We love Boston this time of year, not only for the Fall colors and crisp weather, but for the annual Cardiometabolic Health Congress! This week marks the 12th annual CMHC meeting, and in this report, we detail notable highlights from days #1-2 (much more to come…). Drs. Jay Skyler and Robert Eckel delivered the annual favorite clinical trial updates, focusing on diabetes and obesity, respectively. This was awesome. We attended a brilliant talk by behavioral expert Dr. William Polonsky, who argued that if we want to improve medication adherence (a most worthwhile goal, with implications on outcomes, reimbursement, and the RCT/real-world gap), we have to correct patients’ misconceptions about the safety, efficacy, and overall pro/con balance of their therapies. Dr. Yehuda Handelsman chimed in on the debate over DKA risk associated with SGLT-2 inhibitors (or SGLT-1/2 dual inhibitors, like sotagliflozin) in type 1 care, cautioning that dramatic reductions in insulin dose exacerbate this safety signal – this is a solvable problem, minus the drama. The conference has featured many corporate symposia so far, sponsored by Sanofi, Sanofi/Regeneron, Lilly/BI, Novo Nordisk, and Amgen.
Read on for our top highlights – 10 in total – and stay tuned for more coverage of CMHC 2017. The agenda promises lots more learning on diabetes/obesity, especially with talks by Drs. Anne Peters, Jay Skyler, and Ronald Kahn scheduled for tomorrow. We can hardly wait to hear more from these thought leaders, and if you’re impatient like us : >, we direct you to our full conference preview.
Top 10 Highlights
1. In a review of major diabetes clinical trials from the past year (including CANVAS, DEVOTE, and EXSCEL), Dr. Jay Skyler shared candid views on how data from these RCTs has affected his real-world practice. For one, he’s switched all his patients on canagliflozin (there were only a few) to empagliflozin, because “why deal with this concern if you don’t have to?” We do note we’ve heard many others say that they don’t think their patients are at high risk – this reflects the high level of interest in the SGLT-2 class, early on and mid-way through disease progression.
2. “The field of obesity science is clearly maturing.” This very positive sentiment came from Dr. Robert Eckel as he launched into a rapid-fire overview of major obesity clinical trials from the past year. We’re very happy to hear this given the negativity of the commercial diabetes market until recently, due to Saxenda and to some lesser extent, Contrave.
3. The esteemed Dr. Julio Rosenstock highlighted the multifaceted benefits to fixed-ratio basal insulin/GLP-1 agonist combinations, explaining the rationale behind their creation and the evidence supporting their efficacy. He argued that we need more prescriptive guidelines so that advancement to fixed-ratio combinations actually happens (which we’d love to see). We think the diabetes landscape desperately needs these drugs to be used and we continue to believe they could benefit from far more education and diabetes apps in the spirit of Lilly’s Trulicity.
4. Dr. William Polonsky explained why most interventions to improve medication adherence have not been hugely effective to-date: They target “forgetfulness” (alerts, reminders, etc.) and ignore the major underlying problem – patients’ misconceptions about the safety, efficacy, and overall pro/con balance of taking diabetes drugs. This was a brilliant talk, reminding us of this all-important issue in diabetes management that remains a problem despite efforts to correct it. Dr. Polonsky suggested strategies that reach beyond forgetfulness to affect the underlying psychology of living with chronic disease, and we hope to see these take root in real-world clinical settings in the very near future.
5. CANVAS was a primary focus of Dr. Yehuda Handelsman’s remarks during a Janssen-sponsored product theater, but rather than zeroing-in on cardioprotection, he emphasized weight loss and positive renal effects with SGLT-2 inhibitor Invokana (canagliflozin). On off-label use of SGLT-2 inhibitors in type 1 diabetes, Dr. Handelsman suggested based on his clinical experience that insulin dose should not be dramatically reduced (if at all), as this exacerbates DKA risk. This isn’t well understood in the type 1 community yet but was proven recently by AZ.
6. U Penn cardiologist Dr. Rajat Deo led a Lilly/BI-sponsored product theater on SGLT-2 inhibitor Jardiance (empagliflozin). In response to audience questions, he speculated on both (i) empagliflozin’s mechanism of CV benefit and (ii) possible within-class differences for SGLT-2 inhibitors.
7. Leading a Novo Nordisk-sponsored symposium, Dr. Michael Davidson outlined Victoza’s “transformative” cardioprotective benefits as demonstrated by the landmark LEADER trial. “It’s time that these two diseases, diabetes and CV disease, are treated together as one.”
8. In a Sanofi/Regeneron-sponsored session, Dr. Pamela Morris was very critical of PBMs and formulary restrictions (echoing some of our major concerns regarding PBMs, blockades to patient choice, and overall lack of transparency). She emphasized the substantial burden of prior authorizations (time-consuming for HCPs, access-limiting for patients), focusing especially on PCSK9 inhibitors.
