March 28-31, 2014; Washington, DC; Full Report – Draft

Executive Highlights

We recently attended the American College of Cardiology’s 2014 Scientific Sessions in our nation’s capital, Washington, DC. In this report we bring you our full coverage of the presentations we attended at the meeting. This report contains coverage of 17 new presentations that were not published in our Days #1-3 Highlights report. The titles of the new reports are highlighted in blue, and the titles of our top five highlights are highlighted in yellow. Our top five highlights from ACC 2014 include:

1) A sub-analysis of the EXAMINE cardiovascular outcomes trial suggesting that Takeda’s Nesina (alogliptin) has a CV death benefit for women and people with shorter duration diabetes (≤5 years) and good renal function (eGFR ≥ 60 ml/min/1.73 m²).

2) Another EXAMINE sub-analysis indicating that Nesina appears safe even in patients at high risk for, or with a past history of, heart failure. In light of the 27% increased risk of heart failure seen in AZ’s SAVOR CVOT for Onglyza, the consistency with which Nesina had no heart failure effect in EXAMINE across various subgroups undermines the notion that the DPP-4 inhibitor class may have a heart failure effect.

3) The presentation of three-year results from the STAMPEDE trial comparing metabolic surgery to intensive medical treatment (lifestyle, drugs, etc.) for the treatment of type 2 diabetes therapy (these are now the longest-term RCT data for metabolic surgery in type 2 diabetes; both Roux-en-Y gastric bypass and sleeve gastrectomy far out-performed medical therapy at three-years, although Roux-en-Y gastric bypass showed more durability compared to sleeve gastrectomy).

4) Dr. A. Michael Lincoff’s (Cleveland Clinic, Cleveland OH) presentation of AleCardio results (the CVOT that was terminated early for futility for Roche/Genentech’s PPAR-alpha/gamma dual-agonist. This was the first presentation of the trial’s detailed results. Despite promising effects on lipids observed in phase 2, aleglitazar did not prove to be cardioprotective (a futility analysis at the time 55% of planned events had accrued predicted a 1% chance of success). All in all, Roche’s choice to pull the drug seemed the right one, as the benefit/risk profile was not compelling due to a host of safety issues such as the typical PPAR issues of edema, weight gain, heart failure, and bone fractures as well as an unexpected increase in GI hemorrhages.

5) Dramatic phase 3 data for Amgen’s PCSK9 inhibitor evolocumab, which may be the first of its class to market. While we are certainly not close followers of lipid-lowering medications, we began following PCSK9 inhibitors due to their unprecedented LDL-lowering since many patients with diabetes still struggle with inadequate lipid control.

Our report below begins with themes we noticed at the conference, followed by our detailed coverage of individual presentations.

 

Themes

• New sub-analyses from the DPP-4 inhibitor cardiovascular outcomes trials SAVOR and EXAMINE for AZ’s Onglyza and Takeda’s Nesina, respectively, received significant attention from attendees interested in diabetes. The most exciting sub-analysis was a poster for EXAMINE demonstrating that Nesina (alogliptin) had a significant benefit on CV death for women, people with shorter duration diabetes (≤5 years), and people with good to mildly impaired renal function (eGFR ≥60 ml/min/1.73 m²). We will be interested to see whether Takeda can incorporate this information into Nesina’s label to differentiate the drug from the otherwise fairly homogenous DPP-4 inhibitor class – we certainly expect that it should and we would want patients to have access to this information. How it is interpreted will be closely watched by us. A closer look at heart failure in EXAMINE fought back against the suggestion that the entire DPP-4 inhibitor class might have a negative effect on heart failure; it showed that Nesina was not associated with a significant increase in hospitalization for heart failure, or a combined endpoint of hospitalization for heart failure and CV death, in patients with a previous history of heart failure. Additionally, we saw that baseline levels of BNP (a biomarker of CV health) did not predict hospitalization for heart failure, as it did in the SAVOR CVOT for AZ’s Onglyza (saxagliptin). We look forward to seeing how Takeda plans to showcase this data, and if it plans to mount a full-scale offensive against the theory of a DPP-4 inhibitor class effect on heart failure. A SAVOR sub-analyses presented at this conference demonstrated fairly similar CV effects of Onglyza across patients stratified by renal function, although the drug’s ability to improve microalbuminuria waned for people with the most severe renal impairment (eGFR <30 ml/min/1.73 m²).
  
  • Discussions at the EXAMINE poster presentation also demonstrated a rift in opinions on how to evaluate heart failure. EXAMINE investigators see the combined endpoint of hospitalization for heart failure and CV death as the most robust endpoint (as some patients with heart failure might die before being hospitalized), but so far the SAVOR investigators have not broken out this endpoint, as it wasn’t pre-specified in the trial design.
  • Overall, we did not get the sense that cardiologists were overly concerned about the heart failure findings for DPP-4 inhibitors. We heard several times that a proposed treatment algorithm for type 2 diabetes would now include either a DPP-4 inhibitor or pioglitazone as the preferred second-line agent since overall CV safety has been demonstrated for DPP-4 inhibitors, and pioglitazone’s PROactive demonstrated CV benefit with regard to the secondary composite endpoint of CV death, myocardial infarction, and stroke. Speakers that voiced this sentiment included Dr. Darren McGuire (University of Texas Southwestern, Dallas, TX) and Dr. Silvio Inzucchi (Yale School of Medicine, New Haven, CT).
• Cardiologists are slowly being introduced to the idea of metabolic surgery as a treatment for type 2 diabetes. While the idea is certainly still novel in many diabetes circles, it seems even fresher to the cardiology community. We attended a number of presentations on this topic, including Dr. Sangeeta Kashyap’s (Cleveland Clinic, Cleveland, OH) presentation on the three-year results of the STAMPEDE trial, which compared Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy to intensive medical therapy for the treatment of type 2 diabetes (primary endpoint was % of patients with A1c ≤6%). As was the case in the original one-year results, both surgical groups had significantly greater type 2 diabetes remission than the medical therapy group, but at three years RYGB was significantly more durable than the sleeve. In Dr. Milton Packer’s (University of Texas Southwestern, Dallas, TX) commentary on the presentation, he (frustratingly) criticized the premise that one would want to target an A1c of 6%. He cited ACCORD as “discrediting” such a low target, although his argument was not entirely convincing in our view. He also pointed out that diabetes complications also seemed to occur somewhat more frequently in the surgical arms – we thought the numbers may have been too small to draw meaningful conclusions. On the topic of metabolic surgery for diabetes, Dr. Michael Farkouh (University of Toronto, Toronto, Canada) presented an excellent and quite forward-thinking synopsis of where the field stands; we would not be surprised if his presentation swayed some skeptical cardiologists’ opinions on the benefits of surgery (there are, of course, many long-term questions). He did note that we still lack CV outcomes data for metabolic surgery – most cardiologists likely won’t be convinced that it is a valid treatment for metabolic diseases until they have outcomes data in hand.
• There was an enormous amount of excitement regarding PCSK9 inhibitors, a novel injectable class of monoclonal antibodies that show promise of reducing LDL cholesterol with remarkable efficacy and safety. In our view, Amgen’s evolocumab stole the show, with full results presented for five phase 3 trials demonstrating mean LDL reductions of ~53-75% in a wide variety of applications (monotherapy, add-on to statin therapy of varying intensity, in statin-intolerant patients, and in familial hypercholesterolemia patients). Some of the oral sessions on evolocumab were so popular that they filled both the presentation hall and the overflow screens outside to capacity. Sanofi also presented one phase 3 study of its PCSK9 inhibitor alirocumab – efficacy was certainly strong, but perhaps slightly less so than what we saw with evolocumab. Despite the remarkable data we saw on the new class, there is some uncertainty on how PCSK9 inhibitors will be used, especially given the relatively recent ACC/AHA lipid guidelines that de-emphasize specific LDL targets and place a greater importance on statin treatment. We are also curious on how this class could impact diabetes – using the class to reduce patients’ reliance on high-intensity statins (which can slightly increase blood glucose) is a promising possibility, in our view.

Detailed Discussion & Commentary

Posters: Acute Coronary Syndromes: Comorbid Considerations

Cardiovascular Mortality in Patients with Type 2 Diabetes and Recent Acute Coronary Syndromes from the EXAMINE Trial

WB White, S Kupfer, WC Cushman, GL Bakris, SR Heller, RM Bergenstal, V Menon, AT Perez, PR Fleck, R Oh, CR Mehta, CA Wilson, F Zannad, CP Cannon

This poster presented a sub-analysis of cardiovascular (CV) death in the EXAMINE CV outcomes trial (CVOT) for Takeda’s DPP-4 inhibitor Nesina (alogliptin). As a reminder, the primary results of the EXAMINE trial (n=5,380 patients with type 2 diabetes post-acute coronary syndrome) found that alogliptin had a similar effect vs. placebo on the composite MACE (CV death, myocardial infarction, stroke) primary endpoint. This sub-analysis broke out the individual CV death component of the composite MACE endpoint. Rates of CV death were non-significantly lower on alogliptin (4.1%) vs. placebo (4.9%) (HR=0.85, 95% CI: 0.66, 1.10), and lead author Dr. William White pointed out that the p-value was very close to statistical significance (p=0.07). All-cause mortality and sudden cardiac death were also non-significantly lower on alogliptin than placebo (HR=0.88, 95% CI: 0.71-1.09 and HR=0.80, 95% CI: 0.57-1.12, respectively); p-values not specified. The analysis actually identified some subgroups in which alogliptin conferred a benefit with regard to CV death: in women (HR=0.60, 95% CI:0.40, 0.91), patients with eGFR ≥60 ml/min/1.73 m² (HR=0.67, 95% CI: 0.46, 0.98), and those with a history of type 2 diabetes <five years (HR=0.61, 95% CI:0.37, 1.00) there was a lower rate of CV death in the alogliptin group compared to placebo. This seems to make sense, as it suggests that patients with less severe diabetes achieved greater benefit from alogliptin than those with more severe diabetes at baseline. This is quite notable considering that EXAMINE enrolled a very sick patient population, sicker than the SAVOR population. These sub-group analyses for CV mortality in SAVOR have not been presented. Dr. White remarked that it is unknown why women might have derived greater benefit from saxagliptin than men.

• While the finding of a significant CV death benefit in these subgroups was certainly notable, the drug likely won’t be billed as “cardioprotective” per se. Although in an intuitive sense, “cardioprotection” means protective to the heart and/or vasculature, the term is scientifically reserved for a study that finds a benefit in the pre-specified primary outcome (which was MACE in EXAMINE). While retrospective sub-analyses such as the one presented in this poster give us reason to hope that Nesina might have some CV benefit, at least in some populations, they are ultimately only hypothesis generating. Of course that is unfortunate, given that it is highly unlikely that Nesina will be tested any time soon in a rigorous long-term outcomes study in the specific subpopulations that saw benefit. As an example of how this has played out in the past, Takeda’s Actos (pioglitazone) demonstrated a neutral outcome with regard to its primary composite endpoint in PROactive (CV death, myocardial infarction, stroke), it came out positive for a post-hoc secondary composite outcome of all-cause mortality, myocardial infarction, and stroke. Nonetheless, given the post-hoc nature of the analysis, Actos cannot claim cardioprotection, and its label simply reads “There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ACTOS or any other antidiabetic drug.” However, we do see the results showcased in this poster appealing to providers who currently may have doubts about heart failure with other agents in the DPP-4 inhibitor class (namely AZ’s Onglyza), in a class that otherwise has more similarities than differences.

