August 27-31, 2016; Rome, Italy; Full Report – Draft

Executive Highlights

This report features our full coverage from the European Society of Cardiology’s 2016 Congress held in Rome, Italy. This year’s meeting was its largest ever – drawing 33,000 attendees! We were treated to new sub-analyses of EMPA-REG OUTCOME for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) and TECOS, plus plenty of discussion on what the positive EMPA-REG OUTCOME and LEADER results mean for the future of diabetes and cardiology. We also heard both praise and disappointment with the treatment of diabetes drugs in ESC’s guidelines for heart failure and several opinions on what it might take for broader use of PCSK9 inhibitors in clinical practice. Those who stuck it out until the very end of the conference were treated to a very special guest – the Pope himself! We’re already looking forward to ESC 2017: August 26 - 30 in Barcelona, Spain!

Themes

• Our impression from this meeting overall is that there is overwhelming excitement and interest among cardiologists for the SGLT-2 inhibitor class, and more modest enthusiasm for incretins or other diabetes drugs. Indeed, the Merck-sponsored corporate symposium on TECOS and the Novo Nordisk-sponsored symposium on LEADER (which also demonstrated impressive cardiovascular benefit!) was sparsely attended compared to the absolutely packed, standing-room-only Lilly/BI-sponsored symposia on EMPA-REG OUTCOME (though, to be fair, both the Merck and Novo Nordisk symposia occurred later in the day). We imagine part of this intense enthusiasm for empagliflozin stems for the difficulty of treating heart failure as Novartis’ heart failure drug Entresto (sacubitril/valsartan) appears to have generated a similar buzz among cardiologists – we’re very eager to hear what happens with that drug.
  
  • “Cardiologists want to look at empagliflozin as a cardiovascular drug with a glucose-lowering effect.” This sentiment from an attendee at a Lilly/BI-sponsored corporate symposium illustrated the great enthusiasm among cardiologists for the EMPA-REG OUTCOME results and, by extension, for Jardiance and the SGLT-2 inhibitor class. Another cardiologist at the same session remarked, “I’m an enthusiastic prescriber of this drug based on the results from this trial.” In total, Lilly/BI sponsored three corporate symposia on the EMPA-REG OUTCOME results for ESC 2016 – one that was lecture-based and two that were discussion-based follow-ups to the earlier lecture symposium. All three of the sessions were completely full, with the latter two standing-room-only. Furthermore, a quick poll at the beginning of one of the later sessions revealed that the vast majority of audience members had not attended an earlier session and were unique attendees interested in learning more about the EMPA-REG OUTCOME results. Infamous cardiologist Dr. Steve Nissen (Cleveland Clinic, OH) expressed enthusiastic support for empagliflozin (and liraglutide), asserting that the results from EMPA-REG OUTCOME and LEADER are convincing enough to change clinical practice, largely because of their effect on mortality. As he put it: “If it was just an effect on MI, that would be one thing. But when people are actually living longer on the therapy, we better have a good reason not to give it as survival is the most important endpoint.” Indeed, in many respects, it appeared that the cardiologists at this conference were more enthusiastic about the EMPA-REG OUTCOME results than many people in the diabetes or regulatory fields – the lack of clarity of the mechanism of risk reduction sparked great controversy at the FDA Advisory Committee meeting on a potential label change reflecting the results and the 2016 AACE guidelines update took a fairly conservative view of empagliflozin’s benefit, all things considered. On the other hand, Dr. Lars Rydén pointed out that the published ESC guidelines suggest empagliflozin as an option for patients with heart failure – a faster response to the EMPA-REG OUTCOME results than we’ve seen in most diabetes guidelines.
• Several speakers commented on the treatment of diabetes drugs in the recently-released ESC guidelines for heart failure. Dr. David Fitchett (University of Toronto, Canada) praised the guidelines for recommending the use of empagliflozin to “prevent or delay the onset of heart failure or prolong life” in patients with type 2 diabetes. Indeed, this is a fairly progressive move on the part of the guidelines-writing committee – the recent FDA Advisory Committee meeting on EMPA-REG OUTCOME largely dismissed the heart failure benefit observed in the trial as it was an exploratory endpoint and was not adjudicated rigorously enough to warrant any definitive conclusions (as we understand it, that’s fairly hard to do!). Similarly, the 2016 update to the AACE/ACE diabetes treatment algorithm took a fairly conservative approach to the EMPA-REG OUTCOME results, mentioning only a “possible benefit” for SGLT-2 inhibitors on cardiovascular disease. At the time of their release in January, Dr. Alan Garber (Baylor College of Medicine, Houston, TX) suggested that the reduction in hospitalization for heart failure could not be listed as a benefit because it was not part of the study’s pre-specified primary endpoint – clearly the ESC guidelines writing committee had no such qualms. On the other hand, Dr. Eric Peterson (Duke University, Durham, NC) expressed some disappointment with the heart failure guidelines in that they stated that DPP-4 inhibitors (and GLP-1 agonists) may have a negative impact on heart failure and that there are currently no data on the safety of DPP-4 inhibitors and GLP-1 agonists in patients with heart failure. As Dr. Peterson pointed out, the guidelines completely neglected to mention the TECOS trial for Merck’s Januvia (sitagliptin) demonstrating an absolutely neutral effect on heart failure. In fact, he shared that the TECOS lead investigators have written a letter to the European Heart Journal, where the guidelines are published, in an attempt to get this corrected. Dr. Peterson expressed incredulity that the guidelines could overlook a trial as large as TECOS and noted that evidence from trials that completed later than TECOS made it into the guidelines – EMPA-REG OUTCOME is one example of this.
• In two afternoon corporate symposia on the LEADER results and the EMPA-REG OUTCOME results, sponsored by Novo Nordisk and Lilly/BI respectively, several speakers argued against the notion that the cardioprotective benefit of either trial could be attributed to glucose lowering. Regarding LEADER, Professor John Petrie (University of Glasgow, UK) emphasized that similar o.4% reductions in A1c were seen in other trials and were not associated with a cardioprotective benefit. Dr. Mansoor Husain (Toronto General Research Institute, Canada) took this reasoning one step further argued that we would likely see an even greater difference in cardiovascular outcomes if the A1c in the liraglutide and placebo arms were matched, as that would suggest that potentially less safe agents (such as SUs) were used to achieve the low A1c in the placebo arm. Similarly, Dr. Inzucchi stated several times that the glucose-lowering benefit of empagliflozin cannot alone account for the cardioprotection seen in EMPA-REG OUTCOME. In some respects, the A1c difference in EMPA-REG OUTCOME has become a bit of a double-edged sword in our view – some also suggest on the flip side that empagliflozin is not a very efficacious glucose-lowering drug on the basis of the relatively modest A1c reductions observed in EMPA-REG OUTCOME, though the goal of the trial was treat-to-target and those in the placebo arm were free to modify treatment to try and achieve the target A1c.
• We heard several other strong opinions on the potential mechanism behind the EMPA-REG OUTCOME findings. Dr. Eberhard Standl noted that he suspects the cardioprotective effect can be attributed to a reduction in renal glucotoxicity with the ultimate consequence of intravascular volume contraction and a decrease in blood pressure. On the other hand, Dr. John McMurray (University of Glasgow, UK) strongly favored blood pressure lowering as the main driver of the effect, noting that even small decreases in blood pressure have been shown to have positive outcomes for heart failure in other trials. More generally, several other speakers pointed to some sort of hemodynamic diuretic effect, though most also acknowledged the intriguing fuel energetics (“thrifty substrate”) hypothesis posted by Dr. Ele Ferrannini at ADA 2016. The various commentators virtually all agreed that an atherosclerotic driver of the effect would be likely, as the Kaplan-Meier curves in the EMPA-REG OUTCOME trial diverged rapidly, possibly in a matter of weeks. Dr. Steven Nissen summed that “the road to hell is paved with biological plausibility” and that we often try to create mechanistic hypotheses when we don’t understand a finding, but ultimately we just don’t know.

