American Diabetes Association 75th Scientific Sessions

June 5-9, 2015; Boston, MA; Full Report – Novel Therapies – Draft

Executive Highlights

Even though ADA is a scientifically focused meeting, there continue to be no investigational drug classes that are clearly the “next big thing” for type 2 diabetes; instead, the focus continues to shift towards making better use of existing drugs. Over the past two years, two of the potential frontrunners – GPR40 agonists and FGF21 analogs – took a step backwards with the discontinuation of Takeda’s phase 3 TAK875 (fasiglifam) and poor results on Pfizer and Lilly’s FGF21 analogs. We would wager that the lack of major new drug classes is due in part to the rising regulatory and reimbursement pressures in diabetes. The bar for new therapies is definitely much higher than it was even a few years ago and the considerably higher development costs (one drug that recently came to market is said to be closer to $3-4 billion in development costs rather than $1 billion, the traditional blockbuster cost) and lack of predictability/stability on the regulatory front have led a number of companies away from trying to help people with diabetes. The true costs of the 2008 CV Guidance (namely the tens or hundreds of millions of dollars needed for outcomes trials) are now better understood by manufacturers, who are responding by slowing the flow of new therapies through phase 3 (as with Takeda’s once-weekly DPP-4 inhibitor, which just reached the Japanese market but will not be coming to the US at all) or even leaving diabetes or putting the brakes on future development.

As one emerging bright spot, we saw phase 3 results on Gilead’s anti-angina drug Ranexa (ranolazine) in type 2 diabetes; ranolazine produced A1c reductions of ~0.5-0.6% as monotherapy or as an add-on to glimepiride, though there were no significant effects in combination with metformin. We were glad to see these results, as we have not heard updates on ranolazine’s progress in some time; we would like to learn more about the combinability of this compound with others as presumably this fairly modest efficacy wouldn’t be targeted as monotherapy. Strong outcomes of this and another compound such as an SGLT-2 might well convince payers and providers of the combination product’s value. Sessions on the gut microbiome and brown fat provided hints as to where new diabetes therapies could come from in a longer-term timeframe. One initiative that could help early-stage drug research in these and other areas is the innovative Accelerating Medicines Partnership (an NIH/industry collaboration), which received its own dedicated symposium at ADA. Speakers provided an in-depth look at the Diabetes Knowledge Portal, which aims to harness massive pools of genomic data to better understand risk and identify new therapeutic targets.  

While the new drug development scene for type 2 diabetes was somewhat underwhelming, we continue to be wowed by the exciting new PCSK9 inhibitor class for LDL lowering. These once-monthly injection drugs are hugely relevant for type 2 diabetes patients given the burden of cardiovascular disease in diabetes patients. An analysis from the phase 3 ODYSSEY LONG TERM trial of Sanofi/Regeneron’s Praluent (alirocumab) presented as a poster demonstrated that the drug produced ~60% LDL reductions and no significant increase in adverse events in patients with diabetes, comparable to the results for patients without diabetes. Given that a meaningful number of patients with diabetes do not respond well to statins, we believe this drug could help a large number of people with diabetes.

The conference agenda also included a number of corporate symposia and product theaters related to the class – one particularly stimulating panel discussion touched upon the timely question of whether providers would prescribe the drugs before CV outcomes data is available. As a reminder, both Praluent and Amgen’s Repatha (evolocumab) had FDA Advisory Committee meetings during ADA, which likely reduced visibility and attendance. The discussion and votes at those meetings generally supported a positive risk/benefit profile for the class but suggested that the initial approvals will likely be fairly narrow (possibly restricted to patients with familial hypercholesterolemia) until the ongoing outcomes trials complete in late 2017 to early 2018.

Talk titles highlighted in yellow were among our favorites from ADA 2015; those highlighted in blue are new or expanded full report additions from our daily coverage.

Table of Contents 

Detailed Discussion and Commentary

Oral Presentations: ADA President’s Oral Session

Induced Pluripotent Stem Cells Converted to Myotubes Mirror In Vivo Insulin Resistance in Humans (380-OR)

Salvatore Iovino, PhD (Merck Research Labs, Boston, MA)

In a fascinating presentation, Dr. Salvatore Iovino discussed a human model of insulin resistance in muscle cells. To create this model, he generated and analyzed induced pluripotent stem (iPS) cells from individuals with a genetic form of insulin resistance (IR-Mut) and from healthy individuals of a similar age.  These cells were differentiated over 35-40 days into functional myotubes (early-stage muscle fibers). Myotubes derived from IR-Mut patients showed defects in insulin signaling, insulin-stimulated metabolism, and transcriptional dysregulation that mirrored the defects observed in the patients in vivo. Thus, iPS cells differentiated in vitro to muscle provide a novel model to study the molecular mechanisms of insulin resistance in skeletal muscle.

  • Myotubes derived from IR-Mut individuals showed significant genetic differences compared to the control group. Myotubes derived from IR-Mut patients showed impaired insulin signaling with reduced levels of the insulin receptor (IR) protein and reduced activation of IR, IRS-1, AKT and ERK1/2. These defects led to impairments in insulin-stimulated 2-deoxyglucose uptake, glycogen synthase activation and glycogen accumulation. Expression of insulin-regulated metabolic genes, including HK2, GLUT4 and RAD1, was also significantly reduced in IR-Mut compared to the control myotubes. Furthermore, while control myotubes responded to insulin with significant increases in the expression of the early growth response genes EGR1, cFOS and JUN, these insulin-stimulated transcriptional changes were impaired in IR-Mut myotubes.

Oral Presentations: Combining Basal Insulin and GLP-1 Agonists

LAPS GLP/GCG Dual Agonist, HM12525A, Confirmed Prolonged Pharmacokinetics in Healthy Volunteers: A First-in-Human Phase 1 Study (173-OR)

Marcus Hompesch, MD (Profil, Chula Vista, CA)

Dr. Marcus Hompesch presented results from a phase 1 trial of Hanmi Pharmaceuticals’ long-acting GLP-1/glucagon dual agonist HM12525A showing a positive safety/tolerability profile and the potential for once-weekly dosing. The trial enrolled 40 healthy volunteers who were randomized to one of five dose groups (0.25-4.0 nmol/kg) and received a single subcutaneous injection of either HM12525A (n=6 per group) or placebo (n=2 per group). The primary objective was to evaluate safety and tolerability, with pharmacokinetic (PK) parameters as a secondary endpoint; the total study duration was 56 days. Results showed that HM12525A was well tolerated up to a dose of 2.0 nmol/kg. GI side effects were the most common adverse event, and they tended to occur early and in a dose-dependent fashion. Mean heart rate also increased in a dose-dependent manner, with significant elevations vs. placebo at the two highest doses; Dr. Hompesch cautioned that it is difficult to draw meaningful conclusions about this effect from such a small study and that the signal would need to be assessed in larger trials. Anti-drug antibodies were detected in six subjects, but there were no neutralizing antibodies and there did not appear to be any interference with PK. There were no other significant safety observations, including any clinically relevant changes in blood pressure. HM12525A demonstrated a half-life of 131-178 hours, which Dr. Hompesch said should support at least a once-weekly dosing regimen. Hanmi is currently conducting a multiple ascending dose trial of the candidate in patients with type 2 diabetes (we did not find any trials currently listed on

Oral Presentations: New Concepts and Treatments of Diabetic Dyslipidemia

Evaluation of the Glycemic Effects and Efficacy and Safety of Evolocumab (AMG 145) in Subjects With or Without Dysglycemia or Metabolic Syndrome (258-OR)

Rury Holman, FMedSci (The Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK)

Dr. Rury Holman continued the session’s discussion on PCSK9 inhibitors by reviewing the results of the DESCARTES study, which examined the glycemic effects, LDL-lowering efficacy, and safety of evolocumab (Amgen’s Repatha) in 901 patients stratified by glycemic status. After 52 weeks, no significant differences were seen between the evolocumab and placebo groups in measures of glycemic control. Additionally, no notable differences were seen between groups in weight, BMI, waist circumference, blood pressure, or heart rate. As background, the DESCARTES study randomized patients (following optimization of lipid-lowering therapy) 2:1 to 52 weeks of monthly evolocumab or placebo. Baseline glycemia was categorized as type 2 diabetes (n=120), impaired fasting glucose (IFG, n=293), metabolic syndrome (MetS, n=289), or none of these (n=393); 194 had both IFG and MetS. Overall, evolocumab showed encouraging lipid efficacy and safety at 52 weeks in subjects with or without dysglycemia or MetS, with no notable changes in glycemia, incidence of new onset type 2 diabetes, or key safety parameters.

  • Notably, results also showed that incidence of new onset type 2 diabetes (defined as HbA1c ≥ 6.5% at any post-baseline visit) in those without diabetes at baseline was 4.6% (evolocumab) and 5.4% (placebo). No notable differences in dysglycemia were seen among subjects on various statin doses. Encouragingly, evolocumab also reduced LDL-C by >50% in all groups, with favorable effects on other lipid parameters as well. Adverse events in combined type 2 diabetes, IFG or MetS groups were 73% for evolocumab vs. 70% for placebo.
  • Given these positive results, Dr. Holman emphasized the major potential of PSCK9 inhibitors, especially for patients who cannot achieve LDL-C targets with statins. These results are particularly reassuring given the concerns about increased diabetes risk with statins. Of course, as noted during Q&A, price will likely be one of the more significant obstacles to broad access, and we imagine that this class’ success will be heavily dependent on the level of reimbursement.
  • For more on the DESCARTES study, see our coverage of Dr. Dirk Blom’s (University of Cape Town, South Africa) presentation of primary results at ACC 2014.

Questions and Answers

Q: How will providers decide the criteria that will motivate $50,000/year treatment? How will you tell your patient to undergo a massive weight loss or this will cost you $50,000?

A: It’s interesting that you start with cost. This is remarkable science, and I am more interested in the mechanism that this can help people who are pre-diabetic. I can’t justify the price and I don’t know how this will pan out. For those who can’t currently achieve LDL-C safely, this drug offers a valuable alternative. I agree though that the cost may be difficult to justify.