 

Alogliptin in Patients with Type 2 Diabetes After Acute Coronary Syndromes: Heart Failure Outcomes and Cardiovascular Safety in Heart Failure Patients

F Zannad, CP Cannon, WC Cushman, GL Bakris, SK Heller, RM Bergenstal, V Menon, A Perez, P Fleck, R Oh, C Mehta, S Kupfer, CA Wilson, WB White

In the months since the primary results of the EXAMINE (on Takeda’s Nesina) and SAVOR (for AZ’s Onglyza) CVOTs were shared at ESC 2013, we have heard building discussion regarding a potential DPP-4 inhibitor class effect on heart failure due to the 27% statistically significant increase in heart failure seen in SAVOR and the perceived homogeneity of the DPP-4 inhibitor class. Although there is broad consensus that the current data is not sufficient to recommend a change in overall prescribing behavior for DPP-4 inhibitors, some have expressed concern about prescribing Onglyza (and perhaps all DPP-4 inhibitors, in case of a class effect) in patients with at high risk for heart failure. This poster provided evidence from EXAMINE that Takeda’s agent is safe in that patient group, which could be a notable differentiating factor in a drug class that has very few other differentiating factors, especially based on safety. 

• There was no significant impact of Nesina on hospitalization for heart failure. Hospitalization for heart failure was included as part of a pre-specified secondary expanded MACE composite endpoint (first occurrence of all-cause mortality, nonfatal MI, stroke, urgent revascularization due to unstable angina, and HHF), and heart failure was also analyzed in the classic composite endpoint of HHF plus CV death. A post-hoc analysis also broke out HHF as an individual component. When HHF was broken out from the expanded MACE composite – i.e., when it was only counted if it was the first CV event the patient experienced – the hazard ratio was 1.07 (95% CI: 0.79, 1.46) (P-value not provided). In the post-hoc analysis of HHF as an individual component, which counted all cases, even those that were preceded by another MACE event, the hazard ratio was 1.19 (95% CI: 0.90, 1.58); the latter analysis was first presented by Dr. Deepak Bhatt (Harvard Medical School, Boston, MA) at EASD 2013.
• In patients with a pre-trial history of heart failure, Nesina was not associated with any significant difference in either of two composite outcomes (the expanded MACE endpoint described above, and the composite of HHF + CV death). In those patients with a history of heart failure, the hazard ratio for the heart failure composite endpoint was 0.90 (95% CI: 0.70, 1.17; p=0.446), and the hazard ratio for expanded MACE was 0.94 (95% CI: 0.74, 1.20; p=0.622). This data would not support an assertion that prescribers should avoid using this agent in patients with a history of heart failure. SAVOR’s heart failure analysis presented at AHA 2013 also found no effect of Onglyza on HHF risk in people with a prior history of HF.
• Baseline levels of pro-BNP (a predictive biomarker for heart failure) did not predict worse outcomes in EXAMINE. A similar post-hoc analysis of SAVOR data showed that the majority of the absolute increase in heart failure hospitalization was limited to the quartile of patients with the highest baseline pro-BNP levels. However, the relative risk was not significant significantly different, which means that pro-BNP levels also cannot be used in SAVOR to predict the effect of saxagliptin, but we imagine that some prescribers are worried about avoiding use of Onglyza in patients at high baseline risk for heart failure. In EXAMINE, there was no statistically significant difference in risk for the heart failure composite endpoint (hospitalization for heart failure + CV death) in any of the baseline pro-BNP quartiles, including the uppermost quartile. Although it was not mentioned in the poster, lead investigator Dr. William White mentioned that pro-BNP levels actually decreased slightly during the trial, a promising sign with regards to CV safety.
• Questions remain about the best way to analyze heart failure. The presenters noted that the “heart failure composite” of hospitalization for heart failure + CV death is a more robust measure than hospitalization for heart failure alone, as the latter might exclude patients that died from heart failure before they could be hospitalized. AZ and the SAVOR investigators have not broken out this composite endpoint (it was not one of the pre-specified endpoints of either trial). All the data we have seen so far on Nesina has consistently proven assuring from a safety perspective – we will be interested to see what further sub-analyses Takeda and AZ present at ADA and other coming scientific meetings.

 

Oral Sessions: Stable Ischemic Heart Disease: Basic Sciences and Clinical Studies

Baseline Renal Function and Cardiovascular Risk in Patients Treated with Saxagliptin: Observations from the SAVOR-TIMI 53 Trial

Jacob Udell, MD (Brigham and Women’s Hospital, Boston, MA)

Dr. Jacob Udell presented a secondary analysis of the SAVOR cardiovascular outcomes trial (CVOT) results stratified by baseline renal function. As a reminder, SAVOR’s primary results found that AZ’s DPP-4 inhibitor Onglyza (saxagliptin) had similar CV effects compared to placebo in 16,492 people with type 2 diabetes and cardiovascular disease or multiple cardiovascular risk factors (see primary results here). For this new sub-analysis, patients were stratified by baseline renal function into normal/mild (eGFR >50 ml/min/1.73 m²; n=13,916), moderate (eGFR=30-50 ml/min/1.73 m²; n=2,240), or severe (eGFR <30 ml/min/1.73 m²; n=336) renal dysfunction groups. As would be expected, CV outcomes were worse in those with worse baseline renal function. However, the effect of saxagliptin vs. placebo on CV outcomes was similar regardless of renal function. Saxagliptin’s effect on improving microalbuminuria held true in the normal/mild and moderate impairment groups, but was not statistically significant in the severe impairment group. Saxagliptin lowered A1c after one year regardless of renal function, and this effect persisted to two years except in the moderate impairment group. Interestingly, saxagliptin’s effects on hypoglycemia appeared to improve with worsening baseline renal function (although not significantly). Dr. Udell speculated in Q&A that this may have been due to the very small size of the severe impairment group or the lower use of sulfonylureas in this group. The results of this study suggest that the CV and glycemic safety and efficacy of saxagliptin are fairly consistent regardless of renal function and that saxagliptin may be used in the population of people with type 2 diabetes and CKD – a vulnerable population that has few treatment options.

• This sub-analysis of the SAVOR cardiovascular outcomes trial stratified patients by baseline renal function into normal/mild (eGFR >50 ml/min/1.73 m²; n=13,916), moderate (eGFR=30-50 ml/min/1.73 m²; n=2,240), or severe (eGFR <30 ml/min/1.73 m²; n=336) renal dysfunction groups. By design, the study capped the severe renal impairment group to roughly 300 people. People in the normal/mild group received the standard 5.0 mg/day dose of saxagliptin while people with moderate or severe renal impairment received the reduced 2.5 mg/day dose. A single dose adjustment was made to 2.5 mg/day if a patient’s renal function dropped below an eGFR of 50 ml/min/1.73 m². Otherwise, patients remained on the 2.5 mg/day dose despite eGFR declines or progression to dialysis.
• As would be expected, CV outcomes were worse in those with worse baseline renal function. After two years, the MACE (CV death, myocardial infarction, stroke) event rate in the severe renal impairment group was 17% compared to 12% and 6% in the moderate and normal/mild groups, respectively (p<0.0001). Hospitalization for heart failure followed a similar trend with even rates of 13%, 6%, and 2% in the severe, moderate, and normal/mild groups after two years (p<0.0001).
• However, CV outcomes were similar for saxagliptin vs. placebo regardless of baseline renal function. Rates of the primary MACE endpoint, the secondary MACE+ endpoint (MACE plus hospitalization for heart failure, coronary revascularization, or unstable angina), CV death alone, or MI alone were similar between saxagliptin and placebo groups regardless of baseline renal function (HRs range from 0.79 to 1.30 with all 95% CIs crossing 1.0). As a reminder, SAVOR’s primary results found that saxagliptin and placebo had nearly identical effects on CV outcomes.
  
  • The relative risk of hospitalization for heart failure (HHF) was also similar by renal function, although the absolute risk difference for saxagliptin was higher in the moderate renal impairment group. The hazard ratios for HHF for saxagliptin vs. placebo were 1.24 in the normal/mild group (95% CI: 0.99, 1.55), 1.46 in the moderate group (95% CI: 1.07, 2.00), and 0.94 in the severe group (95% CI: 0.52, 1.71); p-interaction=0.43. Dr. Udell did not dwell on this point, attributing the significant difference within the single moderate impairment category to the relatively small sizes of the moderate and severe renal cohorts. Because the p-interaction value was not significant, baseline renal function and HHF were not considered to have an interaction.
• As found in the primary analysis, saxagliptin improved microalbuminuria more than placebo; this effect held true in the normal/mild and moderate renal impairment groups, but was not significant in the severe impairment group. In the normal/mild group, microalbuminuria improved in ~10% of patients on saxagliptin compared to ~8% of those on placebo (p<0.001); in the moderate group, microalbuminuria improved in 11% of patients on saxagliptin compared to 9% on placebo (p=0.037); and in the severe group, microalbuminuria improved in 14% of those on saxagliptin compared to 11% on placebo (p=not significant).
• Saxagliptin lowered A1c after one year regardless of renal function; this effect persisted to two years except in the moderate impairment group. In the normal/mild group, saxagliptin provided a 0.3% A1c reduction after one year and after two years compared to baseline (whether this value was placebo-adjusted was not specified). In the moderate group, saxagliptin lowered A1c by 0.3% after one year and 0.2% after two years (the latter difference was not statistically significant). In the severe group, saxagliptin produced a 0.6% A1c reduction after one year and after two years.
• Interestingly, saxagliptin’s effects on hypoglycemia appeared to improve with worsening baseline renal function (although not significantly). Hospitalization for hypoglycemia tended to be more common (non-significantly) on saxagliptin in the normal/mild group compared to the moderate group and the severe group (HRs = 1.44, 1.06, and 0.77, respectively; all 95% CIs crossing 1.0). For major hypoglycemia, the HR for saxagliptin vs. placebo was 1.11 in the normal/mild group (95% CI crossing 1.0), 1.91 in the moderate group (95% CI not crossing 1.0), and 0.65 in the severe group (95% CI crossing 1.0).
  
  • Dr. Udell speculated during Q&A that this may be a product of the very small sample size in the severe renal impairment group or that it may be explained by the lower use of sulfonylureas in the severe renal impairment group.

Questions and Answers

Q: It’s rather complicated because I have heard that DPP-4 also degrades bradykinin. And there is a difference between men and women in terms of degradation of bradykinin because women have an additional gene on the X chromosome for amino peptidase D. Did you see any difference in the % of women that developed heart failure and men who developed heart failure during the study? Secondly, was there any difference between women and men who took ACE inhibitors during the study? This could lead to a possible explanation of why saxagliptin produced the increased risk of heart failure.

A: The question is a little tangential to the talk here. Dr. Benjamin Scirica presented a heart failure analysis at AHA, and the full manuscript is still under review. To disclose full details at this point would be premature. I can say that there was no interaction between sex at baseline. The bradykinin analyses are still being performed.

Q: Any thoughts why the people with the most severe renal insufficiency would have less hypoglycemia episodes?

A: Many hypotheses have been postulated. One is to be circumspect of any outcome when the patient population was only 336 patients, especially when the interaction terms did not suggest significant heterogeneity in other outcomes. It could be play of chance. The other possibility is that these patients were on fewer SFUs, so they may be less prone to hypoglycemia.

 

Oral Sessions: Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials

Evaluation of the Dual PPAR-Alpha/Gamma Agonist Aleglitazar to Reduce Cardiovascular Events in Patients with Acute Coronary Syndrome and Type 2 Diabetes Mellitus: The AleCardio Trial

A. Michael Lincoff, MD (Cleveland Clinic, Cleveland, OH)

Dr. A. Michael Lincoff presented results of the phase 3 AleCardio trial, the terminated cardiovascular outcomes trial for Roche/Genentech’s dual PPAR-alpha/gamma agonist aleglitazar. Because of positive effects on lipids observed in phase 2, Roche decided to first pursue a CV indication for aleglitazar in patients with type 2 diabetes to differentiate the drug from other PPAR agonists (and their baggage) and to avoid the treacherous and unpredictable waters of a general diabetes indication. Notably, the futility analysis conducted when 55% of planned events had accrued found that the trial had only a 1% chance of achieving its goal of CV superiority with regards to the primary MACE endpoint (CV death, myocardial infarction, stroke). The final analysis (including 74% of planned events) showed a HR of 0.96 (95% CI: 0.83, 1.11; p=0.57). The lack of CV protection coupled with the myriad other safety concerns that emerged from the trial painted quite an unattractive picture. Aleglitazar was associated with the typical PPAR agonist issues (compared to placebo, it had a 22% trend towards elevated hospitalization for heart failure, 8 lb weight gain, and 30% increase in bone fractures) as well other safety concerns including a dramatic (but reversible) rise in serum creatinine, an unexpected 44% increase in GI hemorrhage, and 60% greater hypoglycemia compared to placebo. The decent glycemic efficacy and benefit on lipids observed in earlier phase 2 trials were reproduced, but it was very clear that the benefit/risk profile was too heavily weighted towards risk. Dr. Lincoff remarked that this trial illustrated the difficulty in developing a PPAR agonist, and he conjectured during Q&A that this may be the end for new PPAR agonist trials. These results were published simultaneously in JAMA.