Detailed Discussion and Commentary

A Perspective on the Effects of Empagliflozin on Cardiovascular Outcomes

Effect of Empagliflozin on Cardiovascular Mortality by Prevalent or Incident Heart Failure in EMPA-REG OUTCOME

David Fitchett, MD (University of Toronto, Canada)

Dr. David Fitchett presented a new sub-analysis of EMPA-REG OUTCOME demonstrating treatment with SGLT-2 inhibitor empagliflozin (Lilly/BI’s Jardiance) led to (i) a risk reduction for a variety of heart failure outcomes and (ii) a risk reduction for cardiovascular death in patients with “heart failure burden.” The originally-published results found a 35% risk reduction in hospitalization for heart failure throughout the trial with empagliflozin treatment. This new analysis found that empagliflozin significantly reduced the risk of a variety of other measures of heart failure including (i) investigator-reported heart failure (HR=0.70; 95% CI=0.56-0.87); (ii) composite of hospitalization for heart failure or investigator-reported heart failure (HR=0.70; 95% CI=0.57-0.87); (iii) introduction of loop diuretics (HR=0.62; 95% CI=0.53-0.73); and (iv) composite of hospitalization for heart failure and introduction of loop diuretics (HR=0.63; 95% CI=0.54-0.73). Furthermore, empagliflozin treatment was associated with a 33% cardiovascular mortality risk reduction in patients with “heart failure burden,” defined as a composite of investigator-reported heart failure at baseline, hospitalization for heart failure during the trial, and investigator-reported heart failure during the trial (HR=0.67; 95% CI=0.47-0.97). Like the Kaplan-Meier curves for CV mortality and hospitalization for heart failure in the original EMPA-REG OUTCOME analysis, the curves for CV mortality in patients with heart failure burden on empagliflozin and on placebo diverged early (within 6 months) and continued to diverge throughout the trial. CV mortality risk trended in the same direction for each of these components individually, but was not statistically significant. Empagliflozin’s CV mortality benefit hazard ratio was similar in patients without heart failure burden at 0.63 (95% CI=0.48-0.84). In patients with heart failure burden, empagliflozin was associated with a 4.9% reduction in absolute mortality, compared to a 1.4% absolute mortality reduction in patients without heart failure burden and a 2.2% absolute mortality reduction overall. Dr. Fitchett attributed this finding to the fact that patients with heart failure burden are a higher-risk group at baseline.

• The talk highlighted that patients with and without heart failure burden benefited from empagliflozin. Patients with heart failure burden, as a higher-risk group, experienced a greater absolute reduction in mortality. Due to the wholly unexpected nature of the finding, a frequently-cited limitation of EMPA-REG OUTCOME is that investigators did not have the foresight to rigorously test for heart failure at baseline; the ~10% of patients who were reported to have heart failure at baseline was likely an underestimate of the true prevalence among participants. These subsequent post-hoc analyses attempt to close the gap, though clear data will likely not be available until the completion of the planned trials of empagliflozin in patients with heart failure, with and without diabetes.
• This analysis is the latest in a series of post-hoc analyses for EMPA-REG OUTCOME which dig further into the surprising heart failure benefit. Previously, Dr. Silvio Inzucchi (Yale University, New Haven, CT) presented data at AHA 2015 (and published in the European Heart Journal) demonstrating that reduced risk for hospitalization for heart failure or cardiovascular death was consistent regardless of heart failure status at baseline. That said, the hazard ratios for hospitalization for heart failure, CV mortality, a composite of hospitalization for heart failure and CV mortality, and all-cause mortality in patients with baseline heart failure were non-significant, though they trended in the right direction. Dr. Inzucchi also shared that empagliflozin led to a 30% risk reduction of investigator-reported heart failure, which Dr. Fitchett reiterated in his presentation. Dr. Fitchett had previously presented a sub-analysis of EMPA-REG OUTCOME data at ACC 2016 showing (i) consistent risk reductions for hospitalization for heart failure and cardiovascular death regardless of baseline usage of loop diuretics and (ii) a non-significant trend toward reductions in cardiovascular and all-cause mortality in patients who were hospitalized for heart failure during the trial.  

Questions and Answers

Dr. Eberhard Standl: In the EMPA-REG OUTCOME trial, only 10% of participants had a history of heart failure at baseline. This is a very low number considering the very high-risk population you’re studying. Can you exclude the possibility of undiagnosed heart failure at baseline? Especially if you consider that SAVOR-TIMI found that close to 50% of its participants may have had heart failure at baseline based on BNP measurements.

Dr. Fitchett: Did we under-diagnose heart failure? I’m sure we did. I think the fact that we have the additional patients with investigator-reported heart failure and with the introduction of loop diuretics is exactly why we included them in this group for analysis. Having said that, there are patients who don’t have this heart failure burden in the trial as well. We can say that it appears that empagliflozin has an extra benefit in this patient population with heart failure burden, but that doesn’t exclude its benefit in others without heart failure burden.

Effect of Empagliflozin on Cardiovascular Death in Subgroups by Age: Results from EMPA-REG OUTCOME

David Fitchett, MD (University of Toronto, Canada)

Dr. David Fitchett presented a reassuring new sub-analysis of the EMPA-REG OUTCOME results, demonstrating that the cardiovascular and all-cause mortality benefits observed in the trial was consistent across all age groups and particularly reinforcing that SGLT-2 inhibitor empagliflozin (Lilly/BI’s Jardiance) is safe in elderly populations. The post-hoc analysis stratified participants in the trial into three age groups at baseline: (i) those under 65; (ii) those between ages 65-74; and (iii) those 75 and over. The analysis was adjusted for sex, baseline BMI, baseline A1c, baseline eGFR, region, and additional treatments. Very reassuringly, the analysis found that the risk reduction for cardiovascular death was sustained across all age groups and remained significant. The hazard ratio was 0.72 (95% CI: 0.54-0.96) for participants under 65, 0.52 (95% CI=0.37-0.79) for participants ages 65-74, and 0.55 (95% CI=0.32-0.94) in participants ages 75 and older – for comparison, the overall hazard ratio for cardiovascular death in the trial was 0.62 (95%=0.49-0.77). There was a slight trend toward greater risk reduction in participants ages 65 and older, but the difference between groups was non-significant (p=0.484 for interaction). Dr. Fitchett pointed out, however, that the Kaplan-Meier curves for cardiovascular mortality for each age subgroup had a larger divergence as the age increased. All-cause mortality was similarly consistent across groups (HR for <65=0.72 [95% CI=0.54-0.96]; HR for 65-74=0.68 [95% CI=0.51-0.92]; HR for ≥75=0.61 [95% CI=0.41-0.93]; compared to HR for all participants=0.68 [95% CI=0.57-0.82]; p=0.836 for interaction).

• Dr. Fitchett pointed out that as patients age, competing risks can often overshadow a cardiovascular mortality benefit and these all-cause mortality results are very reassuring in that context. Overall adverse events, UTIs, volume depletion, acute kidney injury, and bone fractures were more frequent in the older age groups overall, but there was no increase in each of these adverse events in the empagliflozin-treated participants compared to placebo within any subgroup. If anything, older participants experienced a greater reduction in acute kidney injury associated with empagliflozin treatment than those in younger age groups. All other adverse events, including hypoglycemia and genital mycotic infections, were consistent across all age and treatment groups. Dr. Fitchett noted that adverse events can often increase in elderly populations so these results are also reassuring.

Effect of empagliflozin on heart failure outcomes in subgroups by age: results from EMPA-REG OUTCOME

Pedro Monteiro, MD (University of Coimbra, Portugal)

Dr. Pedro Monteiro further demonstrated that empagliflozin’s benefit on hospitalization for heart failure was consistent across all age groups in a new post-hoc analysis of EMPA-REG OUTCOME. Like the cardiovascular and all-cause mortality analysis, this analysis examined the impact of empagliflozin on heart failure in participants stratified into three baseline age groups (i) those under 65; (ii) those ages 65-74; and (iii) those 75 and over. This analysis was adjusted for sex, baseline BMI, baseline A1c, baseline eGFR, region, and additional treatments. The analysis found that empagliflozin was consistently safe in terms of hospitalization for heart failure, regardless of baseline age. In fact, older participants appeared to experience a greater benefit for hospitalization for heart failure with treatment (though the difference was non-significant [p=0.488 for interaction]) and the 75 and older subgroup was the only subgroup in which the reduction in hospitalization for heart failure was statistically significant (HR=0.45; 95% CI=0.22-0.89). Hospitalization for heart failure results certainly trended in the right direction for the under 65 and age 65-74 age groups, but the confidence intervals just barely crossed the line of unity (HR for <65=0.73 [95% CI=0.48-1.10] and HR for 65-74=0.66 [95% CI=0.44-1.00]). For comparison, hospitalization for heart failure in the overall EMPA-REG OUTCOME trial had a hazard ratio of 0.65 (95% CI=0.50-0.85). Subgroup analysis for a composite of heart failure hospitalization and cardiovascular death found similar results. The hazard ratio was 0.78 (95% CI: 0.59-1.03) for participants under 65, 0.59 (95% CI=0.44-0.80) for participants ages 65-74, and 0.52 (95% CI=0.33-0.82) in participants ages 75 and older – for comparison, the overall hazard ratio for the composite of hospitalization for heart failure and cardiovascular death in the trial was 0.66 (95%=0.55-0.79). There was no significant difference in the results between age groups (p=0.240 for interaction).