9. In a Sanofi-sponsored breakfast symposium, Dr. Athena Philis-Tsimikas described practical barriers to treatment intensification and presented insulin titration apps as an important development in countering clinical inertia by facilitating insulin initiation. Dr. Yehuda Handelsman preceded, emphasizing how GLP-1 agonists, SGLT-2 inhibitors, DPP-4 inhibitors, and TZDs are prioritized ahead of sulfonylureas and basal insulin in most of the AACE treatment algorithm, because these non-insulin agents carry lower hypoglycemia risk and are either weight-neutral or weight loss-promoting (the latter isn’t true of TZDs).
10. Leading an Amgen-sponsored lunch session, Dr. Yehuda Handelsman highlighted the LDL-lowering efficacy of PCSK9 inhibitor Repatha (evolocumab). Addressing high cost and poor reimbursement (a topic that’s basically unavoidable when it comes to discussing PCSK9 inhibitor products), Dr. Handelsman highlighted Amgen’s “Repatha Ready” patient assistance program, which offers $5 co-pay cards for commercially-insured patients. We view this as an excellent start, but note that awareness is low and as such, there’s a long way to go in ensuring access for the many patients who could benefit from this drug’s potent LDL-lowering effects.
Top 10 Highlights
1. Dr. Skyler’s Candid Views on Clinical Impact of Recent Trials
Dr. Jay Skyler reviewed major diabetes clinical trials presented in the last year, since CMHC 2016, and shared how these studies have affected his clinical decision-making. CANVAS, J&J’s CVOT for SGLT-2 inhibitor Invokana (canagliflozin), found a 14% risk reduction for three-point MACE (non-fatal MI, non-fatal stroke, or CV death) vs. placebo, on par with the CV benefit seen in EMPA-REG OUTCOME for Lilly/BI’s Jardiance (empagliflozin). On the other hand, amputations were two-fold higher in the canagliflozin group vs. placebo group in CANVAS (HR=1.97, 95% CI: 1.41-2.75, p<0.001), but there was no greater amputation risk with empagliflozin vs. placebo in EMPA-REG OUTCOME. Dr. Skyler acknowledged that this bothers him, and explained that he’s switched all his patients on canagliflozin (there were only a few) to empagliflozin, because “why deal with this concern if you don’t have to?”. This was our initial impression after the CANVAS symposium at ADA as well although we imagine that patients were far sicker, on average, in this group, than many of Dr. Skyler’s patients may be (it goes without saying that patients who would’ve been admitted into that trial, probably a small percent of the total patient population, should not be prescribed canagliflozin). Since then, we’re heard from other thought leaders that they’re not overly concerned about canagliflozin/amputations, given that the background amputation rate is relatively low even in a diabetes population and especially compared to the CV event rate for this patient group. As one example, Dr. Anne Peters told us that some of her patients experience superior A1c-lowering and weight loss with canagliflozin vs. empagliflozin, and she underscored that amputation risk can be manageable with careful monitoring and strong patient education around foot care. Dr. Skyler spoke to this last point, advocating that diabetes care providers pay more attention to the feet – we would love to see this! After all, a majority of amputations in CANVAS were preceded by a known risk factor such as infection (the most common), gangrene, peripheral arterial disease, ulcers, acute limb ischemia, or neuropathy. We’re wary of over-comparison between CANVAS and EMPA-REG OUTCOME due to different protocols for how amputations were collected, different baseline study populations, etc. Moreover, even if providers feel strongly that empagliflozin is the better SGLT-2 choice, canagliflozin may be the only option for their patients on certain insurance plans – most notably, CVS Health has excluded Jardiance in favor of Invokana on its 2018 formulary.
- Dr. Skyler also summarized results from DEVOTE, ACE, TOSCA.IT, and EXSCEL, highlighting some of the “surprise” findings. DEVOTE was designed to evaluate CV outcomes with Novo Nordisk’s Tresiba (insulin degludec) vs. standard of care Lantus (Sanofi’s insulin glargine U100), but the real prize came in hypoglycemia data. Tresiba was associated with a 40% relative risk reduction for severe hypoglycemia (p<0.001) and with a 53% relative risk reduction for severe hypoglycemia overnight (p<0.001). During the ensuing panel discussion, Dr. Robert Eckel asked how much of this hypoglycemia benefit might be attributed to insulin degludec’s longer/flatter PK/PD profile, whereas insulin glargine U100 seems to tail-off. Dr. Skyler agreed, outlining that the mean duration of action for Lantus is 22 hours (not 24), with some patients experiencing even shorter-lasting effects. “We rely on endogenous insulin to take you over the gap,” he explained, “but it may not. 100% of the time that I use Lantus, I prescribe it twice-daily in my type 1 patients.” Dr. Skyler further suggested that Sanofi’s next-gen basal insulin Toujeo (insulin glargine U300) may confer similar hypoglycemia benefits to Tresiba, because it also boasts a longer/flatter PK/PD profile vs. lower-concentration Lantus. The “surprise” positive from ACE (a CVOT for alpha-glucosidase inhibitor acarbose conducted in China, presented at EASD) was the 18% risk reduction for new-onset type 2 diabetes (p=0.005), as Dr. Skyler mentioned in his talk.