Q: Is it possible to figure out how low LDL-C can go on this drug?

A: We know that there is no change in the decremental improvement in risk as you go lower and lower with LDL-C. However, how low you can go with evolocumab wasn’t a question addressed by the DESCARTES study, but I’ll be interested in exploring it in future studies.

Q: 52 weeks is pretty short and the sample size is pretty small, so we’ll need to power this out in a longer term study. Have you looked at patients with high risk factors and family history of dyslipidemia?

A: It is a relatively small trial but was not intended to be an outcome study. Nevertheless I think these are still pretty definitive results with no evidence of worsening glycemia, compared to data in our AFORRD study that showed a 0.3% A1c rise with atorvastatin. The evolocumab data to date has been very consistent and we would not expect any different results in patients at even higher risk. If you have an opportunity for a reasonable cost PSK9 inhibitor, that would likely have better adherence than a statin long-term, then this drug would have value in patients not achieving LDL targets. 

Efficacy and Safety of the PCSK9 Inhibitor Evolocumab (AMG 145) in Patients with Type 2 Diabetes (257-OR)

Dr. Naveed Sattar presented encouraging efficacy and safety data on Amgen’s PCSK9 inhibitor Repatha (evolocumab) in patients with type 2 diabetes. In a pooled analysis of four phase 3 studies (MENDEL-2, LAPLACE-2, RUTHERFORD-2, and GAUSS-2), LDL-C was reduced by 57% and 60% from baseline, respectively, in patients on biweekly or monthly evolocumab. Results were comparable in patients without diabetes: 61% reduction with biweekly dosing and 62% with monthly administration. Additionally, reductions were comparable among all type 2 diabetes subgroups (baseline statin intensity, insulin use, A1c, eGFR, and existing CVD), which Dr. Sattar argued is a promising sign for the drug’s efficacy and safety in a wide range of patients with type 2 diabetes. These results are very timely in light of the recent FDA Advisory Committee meetings for Repatha and Sanofi/Regeneron’s PCSK9 inhibitor Praluent (alirocumab). Both meetings ended with strong votes in favor of approval, but it appears that the initial indications will likely be quite narrow, with broader approvals placed on hold until the ongoing cardiovascular outcomes trials report results.

  • This analysis of the MENDEL-2 (monotherapy), LAPLACE-2 (combination therapy), RUTHERFORD-2 (HeFH), and GAUSS-2 (statin intolerant) phase 3 studies examined the lipid effects and safety of 12 weeks of evolocumab treatment in patients with type 2 diabetes (n=417) vs. patients without (n=2729). Overall, evolocumab significantly lowered LDL-C by 55 to 75%. LDL-C reduction was also comparable among all type 2 diabetes subgroups (baseline statin intensity, insulin use, A1c, eGFR, and existing CVD).
  • More specifically, 88% (biweekly dosing) and 87% (monthly dosing) of patients with type 2 diabetes on evolocumab achieved LDL-C <70 mg/dl compared with only 36% (biweekly) and 29% (monthly) of patients on ezetimibe plus placebo and only 23% (biweekly) and 16% (monthly) of patients on placebo alone. Dr. Sattar also noted that reductions in Lipoprotein(a) (25-30%) and triglyceride (8-15%) levels were comparable in evolocumab-treated patients with and without type 2 diabetes.
  • In terms of safety, 41% of patients with type 2 diabetes on evolocumab experienced adverse effects, compared to 47% of patients on ezetimibe and 35% of patients on placebo. Additionally, only 2% of patients with type 2 diabetes on evolocumab experienced serious adverse effects compared to 4% of patients on ezetimibe and 4% of patients on placebo. 0.4% of patients on evolocumab experienced an adverse effect that led to discontinuation of the study drug compared to 2.7% of those on ezetimibe and none on placebo.
  • For background, evolocumab is a member of the exciting new PCSK9 inhibitor class, which lowers plasma LDL cholesterol by preventing endocytosis of LDL receptors, thus enabling more cellular uptake of LDL cholesterol. For further reading on the PCSK9 inhibitor class, see our coverage of Dr. Marc Sabatine’s (Brigham and Women’s Hospital, Boston, MA) presentation of results from a phase 3 trial (not a dedicated outcomes trial) that found a statistically significant 53% reduction in CV events with evolocumab vs. standard of care alone. Similarly promising 18-month phase 3 results for alirocumab recently published in NEJM found a 48% reduction in CV events. We eagerly await results from the ongoing outcomes trials of these candidates, which are expected to complete in late 2017 to early 2018. Additionally, Pfizer’s PCSK9 inhibitor phase 3 bococizumab remains on track to have outcomes data on pace with Amgen and Sanofi’s candidates. To our knowledge, there are ~10,000 people with diabetes in these trials collectively, and we believe this class will eventually hold great potential in this population.

Questions and Answers

Q: These are not unexpected results. The interesting test will be at the FDA level. I’m curious about patients with new onset diabetes, what do we see in patients with A1c’s of 6 and 6.5?

A: Right. In terms of statin use, most guidelines have come to the conclusion that risks are outweighed by the benefit. Statins may have a specific effect, but they do increase weight.

Comment: Is it potentially that statin weight gain though modest is able to cause that new onset diabetes?

A: I think it could be part of the cause. The new onset diabetes might actually disguise the slight gain of fat, but I’m just speculating. The effect of statin tolerance needs further study. Most people accept that this is part of the therapy and must take lifestyle changes seriously. There is no such thing as a free lunch. [Audience laughter].

Q: Do PSCK9 inhibitors have a significant effect on HDL?

A: ApoB will have come down, so HDL is altered, but predominately because ApoB is altered. I think ApoA1 may have only a trivial effect on HDL. We know that the effect on LDL is causal, but there’s still debate over the effect on HDL. I don’t think that’s a major issue though.

Oral Presentations: Diabetes—A Mixed Bag

Metabolite Profiles Heralding Diabetes Incidence in the Diabetes Prevention Program (DPP) (151-OR)

Geoffrey Walford, MD (Massachusetts General Hospital, Boston, MA)

Dr. Geoffrey Walford presented a study investigating the connection between metabolite profiles and diabetes risk in the Diabetes Prevention Program (DPP) cohort. Previous studies had indicated that increased circulating branched chain and aromatic amino acids (BCAA/As) and decreased glutamine/glutamate predicted type 2 diabetes in white, European populations with an average risk for type 2 diabetes. This analysis paired 427 participants in the DPP study who developed diabetes with 427 participants who did not, matching them based on age, sex, race/ethnicity, treatment, fasting plasma glucose, body mass index (BMI), and hypertension. They profiled 84 different metabolites at baseline and after two years of either intensive lifestyle, metformin, or placebo intervention. The results found that, when adjusted for age, sex, fasting glucose, hypertension status, and BMI, the traditional metabolite markers were no longer significantly associated with type 2 diabetes risk. He also noted that BCAA/A levels were not influenced by the intensive lifestyle therapy or metformin, suggesting that these traditional markers are not part of the causal pathway for diabetes among individuals who are already at a certain risk level. However, four novel metabolites were associated with type 2 diabetes risk in the DPP population:  betaine, serine, methionine sulfoxide, and propionylcarnitine. Dr. Walford focused on betaine as a novel metabolite marker and noted that it has been linked to a beneficial metabolic state and associated with lower triglycerides, adiposity, and blood pressure and higher insulin sensitivity.

Questions and Answers

Q: You’ve tested quite a few metabolites. How did you address the issue of multiple hypotheses?

A: So the concern with our analyses is that we may get false positives. We feel we guard against this using a Bayesian approach. All of the metabolites we explored do have a non-null pre-test probability. Showing nominal significance in this data is at least highly suggestive that they are true findings. The other argument against using a perhaps more strict threshold is the intercorrelation of the metabolites. I didn’t note this but among the branched chain amino acids there is high intercorrelation of metabolites. Although we test eight metabolites the number of independent hypotheses is likely much less than that.

Q: What is the key factor that affects the betaine levels?

A: There’s some very interesting mechanistic work that is being done in animal studies, this will come out shortly we hope. In terms of betaine levels within the plasma, betaine is an essential metabolite; it comes from the diet. The betaine in the plasma is also somewhat affected by your urinary excretion of betaine, this is variable among individuals who are at risk for or have diabetes. Effective betaine levels in the tissue are likely modified by regulated transport of betaine into the tissues as well. Plasma markers are I think a very important biomarker, but more work has to be done in terms of how we understand the influence of the markers.

Prospective Study of N-terminal-proBNP and Risk of Diabetes in Older Adults: The Cardiovascular Health Study (153-OR)

Erika Brutsaert, MD (Yeshiva University, Bronx, NY)

Dr. Erika Brutsaert presented on the potential connection between B-type natriuretic peptide (BNP) and diabetes risk in older adults. BNP plays a role in heart and vascular function and has recently been shown to induce lipolysis. Higher levels of BNP have been linked with decreased diabetes risk in middle-aged adults, but it was unclear if this association persisted in older populations. This study measured a cleavage product of proBNP, N-terminal (NT)-proBNP, in a population of healthy adults 65 and older in the 1992-93 visit of the Cardiovascular Health Study. Existing diabetes, prevalent cardiovascular disease, and history of congestive heart failure were among the exclusion criteria. Primary outcomes of interest were fasting glucose ≥126 mg/dL, non-fasting glucose ≥200 mg/dL, use of anti-hyperglycemic agents, or Centers for Medicare & Medicaid Services (CMS) claims for diabetes. Results were adjusted for traditional risk factors, including age, sex, race, BMI, systolic blood pressure, anti-hypertensive treatment, smoking, alcohol use, and LDL. After 12.6 years of follow-up, the study found that each doubling of NT-proBNP was associated with a reduced risk of incident diabetes (HR=0.91 [95% CI: 0.84-0.99]). However, this association was attenuated when adiponectin was controlled for and abolished with control for HOMA-IR. This led Dr. Brutsaert to suggest that they may play a role in the connection between BNP and diabetes risk. Dr. Brutsaert emphasized that these findings suggest that the natriuretic pathway may be a potential future target for diabetes prevention.