• Like the cardiovascular death results presented by Dr. Fitchett, the Kaplan-Meier curves for the composite of hospitalization for heart failure and cardiovascular death diverged more in older age groups. DPP-4 inhibitors are currently often recommended as the diabetes drug of choice for many elderly patients with diabetes, given their benign safety and tolerability profile. The findings from this sub-analysis and that of empagliflozin’s impact on mortality across age groups could help position empagliflozin or the SGLT-2 inhibitor class as a whole as a preferred alternative, especially given the suggestion that empagliflozin’s impressive heart failure and cardiovascular mortality benefits could be magnified in elderly patients.

Cardiovascular outcomes according to LDL cholesterol levels in EMPA-REG OUTCOME

Gisle Langslet, MD (Oslo University Hospital, Norway)

Dr. Gisle Langslet shared a new sub-analysis demonstrating that the impact of empagliflozin on cardiovascular outcomes and all-cause mortality were consistent across all baseline LDL cholesterol levels. The analysis examined results for the primary outcome of three-point MACE (cardiovascular death, non-fatal MI, and non-fatal stroke) and for the secondary outcomes of hospitalization for heart failure and all-cause mortality in five baseline LDL subgroups: (i) <70 mg/dl; (ii) 70 mg/dl-84 mg/dl; (iii) 85 mg/dl-99 mg/dl; (iv) 100 mg/dl-115 mg/dl; and (v) >115 mg/dl. Like the age sub-analyses, this analysis adjusted for sex, baseline BMI, baseline A1c, baseline eGFR, region, and treatment. Notably, those in the lower LDL cholesterol groups were actually more likely to have coronary artery disease than those with higher LDL cholesterol – presumably, these patients were under more stringent LDL management due to their higher-risk status. Unsurprisingly, those with lower LDL were more likely to be on statins. In the placebo arm, rates of three-point MACE, cardiovascular death, and all-cause death demonstrated a J-shaped curve when stratified by baseline LDL: the two subgroups with the highest baseline LDL experienced the greater event rate, followed by the two subgroups with the lowest baseline LDL, while the middle group had the lowest rates of events overall. However, this J-shape was attenuated in the empagliflozin-treated arm: with empagliflozin treatment, all LDL subgroups tended to experience similar event rates. There was no such J-shaped curve in either the placebo or empagliflozin arms in terms of hospitalization for heart failure. Although there was a degree of heterogeneity in hazard ratios for three-point MACE, cardiovascular death, all-cause death, and hospitalization for heart failure across the LDL subgroups, but p-values for interaction were all non-significant (results summarized in table below). 

Future Direction for Research in Empagliflozin Heart Failure Treatment

Pantelis Sarafidis, MD (Aristotle University of Thessaloniki, Greece)

Dr. Pantelis Sarafidis great enthusiasm over the renal outcomes data from EMPA-REG OUTCOME for empagliflozin, suggesting that empagliflozin on top of best available treatment was able to achieve a stabilization of eGFR that 30 years of diabetic nephropathy drug development has been unable to achieve thus far. He noted that, in the placebo arm of EMPA-REG OUTCOME trial, eGFR declined steadily throughout the trial at a rate that was expected for patients being treated to standard of care. By contrast, participants in the empagliflozin-treated arm experienced an initial decrease in eGFR, followed by subsequent eGFR stabilization that lasted throughout the remainder of the trial. Dr. Sarafidis characterized empagliflozin as an “eGFR stabilizer” and emphasized that these results were just as significant as the very impressive cardiovascular outcomes most of the cardiologists in the room were focused on. After all, he noted, EMPA-REG OUTCOME achieved two publications in NEJM within one year– one with the cardiovascular results and one with the renal results – a feat that, underlines the importance of these findings.

• Dr. Sarafidis also suggested that this nephroprotective effect and delay in chronic kidney disease (CKD) progression could contribute toward the cardioprotective benefits of the drug, as CKD is associated with exponentially higher risk of cardiovascular events. He called for further studies with hard renal endpoints with empagliflozin to better understand this renal benefit and mentioned the ongoing CREDENCE trial to investigate J&J’s SGLT-2 inhibitor Invokana (canagliflozin) in patients with stage two or three chronic kidney disease. As a reminder, the composite primary endpoint is the time to the first occurrence of either end-stage renal disease (ESRD), doubling of serum creatinine, renal death, or cardiovascular death.  According to ClinicalTrials.gov, CREDENCE has an expected primary completion date of February 2019 and a full completion date of January 2020. J&J is also conducting a long-term CANVAS-R renal study, though that study is a biomarker study with progression to albuminuria as its primary endpoint (expected completion in February 2017, according to ClinicalTrials.gov). We’re certainly looking forward to the results of both trials as well – diabetic nephropathy continues to be an area of extremely high unmet need, despite a fairly robust competitive landscape, and many candidates are not advanced past phase 1 or 2 for this indication given the high cost of conducting pivotal trials with hard renal outcomes. It would be a huge win if already-marketed drugs could gain an indication for diabetic nephropathy.

Clinical Trial Update: Prevention

The Relationship Between Severe Hypoglycaemic Events and Cardiovascular Outcomes is Bidirectional: Novel Results from TECOS

Eberhard Standl, MD (Munich Diabetes Research Center, Germany)

Dr. Eberhard Standl presented results from an intriguing new post-hoc analysis of TECOS suggesting that non-fatal cardiovascular events and hospitalization for heart failure are associated with increased risk for subsequent severe hypoglycemic episodes. At baseline, those who experienced a severe hypoglycemic event in TECOS were more likely to be older, insulin-treated, women, and non-white and to have a longer diabetes duration, lower eGFR, and lower BMI. Dr. Standl suggested that these are confounding factors and that previous studies associating severe hypoglycemia with increased CV events and mortality may have failed to adequately account for these variables. The new analysis focused on the 68 participants in the TECOS trial who experienced a severe hypoglycemic episode and either a MACE-plus event (cardiovascular death, non-fatal MI, non-fatal stroke, or hospitalization for unstable angina) and/or hospitalization for heart failure. Of these 68 participants, 34 experienced the severe hypoglycemic episode before the CV event and 41 experienced it after, while seven participants experienced it both before and after. While the unadjusted analysis did find an association between prior severe hypoglycemic episodes and subsequent CV events (including MACE-plus [HR=1.57, p=0.02], MACE [HR=1.71, p=0.007], all-cause death [HR=1.91, p=0.002], and cardiovascular death [HR=1.81, p=0.024]), all of these associations became non-significant after adjusting for the potential confounding factors.

• On the other hand, the association between a prior non-fatal MI or hospitalization for heart failure and a subsequent severe hypoglycemic episode remained significant even after adjusting for the confounding factors. After adjustment, those with a prior non-fatal MI were more than twice as likely to experience a severe hypoglycemic episode (HR=2.39; 95% CI=1.64-3.47; p<0.0001) and those with a prior hospitalization for heart failure were nearly three times as likely to experience a severe hypoglycemic episode (HR=2.80; 95% CI=1.77-4.42; p<0.0001). Unadjusted, prior non-fatal stroke was also associated with subsequent severe hypoglycemic episodes (HR=2.74; 95% CI=1.35-5.56; p=0.0052), but this trend became non-significant after adjusting for confounding factors. Dr. Standl interpreted this to mean that rather than a causal factor for CV events, severe hypoglycemic episodes may be an indicator of patients with type 2 diabetes who are at high risk for both CV events and hypoglycemia.