- In discussing AZ’s EXSCEL trial, Dr. Skyler emphasized how exenatide just narrowly missed statistical significance for cardioprotection, with an upper bound of 95% confidence interval at 1.00 (HR=0.91, 95% CI: 0.83-1.00, p=0.06 for superiority). Picking up on themes from EASD, he underscored the pragmatic trial design and the use of single-dose Bydureon reconstitution kits, which likely contributed to poor adherence and high drop-out rates (43% in the exenatide arm, 40% in the placebo arm). We also find it interesting what Dr. Skyler didn’t say, with no mention of mechanistic differences between exendin-4-based molecules in the GLP-1 agonist class (exenatide, lixisenatide) vs. human GLP-1-based molecules (liraglutide, semaglutide) – he told is in a separate conversation after this talk that he doesn’t see substantial differences between GLP-1 therapies, because EXSCEL trends in the same direction as LEADER (for liraglutide) and SUSTAIN 6 (for semaglutide), missing superiority because of 43% known discontinuation (perhaps even higher with unreported non-persistence). Indeed, many thoughts leaders have recently voiced opposition to the molecular argument for within-class differences to GLP-1 products. As one example, Dr. Francesco Giorgino, who provided the discussant on EXSCEL, claimed that these molecular differences may lead to variations in signaling, but that this is unlikely to translate into meaningful differences on CV outcomes. In our view, EXSCEL does more to support the notion of a cardioprotective GLP-1 class effect than it does to refute it, given the pragmatic trial design, lower-risk population at baseline (27% primary prevention), compelling CV safety data, and extremely narrow miss on superiority (we heard it was about three patients – though have not been able to confirm this).
2. Dr. Eckel Delivers Obesity Clinical Trial Update: “Obesity Science is Clearly Maturing”
“The field of obesity science is clearly maturing.” This very positive sentiment came from Dr. Robert Eckel as he launched into a rapid-fire overview of major obesity clinical trials from the past year. One study (n=160) found that combined aerobic/resistance exercise leads to greater improvements in functional status for people with obesity vs. either physical activity intervention on its own (provided the combination is successful in stimulating weight loss). Another trial (n=100, 69 complete the study in-full) compared alternate-day fasting vs. daily caloric restriction – both were equally effective in terms of adherence to regimen, weight loss, weight maintenance, and cardioprotection. A study (n=134 people with obesity) of bariatric surgery vs. medical management of diabetes found that the former was more successful in controlling type 2 diabetes and CV risk; surgery also resulted in less need for concomitant medications. A 12-year observational study on this topic highlighted much more weight loss with surgical treatment, but reflected on the ongoing uncertainty over which patients will benefit more from bariatric surgery vs. medical management. As Dr. Eckel put it, “I wish we could distinguish these patients upfront,” which would be a stride forward in personalized care, and would also lead to improved health outcomes and lower healthcare expenditures overall. Another paper attempted to answer Dr. Eckel’s wish, outlining factors associated with successful metabolic surgery for obesity (defined as BMI <30 kg/m2 at one-year follow-up): Those who were younger, who had lower baseline body weight/BMI, who were male or white, who made >$75,000 in annual salary, and who had fewer background comorbidities were more likely to have a successful surgical intervention. Lastly, Dr. Eckel presented a meta-analysis on metabolically-healthy obesity (n=3.5 million!), which found that high body weight was still associated with greater CV morbidity over a mean 5.4-year follow-up, despite the absence of other risk factors like dyslipidemia, hypertension, or diabetes. The literature on metabolically-healthy obesity is mixed, but Dr. Eckel suggested that this paper makes a fairly convincing argument for the importance of weight loss regardless. We loved this summary of key science on obesity, and we’re glad that an expert like Dr. Eckel sees the needle moving toward better clinical understanding of this chronic condition. Obesity remains a massive public health problem, due in part to under-diagnosis and under-treatment, so it’s positive to see research identifying effective interventions though the translation to real world is slow. Indeed, implementing these strategies in the real world is a separate battle, one that must also take on stigma, poor reimbursement, a lack of investment in behavior and prevention and a host of other systems-related and commercial challenges.