Questions and Answers

Q: What do you think are the therapeutic implications? 

A: That’s an interesting question. There was a recent study that came out looking at neprilysin, which breaks down natriuretic peptide. This was shown to improve mortality in people with heart failure. It also raises natriuretic peptide levels. So this may be an avenue to look into therapeutic benefit. Some researchers have looked into IV natriuretic peptide and have shown some metabolic benefits with that. The problem with that is I think natriuretic peptide has been shown to worsen renal function and lower blood pressure in people with heart failure.

Oral Presentations: Concepts in Nutrition and Diabetes Prevention and Treatment

Different Phyla Composition of Gut Microbiota in Vegetarians and Non-vegetarians Associated with Inflammatory Status (89-OR)

Ana Moraes, MS (University of Sao Paulo, Brazil)

Ms. Ana Moraes presented her findings on differences in gut microbiota in vegetarians compared to non-vegetarians. Previous evidence suggests that the ratio of firmicutes to bacteroidetes is higher in obese individuals, that there is a correlation between abundance of proteobacteria and a high fat diet and C-reactive protein (CRP) concentration, and that vegetarians have less adiposity and a more favorable metabolic profile. This study analyzed the gut microbiota of vegetarians and non-vegetarians (n=230). The only significant difference in microbiota phyla composition was a higher proportion of Proteobacteria (1.1% in vegetarians vs. 1.9% in non-vegetarians; p=0.007) and Actinobacteria (0.1% in vegetarians vs. 0.3% in non-vegetarians; p=0.002). Ms. Moraes connected these results to the possibility of a pro-inflammatory condition in non-vegetarians. The Q&A session touched on whether the length of vegetarianism could affect gut flora and thus the results, the potential effect of fiber intake on the results, and whether BMI or waist circumference was corrected for, but analysis concerning these factors was not yet available.

Questions and Answers

Q: Can you say the length of time that people were vegetarian in this study?

A: For at least one year.

Q: Is there any data on gut flora in terms of length of being vegetarian?

A: No, we don’t have this kind of data.

Q: Could that affect your findings? Let’s say that the proportion of people who have been vegetarian for a short period of time – say one year or two years – would have a different gut flora than someone who has been vegetarian for longer?

A: We don’t have this kind of analysis comparing time with this diet.

Q: Is there any information about how gut flora changes over time?

A: For our study, no. But we have some papers that were already published with this kind of information.

Q: Did you also record things like fiber intake? Because how can you say that it is actually the consumption of meat and not the absence of fiber that might make a difference in the gut microbiota?

A: We just finished our data collection so we don’t have, yet, this kind of analysis with kinds of diet, but we will have it soon. Maybe there will be some kind of analysis on the specific composition of diet, maybe analysis of high-fat diet and fiber.

Q: Did you correct for BMI or waist circumference in any way in looking at your markers?

A: No not for this kind of analysis, not yet.


Efficacy and Safety of Alirocumab in Individuals with Diabetes: Analyses from the ODYSSEY LONG TERM Study (1296-P)

H Colhoun, H Ginsberg, L Leiter, U Chaudhari, R Pordy, J Robinson

An analysis of the phase 3 ODYSSEY LONG TERM trial found significant LDL-C reductions with Sanofi/Regeneron’s PCSK9 inhibitor Praluent (alirocumab) in people with diabetes, similar to the reductions seen in people without diabetes. As a reminder, the trial enrolled 2,341 patients with and without diabetes, who were either heterozygous familial hypercholesterolemia (HeFH) patients or high CV-risk patients on maximally tolerated doses of statins. Thirty-six percent of individuals in the Praulent group and 35% in the placebo group had a history of diabetes at baseline. People with diabetes experienced a 59% least squares mean placebo-corrected reduction in LDL-C at week 24. This level of LDL-C reduction did not significantly differ from that seen in people without diabetes (p=0.1155): 63% vs. placebo. Most people with (78%) and without (80%) diabetes achieved an LDL-C level <70 mg/dl at week 24 (p<0.0001 vs. placebo). The mean LDL-C reductions maintained significance over 78 weeks in people with and without diabetes, though the ITT analysis showed that the LDL-C level gradually crept up from a nadir of ~55 mg/dl at week 4 to ~80 mg/dl in people with diabetes and ~75 mg/dl in people without diabetes at week 78. The researchers explained this was due to premature treatment discontinuation in both treatment groups, and that the on-treatment analysis showed greater durability. Turning to safety, no increases were seen in adverse events in people with diabetes compared to those without; adverse events that occurred in ≥5% of people in all subgroups were nasopharyngitis, upper respiratory infection, influenza, and urinary tract infections. Injection site reaction happened in 3.4% of people with diabetes on Praulent vs. 3.2% on placebo, and myalgia occurred in 3.1% vs. 2.5%, respectively. The poster noted that treatment with Praulent’s ability to prevent CV events is currently being studied in ODYSSEY OUTCOMES, which will include a “sizeable” proportion of people with diabetes. In a post-hoc analysis of ODYSSEY LONG TERM, Praulent was associated with statistically insignificant reductions in CV events in people with and without diabetes.

  • The PCSK9 inhibitor class has had quite a presence at this year’s ADA with numerous corporate symposia and product theaters, indicating the significance of the class’ implications in the diabetes patient population – we look forward to learning more about how the FDA will respond to these drugs at this week’s EMDAC meetings on Praulent as well as Amgen’s Repatha (evolocumab).

Leucine Synergizes with Phosphodiesterase 5 (PDE5) Inhibitors and Metformin to Reverse Hepatic Lipid Accumulation and Inflammation and Treat Nonalcoholic Fatty Liver Disease (NAFLD) (260-LB)

L Fu, F Li, Q Cao, X Cui, B Xue, H Shi, A Bruckbauer, M Zemel

This NuSirt-sponsored preclinical study provided evidence suggesting that triple combination therapy with leucine, metformin, and the phosphodiesterase 5 (PDE5) inhibitor sildenafil could hold promise in nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). Mice were fed a high fat/atherogenic diet to induce NASH and insulin resistance and randomized to receive treatment with combinations of leucine, low dose metformin (<20% therapeutic dose), and low dose sildenafil (<10% therapeutic dose). Each of these drugs has been found to interact with the AMPK-Sirt1 pathway to decrease lipid accumulation in hepatocytes, and NuSirt recently announced the publication of promising preclinical results with the leucine/PDE5 inhibitor combination in type 2 diabetes and NAFLD/NASH. In the study, the triple combination demonstrated significantly greater stimulation of hepatocyte fat oxidation (~60%, p<0.01) and inhibition of triglyceride accumulation (~70%, p<0.001) compared to either leucine/metformin or leucine/sildenafil. The triple combination also led to greater reductions in alanine aminotransferase, liver mass, and liver fat than either dual combination. NuSirt has stated that it plans to initiate a phase 2a trial of this combination in NAFLD/NASH in the near future pending regulatory feedback, and we are glad to see the company working to address such a great unmet need.

  • Another NuSirt-sponsored study (1237-P) found that leucine/metformin combination therapy improved glucose and fat utilization and increased median lifespan in C. elegans and provided additional mechanistic insights. This combination is currently in a phase 2a trial in type 2 diabetes that is expected to complete this month.

Leucine-Metformin Synergy Activates the AMPK/Sirt1 Pathway to Increase Insulin Sensitivity in Skeletal Muscle and Glucose and Lipid Metabolism and Lifespan in C. elegans (1237-P)

M Zemel, A Bruckbauer

This NuSirt-sponsored study presented recent results in C. elegans on the mechanisms behind leucine/metformin synergy. Previous data has found that adding leucine to metformin improved insulin sensitivity and glycemic control while achieving an ~80% reduction in metformin dose in diet-induced obese mice. These results showed that leucine (0.5 mM) and low dose metformin (50-100 µM) synergistically activate Sirt1 (p<0.001) at low (<100 µM) NAD+ levels typical of energetically satisfied states. This activation of Sirt1 increased insulin-independent glucose disposal in myotubes (~50%, p<0.002) and reduced insulin EC50 (half-maximal effective concentration) by 60%. Furthermore, the increased glucose disposal in myotubes was associated with an increase in AMPK and IRS1 phosphorylation. Normally, in the C. elegans model, exposure to high glucose impaired glucose utilization and shortened lifespan by ~25%. However, when administering leucine and metformin to these high glucose-treated worms, median and maximal lifespan were increased by 29% and 15%, respectively (p=0.023). Additionally, the leucine + metformin administration restored normal glucose utilization and increased fat oxidation almost two-fold (p<0.005). In contrast, metformin alone exerted no independent effect at any concentration (0.1 – 2.0 mM). Leucine and metformin’s synergistic activation of Sirt1 at low NAD+ concentrations may prove to be an exciting target to improve energy metabolism and insulin sensitivity.

  • As background, Sirt1 is a key sensor of energy status and regulator of glucose and lipid metabolism. Insulin resistance and diabetes are associated with impairment of Sirt1, and activation of the AMPK-Sirt1 axis improves hyperglycemia and insulin sensitivity. The amino acid leucine has been shown to activate Sirt1 by lowering the activation energy of NAD+, thus mimicking the effects of caloric restriction, and enabling coactivation and amplification of other AMPK/sirtuin activators like metformin.
  • NuSirt is currently investigating this leucine/metformin combination approach in a phase 2a trial in patients with type 2 diabetes. The goal of the trial, the first in humans, is to determine whether adding leucine to metformin can lead to equivalent A1c reductions at a lower metformin dose, potentially making the drug more tolerable for the approximately 20% of patients who experience serious GI side effects at standard doses. Study completion is expected this month, and NuSirt has suggested that the drug should “hopefully” be available to patients by 2017.