Cardio-diabetology Alliance – The Myth Busters

Metformin Will Remain the First Option in Oral Treatment of Diabetes

Naveed Sattar, MD (University of Glasgow, UK)

Dr. Naveed Sattar suggested that SGLT-2 inhibitors may eventually replace metformin as the preferred first-line therapy in some people with type 2 diabetes, though he ultimately concluded that head-to-head trials and cost effectiveness analyses will be required for a true paradigm shift. Dr. Sattar reviewed the many reasons for metformin’s broad use as a first-line therapy, namely its glucose-lowering efficacy (similar or better than other oral agents), low risk of hypoglycemia, weight neutral/weight loss effect, potential for cardiovascular or cancer risk reduction, and most importantly, it’s very low cost (“cheap as chips!”). Dr. Sattar further noted that metformin has now been shown to be safe in patients with impaired renal function down to eGFR of 30 ml/min/1.73m² and that it’s growing in popularity for indications outside of type 2 diabetes, including prediabetes, type 1 diabetes, weight loss in general, and polycystic ovary syndrome (PCOS). That said, Dr. Sattar offered a more critical view of some of the purported benefits of the drug. Most notably, he suggested that evidence for metformin’s potential cardioprotective benefit is weak by modern standards, as it’s largely derived from 39 events in the UKPDS study (n=342 in the metformin group) that found a 39% risk reduction for MI with metformin therapy. Dr. Sattar pointed out the inconsistency between this touting of metformin’s cardioprotective benefit and the finding from UKPDS that metformin added to sulfonylureas was associated with a 60% higher risk of MI (the latter was dismissed as chance due to small numbers). Furthermore, Dr. Sattar argued that most of the suggested mechanisms of cardioprotection for metformin are unlikely to actually have a significant impact on CV risk, noting that 2 kg of weight loss likely has a minor effect and that metformin’s impact on LDL cholesterol is attenuated in the context of statins (indeed, he emphasized that UKPDS occurred in the pre-statin era).

• Dr. Sattar also pointed out that metformin has potential downsides for patients’ quality of life – the drug is administered two or three times daily and is associated with significant GI side effects in some. He posed SGLT-2 inhibitors an attractive alternative to metformin, especially emphasizing the impressive EMPA-REG OUTCOME results demonstrating a cardioprotective benefit for Lilly/BI’s Jardiance (empagliflozin) with evidence of much higher quality. Dr. Sattar doubled-down on the paradigm- and guideline-shifting nature of the study, but also acknowledged that it’s only a single study in secondary prevention and that empagliflozin and other SGLT-2 inhibitors are many times more expensive than metformin.
• Dr. Sattar concluded that metformin is unlikely to be dethroned as the preferred first-line therapy anytime soon due to its low cost, but he “bets his bottom dollar” that there will be a subset of patients for whom SGLT-2 inhibitors or SGLT-2 inhibitor/metformin combinations will become the preferred first-line option. We’ve heard increasing commentary in recent months suggesting that metformin may be losing its pull as the go-to first-line therapy for patients with type 2 diabetes, though we expect it will continue to maintain its popularity in the broader diabetes population due to its long history on the market, generic status, and low cost. We also hope to see metformin gain broader acceptance as a prediabetes medication.

Cardiovascular Mortality Cannot be Decreased by Antidiabetic Drugs

Eberhard Standl, MD (Munich Diabetes Research Center, Germany)

Dr. Eberhard Standl posited that the glucose-lowering effect of GLP-1 agonist liraglutide (Novo Nordisk’s Victoza) and SGLT-2 inhibitor empagliflozin (Lilly/BI’s Jardiance) cannot be totally excluded to be at least partially responsible for the impressive cardiovascular benefits demonstrated by the two agents in the LEADER and EMPA-REG OUTCOME trials, respectively. Glycemic control in these studies did not meet “glycemic equipoise” as e.g. in the TECOS trial, i.e. with minimal A1c differences in-between randomized groups of no more than 0.2-0.3%. He highlighted the initial 1.5% A1c reduction seen with the liraglutide-treated group compared to the placebo-treated group and the 0.4% differential seen at 36 months in the LEADER trial, despite the fact that the placebo arm was treated to standard of care and given insulin if needed. He also highlighted the A1c difference between the empagliflozin-treated and placebo arms of the EMPA-REG OUTCOME trial was also considerable and about half of that seen in LEADER. Indeed, Novo Nordisk CMO Dr. Mads Thomsen has suggested that glucose reduction plays a role in the positive finding of LEADER, but also suggested that glucose control alone can’t account for the entirety of the benefit.

Corporate Symposium: SGLT2 Inhibition in the Management of CV Risk & T2DM: Ask the Experts (Sponsored by Lilly/BI)

John Eric Deanfield, MD (University College Hospital, London, UK) and Silvio Inzucchi, MD (Yale University, New Haven, CT)

In a corporate symposium on the EMPA-REG OUTCOME results, Drs. Silvio Inzucchi and John Deanfield emphasized how the results herald a new era of cardiologists and diabetologists working together. Dr. Silvio Inzucchi (Yale University, New Haven CT) shared his joy that he could finally, for the first time, offer cardiologists a diabetes drug that impacts cardiovascular events and that it’s “high time” for cardiologists and diabetologists to begin working together. Similarly, cardiologist Dr. John Deanfield (University College London, UK) characterized the post-EMPA-REG OUTCOME period as a new era with cardiovascular disease management within the context of diabetes and added that these new diabetes drugs with cardiovascular benefits have the important effect of bringing diabetologists and cardiologists together to address cardiovascular prevention. Furthermore, Dr. Deanfield pointed out that the novel, largely glucose-independent mechanisms of cardiovascular benefit with empagliflozin and liraglutide – especially coupled with the lack of induced hypoglycemia with these drugs – may lead to expanded indications for use earlier in the course of treatment (perhaps even in primary prevention of cardiovascular disease, or in patients without diabetes). Cardiologists in an ensuing Q&A discussion appeared tantalized by the prospect of cardiovascular prevention in people with prediabetes.

Questions and Answers

Q: This is indeed an exciting new drug. It is often looked at as a glucose-lowering drug with cardiovascular benefits. On the other hand, cardiologists want to look at it as a cardiovascular drug with an antihyperglycemic effect. Would it be rational to design another trial of empagliflozin in prediabetic or non-diabetic individuals with high CV risk? This could be similar to how statins started out as a lipid-lowering drug that we now give to patients with average or even low LDL cholesterol levels.

Dr. Inzucchi: Thank you for bringing up this point. Yes, this drug lowers glucose, but when you look at the EMPA-REG OUTCOME data, the benefit cannot be related to glucose control alone. The next step is to investigate this drug in high-risk patients with overt cardiovascular disease who don’t have diabetes or, first, who have prediabetes. If you or I took an SGLT-2 inhibitor, we would have many of the same metabolic effects, including glycosuria and weight loss, though perhaps not to the same degree. Those studies are being formulated. Empagliflozin opens up a whole new door to our understanding of the disease.

Comment: It’s also important to note that in patients with normal glycemia, SGLT-2 inhibitors don’t bring down the glucose to the point of hypoglycemia.

Dr. Inzucchi: Very good point. One aspect of SGLT-2 inhibition is it is not associated with hypoglycemia, even in diabetic patients. You don’t induce hypo unless a drug’s mechanism involves an increase in insulin supply, such as with sulfonylureas. You should not get hypoglycemia even in a patient that starts off with normal glucose. Once the glucose approaches the low-normal range, insulin production will shut off.

Q: What are the other SGLT-2 inhibitors available and how can compare them? Also, can you talk about the side effects of this class, UTIs especially?

Dr. Inzucchi: There are three SGLT-2 inhibitors available on the market: empagliflozin, dapagliflozin, and canagliflozin. They are similar in terms of their mechanism of action, but the CVOTs for dapagliflozin (DECLARE) and canagliflozin (CANVAS) are currently underway. In the next two to three years, we should have data from these trials. Everyone is asking if this is class effect, but the jury’s still out on that. We’ve been burned before in the diabetes field by assuming drugs in the same class are similar – rosiglitazone and pioglitazone are an example of this.