3. Dr. Rosenstock on the Complementary Benefits in Fixed-Ratio Basal Insulin/GLP-1 Agonist Combinations
The esteemed Dr. Julio Rosenstock highlighted the multifaceted benefits to fixed-ratio basal insulin/GLP-1 agonist combinations, explaining the rationale behind their creation and the evidence supporting their efficacy. Basal insulin decreases hepatic glucose production, resulting in lower nocturnal and fasting blood sugar, and improves beta cell function by reducing glucotoxicity. Meanwhile, GLP-1 agonists improve postprandial glucose by slowing gastric emptying (some more effective than others), and improve fasting glucose by increasing glucose-mediated insulin release (once again, some more effective than others). These complementary mechanisms afford better control over nocturnal glycemia, fasting plasma glucose, and postprandial glucose. Moreover, and very importantly, GLP-1 agonists can counter the weight gain and hypoglycemia risk associated with insulin. If Dr. Rosenstock’s theoretical explanation wasn’t compelling enough, he also summarized key clinical trial data from the pivotal studies for regulatory approval of Novo Nordisk’s Xultophy (insulin degludec/liraglutide) and Sanofi’s Soliqua (insulin glargine/lixisenatide). In LixiLan-O, treatment with Soliqua led to mean A1c decline from a baseline 8.1% to 6.5% after 30 weeks. In DUAL I, Xultophy led to mean A1c decline from 8.3% to 6.4% after 26 weeks. Both are incredible! This glycemic efficacy was consistent throughout the LixiLan and DUAL clinical programs, and occurred against a backdrop of small weight reductions (Xultophy has been associated with more significant weight loss to-date), no increase in hypoglycemia compared to placebo, and low GI side-effects vs. GLP-1 agonist monotherapy due probably to the slow titration. Notably, these were not head-to-head trials, and thus shouldn’t be the basis for any efficacy comparisons between Xultophy and Soliqua, Dr. Rosenstock emphasized. What’s truly exciting, in our view, is how much better this class is than agents that have come before it. We recently heard Dr. Rosenstock tout the favorable efficacy/milder side-effect profile of fixed-ratio combinations at EASD 2017 as well. His take-home message? Titratable fixed-ratio combinations of basal insulin/GLP-1 agonists can give robust glycemic control, with a favorable safety profile, simplified regimen complexity, and ameliorated side-effects compared to each component alone. Moreover, he argued that we need more prescriptive guidelines so that advancement to fixed-ratio combinations actually happens. We would love to see this and believe it’s embarrassing for the diabetes field that this hasn’t already happened. We’ve been incredibly disappointed by the sluggish commercial uptake of Xultophy and Soliqua so far (despite the tremendous enthusiasm from thought leaders), and anything that gets these therapies into the hands of more patients would be a welcome change. For how fashionable it is to be “patient-centered” these days, this uptake is truly embarrassing for the field. (No one, by the way, has asked patient advocates for help that we know of.)
4. Dr. Polonsky on the REAL Reason People with Diabetes Don’t Take Their Meds
Dr. William Polonsky explained why most interventions to improve medication adherence have not been hugely effective to-date: They target “forgetfulness” (alerts, reminders, etc.) and ignore the major underlying problem – patients’ misconceptions about the safety, efficacy, and overall pro/con balance of taking diabetes drugs. While 60% of chronic disease patients report forgetfulness as a key reason for missed treatment doses or prescription refills, Dr. Polonsky argued that this is an oversimplification of the underlying psychology. In one study he presented, the survey participants who endorsed forgetfulness were also likely to question the efficacy of their prescribed medications and to feel burdened by high prescription drug cost (“it’s easy to forget doing something if you don’t like doing it”). Type 2 diabetes makes these beliefs more difficult to address, because hyperglycemia is a relatively invisible condition. Patients taking daily pills or injections for type 2 diabetes are unlikely to experience tangible benefits in the short term. What is more immediately apparent with these therapies is their side-effects, and often their high cost. It’s hard to motivate people to invest in their long-term health when the cons associated with a medication regimen are more tangible/hold greater mental weight, and Dr. Polonsky discussed how this issue is exacerbated when patients don’t trust their providers and thus may question their providers’ assurances that these pills/injections are really helping to prevent complications. Greater physician trust can lead to better medication adherence, according to Dr. Polonsky. Acknowledging that “trust” is a somewhat ambiguous term, he shared clinical evidence to support what works: People trust their HCP when they feel included in treatment decisions, and when they feel their needs are understood and prioritized. He briefly touched upon the inverse relationship between co-pays and adherence – when the former goes down, the latter goes up – again calling attention to the stark contrast between what is visible to patients (cost) and what is mostly invisible (hyperglycemia, maybe a complication down the line). Efforts to enhance adherence need to target these deeper causes (where “forgetfulness” is the superficial answer), and Dr. Polonsky suggested a few strategies to HCPs in the room. Notably, he advocated for more continuous contact between patient/provider, not only to remind, but to show the individual with diabetes that someone cares about their health and well-being – we so hope the powers that be listen to this! He made the astute point that one major difference between RCTs and the real world is this frequency of contact – study participants have a profound sense that someone is invested in their health outcomes, and we know all too well the gap between clinical trial results and what plays out in real-world clinical settings. Instead of asking whether or not a patient is adhering to their treatment regimen, Dr. Polonsky encouraged more subtle questions like “what’s one thing about taking your medications that’s been challenging?” or “aside from forgetting, what else is tough about taking your meds?”. It’s the provider’s responsibility to establish the expectation that chronic disease management is tough, says Dr. Polonsky, though we don’t think this really happens so much in the real world. Adhering to daily medication is understandably challenging for many, and people should feel comfortable admitting this to their HCP so that, together, patient/provider can devise strategies that may help. Above all, Dr. Polonsky emphasized that we need to address the commonly-held misconception that more medications signify diabetes failure. “If you can only focus on one thing, it’s this: spread the message that more medication doesn’t mean you are sicker; less medication doesn’t mean you are healthier.”
