IDF (International Diabetes Federation) Congress

December 4-8, 2017; Abu Dhabi, UAE; Day #1 Highlights – Draft

Executive Highlights

Greetings from Gulf Standard Time! We thought the 12-hour time change from San Francisco might be tough, but we quickly forgot about jet lag once IDF sessions were underway. Day #1 featured lots of learning on the burden of heart failure in diabetes from University of Toronto’s Dr. Subodh Verma, on strategies to encourage insulin initiation from the great Dr. Bill Polonsky, and on caveats in interpreting CVOT data from University of Washington’s Dr. Steven Kahn. All of these leaders are incredibly respected and we’ve loved the learning so far. We also loved the engaging, informative audience polls: ~85% of audience members for Dr. Francesco Giorgino’s presentation on overcoming clinical inertia with GLP-1 agonists endorsed “adding an injectable therapy on top of oral diabetes drugs” as the peak challenge in treatment intensification. What did this same audience say is their primary consideration in selecting a GLP-1 agonist from the class? Scroll down to highlight #5 to find out : >. And while you’re scrolling, you’ll find our key takeaways from day #1 of IDF 2017.

This meeting is off to a fantastic start already, and we can’t wait for what’s to come. Read our conference preview here for a sneak peek at days #2-#5. Today in particular should be quite something, with the experts talking about drug synergy, particularly between GLP-1 agonists and DPP-4 inhibitors and SGLT-2 inhibitors. There’ll also be updates on the number of type 1s in the world (always a topic of controversy) and brand-new estimates and multiple talks on digital health. Very interesting also will be a debate on whether SGLT-2s should be first-line therapy!

Top Six Highlights

1. Heart Failure as the Elephant in the Room – a CV Outcome Too Long Overlooked in Diabetes Care; Dr. Verma Highlights Heart Failure Benefit of SGLT-2 Inhibitors, Discusses Potential for SGLT-2 Agents as First-Line

If there was any doubt that heart failure imposes a huge burden for people with diabetes, University of Toronto cardiologist Dr. Subodh Verma set the record straight. In fact, he advocated for much more focus on non-ischemic CV events from the diabetes field. He displayed graphs showing how rates of atherosclerotic CV events, namely MI (heart attacks) and stroke, have actually declined somewhat in the past 20 years for even the diabetes patient population. Meanwhile, heart failure has been contributing more to CV mortality among people with diabetes. In another study, heart failure was found to be the most common CV complication associated with diabetes, and Dr. Verma emphasized that it was also the most “disabling” and “deadly” – not only is the frequency of heart failure elevated for the diabetes patient population, but the prognosis is poor. The takeaway from this data, as Dr. Verma put it, is that both ischemic and non-ischemic CV events are a challenge in diabetes care: he showed near-equivalent prevalence of heart failure and ischemic complications. Despite recent gains in cardioprotective therapy (Dr. Verma specifically mentioned better anti-platelet agents and better stents), people with diabetes still face high residual risk for stroke/MI compared to the background population, and we’re certainly not done optimizing anti-atherosclerotic treatment for diabetes patients. But Dr. Verma referred to heart failure as “the elephant in the room,” too long ignored as an important CV outcome in the context of diabetes. He suggested that the field has been “fixated” on ischemia, and that this has largely overshadowed heart failure. Indeed, there’s nothing in the FDA’s 2008 CVOT guidance that stipulates heart failure should be investigated, and the most common primary endpoint in diabetes CVOTs completed so far has been atherosclerosis-oriented three-point MACE (non-fatal MI, non-fatal stroke, and CV death). We’ve heard arguments from many thought leaders recently that heart failure should be a primary endpoint in diabetes CVOTs (Dr. Jens Øllgaard at EASD 2017, who pointed out the irony of heart failure being left out of the FDA guidance, Drs. Bertram Pitt and John McMurray at AHA 2017, among others), and DECLARE (for AZ’s SGLT-2 inhibitor dapagliflozin) will be the first. This commentary is certainly valuable in increasing awareness of the diabetes/heart failure overlap (which is clearly necessary, given how the heart failure burden persists), and we’re pleased to see this education happening from day #1 at IDF.