Special Lecture: Banting Medal for Scientific Achievement Lecture

The Multifaceted Roles of Adipose Tissue: Therapeutic Targets for Diabetes and Beyond

Philipp Scherer, PhD (University of Texas Southwestern, Dallas, TX)

Dr. Philipp Scherer gave an engaging and informative Banting Lecture on potential therapeutic targets for the metabolic syndrome related to adipocyte health. As with last year’s Banting lecturer, Dr. Daniel Drucker (Lunenfeld Tanenbaum Research Institute, Toronto, Canada), Dr. Scherer attempted to highlight the clinical relevance of an emerging area of basic and preclinical science. Synthesizing years of rodent data, Dr. Scherer detailed the role of adipocytes in (i) the release of protein factors that impact systemic metabolism, with special emphasis on adiponectin (a protein that plays a key role in both glucose and lipid regulation); (ii) the buffering of critical lipid mediators; and (iii) the release of metabolites that impact one’s basal metabolic rate. First, Dr. Scherer described how adiponectin can be anti-apoptotic (protecting the heart, beta cell, and kidneys from complications of the metabolic syndrome), proangionic (protecting expanding adipose tissue from hypoxia and dysfunction), anti-atherogenic (reducing CV complications), anti-inflammatory, proadipogenic (helping adipose tissue to expand in a healthy manner), and improve hepatic insulin sensitivity. Thus, he expressed confidence that adiponectin-receptor agonists can be a clinically useful new drug class. Second, he dove deeper into how adipocytes, through adiponectin, can influence the levels of beneficial (namely sphingolipids) and harmful (especially ceramides) lipids in the body. Through this mechanism, adiponectin can drive rapid improvements systemic insulin sensitivity. Lastly, he described how uridine biosynthesis (a key metabolite secreted by adipocytes, and building block for a large number of biochemical reactions) could be targeted by the transcription factor xbp1s to increase a person’s basal metabolic rate. This influence on basal metabolic rate would be similar to the promise of therapies of brown fat therapeutics. However, Dr. Scherer hypothesized xbp1s could be safer than brown fat targets because calories would be burned through biosynthetic pathway rather than the generation of heat.

Symposium: ADA Diabetes Care Symposium — Novel Clinical Interventions in Therapy That Impact the Management of Diabetes

The Use of Anti-Anginal Agent Ranolazine for Glycemic Control in Patients with Type 2 Diabetes: Phase 3 Trial Results

Robert Eckel, MD (University of Colorado, Aurora, CO)

The highly respected Dr. Robert Eckel presented phase 3 results on the glucose-lowering effects of the anti-angina drug ranolazine (Gilead’s Ranexa). For background, anti-hyperglycemic properties of ranolazine were first noticed in post-hoc analyses of its angina trials. The studies Dr. Eckel presented were specifically designed to evaluate glycemic endpoints for ranolazine as monotherapy and as an add-on to metformin or glimepiride. From a baseline A1c of 8.0-8.5%, ranolazine provided a 0.56% placebo-adjusted reduction as monotherapy and a 0.50% placebo-adjusted reduction as an add-on to glimepiride. There was no observed A1c reduction with ranolazine as an add-on to metformin, likely because patients’ metformin dose had to be lowered after ranolazine addition because ranolazine interferes with metformin metabolism. Ranolazine’s suspected anti-hyperglycemic mechanism is lowering glucagon. We have not heard updates from Gilead on ranolazine in some time; the company has completed three phase 3 trials of the drug in type 2 diabetes and is currently conducting a phase 4 trial in diabetic peripheral neuropathic pain. We assume the regulatory path to a diabetes indication would be fairly straightforward given that ranolazine is already on the market; that said we are also thinking that the next step may be to explore combination therapy rather than bringing this out as monotherapy.

Questions and Answers

Q: If ranolazine acts like a glucagon antagonist, does it have any effect on the liver? The glucagon antagonists in development were stopped in the early phases because of liver problems.

A: There was no apparent change in liver function.

Symposium: The Accelerating Medicines Partnership in Type 2 Diabetes — A Pharma/NIH Collaboration

Overview: Rationale, Goals, and Implementation

Philip Smith, PhD (NIDDK/NIH, Bethesda, MD)

Dr. Philip Smith, co-chair of the Accelerating Medicines Partnership (AMP) in Type 2 Diabetes, provided an introductory overview of this industry/NIH partnership. The members include: NIH as the government member; Janssen, Lilly, Merck, Pfizer, and Sanofi as the industry members; and ADA and JDRF as the nonprofit members. Dr. Smith opened his presentation by stressing the many challenges and inefficiencies that currently exist in R&D and drug development. With this background, he explained that the AMP strives to bring the private and public sectors together to work on these issues by integrating better targets with emerging technologies, extensive human data, and big data tools. Importantly, the research supported by AMP is meant to be precompetitive and shared broadly, helping make the program as accessible and effective as possible. The AMP has three major focus areas: type 2 diabetes, Alzheimer’s disease, and rheumatoid arthritis (and related autoimmune disorders), each with its specific aims and approaches. In the five-year, $40 million type 2 diabetes program, Dr. Smith explained that the disease area has a significant amount of human genetic data, which AMP aims to link to risk and phenotypes to better identify and enhance therapeutic targets. He briefly introduced the Type 2 Diabetes Knowledge Portal as a groundbreaking tool to achieve this. Looking forward, Dr. Smith stated that the portal will undergo continuous enhancement with plans to develop new analytics and gain new cohorts.

The Type 2 Diabetes Knowledge Portal: A User-Friendly Window into Genomics Data

Mary Carmichael (Broad Institute, Cambridge, MA)

Ms. Mary Carmichael walked attendees through recent screen shots of the Type 2 Diabetes Knowledge Portal (, noting its capabilities. She described the Portal as a “resource for the community, by the community.” The Portal currently contains 28 very large datasets on the genetics of type 2 diabetes and related traits (e.g., fasting glucose). Functionalities of the Portal include, but are not limited to, helping users visualize data, survey prior findings across all available datasets, and hunt for genetic variants that may support or refute their biological hypotheses. Users can also view summaries of current knowledge on genetic variants associated with type 2 diabetes – or volunteer to draft their own summaries. Future directions for the Portal include (i) automated association tests for variants across user-selected sets of samples; (ii) new data, including large exome sequence data sets and annotations from public databases; (iii) new analytical methods for the pipeline; and (iv) new content and features that allow users to directly contribute and annotate information in the portal. Email to join the Portal’s mailing list that will communicate updates (the hope is new features will be rolled out each month).

How the Type 2 Diabetes Knowledge Portal Can Advance Your Science: Genetic Determinants of Insulin Resistance

Geoffrey Walford, MD (Massachusetts General Hospital, Boston, MA)

Dr. Geoffrey Walford took an in-depth look at the Type 2 Diabetes Knowledge Portal, walking attendees through how to make the most out of the tool through the example of investigating insulin resistance. By illustrating that continued understanding of the genetics of insulin resistance is important in advancing therapeutic targets and enhancement, Dr. Walford showed that the portal can help explore insulin resistance’s known genetic architecture and examine the impact of gene variants on various traits. More specifically, he demonstrated the portal’s efficiency in exploring GWAS findings, identifying what findings are novel, and testing new theories. Looking forward, after pointing out the incredible progress that the portal has made (even within the past week), Dr. Walford stated that goals include integrating other datasets over time and developing testing capabilities for genetic risk scores. We are overall impressed with this new collaborative tool that is accessible and applicable to users of all different backgrounds and believe that this can be very powerful in moving type 2 diabetes research forward with its joint, open source philosophy.

Type 2 Diabetes Knowledge Portal: A Call to Action, Community Participation, and Future Directions

Michael Boehnke, PhD (University of Michigan, Ann Arbor, MI)

Dr. Michael Boehnke called for investigators to contribute their data to the Type 2 Diabetes Knowledge Portal. He argued that adding data to the Portal is the right thing to do, given the trust placed in investigators to advance science by study participants who donate their time and DNA and by the government and charitable organizations that fund the work. He also emphasized that submitters will benefit due to the visibility the Portal will give to their research and the opportunities for collaboration, including with pharmaceutical companies, it will create. Additionally, some grant funding is available to help investigators integrate their data into the Portal. Lastly, he stressed that we will all benefit from the Portal containing more data because it offers simplified access to a wider range of genetic results based on large, well-phenotyped, multiethnic studies. Notably, during Q&A multiple attendees took the microphone to urge pharmaceutical companies to contribute the genetic and phenotypic data they collect during trials to the Portal, especially because it may enable companies to more quickly identify the next blockbuster drug. One attendee suggested if pharmaceutical companies are concerned about sharing data associated with proprietary agents, they could instead only upload data from patients who took generic agents. This data could still help researchers make meaningful progress in identifying genetic markers predictive of who will respond to which generic agent. Dr. Philip Smith noted that one of the pharmaceutical companies financially supporting the Portal (Janssen, Lilly, Merck, Pfizer, Sanofi) is already collaborating on data to some extent, and that he hopes others will do the same as the Portal proves its value.

Symposium: Triple G — Genes, Gut, and Glucose

The Bugs Within: The Human Gut Microbiota and Metabolism

Oluf Pedersen, MD, DMSci (University of Copenhagen, Copenhagen, Denmark)

Dr. Oluf Pedersen’s presentation explored the relationship between the gut microbiome and common metabolic disorders. Several observational studies suggest that obese individuals have reduced bacterial diversity. Furthermore, metabolically unhealthy individuals tend to have a low gut bacterial gene count (LGC; defined by <380 K-genes). According to Dr. Pederson, LGC individuals are more likely to be obese, insulin resistant and have elevated markers of low-grade inflammation. Dr. Peterson described a study in which obese recipients were given duodenal infusions of allogenic gut microbiota from lean donors. Six weeks after infusion of gut microbiota, the insulin sensitivity of obese recipients was increased. While such an approach is unlikely to become a widely accepted strategy to improve insulin sensitivity now, it may prove to be an interesting therapeutic alternative in the future. Dr. Pederson concluded his presentation with a discussion of gut microbiota and diabetes. Like individuals with obesity, individuals with type 2 diabetes also have gut microbiota imbalances. In a trans-national study, Dr. Pederson confirmed that patients with type 2 diabetes suffered from a depletion of butyrate producing taxa. In addition to endogenous microbiota deficiency, patients with type 2 diabetes often are prescribed four to 10 medications that also influence their gut microbiota. For example, the metformin-associated gut microbiome was closer to the healthy gut microbiome compared to the microbiome of patients with type 2 diabetes who had never been on metformin. An important remaining question in Dr. Pederson’s exploration is whether gut microbial signatures are valid biomarkers of type 2 diabetes.