- For any doubters in the room, Dr. Polonsky established that poor medication adherence is indeed a major hurdle in diabetes care. After one year, <50% of patients are still taking at least 80% of their prescribed doses of a DPP-4 inhibitor, an SU, or a TZD (note that these are all orally-administered, and adherence is even more challenging for injectable therapies like GLP-1 agonists and insulin, particularly mealtime insulin). After two years, this drops to <40% for DPP-4 inhibitors and SUs, <30% for TZDs. Of course, this data only applies if people pick up their prescriptions from the pharmacy, and Dr. Polonsky emphasized that 31% of diabetes prescriptions are never filled in the first place. He went on to show how poor adherence increases hospitalization risk and overall medical costs. Patients with diabetes face a 39% greater risk for all-cause mortality with poor adherence to oral agents. Notably, says Dr. Polonsky, low adherence dissuades payers from covering advanced therapies, and leads to the persistent gap between RCTs and real-world evidence. As always, we were moved by Dr. Polonsky’s talk, reminded of this all-important issue in diabetes management that remains a problem despite efforts to correct it. We’d love to see Dr. Polonsky’s suggested strategies take root, reaching beyond forgetfulness to affect the core psychology of living with chronic disease.
5. Dr. Handelsman Talks Invokana: Efficacy & Use in Type 1
CANVAS was a primary focus of Dr. Yehuda Handelsman’s remarks during a Janssen-sponsored product theater, but rather than zeroing-in on cardioprotection, he emphasized weight loss and positive renal effects with SGLT-2 inhibitor Invokana (canagliflozin). Dr. Handelsman pointed out that weight loss with Invokana never plateaus, and that average weight change after 6.5 years was 3.5 lbs greater with canagliflozin vs. placebo. Invokana also gave a 0.58% greater drop in A1c over the same period, as well as a 3.9 mmHg greater decrease in systolic blood pressure. Perhaps most exciting, according to Dr. Handelsman, is that despite an initial drop in eGFR with Invokana, kidney function recovered and stabilized near baseline over the study period, while eGFR in the placebo group declined throughout. Moreover, renal outcomes data from CANVAS were positive: Canagliflozin gave a 40% risk reduction for the composite endpoint of renal death, renal replacement therapy, or 40% reduction in eGFR (HR=0.60, 95% CI: 0.47-0.77). On the amputation signal (a frequent topic when discussing CANVAS), Dr. Handelsman reiterated that patients should be screened for prior amputations, neuropathy, and peripheral vascular disease, and that they should be monitored throughout treatment for the development of neuropathy or foot problems – just like any other patient ought to be. When asked about off-label use of SGLT inhibitors in type 1 diabetes, Dr. Handelsman shared his perspective from involvement in AZ’s and Lexicon’s trials of dapagliflozin and sotagliflozin as adjunct treatments. He noted that one program advised reducing insulin dose by no more than 20% (we know this to be AZ’s guidance in DEPICT 1), while another (we would think the inTandem program) asked providers to reduce insulin by up to 30% due to concern over hypoglycemia – and, as Dr. Handelsman pointed out, this program saw more DKA. Dr. Handelsman seemed unconvinced of the need to reduce insulin at all with SGLT-1 or SGLT-2 inhibitors in type 1 diabetes (this echoes Dr. Chantal Mathieu’s commentary from EASD), and the explanation that too much insulin reduction can lead to DKA seems to hold true in the data. We certainly believe (and know personally) that this varies patient by patient but we believe that over 20% insulin drop isn’t typically needed according to AZ’s careful read of earlier-phase data.