• Dr. Lincoff reviewed aleglitazar’s phase 2 SYNCHRONY data showing that aleglitazar reduced A1c by 0.5% (0.8% placebo-adjusted, which was at least as good, if not better, as high-dose pioglitazone in the same trial) while also providing a roughly 30% reduction in triglycerides (44% placebo-adjusted) and a 25% increase in HDL (29% placebo-adjusted).
• AleCardio was a phase 3 cardiovascular outcomes trial for aleglitazar designed to show CV protection in people with type 2 diabetes and recent acute coronary syndrome (ACS). Roche had been investigating aleglitazar for three potential indications: (i) CV risk reduction in people with type 2 diabetes post ACS; (ii) CV risk reduction in people with type 2 diabetes and prediabetes; (iii) general type 2 diabetes. AleCardio was, thus, a superiority trial intended to inform the first indication. The trial enrolled 7,226 patients randomized 1:1 to receive once-daily 150 μg aleglitazar or placebo. It was an event driven trial planned for 950 positively adjudicated primary endpoint events (CV death, myocardial infarction, stroke), anticipated to take about 2.5 years. An interim analysis had been planned at the time when 80% of events had accrued, at which time the data safety monitoring board (DSMB) could recommend early termination for efficacy or futility.
• The trial was ultimately terminated early when the DSMB identified a higher incidence of adverse events in the aleglitazar group at a regularly scheduled safety meeting. They performed an unplanned futility analysis at the time 55% of total events had accrued (522 events). At that point, they found that the primary endpoint had a HR of 1.01 with only a 1% chance of achieving superiority by the end of the trial. As such, the DSMB recommended termination for futility, and the trial ended on July 2, 2013. The trial database was locked on December 17, 2013, at which point 74% of total events had accrued (704 events) with a median follow up of 104 weeks.
• The final analysis of the primary MACE endpoint (CV death, myocardial infarction, stroke) showed neutrality. The event rate was 9.5% on aleglitazar compared to 10% on placebo for a HR of 0.96 (95% CI: 0.83, 1.11; p=0.57). Most other CV endpoints examined (MACE plus hospitalization for unstable angina; the composite of all-cause mortality, myocardial infarction, and stroke; and the individual components of all-cause mortality, CV death, myocardial infarction, and stroke) were also neutral.
  
  • However, when analyzed as individual components, unstable angina and unplanned revascularization were each better in the aleglitazar arm (HR=0.75, 95% CI: 0.57,0.96 and HR=0.79, 95% CI: 0.69,0.90, respectively).
• Aleglitazar demonstrated decent efficacy with regards to glycemic and lipid control. From a relatively good baseline A1c of 7.8% in both groups, aleglitazar provided a 0.6% placebo-adjusted A1c reduction (~0.5% absolute reduction compared to ~0.1% rise on placebo) that was sustained through 36 months. HDL also sustained a 20% placebo-adjusted increase from a baseline of 42 mg/dl, and triglycerides a ~30% placebo-adjusted decrease from a baseline of 152-154 mg/dl.
• Not unexpectedly, aleglitazar was associated with fluid retention and, thus, a trend towards more hospitalization for heart failure. Patients on aleglitazar gained 4.6 kg (10.1 lbs) compared to 0.9 kg (2.0 lbs) weight gain on placebo. Hospitalization for heart failure occurred 22% more in the aleglitazar arm (p=0.14).
• As previously characterized in the phase 2 SYNCRHONY and AleNephro trials, aleglitazar was associated with a reversible decrease in renal function. In AleCardio, aleglitazar elevated creatinine to about 0.10-0.14 mg/dl from a baseline of 0.1 mg/dl within one week of starting the drug, but the effect disappeared within four weeks of discontinuation. The composite renal endpoint of end-stage renal disease (ESRD), doubling of serum creatinine, or 50% increase in serum creatinine leading to study drug discontinuation occurred in 7.4% of aleglitazar patients compared to 2.7%  of placebo patients (HR=2.85, 95% CIL 2.25-3.60, p<0.001). We presume this was driven by the elevations in serum creatinine; Dr. Lincoff did not comment on the incidence of ESRD, which of course is not reversible (as of yet).
• Other safety concerns included an unexpected increase in GI hemorrhage, higher rates of bone fractures, and higher hypoglycemia. GI hemorrhage occurred in roughly 1.5% of aleglitazar patients compared to roughly 0.8% of placebo patients (HR=1.44, 95% CI: 1.03, 2.00, p=0.03). Bone fractures were slightly elevated with the hazard ratio being 1.30 (95% CI: 0.94, 1.80). Hypoglycemia, defined as patients experiencing at least one event, occurred in 17% of the aleglitazar arm compared to 11% in placebo (HR=1.60, 95% CI: 1.41, 1.82, p<0.001).
• Baseline characteristics: patients on average were 61 years old, with BMI of 29 kg/m². About 10% had newly diagnosed diabetes, and the mean duration of type 2 diabetes was nine years. Ten percent had a history of heart failure, and 75% a previous myocardial infarction. About two-thirds of patients were on metformin, one-third on sulfonylureas, and 30% on insulin. The vast majority was taking heart drugs with 95-96% on aspirin and 92-93% on a statin.
• Results were published simultaneously in JAMA.

Questions and Answers

Q: It is disappointing that somehow we can’t find  a way to get the diabetics to have less CV risk. How d you explain the transient renal insufficiency?

A: Two of aleglitazar’s phase 2 studies show pretty clearly that it’s a hemodynamic effect. Like with ACE inhibitors, it is reversible.

Q: In the ACCORD study, with fenofibrate there was an increase in events with women in very dyslipidemic groups. Did you see any gender differences in AleCardio?

A: We have not conducted the subgroup analyses in all of the endpoints, but there is clearly no difference by gender in the primary endpoint.

Q: As a clinician, where do these data put the whole PPAR family for your patients who have diabetes and ACS?

A: Functionally, of course, the relevant drug is pioglitazone. The PROactive trial demonstrated CV benefit, but that is of questionable significance now in the era of high-dose statins. I think it’ll be difficult to see new development of PPARs. AleCardio shows that they are very risky drugs no matter how promising they are in phase 2. I don’t know if we can justify pioglitazone strictly on the basis of cardioprotection, but it is certainly a good diabetic agent for those not at risk for heart failure.

Q: It was interesting to see that in the pioglitazone meta-analysis, the curves began to diverge after about one-to-two years, and unfortunately perhaps we won’t have the answer for this study to see if that would in fact occur. The other comment I had was, certainly given the results of the ACCORD lipid trial, it might be interesting to see whether your subgroup with high triglycerides and low HDL may have benefitted, as well as people perhaps with lesser duration of diabetes.

A: Those are two very important points. Triglycerides, because we used an upper limit of 400 mg, were very weak. There was a borderline significant interaction of 0.06 for HDL. That is also a good point about being too late in the disease progression. If we’re trying to interfere in diabetes win people with established CVD, it may well be too late for these interventions, but to carry out trials in a low risk early diabetes population, that’s the real challenge in terms of logistics because you can’t wait a decade for return on investment.

 

GAUSS-2: A Phase 3 Double-blind, Randomized Study to Assess the Safety and Efficacy of Evolocumab (AMG 145) in Hypercholesterolemic Subjects Unable to Tolerate an Effective Dose of Statin

Erik Stroes, MD (Academic Medical Center, Amsterdam, Netherlands)

Statins are widely accepted as the front-line therapy for the reduction of CVD risk, but studies suggest that anywhere between 10% and 20% of patients are unable to tolerate statins in the real world. These statin-intolerant patients are a key area of unmet need that PCSK9 inhibitors can address, a theme that Dr. Eric Stroes touched upon often as he presented the results of the GAUSS-2 phase 3 trial for Amgen’s evolocumab. The 12-week, randomized, double-blind, ezetimibe-controlled study enrolled 307 patients, and tested evolocumab biweekly and monthly (which were generally clinically equivalent in this study, consistent with other phase 3 studies). All patients had demonstrated intolerance to at least two statins. Compared to other phase 3 studies, where patients were generally relatively well controlled before beginning evolocumab, the mean baseline LDL-C in GAUSS-2 was ~195 mg/dl, evincing the lack of effective therapies for statin-intolerant patients. Evolocumab led to a 56% mean reduction in LDL from baseline, a 38% reduction over ezetimibe (the primary existing option for statin-intolerant patients). Joking that Europeans such as himself “have not forgotten their numbers” and still care about LDL targets, he shared that evolocumab helped ~70-90% of statin-intolerant patients achieve a goal of under 70 mg/dl. The incidence of myalgia (muscle pain, the leading cause of statin intolerance) was high compared to other rates of myalgia in other evolocumab studies, but was lower with evolocumab (8%) than ezetimibe (18%). Dr. Stroes noted that nearly everyone’s statin intolerance is caused by statin-induced myalgia, so the fact that so many of these people were relieved of this symptom when switching to evolocumab is highly significant. Dr. Stroes concluded that an agent that can achieve LDL reductions of over 100 mg/dl in a patient population with such great unmet need is certainly exciting.

Questions and Answers:

Comment: I think it will be important to investigate to see if the effects seen in this trial last longer than 12 weeks.

A: The DESCARTES study ran for a full 52 weeks, and you can see from those results that the drug’s efficacy is sustainable for long periods of time – we are very positive on the sustainability of the effect. We have been fortunate to have most patients want to continue in the open-label continuation phase of our studies.

Q: I am intrigued by these results, but I don’t think we should discount the value of statins in the broader patient population. Do you think there is a benefit in pushing LDL as low as we can?

A: In our center, the majority of patients had tried four or more statins – we are absolutely not in competition with statins, because we have to start with statins. Is lower LDL always better? We can discuss the guidelines, but there is so much data showing that lower is indeed better. We are fond of low values, particularly in high-risk patients.

Q: Regarding myalgia, you still saw myalgia in the evolocumab group. Did you investigate that further?

A: The percentage of patients with myalgia was much higher in the ezetimibe group than the evolocumab group. This was a highly selected patient group that was prone to musculoskeletal side effects. There were around 20% of patients who were on very low doses of statins during the trial, and myalgias were likely more frequent in that patient group.

Comment: If there had been a placebo group in the study, there still probably would have been a high incidence of myalgia there. I agree that I do not think your agent has a significant musculoskeletal safety issue.

 

LAPLACE-2: A Phase 3, Double-blind, Randomized, Placebo and Ezetimibe Controlled, Multicenter Study to Evaluate Safety, Tolerability and Efficacy of Evolocumab (AMG 145) in Combination With Statin Therapy in Subjects With Primary Hypercholesterolemia and Mixed Dyslipidemia

Jennifer Robinson, MD, MPH (University of Iowa, Iowa City, IA)

Dr. Jennifer Robinson took the podium in the enormous “main tent” to present the full results of the 12-week phase 3 LAPLACE-2 study on Amgen’s PCSK9 inhibitor evolocumab. The trial tested the effect of monthly or biweekly evolocumab (vs. ezetimibe or placebo) when added to one of five regimens of moderate or high-intensity statin therapy. Consistent with the rest of the evolocumab phase 3 data we have seen so far, the results for monthly and biweekly dosing were clinically equivalent. The efficacy results from LAPLACE-2 were the most striking we saw out of Amgen’s five phase 3 presentations at ACC: among the various study arms, the addition of evolocumab to statin therapy led to mean LDL-C reductions of 63-75% versus placebo, taking the vast majority of patients (~85-95%, depending on particular statin therapy) to an LDL-C of under 70 mg/dl. The drug also improved other lipid parameters, and there were no major imbalances in adverse events (both consistent with the rest of the phase 3 results we have seen). A key takeaway from this trial was that evolocumab had similar efficacy regardless of whether a patient was on moderate or high-intensity statin background therapy. For patients that have trouble tolerating a high-intensity statin, we wonder if a new option will be to downshift the statin dose and add a PCSK9 inhibitor. This could be a preferred paradigm for type 2 diabetes patients, as statins can slightly increase glucose levels.