  • Dr. Verma elaborated that there’s a high rate of subclinical heart failure in diabetes patients. Compared to atherosclerosis, diastolic dysfunction appears earlier on in the course of disease progression. He outlined the mechanistic underpinnings: heart failure arises in diabetes due to the direct effects of glucotoxicity and insulin resistance on the myocardium, leading to diabetic cardiomyopathy. According to Dr. Verma, this timeline occurs much earlier than the timeline of atherosclerosis in diabetes, and it occurs independently from coronary disease. In a study like CANVAS (CVOT for J&J’s SGLT-2 inhibitor canagliflozin), even people in the primary prevention cohort may have had underlying diastolic dysfunction. “We call them primary vs. secondary prevention, but that’s from an atherosclerotic point of view,” Dr. Verma explained. To this end, he highlighted a recent post-hoc analysis of CANVAS presented at AHA, which found that canagliflozin’s beneficial effects on heart failure hospitalization appeared in both primary and secondary prevention subgroups. The hazard ratio for this endpoint was 0.68 in the secondary prevention cohort (95% CI: 0.51-0.90) vs. 0.64 in the primary prevention cohort (95% CI: 0.35-1.15). In contrast, the primary prevention subgroup did not experience significant benefit with canagliflozin on three-point MACE (HR=0.98, 95% CI: 0.74-1.30). Dr. Verma described how people labeled “primary prevention” weren’t truly primary prevention for heart failure. He reminded the audience that these participants weren’t newly-diagnosed, as they had long duration of diabetes, and this often implies the development of diastolic dysfunction even in the absence of overt atherosclerotic disease.
  • During the ensuing panel discussion, Dr. Verma asked “why not?” in considering SGLT-2 agents as first-line treatment for type 2 diabetes, with the caveat that as a cardiologist he’s more accustomed to seeing patients with longer duration of diabetes. Even if this class doesn’t show cardioprotection in a primary prevention population, he suggested that the weight loss, lack of hypoglycemia, and hope for CV benefit should be enough to introduce an SGLT-2 inhibitor into a patient’s medication regimen early on. Once again, he called attention to the recent CANVAS post-hoc, showing canagliflozin’s significant and meaningful risk reduction for heart failure hospitalization regardless of a patient’s history of stroke/MI. The implication here is exciting – if heart failure appears earlier in the course of diabetes development, before atherosclerosis and ischemic events, a pill that counteracts this elevated risk for people with recent-onset diabetes would be tremendous. From this standpoint, SGLT-2 inhibitors as first-line products seems like a no-brainer to us as well, but we await a debate on this topic scheduled for Tuesday at IDF for in-depth arguments and counter-arguments.
  • Another key focus of Dr. Verma’s remarks was the tight link between heart failure and renal disease. On one memorable slide, he showed how type 2 diabetes in the absence of kidney disease increases 10-year mortality rate by ~4%. Add albuminuria to diabetes, and this 10-year mortality rate rises ~18%. Add impaired eGFR, and the rate grows to ~24%. With type 2 diabetes, albuminuria, and impaired eGFR, the 10-year morality rate is 47% higher vs. the background population, and is nearly 10x that of people with diabetes but without kidney disease. Moreover, Dr. Verma underscored how heart failure increases risk for renal disease, which in turn worsens prognosis for heart failure events. He established the importance of preventing both these complications in approaches to diabetes management. Interestingly, the same CANVAS post-hoc analysis from AHA found similar risk reduction with canagliflozin for the composite renal outcome as well in both primary and secondary prevention cohorts: The hazard ratio was 0.59 in the secondary prevention subgroup (95% CI: 0.44-0.79) and was 0.63 in the primary prevention subgroup (95% CI: 0.39-1.02), compared to a 40% relative risk reduction across the entire study population (HR=0.60, 95% CI: 0.47-0.77).
  • Dr. Verma summarized key details on the ongoing clinical trials of SGLT-2 inhibitors in heart failure and in CKD: EMPEROR HF-Preserved and EMPEROR HF-Reduced for Lilly/BI’s Jardiance (empagliflozin) in heart failure, Dapa-HF for AZ’s Farxiga (dapagliflozin) in heart failure, CREDENCE for J&J’s Invokana (canagliflozin) in diabetic kidney disease, Dapa-CKD for Farxiga in CKD (participants with and without diabetes), and a planned outcomes study of Jardiance in CKD (~5,000 participants with and without diabetes). We highly-recommend a recent JAMA viewpoint authored by Dr. Verma, Dr. John McMurray, and Dr. David Cherney on SGLT-2 inhibitors as a possible “sweet spot” in heart failure management.
  • Dr. Verma ended his pre-conference presentation with a powerful quote, calling on cardiologists to adopt cardioprotective diabetes therapies like SGLT-2 inhibitor empagliflozin (Lilly/BI’s Jardiance) into their clinical practice: “EMPA-REG OUTCOME reminds me of the 4S study, when we cardiologists were forced to begin understanding that statins now had to be part of our toolbox. We cannot be laggards when it comes to empagliflozin – not too much that we do today can reduce CV mortality by 38%.”