The main side effects of SGLT-2 inhibitors relate directly to their mechanism of action. When there’s more glucose in the urine, there’s an increase in genital mycotic infections (in women especially but also even in men). It’s typically just one episode and can be treated with over-the-counter topical treatments, so it’s usually not a big problem.   However, in those with recurrent episodes, the drug should be stopped.  In some studies, UTI rates increased, but we didn’t see this in EMPA-REG OUTCOME.  Polyuria is also frequent and in men with BPH, this can become a significant quality of life issue.  In my mind, the most important side effect is the recent reports of DKA. This has been mainly reported in type 1 diabetes – for whom this class is not approved. DKA tends to occur after a major insulin dose reduction has occurred and often in the context of another insulin, such as a viral illness.  Since the mechanism of action of SGLT2 inhibitors is entirely insulin-independent, there is a temptation to consider them in difficult-t0-control type 1 patients, and this is under active investigation. Personally, I don’t advise using them in type 1 diabetes. I would also point out, however, that DKA can occur in type 2 diabetes, almost always in those already on insulin. We’re not sure what’s going on there – the sense is that these are very insulin-deficient patients, perhaps with autoantibodies, who are behaving more like type 1. As with any drug, there’s a risk-benefit ratio to consider with the SGLT2 inhibitors

Q: In patients with heart failure already on loop diuretics, do you adjust the dose when implementing SGLT-2 inhibitor therapy.

Dr. Deanfield: It’s becoming clear that one of the main mechanisms of action of empagliflozin is its effect on volume diuresis and naturesis that occurs with glucose loss in the kidney. This is probably one of the most important effects driving benefits. In terms of acting like a diuretic, it is a diuretic essentially – like someone previously said, many people may think it’s reasonable to look at it as a cardiovascular drug with a blood sugar side benefit. You do have to adjust diuretics when using them and you do lose volume.

Dr. Inzucchi: On the other hand, I want to caution and point out that no adjustments to loop diuretics were mandated by the EMPA-REG OUTCOME trial. We shouldn’t necessarily a priori reduce the diuretic dose – they’re relatively weak diuretics. That said, if you think a patient is particularly fragile, you may consider a reduction.

Q: I’m an enthusiastic prescriber of this drug based on the results from this trial. Looking at the results, empagliflozin dramatically lowers cardiovascular death, but it doesn’t reduce MI and actually slightly increases the stroke risk. So what were people actually dying of in EMPA-REG OUTCOME?

Dr. Inzucchi: That was my first impression when we first saw the results too. We didn’t expect to see such a dramatic effect on cardiovascular mortality. We showed some of this data at ACC a few months ago, but when you break down the reasons for CV death, every cause moved in the right direction – fatal MI, fatal stroke, heart failure mortality, sudden death, and ‘other.’ “Other” is often a major category in these trials, referring to when a person was found dead without obvious cause and presumed to have been due to a CV cause. So, it was not a single component of CV death driving the risk reduction. But the early temporal divergence and the inconsistency within the components of three-point MACE to me suggests that this is not related to atherosclerosis – it must be hemodynamic. This sparks a big discussion about the potential of this drug to affect heart failure outcomes, and not just in patients with diabetes.

Comment: Two points: one, I think a lot of patients have heart failure and we don’t know it. Two, this is the first drug where patients experienced reduced events, but also it’s the only drug I’ve prescribed where patients say they feel better when taking it.

Dr. Inzucchi: Dr. Fitchett will be presenting some really interesting follow-up data from the EMPA-REG OUTCOME trial later this afternoon. We took patients who had heart failure either during or before the trial and compared event rates in this group to those who had no heart failure at all. I cannot divulge the results as they are still embargoed, but they are very interesting.

Q: A lot of these patients also have hypertension and are taking ARBs or ACE inhibitors. We know that when dealing with these drugs, volume shifts sometimes are a problem. Do you have a specific sub-analysis of patients taking these drugs?

Dr. Inzucchi: Two come to mind. We did a subgroup analysis of those on ACE inhibitors/ARBs vs. those who were on other drugs for hypertension and there was no different in event rate between the two groups. The other analysis was based on GFR. If you’re tentative in that this drug needs reasonable GFR to work, well, we enrolled participants with GFR down to 30 in this trial and there was no heterogeneity – empagliflozin seemed to benefit all across the spectrum of kidney function.

Dr. Deanfield: The background therapy in EMPA-REG OUTCOME was really good – these patients were on statins, RAAS inhibitors, etc. This is an additional benefit on top of classical treatment. Overall, there are lots to learn about this class of drugs. Now, as cardiologists, we should take extra interest in blood sugar treatments.

Corporate Symposium: Addressing Cardiovascular Risk in Type 2 Diabetes – The LEADER Trial (Sponsored by Novo Nordisk)

Lars Rydén, MD, PhD (Karolinska Institute, Stockholm, Sweden), Steve Nissen, MD (Cleveland Clinic, OH), John Petrie, PhD (University of Glasgow, UK), Mansoor Husain, MD (Toronto General Research Institute, Canada)

Both Drs. Lars Rydén and Mansoor Husain suggested that the difference in the neutral cardiovascular effect seen in the ELIXA trial for Sanofi’s Lyxumia/Adlyxin (lixisenatide) and the positive effect seen in LEADER could be attributed to the short-acting nature of lixisenatide versus the long-acting nature of liraglutide. As the half-life of lixisenatide is much shorter than liraglutide but both are dose once-daily, the two suggested that the dosing of lixisenatide may not be adequate to provide continuous efficacy/bioavailability throughout the day. The heterogeneity in CVOT results for GLP-1 agonists thus far is certainly intriguing. Novo Nordisk’s even longer-acting semaglutide has reported topline results demonstrating a cardioprotective benefit for the drug while Intarcia’s implantable ITCA 650, which involves a continuous mini-pump of the short-acting exenatide molecule, demonstrated a neutral effect on cardiovascular outcomes. Novo Nordisk CMO Dr. Mads Thomsen has suggested that there may be a difference in cardioprotective potential between acylated and non-acylated GLP-1 agonists. On the other hand, the differences could be more related to trial design rather than true heterogeneity within the class. After all, both the SUSTAIN 6 trial of semaglutide and the FREEDOM-CVO trial for ITCA 650 were fairly short, small pre-marketing safety trials primarily designed to meet the 1.8 hazard ratio threshold for adequate safety to win FDA approval. It’s quite possible that a cardiovascular benefit for ITCA 650 may emerge in a longer trial where more patient exposure to the drug. If the heterogeneity between the LEADER and ELIXA trials is due to inadequate GLP-1 agonist bioavailability throughout the entire day with lixisenatide, ITCA 650 completely absolves that problem by releasing a continuous, steady dose of exenatide for six months up to a year. On the other hand, Dr. Jay Skyler has previously also suggested that the neutral ELIXA results can be primarily attributed to Sanofi enrolling an extremely high-risk population whose disease was, in a sense, too far advanced for significant modification through the GLP-1 agonist.

LEADER – Cardiovascular Outcomes & The Cardiologist’s Perspective

Steve Nissen, MD (Cleveland Clinic, OH)

With his characteristic candor, Dr. Steve Nissen suggested that he is somewhat vindicated in calling for the FDA’s controversial 2008 CVOT policy in light of the positive LEADER and EMPA-REG OUTCOME results during a Novo Nordisk-sponsored corporate symposium on the LEADER results. In Dr. Nissen’s view, prior to the FDA’s 2008 guidance, there was a huge knowledge gap in the diabetes field on the actual CV effects of diabetes drugs. He attributed this largely to a “misguided regulatory policy” that relied too much on a gluco-centric view of diabetes. He emphasized that the 2008 guidance was designed as a compromise between bringing drugs to market quickly and gathering robust outcomes data for diabetes drugs. While acknowledging that there was significant pushback from the diabetes community at the time, Dr. Nissen emphasized that he and a minority of others firmly believed that we would eventually learn important information from these trials and applauded Novo Nordisk for having the “courage” to design the LEADER trial to be large enough to demonstrate both non-inferiority and superiority. Dr. Nissen characterized the findings from the LEADER trial as a “dawning of a new era of enlightenment,” a “coming out of the dark ages” after “60 years of stagnation.” Moving forward, he suggested that providers and patients will be able to select medications based on their impact on hard clinical outcomes rather than biomarkers – a revolution in his view. While the LEADER (and EMPA-REG OUTCOME) results are clearly groundbreaking, we continue to believe that the FDA CVOT guidance could be revised to maximize efficiency in light of the limited resources within diabetes. We would love to see incentives for companies to conduct CVOTs for drugs that may show cardioprotection (indeed, Novo Nordisk recently reiterated its commitment to scientific discovery and the launch of a larger CVOT for semaglutide even if the company doesn’t strictly need to). We’d also like to see requirements for CVOTs for drugs that may have the potential for harm, but less stringent outcomes requirements for the many products that fall between these two ends of the spectrum. We imagine the high cost of conducting a CVOT serves as a major barrier to entry for smaller biotech companies that might otherwise be interested in investing more seriously in diabetes.