• Dr. Robinson spoke briefly on the relevance of this trial and of PCSK9 inhibitors as a whole in light of the new 2013 ACC/AHA cholesterol guidelines. She acknowledged that Amgen designed the phase 3 program for evolocumab before the release of the new guidelines, which de-emphasize specific LDL targets for most patients and are seen as not favoring PCSK9 inhibitors. However, she pointed out that non-statin therapies such as evolocumab have relevance in statin-intolerant patients, patients with familial hypercholesterolemia, and patients already on statins that need additional LDL lowering. Additionally, outside the US, most countries still recommend a specific LDL target of under 100 or 70 mg/dl, depending on patients’ risk levels.

Questions and Answers

Q: How do you think this therapy fits in with our new guidelines?

A: Trials suggest that we can use evolocumab to achieve additional LDL cholesterol lowering in patients who cannot take high-intensity statins, and in patients who are totally statin intolerant. Another potential use would be patients with familial or genetic hypercholesterolemia, including those who cannot take high-dose statins.

Q: Have you seen any neurocognitive effects with evolocumab? That is an issue that the FDA is looking into.

A: In the entire evolocumab program, there is no signal of imbalance in neurocognitive effects. That is something that we have monitored extremely carefully. When you get older people with such low LDL levels for the first time, neurocognitive function is an area in which we would want to closely examine since LDL is in every cell of the body, but we haven’t seen a signal so far. We’ve even sub-analyzed patients with LDLs below 45 and even 25 mg/dl, and there has been absolutely nothing.

 

Oral Sessions: Joint American College of Cardiology/New England Journal of Medicine Late-Breaking Clinical Trials

Effects of Bariatric Surgery vs. Intensive Medical Therapy on Long-Term Glycemic Control and Complications of Diabetes: 3-Year STAMPEDE Trial Results

Sangeeta Kashyap, MD (Cleveland Clinic, Cleveland, OH)

Dr. Sangeeta Kashyap presented the three-year results of the STAMPEDE trial, an important randomized controlled trial (RCT) in bariatric surgery that has drawn more attention of late for demonstrating the superiority of bariatric surgery (Roux-en-Y gastric bypass [RYGB; n=48 at year 3] or sleeve gastrectomy [VSG; n=49]) to intensive medical treatment (IMT; n=40) for the control of type 2 diabetes (the original one-year results were presented at ACC two years ago). At three years, the percentage of patients experiencing diabetes remission (defined as an A1c ≤6% ) was 38% of the RYGB group, 25% of the VSG group, and 5% of the IMT group, compared to 42%, 37%, and 12%, respectively, at one year. At three years, about 95% of the patients achieving A1c ≤6% on RYGB did so without any diabetes medications, compared to about 83% of the VSG group, and 0% of the IMT group. Relapse of diabetes (those who achieved A1c ≤6% at one year but not at three years) occurred in 24%, 50%, and 80% of patients in the RYGB, VSG, and IMT groups, respectively. There were also some considerable improvements in lipids, with HDL in both of the surgery groups appearing even better than the improvements observed at one year (details below). Rates of adverse events were in line with expectations with no procedure-related deaths occurring and no re-operations beyond the four recorded in year one. The three-year results are the first long-term (≥3 years) RCT data existing to compare bariatric surgery to medical therapy for the treatment of type 2 diabetes. These data were simultaneously published in NEJM. We look forward to watching how this field progresses as there are still a number of questions to be addressed longer-term on nutrition, complications, etc.

• STAMPEDE’s objectives were to (i) compare bariatric surgery vs. medical therapy with respect to achieving biochemical resolution of type 2 diabetes (resolution measured by A1c) and (ii) to compare differences between two types of surgery: Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (VSG). STAMPEDE randomized 150 patients with diabetes 1:1:1 to intensive medical therapy alone (IMT), IMT plus RYGB, or IMT plus VSG. At baseline, patients were around 50 years old with an average diabetes duration of eight years; mean A1c was fairly high, around 9%. Notably, one third of patients enrolled had baseline BMI below the current recommended cutoff for surgery of 35 kg/m² (mean baseline BMI was 36-37 kg/m², quite low for a bariatric surgery study). More than half of patients were on ≥3 diabetes medications, and nearly half were on insulin at baseline.
• For background, the one-year results of STAMPEDE (originally presented at ACC two years ago), showed that 12%, 42%, and 37% of patients in the IMT, IMT + RYGB, and IMT + VSG groups achieved an A1c ≤6.0% by the end of 12 months. At 12 months, all patients who underwent RYGB and went into remission were off of diabetes medications, and about three quarters of the patients who underwent VSG whose A1c normalized were off all diabetes medications.
• At three years, RYGB and VSG were still significantly better than IMT for resolving diabetes. The percentages of patients achieving A1c ≤6% were 37.5%, 24.5%, and 5%, respectively for the RYGB, VSG, and IMT groups. Most patients in the surgery groups were able to achieve A1c ≤6% without diabetes medications, whereas none in the IMT group were able to do so. Diabetes relapse (defined as patients achieving A1c ≤6% at year one who failed to do so at year three) was significantly lower in the RYGB group compared to the IMT group, but diabetes relapse in the VSG group was not significantly different from the IMT group (see table for details). HDL showed a dramatic increase in both of the surgical groups, and interestingly, seemed even better after three years than at one year. There were no differences across treatment groups in changes in LDL, blood pressure, or carotid intima media thickness.

	Intensive Medical Therapy (at 3 years / 1 year)	Roux-en-Y gastric bypass (at 3 years / 1 year)	Sleeve Gastrectomy (at 3 years / 1 year)
N	40 / 41	48 / 50	49 / 49
% patients achieving A1c ≤6.0%	5% / 12%	37.5% / 42%	24.5% / 37%
% patients achieving A1c ≤6% without diabetes medications	0% / 0%	35% / 42%	20% / 27%
Change in FPG (mg/dl) from baseline	-6 / -28	-85.5 / -87	-46 / -63
Relapse of glycemic control from year one to year three	80% / NA	23.8% / NA	50% / NA (not significantly different from IMT)
% change in HDL from baseline	+4.6% / +11.3%	+35% / +29%	+50% / +28%
% change in triglycerides from baseline	-21.5% / -14%	-46% / -44%	-31.5% / -42%

• Medication use remained significantly lower in the surgical groups. Both surgical groups had a sustained reduction in insulin use with only 6% of the RYGB and 8% of the VSG group requiring insulin at 36 months. The IMT group had a slight reduction in insulin use at six months that disappeared by three years. About 69% of patients in the RYGB arm and 43% in the VSG arm required no CV medications at three years compared to only 2.5% of patients in the IMT arm (53% of patients in the IMT arm required ≥3 CV medications).
• BMI reductions appeared more durable in the RYGB arm than the VSG arm. After three years, BMI change from baseline was -9.5 kg/m², -7.2 kg/m², and -1.8 kg/m² in the RYGB, VSG, and IMT groups, respectively, and all were statistically significantly different from each other. In contrast, after one year, the RYGB and VSG groups experienced similar weight reductions of about 10 kg/m² compared to about 2 kg/m² in the IMT group.
• Quality of life (QoL) measures seemed to improve more in the RYGB arm than the VSG arm, and no changes in quality of life were observed in the IMT arm. Five out of the eight QoL domains improved following Roux-en-Y gastric bypass (physical functioning, bodily pain, general health, energy/fatigue, emotional wellbeing). Two improved following VSG (general health, energy/fatigue), and none improved in the IMT group.
• Rates of adverse events seemed reassuring or in line with expectations. There were no procedure-related deaths, and no additional re-operations beyond the four recorded in the first year. As would be expected, there was a greater rate of GI complications in the RYGB group (26% vs. 4% in the VSG group and 5% in the IMT group; no statistical analysis of significance was presented). Weight gain greater than 5% from baseline occurred in 16% of the IMT arm and in 0% of the surgical groups. A few cases of retinopathy, nephropathy, and foot ulcers occurred, which seemed to be clustered in the surgical groups, but the numbers were too small to draw any conclusions.
• Dr. Kashyap noted that the limitations of the study included the fact that it was a small, single-center trial. Multicenter studies are needed to see if results can be generalized, and larger studies are needed to examine CV outcomes and diabetes-related microvascular disease outcomes.
• Results were simultaneously published in NEJM.

Questions and Answers

Q: This is an atypical population for what we consider bariatric surgery. You went as low as a BMI of 27 kg/m². Who would you consider the ideal candidate for what we call a metabolic or bariatric operation, and which procedure would you pick if they were diabetic? Is Roux-en-Y gastric bypass the clear answer? How do you explain the quality of life differences between the two procedures?

A: For the BMI question these surgeries are optimal for people who are heavier. The greater the BMI, the greater the weight loss. However in our subgroup analysis, even patients with BMI under 35 kg/m², the current threshold, had similar metabolic benefits. So these procedures show benefit for BMIs of 30 kg/m² or greater. In terms of the second question of gastric bypass vs. sleeve, both surgeries were effective. In terms of glycemic control both were equally effective. But I would say Roux-en-Y gastric bypass would be the optimal procedure of choice for durability and for greater weight loss. The quality of life issue stems from not taking so many agents. Insulin is incredibly burdensome for patients. Once patients are able to withdraw use of multiple injections/day, quality of life is enhanced. There were also benefits in terms of mobility, physical functioning, and confidence.

Q: Was the lifestyle intervention continued throughout the entire three years of the trial?

A: All patients were counseled every three to six months in the first two years and every six months during the last year.

Q: How do you think this applies across a broad base of the population? How do you think it would be if you just did the surgery? Do we have to have this lifestyle intervention across time to keep these people compliant, and if not is there more relapse with the surgery?

A: Surgery is a tool that initiates the weight loss, but lifestyle will never go away. In fact these for patients, years out, it’s not uncommon to see weight regain. So lifestyle interventions are always key. These patients need screening and counseling at the onset, and all of them did receive counseling. They need ongoing support.

 

Late Breaking Clinical Trials: Deep Dives

Commentary on the STAMPEDE 3-Year Trial Results

Milton Packer, MD (UT Southwestern, Dallas, TX)

In a session chaired by the very well-respected cardiologist Dr. Sanjay Kaul, Dr. Milton Packer provided his critique of the STAMPEDE three-year results (as presented by Dr. Sangeeta Kashyap above). Dr. Milton was fairly critical of the conclusions drawn, and about the rationale for the study in the first place (“I don’t know why anyone would want to achieve [A1c ≤6%]!”). He acknowledged that he “doesn’t know much about diabetes,” (!) and it seemed to show in his very cardiac-centric critique of the trial. Dr. Sangeeta Kashyap, who had presented the full study results (see above), had a chance to provide a rebuttal during the subsequent panel discussion – she argued that a biochemical endpoint such as A1c was the most feasible approach rather than looking at specific microvascular or macrovascular complications.