2. Dr. Kahn Illuminates Key Differences Between Diabetes CVOTs, Warns Against Over-Comparison, Highlights Need for Standardization in CVOT Design/More Head-to-Head Outcomes Data

In reviewing the current state of the field on diabetes CVOTs, the very highly regarded Dr. Steven Kahn (University of Washington, Seattle, WA) elucidated fundamental differences between trials – in study design, baseline population, etc. – affirming our strong sense that there’s a lack of standardization around CVOT design, making it difficult (or, pretty much impossible) to compare among studies and come to strong conclusions. In considering the two SGLT-2 inhibitor CVOTs that have reported full results so far, Dr. Kahn pointed out that CANVAS (for J&J’s canagliflozin) enrolled only 66% of patients with established CV disease, while 99% of participants in EMPA-REG OUTCOME (for Lilly/BI’s empagliflozin) started the trial with a history of CV events. Jardiance (empagliflozin) gave a 14% relative risk reduction in three-point MACE (non-fatal MI, non-fatal stroke, or CV death) but Dr. Kahn underscored that only the 38% relative risk reduction in CV death was significant on its own – and only this component of MACE was included on the updated Jardiance label. Non-fatal MI trended in favor of empagliflozin in EMPA-REG OUTCOME, while non-fatal stroke trended in favor of placebo (again, neither of these effects reached statistical significance). In CANVAS, Invokana (canagliflozin) showed a similar 14% risk reduction in three-point MACE, but no component was significant on its own, though all trended in favor of the SGLT-2 inhibitor. Dr. Kahn posited that these varying results could be due to differences in population: More patients in CANVAS had no prior CV events, possibly contributing to a significant reduction in three-point MACE without any component on its own being significant (i.e. with a larger primary prevention cohort, we might expect a lower event rate for CV death and thus less statistical power to show superiority on this component endpoint relative to EMPA-REG). Turning to the GLP-1 agonist CVOTs, Dr. Kahn summarized the positive findings from LEADER (for Novo Nordisk’s liraglutide) and SUSTAIN 6 (for Novo Nordisk’s semaglutide) vs. the neutral findings from EXSCEL (though AZ’s Bydureon only narrowly missed the threshold for superiority) and ELIXA (for Sanofi’s lixisenatide). The differences in trial design and protocol between EXSCEL and LEADER are notable, with a larger primary prevention cohort (27% vs. 19% in LEADER), no run-in period to exclude individuals with low medication adherence, a wide range of concomitant medications allowed (including DPP-4 inhibitors, which were prohibited in LEADER), etc. Dr. Kahn pointed to another notable incongruity between LEADER and SUSTAIN 6: While liraglutide’s MACE benefit was driven by a 22% risk reduction for CV death (other components were not significant), semaglutide’s most impressive CV benefit was a 39% risk reduction for non-fatal stroke. Dr. Kahn didn’t provide an explicit hypothesis to explain this divergence of findings, but we note that SUSTAIN 6 was a small, pre-market trial (n=3,297 vs. 9,340 in LEADER), which introduces more room for chance. Dr. Kahn warned against over-comparison between diabetes CVOTs, even those investigating agents in the same class, and we continue to believe that real clinical pearls would come from one large head-to-head CVOT that compares all drugs, within-class and between-class. As we push toward personalized medicine in diabetes, HCPs need actionable insights on which therapy to match to which patient, and to this end, we need more head-to-head evaluations if not more standardization of CVOT design.