Symposium: Adipose Tissue – Local and Systemic Influences on Metabolism and Insulin Resistance

Brown Adipose Tissue in Humans: Relevant or Much Ado About Nothing?

Eric Ravussin, PhD (Pennington Biomedical Research Center, Baton Rouge, LA)

Dr. Eric Ravussin began his presentation by cutting to the chase, saying, “I will begin with my conclusion. I don’t think there’s much hope for curing diabetes or obesity with brown adipose tissue.” He argued for a frame-shift in how we think about BAT, acknowledging that “chasing drugs that stimulate energy expenditure” has not been “fruitful.”  He emphasized that while previous studies of activation of brown adipose tissue (BAT) have proven unsuccessful in initiating weight loss alone, Dr. Ravussin believes that BAT may be useful in weight loss maintenance, specifically via cold-induced thermogenesis. In his opinion, the energy balance equation is misleading and the static weight change rule does not account for a new steady state that is reached after weight loss. Instead, this metabolic adaptation stage could be fertile ground for the induction of a possible second drug that increases energy metabolism, i.e. where BAT could be a target for weight loss maintenance. In his team’s study of competitors from the TV show “The Biggest Loser,” researchers found that the metabolic rate after 30 weeks of weight loss was 500 calories per day below what was expected for their new body weight and body composition. He referred to this as a metabolic adaptation – a stage after losing weight in which BAT activation may help maintain a healthy weight in our “obesogenic” environment.

  • Expanding on BAT activation’s potential for weight loss maintenance, Dr. Ravussin presented data from his group’s study with participants from the TV show “The Biggest Loser” (Johannsen et al., JCEM 2012). On average, after 30 weeks, participants lost 38% ± 9% of their initial weight, of which only 17.4% was the loss of fat-free mass (FFM). Notably, researchers found that after 30 weeks of weight loss, the actual resting metabolic rate (RMR) was 500 calories below the predicted RMR based on weight loss of fat mass [predicted RMR= 1.241 +19.2 FFM + 1.8 FM – 9.8 age + 405 (male)]. Even after only six weeks of weight loss, participants had an RMR 244 calories below the predicted RMR.
  • Dr. Ravussin concluded that stimulating energy expenditure, e.g. via leptin replacement, might result in more successful weight loss maintenance. He reviewed data showing that metabolic adaptation, i.e. the unexplained decrease in RMR, was related to a decrease in leptin (Knuth et al., AJCN 2014). Specifically, the larger the drop in leptin concentration, the larger the metabolic adaptation.
  • Dr. Ravussin also reviewed new data showing that people with type 2 diabetes had no defect in cold-induced thermogenesis (CIT) with well-controlled cold exposure compared to lean subjects and age-matched controls (Blondin DP, et al. Diabetes 2015). Additionally, shivering response and BAT volume of F-fluoro-deoxyglucose (FDG) activity was inversely proportional. Dr. Ravussin translated these results as support for the potential of BAT activation specifically with well-controlled cold exposure, since people with type 2 diabetes did not differ in cold-induced oxidative metabolism and total energy expenditure compared to young healthy controls, despite these patients having smaller BAT volume and lower glucose uptake per BAT.

Questions and Answers

Q: Do older patients with type 2 diabetes have significant amounts of brown fat?

A: Older patients have much less brown fat than younger people for sure. Studies in Japan have shown this inverse relationship with age. Brown fat is something we progressively lose, unfortunately for you and I [laughter].

Symposium: Diabetic Dyslipidemia — Where's the Action in 2015?

Metabolic Effects of Bile Acid Sequestration

Bart Staels, PhD (University of Lille, Lille, France)

Dr. Bart Staels described how bile acid sequestrants lower LDL, increase HDL, and improve glycemic control. While bile acid sequestrants improve lipid homeostasis by increasing bile acid synthesis through the deactivation of FXR, they improve glycemia through the TGR5 pathway. Citing several mouse studies for support, he explained that bile acid sequestrants improve glycemia by stimulating the TGR5 pathway, which activates the GLP-1 receptor and eventually suppresses glycogenolysis. Although the majority of this research relies on animal models, bile acid sequestrants have also been demonstrated to induce GLP-1 secretion in humans. In fact, several drugs in this class are already on the market or in development: Daiichi Sankyo markets the bile acid sequestrant Welchol (colesevelam), and GSK has an ileal bile acid transport inhibitor in phase 2.

Professional Interest Discussion Group: Professional Interest Group Discussion on Exercise

A Debate on Exercise Resistance in Diabetes: Pro

Lauren Sparks, PhD (Translational Research Institute, Orlando, FL)

Dr. Lauren Sparks presented evidence in support of the existence of exercise resistance in a pro-con debate on the topic. She began by reviewing data suggesting that while many individuals with type 2 diabetes benefit from exercise, a significant percentage do not achieve the same metabolic results. Much of Dr. Sparks’ talk focused on establishing that different individuals and populations respond differently to exercise, providing support for the existence of a non-responder population. Dr. Sparks then went on to suggest that genetics or epigenetics may play a role in differentiating non-responders from responders. She concluded by presenting the setup and preliminary results from her RESIST study, which examines exercise resistance at the cellular level in a small population with type 2 diabetes.

  • Dr. Sparks proposed that some individuals may be resistant to exercise and may not experience its typical benefits. She emphasized that there is a lack of research into exercise resistance, but that current data does suggest significant variation in responses to exercise.
  • Retrospective data suggests that significant numbers of individuals with diabetes do not respond positively to exercise as expected. Dr. Sparks highlighted the findings from the STRRIDE trial demonstrating variation in insulin sensitivity, muscle mitochondrial density, and muscle lipid content in response to exercise in overweight and obese individuals. A meta-analysis suggested that up to 15-20% of individuals with type 2 diabetes may be resistant to exercise, which could have serious implications for how treatment plans are prescribed and individualized for patients (we do not think they are too individualized as it stands). Dr. Sparks also cited a meta-analysis conducted by Bouchard et al. (PLOS, 2012) indicating that 7% of individuals actually exhibited an adverse response to exercise.
  • Dr. Sparks suggested that there may be a genetic or epigenetic component to exercise resistance. Dr. Sparks pointed to responders and non-responders having distinct basal molecular profiles of muscle tissue, with different genes expressed in responders and non-responders, as evidence for a pre-determined component to exercise resistance. Dr. Sparks postulated that, typically, exercise may lead to gene expression promoting fuel utilization in muscle, which in turn increases insulin sensitivity, oxidative capacity, and mitochondrial content. In her model of exercise resistance, some individuals may have epigenetic control at the muscle cells that inhibits the gene expression response to exercise.
  • Dr. Sparks’ RESIST study examined exercise resistance at the cellular level in a small, homogenous, Caucasian male population. The study conducted exercise training for 10 weeks with 24 males with type 2 diabetes, measuring mitochondrial ATP synthesis and function. The results of the study indicated that there were high and low responders to exercise within the participant group. Looking forward, Dr. Sparks hopes to address whether the described non-responder phenotype in muscle fibers is intrinsic and retained when exercise is mimicked in vitro.

Questions and Answers

Q: What can you tell us about how muscles look under the microscope? We have responders vs. non-responders – does one have more glycogen than the other?

A: So quantitatively, I can tell you we haven’t done anything on that. In that previous study I showed, we weren’t geared towards measuring any of that so I don’t have any data on glycogen content. But I can tell you that in the current study that we’re doing, we are preparing the tissue for immunochemistry and we will look at some of those things.

Q: And what about responders vs. non-responders in terms of strength or endurance?

A: We did do a strength test and there were no differences between the groups, nor in VO2 max responses in those two groups. It seemed to be more at the level of muscle substrate utilization.

Q: Is there something clinical (not a muscle biopsy)? I’m a responder because I work very hard; I’m very religious in what I do. So I would hypothesize that some physical characteristics, some nutritional factors, and environmental factors may be very important.

Dr. Sheri Colberg-Ochs (Old Dominion University, Norfolk, VA): Hey, hey that’s mine. [Laughter]

Q: So I would hope that you’re getting some of those basic fundamental characteristics in your studies. Since it’s the older population that that are trying to get the exercise, that are prediabetic, it may well be sleep apnea or other clinical characteristics that are more relevant than what’s going on in muscle.

A: I completely agree. I can tell you that this study right now is pretty small, so it’s only 24 subjects. Because of my background and because of the data I had to go on, I am still focusing pretty much solely on the muscle and not necessarily environmental factors, which is why the cohort is what it is. So it’s males only, Caucasian only, because we’re looking at this at a more of a molecular level. In the future, I would like to open this up to a much more epidemiological style, public health approach that can compare different types of exercise.

Q: But there’s no reason you can’t get that information in the 24 people. You have all the resources to do that?

A: Yes, I could.

Q: One of the challenges of this kind of study is that if the group is very homogenous in terms of the mechanism that is giving rise to exercise resistance, then this might work out. But if there are 24 people and 30 different mechanisms, it may be challenging. So I’d like to get your thoughts on how likely do you think it is that it’s a homogenous group with respect to the mechanism? Because you can certainly think of many different points in the pathway that could give rise to exercise resistance and that could be a challenge.

A: Yes, it’s definitely a limitation of this study. The reason we’re focusing on this particular mechanism – and like you said, we may not find it – is the precedent we had to go on, the data pointing out these changes in these promoters of these three genes, which is why we chose to focus on them. But we will be doing these methylation arrays as well and hopefully we can tease something out of the data to get more of a clear direction. Because I agree with you, we could totally miss it if we just focus on this part of the pathway.

Q: Has anybody done anything younger to try and get a sense of if it’s possible exercise resistance sets in later because of some factor or is it an inherent defect that you’re born with? I’m think about one study that was done in mice and swim training that showed if they started the training when they were really young, they did much better than if it was brought in later. Is it possible that the non-responders are people who did something different earlier in life or is it always going to be there?