6. Lilly/BI Product Theater Spotlights SGLT-2 Jardiance (Empagliflozin) as Cardioprotective with No Amputation Risk
U Penn cardiologist Dr. Rajat Deo led a Lilly/BI-sponsored product theater on SGLT-2 inhibitor Jardiance (empagliflozin). In response to audience questions, he speculated on both (i) empagliflozin’s mechanism of CV benefit; and (ii) possible within-class differences for SGLT-2 inhibitors. Following Dr. Deo’s detailed overview of EMPA-REG OUTCOME results (14% relative risk reduction for three-point MACE, 38% for CV death, and 35% for heart failure hospitalization), HCPs in the audience wanted to know why and how this works. Dr. Deo provided two hypotheses: (i) The reduction in heart failure hospitalization in the empagliflozin vs. placebo arms could signal a reduction in pump failure that leads to less CV death; this theory is gaining support in the field, and Lilly/BI have even launched a dedicated clinical program for empagliflozin in chronic heart failure. (ii) Dr. Deo also suggested that empagliflozin might confer a benefit on arrhythmic mortality. Ongoing studies that rigorously adjudicate sudden cardiac death and arrhythmic events will evaluate this hypothesis more formally. This possibility could explain why Jardiance led to marked risk reduction for CV death without significantly affecting non-fatal MI or stroke. We expect the conversation on mechanism to continue for the foreseeable future, but in the meantime, we appreciate strong commentary in defense of empagliflozin’s cardioprotective effects – patients shouldn’t have to wait for mechanistic answers before starting a therapy that could extend their life and prevent major CV complications. CANVAS results for J&J’s Invokana (canagliflozin) corroborate the positive findings from EMPA-REG OUTCOME, lending additional support that the Jardiance results were not a fluke, and building a compelling case for a cardioprotective class effect. That said, CANVAS differed from EMPA-REG OUTCOME on safety findings, as canagliflozin was associated with a nearly two-fold risk for lower limb amputations (HR=1.97, 95% CI: 1.41-2.75, p<0.001), while empagliflozin has showed no such signal to date though the trials are difficult to compare given the different study populations. Dr. Deo acknowledged that amputations were adjudicated differently in these two trials – we think this is a very important point, and we caution against over-comparison – but he also spoke to molecular differences that could underlie the diverging amputation results. He pointed out that each SGLT-2 inhibitor on the market has a slightly different ratio of SGLT-1 vs. SGLT-2 inhibition. We heard similar remarks from Dr. Juris Meier at EASD 2017, who alluded to Invokana’s lower selectivity for the SGLT-2 receptor as one possible reason for increased amputation risk. Much more research is needed before we can connect this to amputation outcomes (and indeed, some thought leaders immediately criticized Dr. Meier’s speculation), and Dr. Deo agreed that additional investigations into the biological pathways affected by these therapies are necessary. We look very forward to future studies that elucidate the amputation signal in CANVAS, because this is definitely an important issue to sort out for patients who are at very high risk (presumably, for many patients, this risk won’t be a factor if they do not have other complications). Upcoming DECLARE results for AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin), expected in 2H18, may also shed light on this.
7. Novo Nordisk Symposium Highlights Victoza’s New CV Indication, Calls on Cardiologists to Spread the Word
Leading a Novo Nordisk-sponsored symposium, Dr. Michael Davidson outlined Victoza’s “transformative” cardioprotective benefits as demonstrated by the landmark LEADER trial. A LEADER investigator himself, Dr. Davidson reviewed the trial design and results, clearly enjoying himself when he unveiled the famed 13% risk reduction for the primary outcome of three-point MACE (non-fatal MI, non-fatal stroke, and CV death) with GLP-1 agonist liraglutide vs. placebo. He framed the value of these findings in the context of high residual CV risk in people with diabetes, who have an estimated eight-fold higher risk of acute MI and nearly seven-fold higher risk of stroke vs. a background population, based on 2010 data. As a specialist in preventative cardiology, Dr. Davidson underscored the need for aggressive CV risk management in diabetes with a discussion of life expectancy – we’d love to hear more about this from endocrinologists! On average, type 2 diabetes causes ~eight years of life lost, but this increases to approximately 15 years of life lost for diabetes and a history of stroke, and to a staggering 18 years of life lost for diabetes and a history of MI. As a benchmark, he pointed out that tobacco use, a health risk factor that HCPs aggressively warn against, is associated with a comparably low 10 years of life lost. His message was clear and compelling: CV risk in diabetes should be treated with the same urgency. In particular, Dr. Davidson called on his cardiology colleagues to help lead this charge and “take responsibility for the management of diabetes as a causal risk factor for CV disease.” He encouraged cardiologists in the audience to consider prescribing Victoza for their patients with diabetes, or to educate their patients’ PCPs about it (as the only GLP-1 agonist so far approved to reduce the risk of CV disease though the Bydureon data clearly showed a trend). This FDA approval of Victoza’s CV indication came through in August, following EMA approval of a similar label change in July. We appreciated Dr. Davidson’s closing words: “It’s time that these two diseases, diabetes and CV disease, are treated together as one.”