  • With a nod to the future, Dr. Kahn expressed excitement for the CARMELINA and CAROLINA, PIONEER 6, and CREDENCE trials. CAROLINA, in particular, could lay to rest the debate over the impact of sulfonylureas on CV events, as this Lilly/BI-sponsored CVOT compares DPP-4 inhibitor Tradjenta (linagliptin) head-to-head vs. glimepiride. While we wouldn’t hope any participants experience CV harm, we do see value in this study for potentially pushing SUs out of treatment algorithms – that said, we also strongly believe the “real-world” experience of SU’s vs. a RCT experience will be different. As a reminder, SU’s have been associated with hypoglycemia, weight gain, beta cell burnout over the long term, and possible CV harm. All this is true even though they remain the most common second-line diabetes prescription in the US due to their low cost. CAROLINA could finally provide the concrete evidence that regulators, payers, and guideline-writers need to see in order to de-prioritize this class; actually, we’d love to see it fall out of use entirely. While many say that is impossible given cost, we’d love a more robust view on the cost front to examine short- and long-term costs associated with SU use.

3. Dr. Bill Polonsky: Top Three Effective Strategies to Encourage Insulin Initiation/Continuation

UCSD’s Dr. Bill Polonsky shared major takeaways from the EMOTION study, namely that demonstrating the injection process, explaining the benefits of insulin, and adopting a collaborative communication style are the most effective strategies for getting patients to start and continue on insulin therapy. The EMOTION study (about which we will hear much more this IDF) features a 37-question survey asking 594 geographically diverse type 2s who recently started taking insulin after initial reluctance what convinced them to eventually take the plunge. The results were not surprising, but as Dr. Polonsky pointed out, these are the first ever studies dissecting the factors – bright spots – that help people to start taking insulin. Participants rated providers demonstrating the injection process a 3.07/4 in terms of helpfulness, explaining insulin benefits a 2.97/4, and having a collaborative style a 2.77/4. Dispelling insulin myths (2.77/4), and interestingly, an “authoritarian style” (2.63/4), were also highly rated. Encouragingly, the top three highly-rated actions were also the most commonly observed. Digging a little deeper, demonstrating the injection process was the only action referred to in the survey that was useful in the initiation of insulin, while explaining the benefits of insulin and a collaborative style were more beneficial in preventing the discontinuation of insulin use. A recently-published paper by Dr. Polonsky et al. goes in depth on the question of how to start and maintain insulin therapy, emphasizing that it’s a continual process of proactive follow-up to re-encourage the patient, review injection technique, review the logbook and titrate dose as necessary, and address questions and concerns. Above all, Dr. Polonsky stressed that as busy as “we” (providers) are, it’s always important to take time to be a good listener. The perils of clinical inertia and then maintaining an insulin regimen are all too well documented, so we are very happy to see Dr. Polonsky, UCSF’s Dr. Lawrence Fisher, and others look for what is working. How great would it be if insulin manufacturers began including these tips, and others as they are plucked from the EMOTION results, in supplementary materials targeted at providers? Higher sales volume for pharma, better outcomes for patients, and physicians who are and feel more successful – a winning combination!

  • Dr. Polonsky poignantly reminded the audience, to a sea of nods, that people act rationally given their beliefs. In this framework, proper education is one of the best weapons against resistance to starting insulin. “Everyone with diabetes is educated about their diabetes – it just happens that many are mis-educated.” Countless people are under the impression that once they start insulin they won’t be able to stop, insulin therapy will restrict their lives, that they are failures, etc. On the more extreme side, reluctant patients in one study were >2x more likely to believe that insulin can cause blindness. Dr. Polonsky commented that such sentiments are often accompanied by a story – e.g., they know someone who had type 2 diabetes for 30 years without healthcare intervention and without an issue, and then went to a doctor, started on insulin, and developed complications of the feet, kidneys, and eyes. Without proper education, it isn’t too far a leap to surmise that insulin caused these complications. Correcting these misconceptions in a gentle way can go a long way. The devil is in the details from our view; while few would disagree, how can HCPs be systematically trained to address this problem?