• Notably, Dr. Packer used ACCORD to argue that A1c ≤6% had been invalidated as a treatment target for people with type 2 diabetes. He did not consider how the ACCORD patient population may have differed from STAMPEDE (patients in ACCORD on average had a longer duration of diabetes), or that the excess mortality in ACCORD was in people who failed to reach 6% after one year of intensively treating to target, whereas people whose A1cs drop precipitously after bariatric surgery usually tend to do so with little effort.
• He also pointed out that incidence of diabetes complications seemed to cluster in the surgery groups: there was one case of stroke in the sleeve group vs. none in the IMT or RYGB groups. There were no cases of retinopathy in the IMT group, but one case in the RYGB group and two in the sleeve group. There were four cases of nephropathy in the IMT group but seven in the RYGB group and five in the sleeve group. Finally, there were no cases of foot ulcers in the IMT group but two in the RYGB and one in the sleeve group. Taken alone, none of these seems to be a worrying imbalance, but collectively, they suggest an imbalance in the wrong direction. In our view, the small number of cases and the length of follow-up make it much too difficult to say whether they can be attributable to the surgery. In addition, it has been well documented (e.g., in DCCT) that quick A1c declines may exacerbate retinopathy before it gets better.
• He criticized the conclusion that both Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy should be considered options for treating type 2 diabetes with results durable to three years when RYGB clearly showed better durability. He also criticized the study for excluding certain endpoints that were published with the one-year results, including blood pressure, fasting insulin levels, insulin resistance, CRP, or hypoglycemia (which was the most common adverse event after one year).

Questions and Answers

Q: Dr. Kashyap, you may take a few minutes to respond.

Dr. Kashyap: For someone who doesn’t know much about diabetes I think your comments are right on. Our data are very clear about both surgery types. They were both compared to medical therapy. We didn’t compare the sleeve to its one year value, but we looked at how the sleeve performed at three years to the three year value for the medical arm. Both surgery types did far better. They met the primary endpoint. In our paper, which is online today, we do note that there was a greater relapse rate. There were patients who met that primary endpoint at 12 months, but failed at three years. That was 50% in sleeve, but 80% in the medical group and only 24% in Roux-en-Y gastric bypass. If I were to pick between the two types of procedures, gastric bypass is superior for diabetes. And how do we define diabetes? For this trial, it would have been interesting to choose an end organ effect such as rate of nephropathy or retinopathy, but for a first feasibility study, a biochemical endpoint is more feasible. Obviously end organ damage is far more clinically relevant but we felt an A1c is what defines diabetes. The diagnostic criterion is an A1c of 6.5%. Now in our hospital, we went one step farther. We wanted to see how many achieved remission so we chose a very stringent A1c value of 6%. We said whether they achieve it with meds or without is not the point because it’s very difficult to drive patients to A1c of less than 6% with meds. The last point about ACCORD and ADVANCE is well noted. Hyperglycemia is a very weak CV risk factor. However, hyperglycemia is what defines the disease metabolically. Bariatric surgery is now called metabolic surgery. In this trial we showed it can restore insulin secretion and insulin sensitivity. We did a metabolic sub-study where we were able to show that at two years. We showed quite definitively that both procedures improved insulin sensitivity, insulin action, and reduced leptin levels. Due to funding we weren’t able to show all these endpoints for the entire cohort.

Dr. Packer: A1c does not define diabetes. That’s not the definition of the disease. But why would you target an endpoint that has been discredited? This is not something that physicians seek to achieve right now.

Dr. Kashyap: The diagnostic threshold for diabetes is a glycemic endpoint. It’s either fasting glucose or an A1c value. Glycemia may not be a very important factor for CV events, but it is very import for retinopathy, neuropathy, and nephropathy. These are major morbidities to patients with diabetes.

 

Oral Sessions: Featured Clinical Research

Efficacy and Safety of Evolocumab (AMG 145) Monotherapy Compared With Ezetimibe and Placebo in Hypercholesterolemic Subjects: A Phase 3 Randomized Clinical Trial

Michael Koren, MD (Jacksonville Center for Clinical Research, Jacksonville, FL)

Dr. Michael Koren began the much-awaited series of phase 3 data presentations on Amgen’s PCSK9 inhibitor candidate evolocumab; the session was so popular that both the presentation room and the simulcast screens were packed to capacity. MENDEL-2, which tested 140 mg biweekly and 420 mg monthly doses of evolocumab compared to ezetimibe (a non-statin cholesterol lowering drug) and placebo as monotherapy in patients naïve to lipid medications, was one of the first of Amgen’s phase 3 trials to report topline data (back in December). After 12 weeks, biweekly and monthly evolocumab delivered ~55-57% reductions in LDL-C relative to placebo, and ~38-39% reductions versus ezetimibe. These effects were established by week 2, and were remarkably constant through week 12 (the DESCARTES study, which was presented next [see below], demonstrated durability through a full year). Every patient on evolocumab (n=153) saw a decrease in LDL-C from baseline (generally over 40%), something that could not be said about the placebo (n=76) or ezetimibe (n=77) arms. The drug yielded significant reductions in ApoB, and interestingly, the monthly dose of evolocumab seemed to have a slightly stronger effect on triglycerides than the biweekly dose – this was the only notable difference between the two doses, and Dr. Koren did not characterize it as clinically meaningful. The drug was well-tolerated, with no individual adverse events showing a worrying imbalance. Dr. Koren concluded that, although Amgen anticipates that evolocumab will primarily be useful in high-risk patients in conjunction with statins, it was promising to see that the drug led to marked LDL-C reductions as monotherapy.

• During Q&A, Dr. Koren noted that statin therapy can be seen as a confounding factor in studies of PCSK9 inhibitors, as they upregulate the expression of PCSK9. This counterregulatory effect, he added as an aside, is part of the reason why statins show diminishing efficacy at very high doses. Studying PCSK9 inhibitors such as evolocumab as monotherapy allows investigators to observe the true effect of the drug without this potentially confounding factor.

Questions and Answers

Q: Could you talk about the rationale of conducting a study in patients not on a statin?

A: Statins are known to upregulate PCSK9 levels. It is very possible that in patients who are not on statins, you may see different results. The point of the study was to look at safety and efficacy in patients not confounded by statins. The monotherapy study provides data on the side effect profile of the drug itself.

Q: For the non-lipidologists among us, can you speak a little more about why PCSK9 levels rise with statins?

A: Statins upregulate PCSK9 production, which is a theory explaining why statins lose their incremental effect as one increases the dosage. It is an offsetting mechanism against the primary effect of statins.

Q: Do you have any information on how patients accepted the injectable administration of the drug?

A: We have some information from previous studies and some anecdotal information from this study, and those anecdotal reports indicated that the drug administration was accepted very well. In the OSLER study, patients in a blinded phase 2 study were allowed to proceed to an open-label study phase, and most patients agreed to enroll, showing that they were very accepting of the therapy. That finding was especially notable given that the study used the older injection technology, not the more convenient auto-injector that we use now.

Q: Could you talk more about the auto-injectors?

A: The auto-injector, if I recall correctly, used a 27-gauge needle. It was very easy to use – even I could use it.

 

Long-Term Tolerability and Efficacy of Evolocumab (AMG 145) in Hyperlipidemic Subjects: A 52-Week Phase 3 Double-Blind, Randomized, Placebo-Controlled Study

Dirk Blom, MD, PhD (University of Cape Town, South Africa)

Dr. Dirk Blom presented the results of the phase 3 DESCARTES trial, a long-term, 52-week trial investigating the safety and efficacy of evolocumab in addition to baseline lipid-lowering therapy. The study first stabilized patients on one of four therapies, depending on lipid control: i) diet alone; ii) diet and atorvastatin 10 mg; iii) diet and atorvastatin 80 mg; and iv) diet, atorvastatin 80 mg, and ezetimibe 10 mg. As expected, there were significant differences in baseline characteristics between these four baseline treatment groups. Patients from each group were randomized to evolocumab or placebo injection in equal measure. Following stabilization of baseline therapy, patients were relatively well controlled, with mean LDL-C levels generally between 100-120 mg/dl. Patients on evolocumab saw a striking 57% reduction in LDL-C relative to placebo injection (-51.5% vs. +6.0% for evolocumab and placebo, respectively), and 82% of evolocumab patients achieved an LDL-C goal of <70 mg/dl at week 52 (relative to 6% of patients on placebo). Notably, this efficacy was fairly constant across baseline therapy subgroups, although it did seem to be slightly diminished in patients in the most intensive background therapy subgroup (diet, atorvastatin, and ezetimibe), a group that also saw slightly more modest reductions in PCSK9 levels.

Questions and Answers:

Q: When you say monthly dose, do you mean every 31 days or every 28 days?

A: We administered every 28 days.

Q: You discussed one patient with short-term memory loss, which I believe recovered spontaneously. Was that recovery while the patient was on or off of the agent?

A: I’ve only read what is in the clinical study report, that the patient started a supplement with green coffee bean extract, and then had trouble remembering things. It might have just been the caffeine making her jittery, but in any case, the patient recovered spontaneously while still on evolocumab.

 

Posters: The Roles of Diabetes, Obesity, and Kidney Disease in Stable Atherosclerotic Heart Disease

Prognostic Implications of Simultaneous Biomarker Assessments in Patients with Type 2 Diabetes Mellitus: Observations from the SAVOR-TIMI 53 Trial

BM Scirica, DL Bhatt, E Braunwald, I Raz, PG Steg, J Davidson, MA Cavender, B Hirschberg, A Umez-Eronini, KA Im, P Jarolim, & DA Morrow

Dr. Benjamin Scirica presented an analysis of CV outcomes in the SAVOR cardiovascular outcomes trial based on 12,182 patients’ baseline biomarker status for NT-proBNP (a marker of hemodynamic stress), high sensitivity troponin T (hsTnT; a marker of myocardial necrosis [tissue death]), and high sensitivity CRP (hsCRP; a marker of inflammation). As would be expected, elevated levels of each biomarker were independently associated with increased rates of CV death, myocardial infarction, and hospitalization for heart failure. Notably, saxagliptin did not have an effect on CV outcomes regardless of baseline biomarker status, even in patients at highest clinical risk. This means that even in people with the highest baseline levels of these biomarkers, saxagliptin did not any increased risk relative to placebo for CV events. This is consistent with Dr. Scirica’s analysis of hospitalization for heart failure (HHF) at AHA 2013 where he found no population in which the relative risk of HHF due to saxagliptin was particularly high or low but that saxagliptin’s absolute risk of heart failure was significantly elevated in people with the highest quartile of NT-proBNP levels at baseline.

 

Posters: Familial Hypercholesterolemia, Novel Therapies, and Cardiovascular Risk

First Data with the 75 mg Every 2 Weeks Dose of Alirocumab, a Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor: Superior Lipid-Lowering Versus Eetimibe in a Phase 3 Monotherapy Trial

EM Roth, MR Taskinen, HN Ginsberg, JJP Kastelein, HM Colhoun, JG Robinson, L Merlet, R Pordy, MT Baccara-Dinet

This poster presented the first phase 3 data for Sanofi’s PCSK9 inhibitor, alirocumab. In this 24-week monotherapy study (ODYSSEY MONO; ClinicalTrials.gov Identifier: NCT01644474), 103 patients were randomized 1:1 to 75 mg alirocumab every two weeks (Q2W) or 10 mg ezetimibe (an oral active comparator). Patients on alirocumab could be blindedly uptitrated to 150 mg if LDL remained ≥70 mg/dl at week 12 (14 patients were up-titrated). From a mean baseline LDL of ~140 mg/dl in both groups, alirocumab produced a 47% LDL reduction in the intent to treat (ITT) population and 54% reduction in the per-protocol (PP) population. In comparison, ezetimibe produced a 16% LDL reduction in the ITT population and 17% reduction in the PP population. While comparing trials is inherently challenging, this appears somewhat less impressive than the 12-week and one-year results that Amgen presented at this meeting for evolocumab (AMG 145); LDL reductions in those trials ranged from ~53-75%. In both the ITT and PP population, alirocumab also improved ApoB, non-HDL, HDL, and total cholesterol better than ezetimibe, while changes in Lp(a), triglycerides, and ApoA-1 were not significantly different (Amgen’s evolocumab did generally show differences in these parameters). While Sanofi beat Amgen to announcing topline phase 3 data in late 2013, Amgen will beat Sanofi to submission. Sanofi does not plan to submit alirocumab until 2015, and Amgen expects to submit evolocumab in 2014.