8. Dr. Morris on Access Issues for PCSK9 Inhibitors, with a Critical View of PBMs
In a Sanofi/Regeneron-sponsored session, Dr. Pamela Morris was very critical of PBMs and formulary restrictions. She emphasized the substantial burden of prior authorizations (time-consuming for HCPs, access-limiting for patients), focusing especially on PCSK9 inhibitors. Advanced agents like PCSK9 inhibitors come with increased clinical development costs, which are passed on to payers and consumers, hence the very high price of Sanofi/Regeneron’s Praluent (alirocumab) and Amgen’s Repatha (evolocumab). This cost has hindered patient access, as both private and public payers typically require a prior authorization. Dr. Morris presented a 2014 MGH survey (n=1,774), which found that one in four hours of physician time is spent on administrative responsibilities. What nightmare systems problem! Prior authorizations in the survey were listed as the no. 1 most burdensome task. In a 2016 AMA survey (n=1,000), 75% of practicing physicians described the burden of prior authorizations as “high” or “extremely high,” and 90% reported that this process delays care, with the average HCP filling out >36 prior authorization forms per week. What makes these figures even more troubling is that after providers spend all this admin time, 96% of prior authorization requests for a PCSK9 inhibitor are initially denied by payers, according to a National Lipid Association survey; even after provider follow-up, which takes more time, only 36% are ultimately successful. Dr. Morris turned attention to PBMs to elucidate why the reimbursement system is broken. Formulary management is meant to (i) decrease costs; and (ii) improve patient outcomes by optimizing “appropriate and efficient utilization of medications.” According to Dr. Morris, PBMs actually do meet the first goal, mostly through cost-sharing and prior authorization requirements, but also by using stepped therapy and preferred drug lists (which greatly limit patient choice – a decidedly negative consequence, in our view). On the other hand, Dr. Morris argued that the PBM playbook does nothing to improve patient outcomes – more likely, it makes them worse. She showed how formulary restrictions are associated with reduced medication adherence. The effect of cost reduction strategies on patient outcomes is negative ~50% of the time and neutral ~36% of the time; 70% of the negative effect is on medication adherence. By nature, PBMs work to reduce healthcare expenditures on the most expensive drugs, but this means few patients can access these products, which are often the safest and most-effective options currently available. Overall, Dr. Morris’ talk reinforced our view that we need more transparency from PBMs to fully unravel the complicated pricing scheme for prescription drugs in the US. We’ve long been wary of the mysterious role PBMs play, and we thank Dr. Morris for adding this nuance to our understanding of these organizations.
- Dr. Kim Birtcher followed with a discussion of strategies and resources to support the prior authorization process, emphasizing that HCPs must prescribe only according to FDA-approved indications (for PCSK9 inhibitors, statin intolerance is not one of them). She advised paying attention to definitions of disease states in the FDA indications, and underscored that good documentation is key to prior authorization success. It’s important for HCPs to document disease state, previous medications, any intolerance, and responses to drugs – electronic health records can be used as support. Additionally, Dr. Birtcher suggested that a healthcare practice should have a clear protocol for handling prior authorizations to prevent delays or non-coverage. Having a single staff member dedicated to the process is incredibly helpful, according to Dr. Birtcher, as it cuts down on time to prepare/process forms, increases approval rate, and increases the number of patients who pick up their prescription. She added that patients should be warned of the possibility that a prior authorization is denied. Setting expectations is important, and patients should know upfront that there may be appeals involved, after which co-pay might still be high. We appreciated this practical advice, though it’s hard to get around the fact that reimbursement prospects for PCSK9 inhibitors are extremely poor. As Dr. Birtcher shared, even in a group of people with diagnosed familial hypercholesterolemia – for which PCSK9 inhibitors are indicated – 30% had some coverage denial in the last year, and 75% of those were for PCSK9 agents – this data is absolutely stunningly bad. Optimistically, she suggested that appeals are approved reasonably often in this setting. We hope the needle moves on PCSK9 coverage in the near-future, and our fingers are crossed that payers are swayed by compelling CV data from FOURIER (for Repatha) and upcoming results from ODYSSEY Outcomes (for Praluent).
9. Drs. Philis-Tsimikas and Handelsman on Clinical Inertia and Treatment Intensification
According to Dr. Athena Philis-Tsimikas, barriers to treatment intensification (i.e. difficulty transitioning to injectable therapy) are what’s driving clinical inertia in the real world. In this Sanofi-sponsored breakfast symposium, she went on to describe technology and strategies to overcome said inertia. Data shows that PCPs are more likely to refer patients to specialists when initiating any insulin or GLP-1 agonist therapy. Barriers to insulin initiation itself are well-known: concerns over weight gain, hypoglycemia, proper titration, and lack of care team infrastructure to support all these challenges. Dr. Philis-Tsimikas argued that the way we currently ask people to start and self-titrate insulin is asking too much. In her eyes, even though we have impressive next-gen basal insulins with lower hypoglycemia risk and flatter PK/PD profiles, sending patients home with directions to self-monitor blood glucose, divide to find averages, and up-titrate to target is not easy for most (it’s actually exceptionally difficult). Dr. Philis-Tsimikas reviewed her ideas on best practice insulin initiation, emphasizing early preparation and discussion of insulin therapy (what are the patient’s concerns?), followed by initiation with effective explanation of titration, ongoing support through titration, and continual monitoring and adjusting of therapy. She pointed to titration as the most difficult aspect, and shared a number of insulin titration apps to help with this. Right now, there are ~125,000 healthcare apps available, and ~60,000 have some relevance to diabetes, with a few dozen performing titration calculations. While most of these are not FDA-approved, Voluntis’ Insulia, Amalgam Rx’s iSage Rx, Sanofi’s My Dose Coach, and Lilly’s Go Dose have all been cleared by regulators. Patients/providers alike should be wary of unapproved titration apps, but Dr. Philis-Tsimikas also presented a small study (n=61) of patients starting insulin glargine, which found that mobile communication in support of basal titration helped patients reach their optimal insulin dose (88% vs. 37% in usual care), demonstrating the distinct positive impact technology can have in this area.