• Dr. Nissen concluded by urging his fellow cardiologists to learn to prescribe glucose-lowering medications themselves rather than automatically referring patients to endocrinologists for their diabetes management. He emphasized that, as a cardiologist, he treats his patients’ blood sugars as he does any other risk factor (such as cholesterol, blood pressure, etc.). As further strategies to modify residual CV risk in patients with diabetes come to light, we imagine the line between endocrinologists and cardiologists will become further blurred. We also imagine having a single provider prescribe cardiovascular and diabetes medications could improve continuity of care and reduce the burden of doctors’ visits for the patient. That said, Dr. Nissen acknowledged that he still refers some of his more complex cases – such as patients requiring complicated insulin pump therapy – to endocrinologists for their diabetes care.

Questions and Answers

Dr. Rydén: Both EMPA-REG OUTCOME and LEADER were performed in people with cardiovascular disease with quite advanced or longstanding type 2 diabetes. What are your opinions on when this will appear in the guidelines and what do you think is the future when you’re choosing what diabetes agents to use?

Dr. Nissen: I do think it should influence what we do. That said, the newer agents are much more expensive than metformin – by the way though, I’m not at all convinced that if metformin were studied in a formal outcome trial, it would show vascular benefit. Now we need to make a decision on which patients to treat with newer agents, recognizing that they’re more costly and are sometimes harder to give (liraglutide is an injection for example). What makes me want to change clinical practice is the effect on mortality. If it was just an effect on non-fatal MI, that’s one thing, but when people live longer on a therapy, we better have a good reason not to give it. Survival is the most important endpoint.

Dr. Husain: Within a year of the publication of EMPA-REG OUTCOME, the Canadian diabetes guidelines identified that providers can consider giving empagliflozin earlier in individuals with cardiovascular disease. It remains to be seen how the cardiology guidelines follow.

Dr. Rydén: In the new ESC guidelines that just came out, SGLT-2 inhibitors are mentioned, and their use is recommended in patients who are sensitive or prone to heart failure. The problem with the European guidelines, which we’ve addressed in a comment to the European Heart Journal, is that there were some faulty statement about incretins by large, suggesting that they may have a negative impact on heart failure whereas the impact is actually variable across different agents. I believe the guidelines will pick up the results of EMPA-REG OUTCOME and LEADER quickly because we haven’t seen results like these is a long time and they’re really quite amazing.

Another question: we have these unexpected results and now two different types of drugs – SGLT-2 inhibitors and GLP-1 agonists – that show beneficial effects and we don’t know exactly why. This opens the door for new studies, new mechanistic trials, and attempts to understand why. One agent takes a long time to act and the other acts quickly – why do you think that is?

Dr. Husain: I don’t fully understand why the one works so quickly. There’s some nice data that it improves markers like arterial stiffness and filling pressures in the heart, but one can’t make a fully credible hypothesis on how it reduces heart failure. To me, the slower divergence of curves in LEADER is not as surprising – perhaps it is more targeting atherosclerotic properties; this wouldn’t happen in weeks or days like a hemodynamic drug would.

Dr. Nissen: Diuretics are good blood pressure lowering drugs, but they have adverse metabolic effects. Perhaps one of the reasons we haven’t seen better results with diuretics is because they are associated with worse glucose control, which might have a negative impact on cardiovascular outcomes. At the end of the day, a favorite saying of mine is “the road to hell is paved with biological plausibility.” When we get a result that we don’t understand, we often come up with a billion reasons to try to understand it, but rarely do we fully understand it at the end of the day.

Q: If the difference in A1c was the same in the two groups, do you think you’d have this cardiovascular benefit?

Professor Petrie: I think there’s plenty of drugs that lower A1c by 0.4% that haven’t shown a cardiovascular benefit, so I don’t think you can attribute the benefit to the glucose-lowering effect.

Dr. Husain: I’d take it a step further. If the placebo arm had managed to achieve the same glucose control, I think the curves would’ve diverged even more because the placebo arm would’ve been using drugs that I don’t consider safe.

Dr. Rydén: The hypoglycemia reduction with liraglutide seen in LEADER may be related to that. One interpretation of the LEADER trial is that the addition of a GLP-1 agonist in patients on insulin will reduce the risk for not the least severe hypoglycemia, perhaps due to a reduced need for insulin. In addition, more participants in the placebo arm initiated sulfonylureas and insulin throughout the trial, which could be a reason for their higher hypoglycemia rates. This is an important point.

Dr. Nissen: There’s lots of plausible mechanisms for the cardiovascular benefit and the hypoglycemia reduction could be one of them. That said, the ACCORD investigators tried very hard to implicate hypoglycemia as the cause of the increased all-cause mortality, but they had a very hard time statistically pinning it on that.

Dr. Rydén: On the other hand, in the ORIGIN trial, we showed that there was a higher mortality in those with non-insulin induced hypoglycemia. Sulfonylureas may be the problem.

Q: I have a question about prediabetes. As cardiologists, we are definitely treating a lot of patients with type 2 diabetes, but we’re also faced with many patients with insulin resistance. What’s the current view on whether to medicate now or in the future?

Professor Petrie: There’s been a number of trials in prediabetes. The use of SGLT-2 inhibitors in this population is especially attractive. While the currently-available GLP-1 agonists are injectable (though there’s an oral formulation in development), SGLT-2 inhibitors are oral so it’s quite an attractive option to prevent diabetes. There are two companies doing trials with a co-primary endpoint of prediabetes or cardiovascular disease.

Dr. Nissen: I still think there’s plenty of reason to give metformin to those patients. It’s proven and very safe in prediabetes, and it’s certainly a very cost-effective approach.

Dr. Rydén: For the time being, I agree with you. There’s nothing that contradicts the use of metformin. It has a mode of action that is attractive by increasing insulin sensitivity in the liver, it is safe, and you can use it in patients with a modestly compromised renal function. But then the question becomes, what will you add? Usually you add a sulfonylurea, but that’s perhaps a less safe alternative. If you add a sulfonylurea, compared to a DPP-4 inhibitor, it is less good from a cardiovascular point of view. The question arises what is the next drug down the line in the future?

Professor Petrie: Now we’re talking about people who actually have diabetes – I wouldn’t do dual therapy in prediabetes at this point. This is where cost comes into play. Sulfonylureas have a role as a short-term therapy in people with osmotic symptoms to bring those under control. But we should try to minimize their use and move on to agents with better safety. I think that gradually, they’ll be replaced by agents that we have better knowledge about.

Dr. Rydén: That’s right, sulfonylureas haven’t been tested in a cardiovascular outcomes trial before. Steven, what is the next move for you?

Dr. Nissen: There’s currently a trial underway comparing DPP-4 inhibitors to sulfonylureas directly – the CAROLINA trial of linagliptin. I think that for many cardiologists, if sulfonylureas abolish ischemic preconditioning, they may lead to cardiovascular harm and suspicion has hung over these drugs for a very long time.

Q: I’m curious about the long-term prospects of CVOTs in diabetes. So far we’ve learned a lot from a safety perspective. Some critics have said that the design is always the same – enrolling patients with advanced disease, conducting the trials in the same time frame. Do we learn enough repeating this framework?