 

Symposium: How to Navigate the Maze of Pharmacotherapy in Diabetes

It’s Not Just Alphabet Soup! A Primer on Diabetic Medications

Silvio Inzucchi, MD (Yale University School of Medicine, New Haven, CT)

Dr. Silvio Inzucchi’s aptly-titled presentation (DPP, SGLT, GLP, SFU – alphabet soup indeed, at least to the uninitiated) provided a basic and balanced overview of the field of diabetes drug candidates. His opening slide compared the growth in the number of classes of drugs for hypertension and for diabetes: while hypertension drugs classes have gradually been introduced over the last three decades, the number of diabetes drugs have skyrocketed at a rate of ~1/year since the introduction of metformin. Dr. Inzucchi ran through the common pros and cons without any surprising remarks. He did raise a brief question about heart failure with AZ’s DPP-4 inhibitor Onglyza, but did not mention it by name, and he did not suggest that the risk was well-defined. As an example of a logical progression of therapy for a hypothetical “average” patient, he suggested starting with metformin (after diet and exercise), then adding a DPP-4 inhibitor, followed by a TZD, SFU, or insulin, if necessary.

Questions and Answers

Q: How do you propose that we, as cardiologists, should manage these patients?

A: If you are managing their glucose levels, it is a complicated discussion after metformin. Metformin is easy, if the patient does not have renal insufficiency. Beyond that, there is a heart failure concern with TZDs and maybe DPP-4 inhibitors, and the choices get more complex. I think that we must analyze the advantages and disadvantages of each drug class, trying to partner with the patient to understand what side effects they are best able to withstand.

Q: In the algorithm you put up, you mentioned that hypoglycemia risk is high with insulin. I found that surprising, because in my experience, basal insulin is unlikely to cause hypoglycemia.

A: At doses that are more modest, hypoglycemia would be less anticipated than at higher doses, although there are data that even in patients that are not at high doses, they are still at risk for hypoglycemia. It is true that at more modest doses, the risk is lower, although it is certainly higher than with many other drug classes.

Q: What do you think about starting basal insulin immediately after metformin?

A: I generally don’t do that, because most patients don’t want to go to an injectable if pills are still an option. However insulin can be a rational second-line therapy, especially if the patient cannot take other drug classes or needs particularly potent control.

 

What Do I Need to Know About the CV Risks of Diabetic Agents?

Darren McGuire, MD (University of Texas Southwestern, Dallas, TX)

Dr. Darren McGuire provided a cardiologist’s view of the CV considerations involved in prescribing diabetes drugs (he reviewed sulfonylureas, metformin, TZDs, DPP-4 inhibitors, and SGLT-2 inhibitors – disappointingly he did left out GLP-1 agonists). Notably, he suggested that if the DPP-4 inhibitor heart failure effect were real, that it was comparable to heart failure seen with TZDs (if one annualizes the rate of heart failure seen in the CVOTs for Actos, Onglyza, and Nesina, they come out to around 0.3-0.4%). We thought this was somewhat misleading and premature to speculate on. He briefly touched on SGLT-2 inhibitors, saying that there is hope that they may actually be beneficial for heart failure. As would be expected for a cardiologist, he was very harsh on sulfonylureas, stating “I personally don’t use SFUs. I don’t care if they’re cheap; placebo is cheap as well and doesn’t increase mortality.” He ultimately proposed an updated algorithm for treating diabetes patients with/at risk for CVD (updated from the original algorithm he published with Dr. Silvio Inzucchi in 2008 in Circulation) in which metformin is the first line therapy, pioglitazone the second, DPP-4 inhibitors the third (now that there is good CVOT data for them), GLP-1 agonists or SGLT-2 inhibitors the fourth, and insulin secretagogues and alpha-glucosidase inhibitors the last non-insulin choice.

• With regard to sulfonylureas, Dr. McGuire exclaimed, “I personally don’t use SFUs. I don’t care if they’re cheap; placebo is cheap as well and doesn’t increase mortality.” SFUs’ association with CV mortality primarily comes from the 1970 UGDP trial where the first generation SFU tolbutamide was associated with about 50% excess mortality compared to placebo or insulin. Later, UKPDS found no deleterious CV effects of the second generation SFUs glyburide or glyclopyramide, but a 2011 Danish registry study found that every SFU except gliclazide increased all-cause mortality compared to metformin. While this was an observational study, making cause/effect difficult to attribute, Dr. McGuire remains staunchly opposed to the use of SFUs.
• On DPP-4 inhibitors, he reviewed SAVOR and EXAMINE results, which found that AZ’s Onglyza (saxagliptin) and Takeda’s Nesina (alogliptin) were safe with regard to overall CV safety. He remarked that the 27% increase in risk of hospitalization for heart failure in SAVOR was a complete surprise finding. He suggested that the non-significant 19% increase seen in EXAMINE was also real but that the study just wasn’t powered for it to demonstrate significance. To put the heart failure findings into perspective, he noted that “this signal is not dissimilar to what we’ve seen before with the TZDs with regards to annualized event rate: from pioglitazone’s PROactive trial, the annualized heart rate incidence was 0.45% compared to 0.33% for saxagliptin and 0.4% for alogliptin.
  
  • We saw this as a somewhat misleading comparison. As we understand it, it is too early to draw any similarities between the severity of the risk of heart failure of DPP-4 inhibitors and TZDs. While the mechanism through which TZDs produce heart failure (edema) is well understood, currently there is no mechanistic explanation for why DPP-4 inhibitors should cause heart failure if they do at all. In addition, the increased risk of heart failure in SAVOR was not accompanied by increased mortality or occurrence of either the primary or secondary composite endpoints.
• Dr. McGuire briefly touched on SGLT-2 inhibitors noting that cardiologists anticipate that the drugs may have a favorable effect on heart failure. The reasoning was not completely clear to us, but beneficial reductions in blood pressure through diuresis might play a role.
• While metformin initially suffered a bit of defamation due to its association with phenformin, its restrictions have been increasingly relaxed. In the US metformin is contraindicated in women with creatinine >1.5 mg/dl and in men with creatinine >1.6 mg/dl based on concerns with phenformin and lactic acidosis. However,  Dr. McGuire noted that as far as we can tell, metformin does not lead to a meaningful increase in lactic acidosis. Renal warnings for metformin are falling out of favor around the world, with some geographies not restricting based on renal function anymore (Lipska et al., Diabetes Care 2011). In addition, he noted that the restriction of metformin in people with heart failure was removed around 2008 with no fanfare, but it was based on the same “mythical” concerns about lactic acidosis.
• Of course, TZDs must be used cautiously in people with heart failure. Dr. McGuire highlighted the differences between pioglitazone (Takeda’s Actos) and rosliglitazone (GSK’s Avandia). Rosiglitazone appears to be associated with a 118% increased risk of heart failure compared to 30% for pioglitazone (Lago et al., Lancet 2007). He noted that lower doses of pioglitazone have a much better heart failure profile. Meanwhile, rosiglitazone has a roughly 30% increased risk of myocardial infarction (MI) while pioglitazone does not – he expressed uncertainty as to whether the FDA’s decision to reverse its position on rosiglitazone’s MI risk was right or wrong.
• Finally, Dr. McGuire proposed an updated treatment algorithm for people with type 2 diabetes and with/at risk for CVD (based on the algorithm he published with Dr. Silvio Inzucchi in Circulation in 2008). He would still start with metformin and then intensify to pioglitazone, as the original algorithm states, and then add a DPP-4 inhibitor since we now have CVOT data on DPP-4 inhibitors. The next choice would be a GLP-1 agonist or SGLT-2 inhibitor, and insulin secretagogues and alpha glucosidase inhibitors were his last non-insulin choice.

 

Are All Diabetics High Risk?

Amit Khera, MD (University of Texas Southwestern, Dallas, TX)

Dr. Amit Khera tackled the now age-old question of whether diabetes is a coronary risk equivalent (the term popularized by Steve Haffner’s East West Study in NEJM 1998). The consensus seems to be a resounding “no,” but Dr. Khera cautioned that people with diabetes are still at higher risk for CVD than the general population, and that there is a significant amount of heterogeneity of risk amongst people with diabetes. People with shorter duration diabetes are at much lower risk than people with longer duration diabetes. He reviewed several risk calculators that can help physicians quantify this risk and guide actionable decisions – these included the UKPDS and Framingham risk models. He cautioned that the Framingham model tends to underestimate risk.

 

Symposium: Consensus and Controversies in Management of Cardiovascular Risk in Diabetes

Glycemic Control

Silvio Inzucchi, MD (Yale University, New Haven, CT)

Dr. Silvio Inzucchi discussed the issue of whether glucose control or specific glucose lowering agents have an impact on cardiovascular events. Based on the title of his talk we had hoped he might also touch on the controversial issue of glycemic targets for people with CVD, but he did not. Epidemiological evidence clearly shows a higher risk of CVD in people with elevated blood glucose. However, as is generally the consensus in the diabetes community, Dr. Inzucchi remarked that the evidence is weak for glucose-lowering itself improving CV risk and that intervention is required before atherosclerosis is established (“legacy effects” were observed in UKPDS and DCCT/EDIC long-term follow-ups, but no evidence of benefit was observed in ACCORD, ADVANCE, or VADT. In terms of specific agents that may lower CV risk, he highlighted pioglitazone (Takeda’s Actos) as having the strongest data to support CV benefit (although TZDs obviously come with so much extra baggage that few people prescribe them anymore) – the secondary MACE endpoint in PROactive showed pioglitazone’s modest 16% benefit with regard to CV death, MI, and stroke. He noted that metformin in the UKPDS study appeared to improve CV risk, but that the study population was only 382 patients. Finally, he relayed that SAVOR had demonstrated neutral CV effects for the DPP-4 inhibitor saxagliptin (AZ’s Onglyza). Dr. Inzucchi remarked that there are literally now hundreds of thousands of patients in ongoing CVOTs, which will tell us more in the next four-to-five years about different drugs’ CV profiles.

Questions and Answers

Q: So it may not be glucose we need to correct. Perhaps we don’t have the modality of treating glucose without off target side effects. 

A: We thought we had it with the TZDs, but the discussion got very confusing with the heart failure signal and the rosiglitazone controversy. I believe that these PPAR-gamma therapy studies have been biased. I think we’ve been spoiled by statins. We can’t expect glucose control over the three-to-five years short duration in current studies to show an effect. It may take longer study, but it’s impossible to fund an RCT for 12 years.

 

Bariatric Surgery

Peter McCullough, MD, MPH (Baylor University Medical Center, Dallas, TX)

Dr. Peter McCullough did not come across as an expert on obesity therapies (in his review of current drug options, he did not mention Qsymia or Belviq, and in his review of future drug options, he did not mention Contrave or Victoza), but there was one particularly striking figure he cited that we thought illustrated well just how hard it is to treat obesity with lifestyle intervention. He relayed that the television show The Biggest Loser, a show where people compete to lose weight through intensive lifestyle intervention, recently published a paper expounding the fact that 17 people on the show had achieved bariatric levels of weight loss through lifestyle alterations alone. The paper’s suggestion was that if we could just get people to exercise enough, then everyone could lose that much weight. However, he pointed out that The Biggest Loser had to screen and work with 47,000 people to get to those 17 whose were lucky enough to have genetic backgrounds that were highly responsive to lifestyle intervention.

 

Symposium: Cardiovascular Update for the Clinician – A Symposium by Valentin Fuster at ACC.14

The Link Between Diabetes and Obesity: Are We Ready For Bariatric Surgery?

Michael Farkouh, MD (University of Toronto, Toronto, Canada)

Dr. Michael Farkouh explained why he believes bariatric surgery will become the standard of care for overweight people with type 2 diabetes and discussed key considerations for the future of bariatric surgery. He reviewed data showing that bariatric surgery can produce about 80% resolution of diabetes, with the best results seen with biliopancreatic diversion (a relatively risky procedure). He commented that the sleeve gastrectomy, despite being less invasive than the gold-standard Roux-en-Y gastric bypass, seems to have similar metabolic effects. He reviewed data from the STAMPEDE trial (Schauer et al., NEJM 2012) and the Mingrone Study (Mingrone et al., NEJM 2012), both of which compared surgery to medical treatment for type 2 diabetes and found drastically better improvements in glycemic measures, diabetes resolution, and ability to come off of diabetes medications in the surgical groups, again with biliopancreatic diversion seeming to produce the best results. Dr. Farkouh cautioned that BMI may not be the best criterion for selecting patients for surgery – the SOS trial has shown that baseline BMI does not predict benefit derived from surgery, and instead those with the highest insulin levels at baseline enjoyed the greatest benefit (Sjöström et al., JAMA 2013). With regards to safety, he noted that laparoscopic bariatric surgery has a risk profile very close to that of appendectomy (~6% complication rate and 0.06% mortality; Ngyuen et al., ASMBS Abstracts 2012). Looking to the future, he noted that we will need to press for CV outcomes, and he made the astute remark that we might want to start looking at surgery as an earlier option rather than using a “salvage” approach. Finally, he advocated for lowering the BMI cutoff for bariatric surgery from 35 kg/m² to 30 kg/m².