- Dr. Yehuda Handelsman preceded Dr. Philis-Tsimikas, offering his own perspective on clinical inertia and emphasizing non-glycemic guidelines. In his words, you can’t say you’re a diabetologist and only care about glucose control. The 2017 AACE treatment algorithm has step-by-step models for evaluating and treating overweight/obesity, dyslipidemia, and hypertension, and Dr. Handelsman endorsed this comprehensive approach. Diving into the AACE glycemic control algorithm, he pointed out that insulin therapy is de-prioritized below GLP-1 agonists, SGLT-2 inhibitors, DPP-4 inhibitors, and TZDs in dual therapy, and is below all of these except DPP-4 inhibitors in triple therapy. Only for patients with entry A1c >9% who are showing symptoms should insulin be immediately considered. Dr. Handelsman attributed this tipping of the scale toward newer, non-insulin therapies to the fact that they come with no weight gain or sometimes spur weight loss, as well as mitigated hypoglycemia risk. We certainly appreciate that AACE has taken a more progressive/aggressive approach in its guidelines, particularly as the ADA algorithm does not clearly rank the efficacy and safety of different drug classes (though it does provide general information about efficacy, hypoglycemia, weight effects, side-effects, and cost).
10. Dr. Handelsman Touts LDL-Lowering Efficacy of Amgen’s PCSK9 Inhibitor Repatha (Evolocumab)
Leading an Amgen-sponsored lunch session, past AACE president Dr. Yehuda Handelsman highlighted the LDL-lowering efficacy of PCSK9 inhibitor Repatha (evolocumab). He emphasized Repatha’s patient-friendly dosing options (a pen injection once every two weeks, or a once-monthly injection mediated by the hands-free Pushtronex on-body infuser device) and reviewed data from select clinical trials. In LAPLACE-2 (n=2,067), the addition of Repatha to statin therapy led to mean LDL reductions of 63%-75% vs. placebo. Impressively, more than 85% of patients randomized to Repatha achieved an LDL goal <70 mg/dl over the 12-week study duration. In the DESCARTES trial (n=901), patients randomized to evolocumab experienced a mean 57% reduction in LDL vs. placebo injection (-51.5% vs. +6.0%), and 82% of evolocumab-treated patients achieved an LDL goal <70 mg/dl at week 52 (compared to 6% of patients on placebo). Affordability has been a major concern with products in the PCSK9 class (also including Sanofi/Regeneron’s alirocumab, branded Praluent), and to this end, Dr. Handelsman noted that Repatha is covered under the majority of commercial and Medicare Part D plans. He further highlighted Amgen’s “Repatha Ready” patient assistance program, which offers $5 co-pay cards for commercially-insured patients. We view this as a good start, but note that there’s a long way to go in ensuring access for the many patients who could benefit from this drug’s potent LDL-lowering effects.
- In past earnings updates, Amgen management has expressed optimism regarding ongoing payer negotiations to improve reimbursement for Repatha, citing a proposed label update based on the FOURIER CVOT as a promising source of momentum on this front. With FOURIER, Repatha became the first PCSK9 inhibitor to report a cardioprotective effect (demonstrating a 15% risk reduction the composite primary endpoint of CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, or coronary revascularization). A Supplemental Biologics License Application (sBLA) to have this positive CV outcomes data reflected on Repatha’s label is currently under priority review with the FDA – a decision is expected as soon as December 2, 2017.
- Although this wasn’t emphasized in Dr. Handelsman’s remarks, we note particular promise for this drug in people with diabetes, many of whom have hyperlipidemia and high residual CV risk. This was reinforced by a pre-specified sub-analysis of people with diabetes within the FOURIER trial, which revealed that Repatha reduced risk for the composite primary endpoint by 17% (HR=0.83, 95% CI: 0.75-0.93, p<0.0008) and for the key secondary endpoint of three-point MACE (CV death, non-fatal MI, or non-fatal stroke) by 18% (HR=0.82, 95% CI: 0.72-0.93, p<0.0021). This translates to a similar relative reduction for CV events with Repatha compared to the non-diabetes population, and, notably, for a larger absolute risk reduction given the higher baseline CV risk for people with diabetes. We hope this data, as well as the main FOURIER results, is compelling in the eyes of payers and providers alike, as we’d love to see greater uptake of Repatha among people with diabetes for the prevention of CV disease.
-- by Ann Carracher, Abigail Dove, Payal Marathe, and Kelly Close