4. Changing the Definition of Severe Hypoglycemia to Boost Insulin Initiation/Continuation?; Hypoglycemia During Ramadan

Dubai Hospital’s Dr. Mohamed Hassanein endorsed the International Hypoglycemia Study Group’s glucose level-independent definition of severe hypoglycemia, implying that widely implementing such a definition may attenuate fear of starting/continuing insulin because of hypoglycemia concerns. To support this point, Dr. Hassanein showed un-published data; a six-month retrospective + four-week prospective study of the rates of self-reported severe hypoglycemia and hospitalization in thousands of insulin users at 300 sites in nine countries. As seen in the figure below, across all data sets (type 1, type 2, retrospective, prospective), only ~3%-19% of severe hypoglycemia cases resulted in hospitalization. In other words, being told that they had three severe hypoglycemia episodes in the last week – despite no hospitalizations – may cause patients to experience excessive distress and a desire to discontinue insulin. On the other hand, if glucose levels less than 70 mg/dl are referred to as “alert” or “level 1” hypoglycemia, and levels less than 54 mg/dl are referred to as “clinically important” or “level 2” hypoglycemia (as recommended by the International Hypoglycemia Study Group), patients may not be as fearful of insulin. This idea is ripe for an RCT. We acknowledge that patients in the study may have been (a) under-hospitalized and/or (b) surrounded by very capable assisters, thus preventing hospitalization, but we can get on board with the idea of re-framing low blood glucose values in the interest of keeping patients on insulin.

  • A survey conducted by Mark Peyrot et al. found that 31% of people who stopped insulin did so because of hypoglycemia – only 48% of those who fell into this group actually reported hypoglycemia during insulin use. Fear, even of the unknown in ~50% of cases in the survey, is enough to deter people from insulin use. This underscores the tremendous need for education, blood glucose monitoring, and effective algorithms to help people dose more safely and with less anxiety.
  • The CREED study of hypoglycemia during Ramadan showed the importance of risk-stratifying based on factors such as lifestyle (religion): The study found that Ramadan-observing (fasting) individuals who experienced no episodes of hypoglycemia in a period before Ramadan (n=3,012) were very unlikely to have hypoglycemia during Ramadan (only 5% did). Contrarily, 35% of people who experienced ≥1 episode of hypoglycemia before Ramadan (n=238) had ≥1 episode during Ramadan. Prioritizing the education of people in the latter group leading up to the fasting month would clearly be a wise allocation of resources.

5. Dr. Giorgino Presents the Severe Negative Consequences of Clinical Inertia, Shows How We Might Overcome it with GLP-1 Agonists; One-Third of Audience Prioritizes CV Impact in Choosing a GLP-1 Agonist from the Class

In a Lilly-sponsored symposium, Dr. Francesco Giorgino lambasted the negative impact that clinical inertia has on patient outcomes in diabetes, using this to frame the benefits of the GLP-1 agonist class. He presented compelling data to show that a one-year delay in treatment intensification for a patient with high A1c is associated with a 67% increase in MI, a 51% increase in stroke, and a 64% increase in heart failure. Clinical inertia has also been linked to increased incidence of diabetes-related retinopathy and shorter time to progression of retinopathy. Enter GLP-1 agonists, known for their profound A1c-lowering efficacy (to reduce microvascular risk) and possible cardioprotective effects (for fewer macrovascular complications). Dr. Giorgino emphasized the agents’ broad range of biologic activity, associated weight loss, lower risk of hypoglycemia compared to insulin, and A1c-lowering efficacy at least on-par with insulin. He also discussed how GLP-1 agonists are differentiated based on administration: Lilly’s Trulicity (dulaglutide) is the only product in this class that does not require a needle to be attached (it’s part of the device), and to be sure, we’ve heard an abundance of positive patient feedback on the IDEO-designed Trulicity pen. Novo Nordisk management has shared that Ozempic (semaglutide, FDA approval anticipated by year-end) will be available in a FlexTouch only, which requires only 1-2 newtons of force to inject vs. ~15 with the FlexPen; the potential downside is that the FlexTouch is an inherently costlier device, so we’re not quite sure how Ozempic will be priced relative to Victoza – we would love to see the pricing remain consistent with Victoza even though short-term margins would go down. AZ’s Bydureon BCise autoinjector is another substantial improvement over the single-dose reconstitution kits or dual chamber pen for Bydureon, offering more patient-friendly, adherence-prone administration (the device was FDA approved in October and US launch is slated for 1Q18). We certainly see potential for more patient-friendly devices to reduce clinical inertia in diabetes care, encouraging patients/providers to try treatment intensification earlier on if there’s less overall injection burden. We continue to believe that many more patients should be taking a GLP-1 agonist – this class accounted for only 7% of second-line diabetes prescriptions in the US in 2016 – and while inertia is only one aspect of this (we can’t ignore access/reimbursement issues), more advanced, efficacious products with ease of administration could start to shift prescription habits for the better.

