CMHC 2017 (Cardiometabolic Health Congress)

October 4-7, 2017; Boston, MA; Day #4 Highlights – Draft

Executive Highlights

As we say a sad goodbye to Boston (one of our favorite conference cities!), we bring you one last installment of highlights from CMHC 2017. This report includes practical clinical advice from none other Dr. Jay Skyler, Ms. Davida Kruger, Dr. Robert Eckel, Dr. George Bakris, and Dr. Christie Ballantyne – a powerhouse panel if we’ve ever seen one. We also glimpsed into the future of CVOTs with Brigham and Women’s Dr. Benjamin Scirica, who suggested we focus more on microvascular outcomes and heart failure, in addition to the classic three-point MACE. Keep reading for our top four highlights from the last ~24 hours of CMHC 2017. Want to look back at days #1-2 or day #3? Just click the links!

Top Four Highlights

1. Ms. Davida Kruger and Drs. Jay Skyler, Robert Eckel, George Bakris, and Christie Ballantyne participated in an interactive discussion of three audience-submitted patient cases. This wide-ranging discussion featured some of the meeting’s greatest clinical pearls, and covered a few key themes, including (i) the importance of renal outcomes in diabetes (and potential for SGLT-2 inhibitors in renal risk reduction), (ii) the value of nutrition education and psychosocial support for people with diabetes, (iii) strategies to avoid hypoglycemia, and (iv) the ever-present issue of access/affordability to advanced diabetes therapies.

2. What should we expect next from CVOTs? Dr. Benjamin Scirica outlined several possibilities, including head-to-head studies (should metformin still be first-line?), more data on microvascular outcomes, and more data on heart failure effects. He revealed that heart failure will be a primary endpoint in DECLARE for AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin), which is great news, in our view.

3. Harvard neurologist Dr. Roy Freeman called attention to the surprisingly high prevalence of peripheral diabetic neuropathy in the real world. He emphasized its association with pain (i.e. substantially reduced quality of life), heightened risk for amputation (all eyes are on this following CANVAS results), and risk for sudden death, ultimately arguing that this diabetes complication “isn’t being taken seriously enough.”

4. Dr. Kumar Sharma kicked-off the final day of CMHC with a compelling talk on how metabolomics could improve drug development for diabetic kidney disease (DKD). His research represents exciting work on the path to precision medicine for diabetes, though there is certainly a long road ahead.

Top Four Highlights

1. Thought Leaders Take on Challenging, Real-World Type 2 Diabetes Cases

Ms. Davida Kruger and Drs. Jay Skyler, Robert Eckel, George Bakris, and Christie Ballantyne participated in an interactive discussion of three audience-submitted patient cases. The experts urged HCPs to swiftly address the renal complications of diabetes, and expressed optimism for potential applications of SGLT-2 inhibitors in chronic kidney disease (CKD). To avoid hypoglycemia, Dr. Skyler advocated for a more advanced, next-generation basal insulin product like Novo Nordisk’s Tresiba (insulin degludec) or Sanofi’s Toujeo (insulin glargine U300). Dr. Eckel argued that basal insulin should never cause hypoglycemia – as he put it, it’s a matter of figuring out the appropriate basal rate, which is too-often overlooked in diabetes management (given how busy PCPs and endos can be). Ms. Kruger underscored the value of a nutritionist as a member of the diabetes care team. All five panelists agreed that psychosocial support is critical for people with diabetes (but still, is often missing), and there was no circumventing the ever-present issue of access/affordability for the safest, most effective diabetes drugs. This CMHC session featured some of the meeting’s greatest clinical pearls, and we summarize each patient case discussion in more detail below:

  • Patient #1 was a 78 year-old white male with hypertension, hyperlipidemia, type 2 diabetes, coronary artery disease, and chronic kidney disease (CKD). For hyperglycemia, he was taking sitagliptin (Merck’s DPP-4 inhibitor Januvia) 100 mg daily. The panel discussed possible use of an SGLT-2 inhibitor, of linagliptin (Lilly/BI’s DPP-4 inhibitor Tradjenta) in place of sitagliptin, and of CGM. The patient was concerned with the additional expense of adding an SGLT-2 inhibitor to his medication regimen, even though this would promote CV and renal risk reduction (Dr. Bakris recommended Novo Nordisk’s GLP-1 agonist liraglutide, branded Victoza, for this dual risk reduction as well). These cost concerns should not be underemphasized, given that cost is the biggest driver of treatment decisions for real-world type 2 diabetes patients. The panelists also pointed out that SGLT-2 inhibitors are currently contraindicated for people with eGFR <30 ml/min/1.73m2 (or a CKD diagnosis), though Dr. Ballantyne proposed that future studies evaluate SGLT-2 agents in patients like this. Indeed, all three SGLT-2 products currently on the market are being investigated for CKD: J&J’s CREDENCE trial for Invokana (canagliflozin) is furthest along, expected to complete in June 2019, while AZ’s Dapa-CKD study for Farxiga (dapagliflozin) is expected to complete in November 2020; Lilly/BI have announced plans for a trial of Jardiance (empagliflozin) in people with CKD with or without diabetes, but no timing details have yet been shared. We look very forward to results from all three trials, which could greatly expand the number of patients who can benefit from this advanced therapy class. Hopefully, additional evidence showing improved renal outcomes with SGLT-2 inhibitors will also sway payers to improve reimbursement. Interestingly, Dr. Bakris suggested that linagliptin should be substituted for sitagliptin if the patient has access. We heard from Dr. Per-Henrik Groop at EASD that Tradjenta is the only DPP-4 inhibitor that doesn’t have to be adjusted as eGFR falls, since linagliptin is excreted via the gut rather than the kidneys. This is certainly intriguing as we continue to realize the limitations of class effects – to this end, the upcoming CARMELINA CVOT for Tradjenta, expected to complete in December 2017, will reveal linagliptin’s impact on micro and macrovascular outcomes. Lastly, Ms. Kruger noted that using CGM would be helpful to get a better picture of this patient’s glycemia, because his A1c seemed so low. In general, the panelists had a hard time believing that this was an actual patient, considering the contrast between his comorbidities and his relatively good glycemic control.
  • Patient #2 was a 79 year-old woman with two recent hospitalizations for hypoglycemia (once found unresponsive in her home) and an A1c near 10%. Panelists advocated for dietary intervention or a next-generation basal insulin to reduce her hypoglycemia risk. The patient was taking 16 units of insulin glargine (Sanofi’s Lantus) at night, plus two-eight units/day of insulin lispro (Lilly’s Humalog) dosed on a sliding scale. Ms. Kruger immediately suggested that inconsistent eating may be the culprit for this individual’s severe lows, and for this, she recommended referring the patient to a nutritionist. Dr. Eckel argued that basal insulin should never cause hypoglycemia, and stated that he’d hospitalize this woman for three or four days to figure out her appropriate basal rate. Dr. Skyler suggested Novo Nordisk’s next-gen Tresiba (insulin degludec) – which comes with a longer/flatter PK/PD profile and flexible dosing, not to mention lower hypoglycemia risk vs. Lantus as seen in the SWITCH and DEVOTE studies – or Sanofi’s next-gen Toujeo (insulin glargine U300). Unfortunately, panelists were unsure if Tresiba/Toujeo would be accessible for this patient, again underscoring the critical issue of affordability and reimbursement for the safest, most effective diabetes drugs.
  • Patient #3 was a 52 year-old female, struggling to improve her glucose control and frustrated by 17 lbs of weight gain in the past 11 months (BMI 43 kg/m2). This individual felt too busy to exercise (she owned a struggling business with her husband), and was also experiencing depression and diabetes distress (alongside her retinopathy, polyneuropathy, nephropathy with microalbuminuria, obesity, hypertension, and dyslipidemia). The panelists launched into a discussion of psychological supports for this patient, and we were so glad to hear this theme come up at CMHC. Dr. Bakris advocated for visits with a nutritionist and psychologist, though Dr. Ballantyne reminded everyone that nutritionists and psychologists are poorly covered by insurance, as things stand. Ms. Kruger emphasized that this patient would benefit from nutrition education, while Dr. Eckel floated the idea of considering gastric bypass or a gastric sleeve (to quality, he noted that she has likely had diabetes for ~20 years and possibly would not do well with these surgical interventions). Overall, the panel agreed that this woman needs support from many different specialties, underscoring the importance of a diabetes care team/comprehensive approach to diabetes management.

2. Dr. Scirica on the “Third Wave” of Diabetes CVOTs: DPP-4 Agents are CV Safe, SGLT-2 and GLP-1 Agents are Cardioprotective, So What Next?