A: As far as I know, it hasn’t been looked at directly, but I would love to take this into kids. I have this memory of these presidential fitness tests when I was a kid and every year there were always those kids who couldn’t run the mile in 10 minutes or couldn’t do the 100 sit-ups. So I truly think that it is something that probably is starting very early. Maybe if you could interfere earlier, then maybe that could change the outcome so that they’re not necessarily always a non-responder.

Q: One of the things I was curious about is your proposed study where you’re looking at diabetes vs. athletes? How are you defining your diabetics? The reason I ask that is that we had tried to tackle some of this exercise resistance question by looking at different phenotypes of impaired fasting vs. impaired glucose tolerance or a combination of both. What we find is that the combination actually don’t seem to respond as well in comparison. And going back to the question about clinical outcomes, it seems to really directly impact their improvement in glucose tolerance and two hour blood glucose.

A: So the way we’re defining these guys, again because we’re focused on the molecular mechanisms and keeping it as clean as possible, we decided to go with their A1c range from 6.5-8.5%, and we’re also doing oral fasting glucose. The biggest thing is because of this exercise and medication factor, we want them on monotherapy so that they can wash off of or they’re just not on medication at all. So we’re trying to keep that as clean as possible. We also know that the duration of diabetes relates to the exercise response as well, and we looked at that in a previous study. There are lots of issues around this; it’s not a magic bullet or one single answer for exercise resistance. I think it will be many different answers from many different people. As cleanly as we can, that’s how we’ve chosen to approach this study and hopefully we can get some answers. But I know that previous hyperglycemia can also have an effect on the exercise response.

A Debate on Exercise Resistance in Diabetes: Con

Sheri Colberg-Ochs, PhD (Old Dominion University, Norfolk, VA)

Dr. Sheri Colberg-Ochs raised important considerations in the exercise resistance debate based on her own experiences conducting exercise-related research on individuals with diabetes. She began by questioning the relevance of many of the animal and in vitro studies that suggested processes for exercise resistance. She then questioned whether the clinical studies that concluded that some individuals with diabetes do not experience the usual metabolic benefits of exercise had adequately controlled for a multitude of confounding factors. In her own experience, despite best intentions, there are often variations in training intensity, daily energy expenditure, and diet that are not adequately taken into account in exercise studies. Dr. Colberg-Ochs also suggested that studies that saw exercise resistance in individuals might have simply not continued the training long enough to see results. Ultimately, the theme of her arguments was that one should never assume all factors are adequately controlled for and that this may have severe repercussions for the results.

  • Dr. Colberg-Ochs questioned the relevance of much of the current evidence supporting the existence of exercise resistance. She pointed out that studies in rats involve successive breeding for certain traits that results in a homogeneity not seen in the human population. In addition, she questioned the extrapolation of findings at the myotubule level to the whole human body and argued that the way muscle cells respond in vitro may not necessarily be the same as how whole muscles or the whole body responds.
  • Dr. Colberg-Ochs argued that many confounding factors are not adequately accounted for in exercise resistance studies. For example, the setup of exercise-based studies involves initially setting a maximal aerobic capacity. However, despite best intentions, many participants may underestimate their maximal aerobic capacity if they did not push themselves hard enough because they are unused to physical activity, lack motivation, or experience localized muscle fatigue or other limitations. As a result, training intensity throughout the study may then be based on an artificially low maximal aerobic capacity. Dr. Colberg-Ochs also suggested that non-training daily energy expenditure and diet are not adequately accounted for in many of these studies and these factors can have a large confounding effect on the observance of exercise resistance.
  • Dr. Colberg-Ochs proposed a handful of alternate explanations for observed exercise resistance. These included a failure to fully control for diet, variation in the amount of training done by some subjects, variation in daily activity energy expenditure, factors affecting insulin action and glycemic balance, medication effects, and failure to take body fat composition into account in BMI measures.

Questions and Answers

Q: I want to follow up on one of the points you made about setting up your training intensity based an initial exercise capacity test. Is this something that we all have to deal with? It’s very easy to get athletic people to push through, and then you struggle with people who are unaccustomed to exercise or have limitations. So what kind of solutions have you worked through to resolve that issue?

A: I wish I had a good response to that. I’ll tell you what I did one time. I did a study and we had one guy who was a lean type 2 and he did a lot of running and that stuff. He wanted to be in the study so I went ahead and included him. But when we got to the end and we looked at the data, he was such an outlier, we threw the data out. That was my response: I can’t include this person because he’s just not like all the others and it’s going to skew all the means. I think we might need a better way of initially assessing what would be a starting point, and I don’t know what that is.

Q: Have you taken data on the participants’ readiness measure? I know in other studies that I’ve done, that’s a variable to consider – their readiness to participate.

A: Do you have a particular physical readiness thing that’s more physiologic? We have a physical activity readiness questionnaire that asks questions like “do you have chest pain when you exercise?” I’m not aware of a really effective one other than that. We don’t have anything else.

Q: I think you made a very important point that if people don’t exercise or exercise as much, they may appear to be non-responders. I’m not sure that that’s evidence against genetics. Could there be genes that affect people’s tolerance for exercise or the amount of exercise they’re interested in?

A: I totally agree. I wasn’t trying to rule that out entirely. Likely there are some people who truly don’t respond. Maybe you have someone who doesn’t respond to aerobic training but responds to resistance training. It may be that what we’ve been doing for years is prescribing exercise for people and saying you need to do this, you walk for 30 minutes, instead of letting people gravitate to activities that they prefer to do. Maybe for genetic reasons they like to do one activity more than another. We certainly know that there is different muscle fiber typing that might affect how people respond.

Comment: You pointed out correctly that if you take this sedentary person and try to do an aerobic capacity on them it’s hard to get them to the point where they will have increasing heart rate. So what you end up with is peak exercise rather than anaerobic capacity. I highly recommend that you plot on the horizontal axis work load and on the vertical axis the heart rate and you look at the slope. As the person becomes more fit, the slope will become flatter and flatter. You don’t have to worry about this problem of getting them to plateau.

Point two is that at least four decades ago, the Danes pointed out in their research that if you prevent the core temperature from going up, there will be no improvement in aerobic capacity.

And the last point is that about three decades ago the Norwegians showed that if you train just below your anaerobic threshold, you can get much better improvement in aerobic capacity than if you go above the anaerobic threshold. And that’s controversial because there’s a whole group of people, myself included, that believe you need to go above anaerobic threshold for three minutes, and then below anaerobic for three minutes to recover. But the point is that somewhere above and below the anaerobic threshold is where the optimal exercise needs to be and as they improve that anaerobic threshold, the exercise load has to follow to keep them in that prime spot.

A: Right, so basically training is a moving target and I think it moves faster for some people.

Comment: So when you take the highly fit mice, and you train them, they don’t get any fitter and they don’t improve metabolically. Maybe we all have an inherent gene that makes it such that we can’t improve any further. We haven’t identified that. The only way real way we can do that is have the DNA and have the VO2 max measure on the people to look for those genes in genome wide scans and that would be very interesting. In contrast, when unfit mice put on treadmill and made to run, they do get fitter and they do improve metabolically, although they cannot reach the level of fitness of the mice bred to be fit. That’s a very interesting model that provides some very intriguing possibilities for these two approaches to defining who’s a responder and who’s not a responder. It comes down to collecting all the data you can possibly think of and what is great is you have this opportunity to look at that.

I think some of the answers may be in studies of master athletes. Back in the 1990s in my lab, we were able to raise the VO2 max of the master athletes substantially with training and when we de-trained them, we uncovered dyslipidemia and then we looked at genes that might predict that. So there are interesting things that can be found out from just working to get that volunteer who’s interested in their training responses to get the data we want and need to make those analyses possible.

A: I agree, thank you for that comment.

Corporate Symposium: Novel Mechanisms and Advancing Therapeutic Paradigms for Optimizing LDL-Focused Management and Cardioprotection in the Diabetic Patient (Sponsored by Sanofi/Regeneron)

ADA and ACC/AHA Guidelines for Improved LDL-Targeted Atheroprotection in Diabetic Patients: Unique Considerations and Target Goals in the Setting of T2D: What Works? How Well? What Doesn’t Work? How Low Should We Go? Why?

Vivian Fonseca, MD (Tulane University, New Orleans, LA)

The renowned Dr. Vivian Fonseca discussed the link between diabetes and cardiovascular risk, emphasizing current gaps in our knowledge and potential future therapeutic strategies. Following a review of the complex data behind glycemic control and cardiovascular risk, he suggested that moving forward, modifying multiple risk factors concurrently may be a more effective approach than focusing solely on A1c. He touched on the potential role of inflammation in the development of cardiovascular disease, asking whether newer agents may also play a role in modulating that risk factor. He concluded by asking what the optimal goal for LDL is in minimizing cardiovascular risk.

  • Dr. Fonseca opened by noting the current gaps in our knowledge with regard to diabetes and cardiovascular risk. While LDL and blood pressure control have demonstrated beneficial effects on cardiovascular outcomes, he noted that results with various diabetes therapies and glycemic control have been less clear. While the UKPDS took roughly a decade to show cardiovascular benefit, researchers expected improvement in outcomes in ACCORD and ADVANCE over shorter time periods. Moving forward, he suggested that modifying multiple risk factors concurrently (hyperglycemia, hypertension, and dyslipidemia) may be a more effective approach than focusing on lowering A1c alone.
  • With regard to ACCORD, Dr. Fonseca noted a recent study (Hempe et al., Diabetes Care 2015) demonstrating increased hypoglycemia and mortality in subjects with high glycation indexes. These patients have a higher A1c than would be predicted by their blood glucose levels, which could potentially lead to overly intensive treatment that increases hypoglycemia risk. Therefore, taking hemoglobin glycation index into account may enable providers to identify subpopulations at higher risk and better optimize their diabetes management.
  • Dr. Fonseca reviewed the potential role of inflammation in the development of cardiovascular disease. He noted multiple therapies with possible effects on inflammation, including a low fat diet, aspirin, statins, and insulin sensitizers. He questioned whether newer agents may also affect inflammation.
  • Dr. Fonseca concluded by asking what the optimal goal for LDL is in minimizing cardiovascular risk. With the idea that lower is better, he noted that current trials may not have gone low enough. He hoped new trials would help uncover the optimal goal for patients moving forward. The ongoing cardiovascular outcomes trials of PCSK9 inhibitors, which can bring some patients down to very low LDL levels, should hopefully provide more clarity on this issue – as we understand it, this and neurocognitive effects represent the main safety issues at presents. CVOT outcomes must come before approving the drug, except for the most needy patients, e.g., those with hypercholesterolemia. .