  • When Dr. Giorgino polled the audience on where they find it most challenging to intensify treatment, a striking ~85% voted “adding injectable to second oral anti-diabetic medication.” This underscored for us how seriously injection burden – including the impact it has on lifestyle, the discomfort patients feel, and concerns about side-effects – can impact the overall quality of diabetes management, often delaying the initiation of a drug that could greatly improve an individual’s A1c, body weight, and risk profile for microvascular and macrovascular events. While once-weekly GLP-1 formulations can reduce this burden, these aren’t always the best choice for all patients in terms of adherence (some thought leaders have suggested that once-weekly doses are harder to remember vs. once-daily doses though presumably there is technology that can help with this). Still, as far as injectable therapies go, GLP-1 agonists hold particular advantages over insulin because they offer similar glucose-lowering capacity and promote weight loss rather than weight gain, don’t increase hypoglycemia risk, and in many cases can be more flexibly-dosed. Although they are, admittedly, far less affordable as things stand, we hope to see far more investment in getting more patients onto GLP-1, particularly given the cardiovascular risk reduction benefits of Victoza and others that trend toward risk reduction.  
  • We were also struck that ~34% of the audience picked “CV prevention/safety” as the most important characteristic they consider when selecting a GLP-1 agonist. This implies that HCPs can compare CV outcomes among agents, which we do not think is possible at this stage. Efficacy edged this out with ~40% of the vote, and dosing frequency followed at a distant 13%. We were very surprised that so many providers in the room were so keen on CV risk reduction with GLP-1 agonists and very glad to see this. This paradigm shift in diabetes management, where CV risk mitigation is at the center, may be seen by some as inevitable, but we imagine it will take time and concerted effort to get this changed mindset/approach disseminated widely among all the real-world HCPs who treat diabetes. Following the addition of a first-ever GLP-1 agonist CV indication for Victoza (Novo Nordisk’s liraglutide), we’ve been watching provider uptake of this agent for reducing CV risk in patients with established CV disease. At the company’s recent Capital Markets Day, Novo Nordisk management described the “re-launch” of Victoza with its CV indication, including direct-to-consumer advertising and directed HCP campaigns. We would like to see investment in a CVOT with multiple GLP-1 agents and SGLT-2s – rather than industry sponsored, perhaps this could be investigator initiated.
  • Dr. Giorgino mentioned diabetes-related retinopathy multiple times throughout his presentation, which we found notable  in light of the safety signal for retinopathy seen in SUSTAIN 6 for Novo Nordisk’s once-weekly GLP-1 agonist semaglutide. While panelists at the recent FDA Advisory Committee meeting for semaglutide overwhelmingly felt that this risk would be manageable in the real world with screening and monitoring (suggesting that the safety concern should not hinder approval), we imagine that some patients and HCPs will exhibit some worry about GLP-1 agonists/retinopathy. It’s thus important to discuss risk mitigation strategies and protocols, even though we don’t believe the retinopathy signal holds a candle to semaglutide’s remarkable potency in glucose-lowering, weight loss, and possible cardioprotection.

