its Australian counterpart, the Greater Green Triangle DPP. Given these examples of success, Dr. Barengo concluded that “the question in prevention is not ‘what’ but ‘how’.” That is, we know what kinds of measures can effectively prevent diabetes at the population level and high-risk level alike – the issue is how to scale these more widely. This is certainly an uphill battle. For more on the pioneering work ongoing in diabetes prevention, see our coverage of WCPD 2016, the World Congress on the Prevention of Diabetes and its Complications.
Corporate Symposium: Are SGLT-2 Inhibitors the Key to the Future? (Sponsored by AZ)
Too Big to Fail: The Critical Intersection of Type 2 Diabetes, Heart Failure, and CKD
Mikhail Kosiborod, MD (University of Missouri School of Medicine, Kansas City, MO)
Dr. Mikhail Kosiborod advocated for “CV risk centric” approach to diabetes treatment, rather than the current A1c-centric approach. He pointed out the correlation between type 2 diabetes, heart failure, and diabetic nephropathy, noting that the outcomes for patients with more of these comorbidities are proportionally worse. Thus, he suggested that a drug that can treat diabetes while simultaneously improving heart failure and chronic kidney disease would be the “holy grail.” In his view, SGLT-2 inhibitors could potentially achieve this triple aim, based on data from the EMPA-REG OUTCOME trial for Lilly/BI’s Jardiance (empagliflozin) that found a cardio- and renal-protective benefit for the therapy. While the results were certainly impressive, Dr. Kosiborod acknowledged that several answered questions remain, including (i) are the results applicable to real-world practice?; (ii) are the observed benefits specific to empagliflozin or do they represent a class effect?; and (iii) can similar benefits be expected in a broader type 2 diabetes population that does not necessarily already have established cardiovascular disease? He suggested that the CVD-REAL observational study could indicate potential answers – full results from the analysis were presented at ACC 2017 three days later and found that, based on the medical records of more than 300,000 participants, SGLT-2 inhibitor therapy (~93% on dapagliflozin or canagliflozin) reduced the risk of hospitalization for heart failure by 39% (p<0.001) and reduced the risk of all-cause mortality by 51% (p<0.001). While these results are certainly promising, we won’t have a more definitive answer to whether or not EMPA-REG OUTCOME is a class effect until CANVAS for canagliflozin reports at ADA 2017 and DECLARE for dapagliflozin reports in 2019 – we can’t wait!
- Dr. Kosiborod proposed a type 2 diabetes treatment approach focused on targeting therapies to the stage within the spectrum of cardiovascular disease that the therapy is most likely to benefit. The spectrum is as follows:
- CVD risk factors only – Treat with GLP-1 agonists, metformin and possibly SGLT-2 inhibitors
- Established CVD – Treat with GLP-1 agonists, metformin and SGLT-2 inhibitors
- History of MI/stroke – Treat with GLP-1 agonists, metformin, and SGLT-2 inhibitors
- Recent acute coronary syndrome – Treat with SGLT-2 inhibitors or possibly GLP-1 agonist or metformin
- Recent stroke – Treat with TZD pioglitazone
- Asymptomatic left ventricular dysfunction – Not adequately studied
- History of heart failure – Treat with SGLT-2 inhibitors
- Symptomatic heart failure or hospitalization for heart failure – Not adequately studied
- End stage heart failure – Not adequately studied
Corporate Symposium: Glargine 300 U/ml (Sponsored by Sanofi)
New Generation Ultra-Long Acting Insulins; EDITION Program and Real World Data
León Litwak, MD (Hospital Italiano de Buenos Aires, Argentina), Félix Puchulu, MD (Santa Maria de la Salud, Buenos Aires, Argentina), and Ariel Zisman, MD (Endocrine Center Aventura, FL)
In this Sanofi-sponsored lunch symposium, Drs. León Litwak, Félix Puchulu, and Ariel Zisman made the case for why providers should prescribe Toujeo (U300 insulin glargine) for basal insulin therapy. The speakers took turns presenting – in a mixture of both Spanish and English! – on Toujeo’s pharmacology, clinical data, and administration before walking through different case studies to demonstrate how to dose for a wide range of patients, from newly-diagnosed LADA patients who are insulin-naïve to longstanding type 2 diabetes patients already on basal-bolus therapy. Notable features of Toujeo that were emphasized again and again included its impressively long and flat action profile and convenient flexible dosing (+/- three hours – though of course Novo Nordisk’s Tresiba [insulin degludec] offers even more flexible dosing with the ability to take a missed dose at any time as long as it’s at least eight hours before the next dose). Furthermore, as demonstrated in the EDITION phase 3 trial comparing Toujeo and its first-generation counterpart Lantus (insulin glargine), Toujeo has equal efficacy in reducing A1c, but carries less risk of nocturnal hypoglycemia and less weight gain. Dr. Puchulu noted that Toujeo truly meets a higher bar than the insulins available in past eras of diabetes care; we got the sense that Toujeo fits better into patients’ lives – rather than patients having to fit their lives around the insulin, which they sometimes won’t do.
-- by Abigail Dove, Helen Gao, and Kelly Close