Evolving Clinical Paradigms for LDL Lowering: Focus on Efficacy, Implications, Side Effects, and Safety Results of Landmark Trials Evaluating PCSK9 Inhibition, ApoB Suppression, and Other Novel Targets – Implications for the Diabetic Patient

James McKenney, PharmD (Virginia Commonwealth University, Richmond, VA)

The wonderful Dr. James McKenney gave a thorough overview of the clinical studies supporting the PCSK9 inhibitors in development, discussing optimal indications for their use. Dr. McKenney opened with encouragement, suggesting “we may be on the front edge of another era in cardiovascular therapies.” Following a review of the mechanism of action of the drug class, he underlined three potential populations for which these drugs could be most useful: familial hypercholesterolemia patients, patients with high CV risk uncontrolled on statin therapy, and patients intolerant to statin therapy. In addition to strong effects on LDL reduction, he praised the minimal adverse event profile of the class. He concluded by noting the ongoing long-term outcomes trials of the class – while he suggested results from these studies were necessary to draw definitive conclusions, he felt the early evaluation of adjudicated CV events with PCSK9 inhibitors provided reason to be hopeful for positive results.

  • Dr. McKenney opened with encouragement, suggesting “we may be on the front edge of another era in cardiovascular therapies.” He highlighted the numerous new mechanisms being researched, including PCKS9 inhibitors, Apo B antisense, MTTP inhibitors, and CTEP inhibitors. Focusing on the PCSK9 inhibitors, he reviewed the candidates in development, including Sanofi/Regeneron’s Praluent (alirocumab; under review), Amgen’s Repatha (evolocumab; under review), Pfizer’s bococizumab (phase 3), Lilly’s LY3015014 (phase 2), Alnylam’s ALN-PCS siRNA (phase 1), and AFFIRIS AG’s peptide-based vaccines (preclinical).
  • Dr. McKenney briefly reviewed the mechanism of action of the PCSK9 inhibitors, correlating it with their downstream clinical effects. He noted that the inhibitors that produce an initial 100% blockade of PCSK9 result in a maximum reduction in LDL-cholesterol of about 60%. The body continues to secrete PCSK9 and so increasing the dose of the PCSK9 inhibitor prolongs the effect but does not increase the reduction. Looking at single ascending dose studies, this was demonstrated with a roughly 60% decline in LDL-cholesterol with both alirocumab 150 mg SC Q2W and evolocumab 140 mg SC Q2W. At the selected doses for market, alirocumab 75 mg every two weeks produces a roughly 50% decline in LDL-cholesterol and 150 mg every two weeks produces a decline of 66%; evolocumab 140 mg every two weeks produces a 66% decline while 420 mg every four weeks produces a 50% decline. In Dr. McKenney’s clinic, he suggested about half of his patients prefer bimonthly administration as opposed to monthly.
  • Dr. McKenney underlined three potential populations for which these drugs could be most useful: familial hypercholesterolemia patients, patients with high CV risk uncontrolled on statin therapy, and patients intolerant to statin therapy. He reviewed positive results for PCKS9 inhibitors in these populations, with a 61% decline in LDL-cholesterol in heterozygous familial hypercholesterolemia patients with evolocumab 140 mg every two weeks and a 55% decline with 420 mg monthly dosing (baseline LDL 155 mg/dl). For high-risk patients on maximum tolerated statin therapy, he noted the 51% decline in LDL-cholesterol in patients treated with 75 mg alirocumab every two weeks in the ODYSSEY COMBO II study (baseline 109 mg/dl). Lastly, for statin intolerant patients, he showed the 45% decline in LDL-cholesterol in patients unable to tolerate two different statins in the ODYSSEY Alternative study (baseline 191 mg/dl).
  • With regard to the safety profile of the class, looking to the Osler (evolocumab) and ODYSSEY Long Term (alirocumab) studies, he noted no signal for elevation in transaminase levels, myalgias, GI side effects, or neoplasms. At the planned FDA Advisory Committee meetings on the drugs, he suggested the agency would be interested in the effects on neurocognitive events/disorders, which occurred infrequently in these studies but showed  a slight increase relative to control groups – he suggested large outcome studies would be needed to elucidate this further. Neurocognitive events did emerge as one of the main safety-related discussion points in the meetings for Praluent and Repatha, along with the unknown effects of very low LDL levels, and (surprisingly to us) a potential risk of diabetes comparable to that seen with statins.
  • Dr. McKenney concluded by noting the ongoing long-term outcomes trials in the class. These included ODYSSEY Outcomes for alirocumab (estimated completion January 2018), SPIRE-1 (estimated completion April 2018), and SPIRE-2 (estimated completion January 2018) for bococizumab, and FOURIER (estimated completion October 2017) and GLAGOV (estimated completion July 2016) for evolocumab. While he suggested results from these studies were necessary to draw definitive conclusions, he felt the early evaluation of adjudicated CV events with PCSK9 inhibitors provided reason to be hopeful for positive results.

Panel Discussion

Vivian Fonseca, MD (Tulane University, New Orleans, LA), Deepak Bhatt, MD (Harvard Medical School, Boston, MA), Michael Davidson, MD (University of Chicago, Chicago, IL), James McKenney, PharmD (Virginia Commonwealth University, Richmond, VA)

The corporate symposium concluded with a fascinating panel discussion that addressed a notable question: Would panelists use PCSK9 inhibitors prior to cardiovascular outcomes trial data being available? The discussion turned particularly animated on this point, as three of the four panelists were in favor of prescribing the class - Dr. Vincent Forlenza was the sole holdout: “I don’t know.” The others cited impressive cholesterol data that was “too compelling” to ignore in patients at an already high risk for a coronary event. All three, however, qualified their statement by noting that in patients with low or medium risk of a cardiovascular event, the decision was more nuanced and required a unique benefit-risk assessment per individual. Last, all four panelists agreed that the bigger question was on the reimbursement front: Would payers jump on board without CVOT data? We heard healthy skepticism in response and a consensus that coverage and cost would pose some of the greatest challenges for the class moving forward. Based on the discussion and votes at the recent FDA Advisory Committee meetings for Praluent and Repatha, it appears that the initial indication for the products will likely be quite narrow (possibly just for patients with familial hypercholesterolemia) and that broader labels more applicable to patients with diabetes will likely be placed on hold until CV outcomes data is available.

Q: Let’s assume things go well and PCSK9 inhibitors are approved … should we use them prior to CVOT data being available? Would you use them in someone at high risk for cardiovascular disease?

Dr. Fonseca: I would use them in statin intolerant patients. With patients with diabetes, I would discuss the consequences and costs with them. I would say that I couldn’t promise that the therapy will reduce the risk of cardiovascular events, but the LDL data is so strong that I might still use it. Cost and coverage will be important.

Dr. McKenney: I would use them in people with high CV risk and elevated LDL-cholesterol levels in spite of statin therapy. The question will be ultimately answered by the payers. Payers are likely to say that they want to see CVOT data.

Dr. Davidson: I don’t know the answer but I think it’s going to be about who can afford it. We’re going to want to use it in all patients.

Q: If cost isn’t an issue – in someone’s who LDL at a mid-level, but has had three myocardial infarctions in the past year – would you use a PCSK9 inhibitor in the absence of CVOT data?

Dr. McKinney: Yes.

Dr. Davidson: Yes.

Dr. Fonseca: I don’t know.

Q: Is there any data on prediabetes being a risk factor for cardiovascular disease?

Dr. Fonseca: There is a continuum, but it’s not a straight-line relationship. There are very few clinical trials on pre-diabetes being linked to cardiovascular risk. There’s just not enough data here.

Q: Statin adherence for primary prevention is suboptimal. Given the more invasive nature of PCSK9 antibodies how do you foresee adherence?

Dr. Bhatt: In the real world we’ll have to see. Of course in clinical trials it’s closely monitored. I can see adherence being worse in clinical trials. In the other hand I can see it being better given it’s an injection every two weeks or month versus a pill every day. So it may depend on the patient.

Q: Can you talk about the relationship of PCSK9 inhibitors on CRP levels?

Dr. Davidson: It does not lower CRP levels. That has been thought about statins. No evidence of that with PCSK9 antibodies.

Dr. McKenney: I agree that PCSK9 inhibitors do not alter hsCRP. However, the key biomarker for risk reduction is LDL-cholesterol. And I would remind everyone that we have gone through a slow process of determining what the optimal LDL-cholesterol should be. Our treatment guidelines recommended <130 mg/dl in 1988, <100 mg/dl in 1993, and <70 mg/dl in 2004 for high risk patients. The goal has changed with time to become lower and lower because of outcome trial results. The ongoing outcome studies with PCSK9 inhibitors are going to result in mean LDL-cholesterol levels in the 30s or so. I suspect, if they are positive, we will redefine what our desirable level should be again.

Q: Please comment on the functioning beyond liver.

Dr. McKenney: PCSK9 only targets LDL receptors. Even though PCSK9 is made by the liver and kidneys, the only target is LDL receptors. So a monoclonal antibody that binds to PCSK9 to allow the LDL receptors to pull more circulating cholesterol into the liver is the unique effect of these drugs. There are no other biological targets. That’s why, in my opinion, these therapies seem so safe.

Q: Can you talk about antibody production with PCSK9 inhibitors? Is there a loss of efficacy?

Dr. Davidson: Difference between the different types of antibodies. Evolocumab and alirocumab are fully human. They both show some evidence of antibody production. There has been maybe on or two cases where there was a loss of efficacy, but that’s it. As of now, the rate of antibody production is very low. There is no evidence of safety issues.

Q: What about in type 1 diabetes?