 

Lipids – Are Evolving Guidelines Less Dependent on LDL-C or HDL-C Targets? Are PCSK9 Inhibitors Poised for a Breakthrough?

Sidney Smith Jr., MD (University of North Carolina at Chapel Hill, NC)

The two questions posed in the title of Dr. Sidney Smith’s presentations are intertwined: the new ACC/AHA lipid guidelines emphasize the importance of statin treatment and de-emphasize the pursuit of specific LDL targets, a paradigm that may reduce the relevance of PCSK9 inhibitors, which are being pursued as extremely potent LDL-lowering agents. Dr. Smith covered a range of experimental evidence demonstrating that statins have a benefit even in patients below the traditional LDL target of 100 mg/dl. However, he also characterized PCSK9 inhibitors as the most exciting current development in the effort to lower cholesterol levels. He surveyed the ongoing trials for PCSK9 inhibitors in development, which include Amgen’s evolocumab (phase 3; expected 2014 filing), Sanofi’s alirocumab (phase 3; expected 2015 filing), Pfizer’s bococizumab (phase 3), Roche’s RG7652 (phase 2), Lilly’s LY3015014 (phase 2), and Catabasis’ CAT-2003 (phase 2). The three furthest-along candidates have ongoing outcomes trials (FOURIER for evolocumab, ODYSSEY OUTCOMES for alirocumab, and SPIRE 1 & 2 for bococizumab), all of which are investigating a PCSK9 inhibitor on top of relatively intensive statin therapy (which is how PCSK9 inhibitors will likely be used, at least initially, except for statin-intolerant patients). Dr. Smith concluded that the answer to “are evolving guidelines less dependent on LDL-C or HDL-C targets?” and “are PCSK9 inhibitor poised for a breakthrough?” are both yes. Hard outcomes data for PCSK9 inhibitors will likely be essential for any new guidelines to reconsider the recommendation to aggressively pursue low LDL levels.

 

Panel Discussion – Selected Q&A

Q: Given that the modification of risk factors is so important, should we begin by referring patients to weight management clinics and diabetes clinics?

Dr. Michael Farkouh (Mount Sinai Hospital, New York, NY): There are diabetes clinics, as you know, but I think they have had big problems with reimbursement. These multidisciplinary clinics have not survived in the current model of reimbursement. If we work with our colleagues in the government and in industry, we can develop these types of teams. I think it is very important, and also that working with the bariatric surgeon community is important.

 

Symposium: Statins in the Real World: Concerns, Conundrums, Controversy

I Have a Family History of Diabetes and Coronary Heart Disease: Should I Take Statins and Risk Diabetes or Avoid Statins and Risk Heart Disease?

Christie Ballantyne, MD (Baylor College of Medicine, Houston, TX)

In front of a standing-room-only audience, Dr. Christie Ballantyne discussed the hot-button issue of how to manage the tradeoff between statins’ slight increase in risk of diabetes and their powerful benefit for preventing CVD. According to the new 2013 ACC/AHA cholesterol guidelines, low-intensity statin therapy causes 0.1% excess cases/year of diabetes, and high-intensity statin therapy about 0.3% excess cases/year. These typically occur in people already at high risk of diabetes. The guidelines state that the risk for new-onset diabetes is small compared to the benefit of moderate-intensity statin therapy for primary prevention in people with 10-year CVD risk >5%, and in people with 10-year CVD risk ≥7.5% or established CVD, the risk of new-onset diabetes on high-intensity statin therapy is also smaller than the benefit from CVD risk reduction. Dr. Ballantyne noted that lifestyle changes appear to be more effective at preventing diabetes than preventing CVD, citing the DPP trial. He urged audience members to send their patients home with not only a prescription for statins, but a prescription for exercise as well.

Questions and Answers

Q: We know statins are useful in people who already have diabetes as well. The question for you is how many patients will become diabetic and require therapy based on A1c? We know that if A1c is 6.5%, we could harm them by causing hypoglycemia. Do you have numbers for how many actually require therapy?

A: This is a good question. If you shift someone from a 6.4% to a 6.5%, which is what happened in the vast majority of patients in these trials, you’re talking about a 0.1% change in A1c. A lot of that would not alter therapy at all. It’s an arbitrary cut-point. If someone is doing well at 6.6% with lifestyle, the evidence for drug therapy is not clear.

Q: So why measure it? Why look for mild glucose elevations?

A: The reason we look at glucose is that it’s very preventable. We have more data that you can prevent diabetes with lifestyle than you can prevent CVD.

 

Symposium: Preventative Cardiology

Diabetes and Cardiovascular Disease

Erin Michos, MD, MHS (Johns Hopkins University School of Medicine, Baltimore, MD)

Cardiologist Dr. Erin Michos presented on the important and complex relationship between diabetes and cardiovascular disease, citing a wealth of data from landmark RCTs. Her by-the-data approach led to some sharp conclusions on issues that might have deserved slightly more nuance – for example, she concluded that the approach used to achieve glycemic control (insulin vs. insulin sensitizing drugs) does not have an impact on CV outcomes, based on the BARI 2D study. In her view, preventing cardiovascular disease in patients with diabetes hinges on diagnosing diabetes earlier, individualizing therapy appropriately, emphasizing lifestyle interventions, and focusing broadly on cardiovascular disease risk factors beyond hyperglycemia (see below). 

• Dr. Michos discussed the “ABCs of cardiovascular risk reduction as they apply to diabetes patients:
  
  • (A)spirin has failed to show an improvement in CV outcomes in patients with diabetes, due perhaps to low study event rates and non-compliance, among other issues.
  • (B)lood pressure trials in diabetes patients have had mixed results. While the UKPDS and HOT trials demonstrated improvements in outcomes with tighter blood pressure control, the ACCORD and INVEST studies generally did not (ACCORD showed an improvement in stroke, but not in the composite primary outcome).
  • (C)holesterol: Statins have shown a clear benefit on CV outcomes in diabetes patients, but studies (such as ACCORD Lipid) have not shown consistent benefits with fenofibrates (drugs that lower cholesterol and triglycerides).

 

Symposium: ESC/ACC Joint Symposium – Obesity and Cardiovascular Risk: Focus on Bad Fat

Healthy Fat, Unhealthy Fat, and Infected Fat

Richard Atkinson, MD (Virginia Commonwealth University, Richmond, VA)

Much of Dr. Richard Atkinson’s talk was dedicated to the adenovirus infection theory behind the obesity epidemic, and he began by reviewing characteristics of healthy and unhealthy fat. Healthier adipose tissue is generally lower in the body, subcutaneous, contains small adipocytes, and is more insulin sensitive. Contrastingly, unhealthier fat is visceral, pericardial, hepatic, intrathoracic, or hepatic; it is often inflamed, norepinephrine-sensitive, and less insulin-sensitive. Overall, Dr. Atkinson did not put much stock in the “healthy obesity” theory; likening it to symptomless hypertension, diabetes, or early cancer, he emphasized the need to treat the underlying defect even if complications have not yet developed. The talk took a slightly more controversial turn when he argued that the obesogenic environment, including large sodas and fast food, is not the root cause of the obesity epidemic, as it cannot explain the rapid rise in obesity prevalence. Instead, he believes that adenovirus infection might be a major culprit; in our view, the timescale of the obesity epidemic is certainly not sufficient to rule out the broadly accepted impact of our obesogenic environment. Research on the impact of adenoviruses on obesity is in its early stages, but is worth examining. In multiple animal models, infection with the specific adenovirus Adv36 led to significant increases in body weight and fat, and obese individuals have a much higher infection rate than non-obese individuals (30% vs. 11%; Atkinson et al., Int J Obesity 2005).

 

Overview of Therapeutic Strategies to Reduce Weight

JoAnne Foody, MD (Brigham and Women’s Hospital, Boston, MA)

Dr. JoAnne Foody’s presentation on obesity therapies was built around the AHA/ACC/TOS 2013 guidelines for obesity management (see our AHA 2013 Day #5 Report), which place a relatively high focus on lifestyle interventions and bariatric surgery over pharmacotherapies (the guidelines were drafted before the approval of the most recent generation of anti-obesity drugs). At a high level, Dr. Foody recommended that providers stratify patients based on comorbidities, combine exercise, diet, and behavior modification, set a reasonable goal of 5-10% weight loss, and recommend that patients slowly ramp up their exercise habits. She recommended considering medication and surgery only for high-risk patients, once other options have been exhausted.

 

Panel Discussion – Selected Q&A

Q: We know that lifestyle modification is challenging. How many patients can achieve sufficient weight loss to be non-obese?

Dr. JoAnne Foody (Brigham and Women’s Hospital, Boston, MA): This is the crux of the issue – the challenge is that as much as we recommend lifestyle, there are relatively few individuals who can move from obesity to non-obesity as measured by BMI.

Dr. Sheldon Litwin (Georgia Health Sciences Medical Center, Augusta, GA): Obviously there is a huge disconnect between the guidelines and reality. As much as I am an advocate of exercise and lifestyle, you only get a 25% response rate in the patients who are even willing to undergo an intensive effort. The reality is that even when weight loss is achieved, it is not maintained. That is what is compelling about the surgical option. Data there shows the maintenance of weight loss for up to ten years. If we’re trying to set the clock back on diabetes, we need interventions like that.

Dr. Foody: I think a challenge is that we need to be sure that we make those referrals. We understand now that in patients with BMIs that are not all that high, they can still benefit from bariatric surgery.

Dr. Keith Fox (University of Edinburgh, UK): It seems like we are seeing a massive rise in bariatric surgery procedures. What will the landscape look like for bariatric surgery in the future?

Dr. Litwin; It is very effective, and most cost-effectiveness studies suggest that it will save us money in the long term. But hospital administrators and payers are looking at the next quarter’s budget statement and not what will happen in ten years, when someone else will have their job. There will be cost benefits in the future; it’s just a matter of how far forward we can look.

Dr. Richard Atkinson (Virginia Commonwealth University, Richmond, VA): I totally agree that obesity surgery works – it seems like nothing that I do or that internists or GPs do for obesity works. The best behaviorists in the world have gotten five percent weight loss, at the maximum. But in twenty years, as much as I admire surgeons, we will probably be able to figure out the complex interplay and changes in gut hormones that occur during bariatric surgery, and we’ll be able to reproduce them without surgery and put the surgeons out of business. We don’t yet have drugs good enough to get patients where they need to be. Look AHEAD was stopped due to futility – they achieved 5% weight loss and had no measurable effect on outcomes. You need to have at least 10% weight loss to see any difference.