Dr. Nissen: The problem is that the way we developed the guidance, we said first rule out a 1.8 hazard ratio and then rule out a 1.3 hazard ratio. If you want an answer quickly, you enroll the highest risk patients and end up with a short treatment period. Sometimes the benefits of these therapies will take a while to develop. I’d personally like to see industry being in a little bit less of a hurry and do trials in a lower-risk population and keep them on the drug longer. If all we study are those at very high risk, we don’t get the answer for most of the patients we see as most of our diabetes patients are in the primary prevention space.

Dr. Rydén: On the other hand, it’s difficult to continue a study that shows a clear benefit. The data safety monitoring committee wouldn’t allow that. These trials show that the drug when given to patients with severe disease actually rescued them from premature mortality. If the investigators had continued the study the DSMB would probably recommend that the study should be stopped due to benefits.

Rapid-Fire Abstract: Improving Diabetes Outcomes – Beyond Glucocentricity

Nephro-protective Effects of Dapagliflozin in Patients with Type 2 Diabetes

Masafumi Nakayama, MD (Tokyo Medical University, Japan)

Dr. Masafumi Nakayama shared intriguing data suggesting potential positive renal outcomes with SGLT-2 inhibitor dapagliflozin (AZ’s Farxiga) treatment, though admittedly from a small, single-arm trial. The trial investigated eGFR (calculated using cystatin C) and 24-hour sodium excretion in 30 patients with type 2 diabetes after six and 12 months of dapagliflozin 5 mg treatment. 24-hour sodium excretion was significantly increased in these patients both after six months (290 mmol/day at six months vs. 231 mmol/day at baseline, p<0.001) and after 12 months (283 mmol/day, p=0.002). While there was no significant difference in eGFR after six months of dapagliflozin treatment, eGFR was significantly improved after 12 months of treatment (102 ml/min/1.73m² at 12 months vs. 93 ml/min/1.73m² at baseline, p<0.001). Urine albumin to creatinine ratio was numerically lower at both six and 12 months, but the difference was nonsignificant compared to baseline. Notably, the trial was not randomized and did not include a placebo comparator, which limits the conclusions that can be drawn from the trial. Furthermore, the trial did not enroll patients with impaired kidney function, so it’s difficult to extrapolate a nephroprotective effect. Nonetheless, the findings are encouraging and intriguing, especially given the short time frame of the trial and in light of the very positive renal data from the EMPA-REG OUTCOME trail for empagliflozin (Lilly/BI’s Jardiance), and we look forward to a more rigorous analysis of renal outcomes with dapagliflozin from the ongoing DECLARE outcomes trial.

PCSK9 Inhibitors: Ready to Embrace?

PCSK9 Inhibitors are Ready for Daily Life Clinical Use – CON

Terje Pedersen (Aker University Hospital, Norway)

In a heated debate, the legendary Aker University Hospital’s Dr. Terje Pedersen (lead investigator of the landmark 4S statin trial) argued against the widespread use of PCSK9 inhibitors in clinical practice at this point, citing the current lack of long-term outcomes data and the high cost and limited access to these drugs. He pointed out that the currently-published clinical evidence for these agents are generally from trials of short duration (6-12 months), in which endpoints were often not adjudicated, and were often conducted in populations of special interest. Furthermore, while he acknowledged that monoclonal antibodies have been used to great success in cancer and anti-inflammatory conditions for some time, previous indications for monoclonal antibodies were focused on improving symptoms and prognosis in the short term. On the other hand, PCSK9 inhibitors may improve prognosis in the long-term by reducing a biomarker of atherosclerosis – a different story entirely and a situation in which Dr. Pedersen recommends proceeding with caution. Dr. Pedersen also expressed particular concern about the potential neurocognitive adverse effects of PCSK9 inhibitors, citing a meta-analysis (Lipinski et al., 2016) suggesting an excess of neurocognitive events associated with alirocumab (Sanofi’s Praluent) and evolocumab (Amgen’s Repatha) compared to placebo. While Dr. Pedersen acknowledged that none of the ongoing outcomes trials (ODYSSEY OUTCOMES for Praluent, FOURIER for Repatha, and SPIRE 1 and SPIRE 2 for Pfizer’s bococizumab) have been stopped due to safety concerns, he also shared that he has sat on several data safety monitoring boards himself and, in his experience, trials accumulating adverse events in the treatment arm may continue if they are balanced out by positive effects of the treatment. Thus he concluded that we can’t rule out that PCSK9 inhibitors have an adverse neurocognitive effect until the full results from the outcomes trials are available. Beyond the unknowns of the clinical profile of the drugs,

• Dr. Pedersen also suggested that PCSK9 inhibitor therapy is not cost-effective for the majority of patients in “daily clinical practice” – those with existing cardiovascular disease and an LDL cholesterol above 70 mg/dl. He highlighted ICER cost effectiveness analyses suggesting that cost per quality-adjusted life year gained is $302,000. For comparison, he pointed to a cost-effectiveness analysis from the 4S study that found that the cost of a life-year saved was just NOK 62,300 (~$7483). Dr. Pedersen also pointed to data suggesting that even if the actual cost of the PCSK9 inhibitors was substantially discounted to about a fourth of its list price (~$3,166 per patient per year instead of $14,350), it would still cost the US health system almost $12 billion per year to provide the medication to the entire indicated population. Finally, Dr. Pedersen also suggested that, among patients who are not at their LDL cholesterol goals, not enough patients are taking maximum-strength statins and ezetimibe and intensification of existing, less-expensive treatments may be a more cost-effective approach to managing cholesterol. That said, Dr. Pedersen highlighted two specific groups in which he felt PCSK9 inhibitor use would be justified today, despite their high cost and lack of long-term data: (i) patients with FH and intact LDL receptors on plasmapheresis (a dialysis-like last-resort procedure to remove LDL cholesterol from the circulation) and (ii) patients with FH with LDL cholesterol far above goal, despite optimal treatment with statins and ezetimibe. Dr. Pedersen also emphasized that this recommendation should be revisited after the publication of the outcomes data and after a cost-effectiveness analysis is completed using the actual outcomes data.

PCSK9 Inhibitors are Ready for Daily Life Clinical Use – PRO

Eliano Navarese, MD, PhD (Heinrich Heine University, Düsseldorf, Germany)

“Patients are having cardiovascular events today and tomorrow. We can’t wait for the large trials to complete. Patients are dying today.” On flip side of the argument, Dr. Eliano Navarese argued that the currently-available data for PCSK9 inhibitors is compelling enough to recommend their use in daily clinical practice. He pointed out that the field has had 30 years of experience demonstrating that lower LDL is associated with improved outcomes and that we don’t need a long-term trial to know that PCSK9 inhibitors will help these patients. Evidently, many of the attendees agreed with Dr. Navarese’s view – he narrowly won the debate according to an informal poll at the end and was crowned with a “gladiator’s” laurel for his efforts.

Corporate Symposium: Advancing Approaches to Dyslipidemia Management: Optimizing Risk Reduction in Primary and Secondary Prevention Populations (Sponsored by Pfizer)

Current Challenges in CV Risk Reduction for High-Risk Primary and Secondary Prevention Populations

Michael Gibson, MD (Harvard Medical School, Boston, MA)

In a Pfizer-sponsored corporate symposium, Dr. Michael Gibson reviewed the design of the ongoing cardiovascular outcomes trials for Sanofi’s Praluent, Amgen’s Repatha, and Pfizer’s bococizumab, emphasizing that Pfizer’s program supports the broadest potential indication. The SPIRE 1and SPIRE-2 trials for bococizumab are uniquely investigating the compound in primary as well as secondary prevention. While the ODYSSEY OUTCOMES trial for Praluent and the FOURIER trial for Repatha are enrolling patients who had a prior cardiovascular event, SPIRE-1 and SPIRE-2’s entry criteria includes participants who have high risk factors and comorbidities for cardiovascular disease, including diabetes and chronic kidney disease. In addition, SPIRE-1 and SPIRE-2 are explicitly looking at two different ranges of baseline LDL cholesterol – SPIRE-1 is enrolling patients with LDL between 70 mg/dl and 100 mg/dl and SPIRE-2 is enrolling patients with LDL ≥100 mg/dl. Bococizumab will be the third PCSK9 inhibitor to market, substantially behind Praluent and Repatha, which were launched within weeks of each other a year ago in the fall of 2015. However, Pfizer management has repeatedly emphasized in quarterly updates that the company expects results from its outcome trials to be available in around the same timeframe as ODYSSEY OUTCOMES and FOURIER. Based on the design of the trials, it appears that Pfizer may seek to differentiate itself in the marketplace with a broader indication that includes primary prevention. Indeed, two of the three patient cases studies presented earlier in the corporate symposium focused on primary prevention in patients with diabetes and chronic kidney disease, respectively, clearly underscoring the opportunity Pfizer sees for bococizumab in patients with these conditions. We’re particularly excited for the potential of PCKS9 inhibitors to address residual cardiovascular risk in patients with diabetes and hope that Pfizer will conduct sub-analyses on the impact of bococizumab as primary prevention in patients with diabetes.