Dr. Fonseca: I’m pleased to see this question. Guidelines suggest a statin for patients after a certain age, though there are no trials in a type 1 population. There is actually no PCSK9 trial in diabetes, only sub-analysis in diabetics. There may be some type 1s in trial; I really don’t know. We’ll have to look at that.

Q: Is there anything that compels you to stop treatment?

Dr. Bhatt: The epidemiological data with PCSK9 inhibitors seems pretty safe.

Q: Do PCSK9 inhibitors actively do anything good?

Dr. Davidson: It is a counter regulatory protein that maintains cholesterol homeostasis.

Dr. Bhatt: To date with statins, they have been very safe. There might be some benefits of statins in terms of dementia that could extend to PCSK9 inhibitors. We’ll get a definite answer in some years.

Q: There is also a question about children.

Dr. McKenney: PCSK9 monoclonal antibodies have been found surprisingly effective in children with homozygous familial hypercholesterolemia. These patients have loss of function LDL-receptor mutations inherited from both parents. Their mutation may be negative, which means that the receptor has no function, or defective, which means it has 2-25% of function. Patients with a negative/negative profile don’t respond at all to PCSK9 inhibition. But patients with any other combination of defective/negative or defective/defective experience a 25-40% reduction. This outcome was not expected but was a very welcome result.

Q: Have you seen any data about patients that don’t respond to treatment with PCSK9 inhibitors?

Dr. McKenney: I haven’t seen any. Everybody seems to respond. In fact, compared with the standard deviation of cholesterol values around a mean in an untreated population, the standard deviation after PCSK9 inhibition is substantially compressed.

Q: I have questions about other drugs.

Dr. Fonseca: Cycloset had a one-year diabetes safety trial; they didn’t continue the trial unfortunately. We have nothing with metformin. Tadalafil with chronic low-dose use may well have a beneficial effect, but it was never tested for that with its so-called side effect. You may not live longer but certainly a lot happier according to the commercials.

Dr. Bhatt: You’re right normally it was an anti-anginal – it wasn’t effective. It can be used in pulmonary hypertension.

Q: If these are approved, is there room for other agents with other mechanisms of action? Will it be ethical to do these studies?

Dr. Bhatt: There is always room for innovation. We have to see how PCSK9 inhibitors fair in CVOTs. We’ll have to look at how the drugs do in patients with low LDL cholesterol levels? I have not been very concerned, but we really have to see how these drugs fair. I wouldn’t dismiss innovation, especially ones that are complementary to this pathway. It would be ethical but the study might have to include PCKSK9 inhibitors.

Q: Is there a possibility for an oral therapy?

Dr. Davidson: It’s very difficult with protein and protein interactions in the liver for it to work orally. One big question is when to use these drugs – I think that will be big in FDA panel next week. It will be a regulatory question and an insurer question. I think there will be lots of patients not having success on statins that will be using it frequently.

Q: Why should we keep statin therapy around?

Dr. Bhatt: All the data I showed you were of PCSK9 inhibitors acting on top of statins. So, the effect is additive. We have studied PCSK9 inhibitors as a monotherapy, and you don’t see the same benefit.

Q: Where would you put these in the algorithm for therapies?

Dr. McKenney: I believe these are statin-plus therapies out of the gate. Their use will be for patients with high CVD risk or recurrent events while on statins, patients with intolerance to statins, and patients with familial hypercholesterolemia. When the outcome studies are complete and demonstrate substantial CV risk reduction when added to a statin, I suspect we will then see studies to demonstrate similar utility as monotherapy.

Q: Can you talk about gene therapy to knockout PCSK9 inhibitors?

A: There is a whole separate set of issues there, but I’d like to see how that plays out.

Q: How will physicians distinguish between evolocumab and alirocumab?

A: I don’t know. Some will like the idea of having doses to choose from. Some might like to start at a higher dose. Some might like the once-a-month approach vs. every two weeks. Cost is going to be a big factor.

Q: Would you use these in metabolic syndrome versus statins given the effect on insulin?

Dr. Fonseca: I think the effect of statins on glycemia is very small. But I think there’s a clear benefit in cardiovascular outcomes, so I would still use them. We need to do more analysis on this subset from outcomes trials.

Corporate Symposium: Managing the High Risk Patient – LDL and Beyond: Contemporary and Future Approaches (Amgen)

Understanding Pathophysiology of Lipid Disorders, Focusing on the Role of PCSK9 in LDL-C Homeostasis

Jorge Plutzky, MD (Brigham and Women’s Hospital, Boston, MA)

The renowned Dr. Jorge Plutzky reviewed the pathophysiology of lipid disorders and the involvement of PCSK9, setting the stage for the rationale of using PCSK9 as a therapeutic target. After opening his presentation by labeling PCSK9 inhibitors as “one of the most clear-cut approaches” in medicine, Dr. Plutzky walked attendees through much of the preclinical, genetic, and therapeutic data on the relationship between LDL levels and CV risk. He reviewed the mechanisms of cholesterol transport and explained PCSK9’s role as a secreted protein that targets the LDL receptor for degradation. Specifically, he discussed genetic models of PCSK9 showing how people with gain of function PCSK9 mutations have higher LDL levels and increased CV risk while loss of function PCSK9 mutations confer lower LDL levels and protection against CV risk. With these data, Dr. Plutzky concluded that PCSK9 inhibitors are a new class of therapies backed by a strong body of evidence.

Cardiovascular Disease and the High-Risk Person: Epidemiology, Pathophysiology, and Contemporary Guidelines

James Underberg, MD (NYU School of Medicine, NYC, NY)

Dr. James Underberg discussed the current guidelines for managing patients at high risk of developing cardiovascular disease. Although in the past, there was some controversy regarding the value of using statins in reducing atherosclerotic cardiovascular disease (ACSVD) events, Dr. Underberg advocated for their use at moderate or high levels in high-risk individuals. According to Dr. Underberg, individuals at high risk are those with clinical ACSVD, those with LDL levels ≥ 190 mg/dl and/or patients between the ages of 40-75 with type 1 or type 2 diabetes. In terms of treatment, Dr. Underberg did not indicate which guidelines he thought were most helpful; however, he noted several common themes from ACC/AHA, ADA, NLA, and AACE/IAS guidelines for high-risk patients. These are as follows: (i) patients with established ASCVD should be aggressively treated; (ii) statins should be used as the first line therapy for these high-risk patients; and (iii) moderate to high intensity statins should be used if they can be tolerated by the patient; however, side effects such as muscle pain and damage should be considered.

Addressing the Residual Risk

Howard Weintraub, MD (NYU School of Medicine, New York, NY)

In his presentation on addressing residual risk for patients at high risk of cardiovascular disease, Dr. Weintraub outlined several trials that failed to show a benefit of increased HDL concentrations in reducing atherosclerotic cardiovascular disease (ACSVD) risk. For example, even though HDL concentrations increased in individuals in the AIM-HIGH trial, there was no evidence of ACSVD risk reduction. Furthermore, in the ILLUMINATE trial, patients receiving torcetrapib, a cholesterol ester transfer protein (CETP) inhibitor had a 72% increase in HDL concentration after 12 months; however, the trial was stopped early due to an increase in major cardiovascular events and overall death. Despite the current very limited evidence that increased HDL concentrations improve cardiovascular outcomes, companies such as Merck and Lilly have CETP inhibitors (anacetrapib and evacetrapib, respectively) in phase 3 trials.

Emergent Options for the Management of Lipid Disorders: Clinical Data from Novel Classes of Drugs

Lawrence Leiter, MD (University of Toronto, Toronto, Canada)

Dr. Lawrence Leiter provided an overview of clinical data on the value of LDL reduction and the role of PCSK9 inhibitors as a treatment option for patients who have not achieved their LDL targets. He shared data showing an ongoing treatment gap including a study that revealed that 43% of Canadian patients with diabetes are not at their LDL target. He noted that there are many reasons for this, including overreliance on diet, use of insufficient starting doses of statins, complacency, and lack of follow-up for up-titration. Dr. Leiter thus emphasized the need for additional lipid lowering agents, as statin monotherapy may not allow many patients to achieve their targets. He pointed to PCSK9 inhibitors as promising therapies that are close to market and reviewed clinical data on Amgen’s Repatha (evolocumab), Sanofi/Regeneron’s Praluent (alirocumab), and Pfizer’s bococizumab, showing relatively consistent LDL reductions in the range of 50%-60%. While acknowledging that there are not yet much data in people with diabetes, he highlighted the OSLER study findings showing that the diabetes population experienced very similar reductions in LDL despite their differences in glycemic status. We certainly believe that PCSK9 inhibitors can have huge beneficial implications for diabetes care, though the initial approved indications will likely be narrow until the ongoing cardiovascular outcomes trials report results – please see our coverage of the FDA EMDAC meetings on Praulent and Repatha for more.

Product Theater

The Prevalence of Elevated LDL-C in Diabetes: Cholesterol Management and the Role of PCSK9 in Cholesterol Homeostasis (Amgen)

Harold Bays, MD (Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY)

Dr. Harold Bays presented his “clinical researcher” perspective on the role of PCSK9 in cholesterol homeostasis. He opened by stressing the high prevalence of elevated plasma LDL levels in people with diabetes and the low percentage of patients who achieve their LDL treatment goals. Dr. Bays elaborated on the many barriers to achieving LDL goals. In an informal poll of the attendees, ~30% responded that they manage patients with statin intolerance. Dr. Bays proceeded to discuss the mechanisms of how PCSK9 maintains cholesterol homeostasis by regulating the recycling of LDL receptors, with the rest of his presentation focusing on the genetic models of PCSK9 function in people with either gain of function or loss of function mutations. He ultimately concluded that from a scientific standpoint, PCSK9 plays an important potential role in cholesterol homeostasis, which may include patients with diabetes. We certainly agree – see our coverage of the recent FDA EMDAC meeting on Sanofi/Regeneron’s Praluent (alirocumab) and Amgen’s Repatha (evolocumab) for more.


-- by Melissa An, Eric Chang, Hannah Deming, Helen Gao, Varun Iyengar, Emily Regier, Mallika Tamboli, Jenny Tan, and Kelly Close