 

Symposium: Joint ACC/Caribbean Cardiac Society/Emirates Cardiac Society Symposium: The Rising Burden of Cardiovascular Diseases in the Developing World

Imminent Epidemic of Obesity, Metabolic Syndrome, and Vascular Disease

Cother Hajat, MBBS, PhD, MPH (United Arab Emirates University, Al Ain, UAE)

Dr. Cother Hajat provided a comprehensive overview of the cardiovascular disease epidemic in the United Arab Emirates (UAE). The UAE is a relatively high-income country with a very young, heterogeneous population (composed mostly of expatriates). The prevalence of diabetes in the UAE is extremely high, with worryingly high rates of diabetes and prediabetes, even in relatively young age groups (the combined prevalence of diabetes and prediabetes is ~30% in 18-20 year olds). However, IDF Diabetes Atlas data from the past decade shows that overall diabetes prevalence appears to be plateauing at around 19%, and in the IDF’s most recent Diabetes Atlas the UAE is no longer in the top five countries in the world by prevalence. Roughly two-thirds of diabetes cases in the UAE are diagnosed, and an impressive 89% of those patients are on medication, but the majority (~two-thirds) are still poorly controlled. Adherence might be the key to understanding that discrepancy; a study comparing adherence to CV medications post-myocardial infarction in Sweden and the UAE showed a much steeper drop in adherence after a year in the UAE, and we imagine the same might be happening in diabetes. The lack of a single locally relevant definition for obesity is an issue in the assessment of obesity and the prevention of cardiometabolic disease – a database study of ~3,000 recently-diagnosed type 2 diabetes patients showed that only 54% were obese as diagnosed by BMI, but 82% were centrally obese (as assessed by waist circumference), perhaps indicating that a locally relevant obesity definition should include waist circumference. To conclude, Dr. Hajat emphasized the need for better surveillance through disease registries, and for the UAE healthcare system to focus more on preventative care.

Questions and Answers:

Comment: We in the Caribbean see a similarly poor rate of adherence to therapy after a CV event.

Q: You showed that the UAE dropped from #2 to #10 in the IDF’s list of top countries effected by diabetes. Was that drop driven by any policy changes on the part of the government?

A: Since 2005, decision-makers noted that measures were needed in the UAE to control diabetes in particular. In 2007, a population-wide screening program was put in place in Abu Dhabi, which screened the majority of the population and plugged patients into the healthcare system. It is difficult to prove whether that program had a direct effect, but the markers are moving in the right direction. Since 2007, there have been multiple other screening programs put in place, with an emphasis on media, marketing, and education.

Q: I found it interesting that the UAE has such as vast population of expatriate workers. I am assuming that it is largely a transient population, and am wondering if there are differences in access in those groups?

A: It is a very heterogeneous population, which does bring with it a lot of challenges. I would say that the UAE is doing well to meet those challenges. Although there is a high transient population, most employers provide insurance, and access to healthcare is good for the majority of the population. In terms of being able to screen the whole population, that brings a lot of challenges, because there are sub-populations with high endemic rates of cardiovascular disease. If we put targeted screening programs into place, they would need to target different parts of the population in different ways. Language barriers are another challenge to deal with.

 

Innovation Theaters

A Novel Treatment Option for Chronic Weight Management (Sponsored by Eisai)

Robert Chilton, DO (University of Texas Health Science Center, San Antonio, TX)

Dr. Robert Chilton presented on Eisai/Arena’s obesity medication Belviq (lorcaserin) to a group of approximately 40 attendees at the Expo Hall Innovation Theater. Well aware that he was speaking to a room of cardiologists, he began by addressing the cardiovascular safety issues associated with previous weight loss medications (namely Phen-Fen). He directed those with valvulopathy concerns to an abstract being presented by Dr. Neil Weisman showing that patients with pre-existing valvulopathy treated with Belviq did not show a progression of valve disease through one year. Citing the frequency with which cardiologists see patients with diabetes (including undiagnosed diabetes), Dr. Chilton underscored the connection between weight loss and diabetes control and prevention (he slid in a joke that the attendees at ACC looked more fit than the attendees he generally sees at endocrinology conferences). Quoting colleague Dr. Ralph DeFronzo, he suggested that solving obesity could get rid of around 70% of type 2 diabetes incidence. Out of Belviq’s three pivotal phase 3 studies, he sees BLOOM-DM (which showed a 0.9% absolute, 0.5% placebo-adjusted A1c decrease in addition to improved weight loss at one year) as the most important. Pooled phase 3 results show multiple modest improvements in CV risk parameters such as blood pressure and lipid levels. Dr. Chilton acknowledged that Belviq does not currently have long-term cardiovascular outcomes data, but emphasized that the CAMELLIA CVOT for Belviq is enrolling patients and should report data in the coming few years.

• See page 6 of our Cardiometabolic Health Congress 2013 Day #1 Report for our coverage of similar talk Dr. Chilton delivered on Belviq.

 

Advancing Paradigm Changes in Type 2 Diabetes Management

Matthew Budoff, MD (UCLA, Los Angeles, CA)

Dr. Matthew Budoff took the Innovation Stage podium in the Exhibit Hall to discuss Invokana, focusing on its pleiotropic effects on CV risk factors as well as its glycemic efficacy. Reviewing data from Invokana’s phase 3 clinical program, Dr. Budoff highlighted Invokana’s durable effects on A1c, fasting plasma glucose, body weight, and blood pressure. He straightforwardly acknowledged that genital mycotic infections happen “a lot more” on Invokana, and that prescribers should be cognizant of that risk, although most occurrences are mild and do not lead to discontinuation of treatment. Given that the audience was composed mostly of cardiologists, we were not surprised to hear slightly more focus on the rise in LDL cholesterol seen with Invokana treatment, although Dr. Budoff emphasized that the change is fairly modest and also accompanied by a rise in HDL cholesterol. During Q&A, an audience member expressed hope that the blood pressure and weight effects would counteract any negative effect the rise in LDL might have.

Questions and Answers

Q: To counteract the rise in LDL, can you prophylactically raise the patient’s statin dose?

A: I would say to wait and see, because on average there is only a 4% increase in LDL, which may not push the patient over any danger threshold. I usually wait and only put patients on a statin reactively, not proactively. There has been relatively little need to raise statin doses in the clinical trials for Invokana.

Q: Would you propose that Invokana should be investigated in patients with only impaired glucose tolerance?

A: It has so far only been studied in established type 2 diabetes. There are ongoing studies now where they are looking into type 1 diabetes and pediatric patients. In the future, I imagine it is possible that there will be studies in patients with metabolic syndrome.

Q: What is the impact of this agent on the progression of diabetes, including beta cell burnout or patients’ progression to insulin?

A: We now have two-year follow-up data on this agent, and the effect on A1c is consistent and A1c remains low. To me, that implies that the reduction in blood glucose may help prevent beta cell burnout. I don’t know if they have looked at beta cell function, but that would be a good area to investigate.

Q: In individuals who lack the SGLT-2 transporter gene, do you see mycotic problems?

A: I do believe that the congenital population that had persistent glycosuria did have an increase in mycotic infections, which is often times how they were diagnosed.

Q: Do you think the weight loss and blood pressure reductions seen with SGLT-2 inhibitors would counter whatever impact on outcomes the small increase in LDL might have?

A: There are ongoing studies that are looking closely at outcomes, both in an observational cohort follow-up of the broad phase 3 population as well as a prospective CV outcomes trial. We can try and surmise things, but I think we really need to wait and take a look at the data when we get it.

 

Corporate Webcast

Amgen Cardiovascular Update

Amgen management held a webcast to discuss the exciting phase 3 data presented on the company’s PCSK9 inhibitor evolocumab. Summarizing the five studies presented, management stated that the wealth of data (from over 4,000 patients) have shown a clear safety record and consistent LDL reductions of at least 50% (across study arms, mean LDL reductions ranged from ~53-75%). The studies presented demonstrate long-term (one-year) safety and efficacy (DESCARTES), efficacy in statin-intolerant patients (GAUSS-2), efficacy as monotherapy (MENDEL-2), efficacy as an add-on to statin therapy of varying intensity (LAPLACE-2), and efficacy in familial hypercholesterolemia (RUTHERFORD-2). Q&A yielded some notable findings: the company now has all the data it needs for the core LDL-lowering indication, although the timing of filing in the US will be contingent upon the progress of the cardiovascular outcomes trial FOURIER. The company sees evolocumab as a second-line agent after statins, which are well established as the first-line therapy (except in statin-intolerant patients). Management forecast that, at least initially, use of the drug will be focused among a focused subset of non-invasive cardiologists, endocrinologists, and perhaps internists and a small proportion of primary care physicians.

• Management shared that, in addition to the relatively new auto-injector pen, Amgen has developed an automated “mini-doser” for easy monthly administration. Patients begin by adhering the device, which is the size of a small pager, to their skin. Over the course of a few minutes, the device delivers the once-monthly 420 mg dose. Subsequently, the device can be removed and discarded in a sharps container. Given that many patients at high risk for atherosclerotic CVD are primarily treated with oral drugs (mainly statins), “needle-phobia” may be a barrier to initiation, making the development of this automated device a smart move for Amgen. We are uncertain at what stage in the development process this patch is, and we are curious if this delivery method could be translated for other injectable agents such as GLP-1 agonists or insulin.

Questions and Answers:

Q: Now that you have reported five phase 3 trials, what is the gatekeeper for filing?

A: We now have available the dataset to file globally for the LDL-C lowering claim. In some locales, including the US, we are going to judge the timing based on the progress being made in the outcomes trial, and will be tasking with the agency on how to time that. For the rest of the world, we are on the usual track of pulling together a large and complex file with the usual timeline. This is a high priority for us.

Q: How do you see primary care responding to this drug? Who do you see prescribing it?

A: In the short run, we imagine that the use will be focused in a very specific group of providers who have interest in this area. That would likely mean a subset of non-invasive cardiologists, endocrinologists, internists, and some primary care physicians. My guess would be that, up front, it would be a focused group.

A: I envision that after a specialist puts a patient on the therapy appropriately, then scripts can continue and that a primary care physician can manage the care, since measuring LDL levels is pretty easy.

Q: When you look at the data, it is very consistent across the board, whether it was used as monotherapy or in combination with other agents. Will this drug be used as monotherapy?

A: We performed the monotherapy studies largely to understand safety in a clear environment. It would be a lot to ask initially for a new therapy to be used as a first-line instead of statins, and would probably not be appropriate for most patients.

A: Statins are used first, of course. In patients that can’t take statins, then they could have value.

Q: When will we see the outcomes data from FOURIER?

A: We are pleased with the progress we are making with our outcomes study. It is an event-driven study, so it is hard to predict when it will be completed.

Q: How would you plan on this drug being used in the near-term before we have outcomes data, and how might outcomes data from FOURIER change that?

A: Prior to the outcomes studies, I would still be focused on the ATP III goals. I would start patients on a statin, and if they come back and need more of an LDL reduction, I would give them something else. That would be one target group for evolocumab. Another would be patients with familial hypercholesterolemia that are on multiple drugs already and not at target. Finally, statin-intolerant patients are another important group to target. In terms of outcomes data, I think it could support us bringing LDL down to even lower levels. Based on ATP III, the target is 70 mg/dl. If an outcomes trial shows broad safety, we could take it much lower, and perhaps be more aggressive with those levels.

Q: What might the imaging study tell us, particularly in relation to the outcomes study? Will data from the imaging study be important for the filing?

A: Our initial filing will be based on LDL, and what people are ultimately interested in is outcomes. The imaging study is a bridge between LDL and outcomes. In that study, we would hope to show that plaque volume goes down, which will increase confidence that the outcomes data will be positive. In terms of how regulators might see it, we will try and file it for that indication, and whether or not we get the indication to reduce coronary atherosclerosis in advance of the outcomes trial – we will have to see.

Q: What is the importance of the GAUSS-3 study? Is it needed for filing?

A: At a high level, when we started our clinical trial program in statin-intolerant patients, this was really groundbreaking territory for regulatory agencies. Amgen has partnered closely with regulatory agencies through the design of GAUSS-1, -2, and -3. We’ve also worked closely with the cardiology community on what the best scientific questions are. GAUSS-1 and -2 were different than GAUSS-3, and used a more pragmatic, real-world definition of how clinicians define and treat patients with statin intolerance. The fact that patients here had LDL levels of around 190 mg/dl at baseline is concerning. In GAUSS-3, we will begin with a double-blind randomized re-challenge with a statin. Only if patients have symptoms with a statin and not placebo will they move on to the next part of the study, which will test evolocumab.

Q: What do you think will be the preferred device among providers, the biweekly or monthly?

A: We don’t know what the distribution for the product will be like exactly, but monthly seems to be the logical way to go, in my opinion.

 

-- Jessica Dong, Manu Venkat, and Kelly Close