6. Takeda Symposium Highlights Alogliptin/Pioglitazone Combination Therapy; Could There Be a Possible CV Benefit?

A Takeda-sponsored symposium offered a deep dive into DPP-4 inhibitor/TZD dual therapy, focusing especially on the clinical benefits of combining Takeda’s Nesina (alogliptin) with Actos (pioglitazone; now generic). Overall, we have been surprised that this combination has not done better commercially though it probably mainly reflects negative perspectives on TZDs. Dr. Guntram Schernthaner framed the logic of the DPP-4/TZD combination in terms of the “ominous octet,” noting that together, alogliptin and pioglitazone target six of the eight pathophysiological defects in type 2 diabetes, including insulin resistance. Alogliptin enhances the incretin effect in the gut and decreases pancreatic glucagon secretion, pioglitazone decreases hepatic glucagon secretion and increases muscular glucose uptake, and both agents increase pancreatic insulin secretion. Indeed, three phase 3 studies of alogliptin/pioglitazone combination therapy (as an add-on to metformin, as initial combination therapy, and as an add-on to metformin/pioglitazone therapy) all found superior glycemic efficacy with both agents vs. either monotherapy. Moreover, the combination with alogliptin also neutralizes some side-effects of pioglitazone, including bone fracture risk and elevated LDL cholesterol and triglycerides. Both DPP-4 inhibitors and TZDs have been the subject of considerable controversy when it comes to CV safety, but cardiologists on the panel assured that they don’t find these concerns especially compelling. Thought leaders seem largely worry-free on DPP-4 agents and heart failure hospitalization, although in a conservative move, FDA did recently add heart failure warnings to all DPP-4 inhibitor product labels (including Merck’s Januvia, Lilly/BI’s Tradjenta, AZ’s Onglyza, and Takeda’s Nesina). This followed a signal for heart failure hospitalizations associated with Onglyza (saxagliptin) in the SAVOR-TIMI study, but panelists agreed that this broad-sweeping warning is an overstep when all data suggests that the safety signal is unique to Onglyza. Speakers at this Takeda symposium cited no significant heart failure risk in the EXAMINE trial of Nesina (though results did trend in favor of placebo for this outcome), and also emphasized the resoundingly neutral hazard ratio of 1.00 for heart failure hospitalization seen in the TECOS trial for Januvia (sitagliptin). They also reviewed meta-analyses showing no signal across the DPP-4 inhibitor class as a whole. On TZDs, esteemed cardiologist Dr. Robert Chilton lamented the bad reputation this class has been assigned following the infamous rosiglitazone scare (rosiglitazone’s link to increased risk of MI and CV death was major inspiration for the FDA’s 2008 guidance mandating diabetes CVOTs). He noted that this, too, appears to be an agent-specific and not class-wide effect, and he argued that it’s an oversimplification to equate pioglitazone’s tendency to increase fluid retention with any additional risk of heart failure. We’ve heard Dr. Chilton remark on this important point several times before, and particularly appreciated his remarks at EASD 2017 that a diuretic would likely be an effective risk mitigation strategy for heart failure in the context of TZD therapy.

  • Beyond CV safety, the panelists went as far as to suggest that pioglitazone and alogliptin may even have beneficial CV effects – this is not surprising in light of the PROactive trial results that Dr. Schernthaner pointed to, which demonstrated a definitive 16% risk reduction for the secondary outcome of three-point MACE with pioglitazone (HR=0.84, 95% CI: 0.72-0.98, p=0.027). We note this was a secondary endpoint and can’t be considered truly significant because the study’s primary seven-point MACE outcome did not reach statistical significance. We think this is a classic example of the pitfalls of what Dr. David Matthews memorably termed “statistical fundamentalism” and regret that this statistical formality is reinforced so rigidly in the interpretation of clinical trials, preventing wider discussion of this benefit for pioglitazone. Furthermore, both Drs. Sanjay Rajagopalan and Stefano Genovese pointed to a significant 24% risk reduction in the primary composite endpoint of fatal and non-fatal stroke and MI in the IRIS trial (HR=0.76, 95% CI: 0.62-0.93, p=0.007) in people with insulin resistance (but no overt diabetes) and a history of recent stroke or transient ischemic attack. Dr. Rajagopalan went as far as to say that “pioglitazone needs to be considered in all our patients with existing CV events,” and Dr. Genovese raved “I love pioglitazone and think it’s one of the best drugs we have for people with diabetes.”
  • On DPP-4 inhibitors, Dr. Chilton highlighted the SPEAD-A trial, in which alogliptin decreased carotid intima-media thickness, indicating a protective effect against atherosclerosis, an important precursor of CV events. We were encouraged to hear reinforcement of the CV safety of pioglitazone and alogliptin reiterated by these experts in no uncertain terms. That said, the evidence for CV benefit with these agents remains rather less certain to date in comparison to the rich body of evidence for the cardioprotective effects of GLP-1 agonists and SGLT-2 inhibitors. Still, the speakers made a compelling point that the cost-effectiveness of now-generic TZDs and to a lesser-extent DPP-4 inhibitors makes them the best therapeutic option for many people with diabetes. While we’re incredibly fortunate to live in a time when diabetes drugs that have CV safety as well as a possible CV benefit are more widely accessible, we hope for a future in which cost is not part of the equation when it comes to determining optimal diabetes therapy (in other words, the safest, most effective medicines should be accessible to all patients in-need).

 

-- by Ann Carracher, Abigail Dove, Brian Levine, Payal Marathe, and Kelly Close