Improving Secondary Prevention of Atherosclerotic Disease

Lipids Lowering in Diabetics – What is the Best Way?

Frans Van de Werf, MD (University of Leuven, Belgium)

In an overview of various lipid-lowering strategies for patients with diabetes, Dr. Frans Van de Werf was particularly positive on the combination use of statins and ezetimibe and offered a fairly skeptical view of long-term use of PCSK9 inhibitors. Dr. Van de Werf highlighted results from an IMPROVE-IT sub-analysis that demonstrated that the combination of statins and ezetimibe had a significantly greater impact on cardiovascular risk reduction in patients with diabetes compared to those with diabetes. Furthermore, Dr. Van de Werf pointed out that the use of ezetimibe in combination with statins significantly improved LDL cholesterol, HDL cholesterol, and ApoB/ApoA1 compared to statin use alone. Regarding PCSK9 inhibitors, Dr. Van de Werf noted that he is eagerly awaiting the results of the long-term outcomes trials – as is the rest of the cardiology and diabetes communities! – but largely reserved judgment on their use in patients with diabetes at this point. Dr. Van de Werf did share in Q&A that he doesn’t imagine that PCSK9 inhibitor efficacy will be significantly different in patients with diabetes compared to those without diabetes. That said, Dr. Van de Werf pointed out that lipid-lowering agents are currently recommended to reduce cardiovascular risk in all patients with type 1 or type 2 diabetes ages 40 and over. Based on this recommendation, Dr. Van de Werf didn’t feel that widespread use of these drugs would be likely as that initiation of a PCSK9 inhibitor at the age of 40 could mean “30 years of injections.” Of course, PCSK9 inhibitors are only injected once every two weeks or even once a month, which we don’t anticipate will be the largest barrier to initiation for many patients with diabetes, considering that basal-bolus insulin therapy involves at least four daily injections. We expect the fairly narrow initial indication and the high cost of the drugs (and the associated reimbursement and administrative hurdles) are much more likely to give pause to some patients with diabetes and their providers, though we hope those issues are addressable.

Breaking Down Barriers in Secondary Prevention

Management of Overweight and Obesity in Patients at High Cardiovascular Risk Across Europe: Results from EUROASPIRE IV Survey

Kornelia Kotseva, MD (Imperial College London, UK)

Dr. Kornelia Kotseva presented results from the EUROASPIRE IV survey indicating that there is a high prevalence of obesity and central obesity in patients at high risk of developing CVD in 14 European countries, but not enough patients are receiving recommendations for lifestyle intervention from their healthcare providers. EUROASPIRE IV examined 6,700 medical records and interviewed 4,579 patients (68% of records examined) across 14 countries. These patients were prescribed blood pressure, lipid-lowering, and/or diabetes medications in the 6 months-3 years prior to the interview, but had no history of coronary or other atherosclerotic disease. The study found that the overall prevalence of overweight (defined as a BMI≥25 kg/m²) in this population was 83% (86% among men, 82% among women, 83% among those younger than 60, 84% among those 60 and older). However, there was significant heterogeneity among the countries surveyed, with Serbia at the low end with 66% prevalence of overweight in the population and Bosnia Herzegovina at the high end with a whopping 91%. Overall prevalence of obesity (BMI≥30 kg/m²) in this population across the 14 countries was 44% (40% in men, 46% in women, 44% in those younger than 60, 43% in those 60 and older). Like the overweight prevalence, the prevalence of obesity also varied widely between countries with a high end of 57% prevalence in Russia. Surprisingly, Bosnia Herzegovina actually had the lowest prevalence of obesity in this high-risk population according to this study – a comparatively very low 18%. Bosnia Herzegovina also had the lowest prevalence of central obesity – 50%, compared to Bulgaria’s highest prevalence of 86% and the overall average prevalence of 64% (52% in men, 72% in women, 62% in those under 60, 66% in those 60 and older). Worryingly, among those with obesity who were interviewed, only 80% had ever been told by a healthcare professional that they were overweight. This means that a fifth of individuals with obesity in this high-risk cohort had never been counseled that they were overweight, much less had obesity.

• Furthermore, among these population with obesity, only 65% had been given personal advice on following dietary recommendations and only 59% had been given advise on participating in regular physical activity in the last 3 years. Even fewer had actually taken steps to follow dietary recommendations (50%) or participate in regular physical activity (37%) in the last three years. Consequently, it’s not entirely surprising, though still very worrisome, that only 45% of these high risk individuals with obesity report actively trying to lose weight in the last month and only 52% report seriously considering trying to lose weight in the next month. Dr. Kotseva concluded that these results suggest that patients’ awareness and interventions for obesity are less than adequate and that more intensive preventive cardiology programs must be implemented. Furthermore, she suggested that interventions should focus on lifestyle therapy and be adapted to the cultural settings of each country to improve their chances of success.

Exhibit Hall

We were thrilled to see a larger presence for diabetes companies in ESC’s exhibit hall this year. Most notably, Lilly/BI hosted a large booth devoted to educating attendees on the increased risk for various cardiovascular events associated with diabetes and on the EMPA-REG OUTCOME results. The booth also promoted the ACROSS T2D program, which aims to provide greater education on CVOTs for diabetes drugs. AZ’s also devoted a small corner of its massive booth to its diabetes drugs, primarily emphasizing Farxiga (dapagliflozin) and Xigduo (dapagliflozin/metformin) with large touchscreens underscoring the positive effects of dapagliflozin on many cardiovascular risk factors (weight, blood pressure, etc.) Logos for Onglyza (saxagliptin), Komboglyze (saxagliptin/metformin) and Bydureon (exenatide once-weekly) were also present, though there was no further promotion of these products. A representative expressed positive excitement over the recent approval of Qtern in Europe, but noted that it is not yet available in Italy. While Novo Nordisk did not have a booth in the exhibit hall, a Novo Nordisk representative shared with us that its corporate symposium on the LEADER results marks the first time the company has had a presence at ESC and it is “testing the waters” in a sense – we anticipate we’ll start seeing a larger presence from Novo Nordisk in future cardiology meetings. On the PCSK9 inhibitor front, both Sanofi/Regeneron and Amgen offered cholesterol and cardiovascular risk screenings at their booths to entice attendees to learn more about the role of LDL cholesterol in CV risk.

Special Appearance

His Holiness Pope Francis

ESC 2016 closed with a visit from a very special guest indeed – Pope Francis graced the attendees with a short address emphasizing the role of science and service in medicine (and was gifted a red stethoscope by the conference organizers!) Pope Francis’ speech focused on the how the work of advancing human understanding through scientific discovery reaffirms God’s plan. The Pope also emphasized the importance of viewing humans in their totality in order to have a “profound understanding of the poor, those most in need, and the marginalized.” He also acknowledged attendees to relinquish their individual biases in the pursuit of higher scientific discovery. Importantly, the Pope emphasized the Catholic Church’s full support for research to understand and improve human life and health. The full English-translated text of the Pope’s address is viewable here. We so appreciated the clear value Pope Francis places on medicine and scientific inquiry and view his visit as a recognition of the large and growing burden of cardiovascular disease globally. The thousands of attendees who stayed until these very final moments of ESC were clearly moved and we imagine departed the conference with a renewed sense of purpose in their work.

--by Helen Gao, Payal Marathe, Abigail Dove, and Kelly Close