What should we expect next from CVOTs? Dr. Benjamin Scirica outlined several possibilities, including head-to-head studies, more data on microvascular outcomes, and more data on heart failure effects. As Dr. Scirica put it, each of these represents an outstanding question in diabetes research. In turn, the answers could improve best practice diabetes management and could help reduce micro and macrovascular complication rates in the real world. Few diabetes CVOTs to-date have compared outcomes between two active agents: The TOSCA.IT study of TZD pioglitazone vs. sulfonylureas, presented at EASD 2017, was one of the first, and Lilly/BI’s ongoing CAROLINA study is evaluating CV effects of DPP-4 inhibitor Tradjenta (linagliptin) vs. SU glimepiride (expected to complete March 2019). In real clinical settings, HCPs face tough decisions between drug classes, and sometimes between different agents in the same class, but never between a treatment and placebo – Dr. Scirica alluded to this irony as he advocated for head-to-head comparisons in the next wave of diabetes CVOTs. Importantly, he was very positive about this set of trials overall, explaining how the first wave of CVOTs largely confirmed safety (of DPP-4 inhibitors), while the second wave offered groundbreaking data showing CV efficacy (for SGLT-2 inhibitors and GLP-1 agonists). He expressed high hopes for the third wave of diabetes CVOTs to continue this momentum with more clinically useful findings. A head-to-head, for example, could identify a population of patients for whom metformin shouldn’t be first-line therapy, allowing providers to intervene more swiftly with more effective agents for cardio- and renal protection in those at highest risk (boy would we love to see this!).

  • Dr. Scirica also warned against “a slavish focus just on macrovascular outcomes,” calling attention to renal outcomes and changes in eGFR with different diabetes therapies. To this end, we’re happy to note that all three SGLT-2 inhibitors on the market are being investigated in chronic kidney disease (CKD). J&J’s CREDENCE trial for Invokana (canagliflozin) is expected to complete in June 2019, AZ’s Dapa-CKD study for Farxiga (dapagliflozin) is expected to complete in November 2020, and Lilly/BI have announced plans for a clinical trial of Jardiance (empagliflozin) in CKD, though no timing has been disclosed.
  • Dr. Scirica suggested that it will be important for future CVOTs to include heart failure as a primary endpoint, and he revealed that the DECLARE trial for AZ’s Farxiga (expected to complete in 2H18) will do just that. Knowing this, we’re even more eager to see full DECLARE results, given that both canagliflozin and empagliflozin demonstrated significant risk reduction for heart failure hospitalization in CANVAS and EMPA-REG OUTCOME, respectively. With heart failure as a primary endpoint in DECLARE, we wonder if relevant changes to the product label or to diabetes treatment algorithms might be implemented more swiftly for Farxiga. Moreover, AZ has launched a dedicated study of dapagliflozin in patients with chronic heart failure (Dapa-HF), and Lilly/BI have done the same with their EMPEROR clinical program for empagliflozin in chronic heart failure.

3. Dr. Freeman: “Diabetic Neuropathy Isn’t Being Taken Seriously Enough”

Harvard neurologist Dr. Roy Freeman called attention to the surprisingly high prevalence of peripheral diabetic neuropathy in the real world. He emphasized its association with pain (i.e. substantially reduced quality of life), heightened risk for amputation, and risk for sudden death, ultimately arguing that this diabetes complication “isn’t being taken seriously enough.” According to Dr. Freeman, diabetic neuropathy affects 66% of people with type 1 diabetes and 59% of people with type 2 diabetes in the US. Between 13%-34% of these cases present as painful neuropathy. Given the tens of millions of people with diabetes in America, these figures are not at all trivial. Dr. Freeman focused his discussion on two forms of neuropathy in particular: (i) neuropathy associated with impaired glucose tolerance and (ii) treatment-induced neuropathy. The first involves pain, abnormal skin sensation, and impaired touch sensation. Most notably, Dr. Freeman pointed out that unlike other microvascular complications of diabetes, which typically emerge after several years of disease, 10% of diabetes patients with this form of neuropathy present at the time of diagnosis. Treatment-induced neuropathy is rarer and involves acute, excruciating pain that even opioid therapy can’t relieve. Dr. Freeman explained that this latter form of neuropathy is usually precipitated by a rapid drop in A1c (at least 2%-3%). He urged HCPs in the audience to be aware of this risk in patients with high A1c about to undergo an intensification in their glycemic management. We were fascinated by this deep dive into neuropathy as a diabetes complication, and we appreciated the call-to-action. Dr. Freeman’s presentation reinforced our sense that with few available treatments and very little awareness, neuropathy remains an area of enormously high unmet need in diabetes care today. Moreover, the amputation signal seen in CANVAS for J&J’s SGLT-2 inhibitor Invokana (canagliflozin) came as a stark reminder of gaps in patient education around foot care and amputation risk more generally. The diabetes field needs greater awareness of all risk factors for amputation, including neuropathy, as Dr. Bruce Neal outlined at EASD last month, neuropathy was one of the common precipitating factors for amputations in CANVAS across both canagliflozin and placebo groups.

4. Dr. Sharma’s Metabolomic Approach to Diabetic Kidney Disease – Precision Medicine for a Diabetes Complication?

Dr. Kumar Sharma kicked-off the final day of CMHC with a compelling talk on how metabolomics could improve drug development for diabetic kidney disease (DKD). A major theme of his remarks was the value of big data techniques to “de-convolute” complex conditions like kidney disease in order to generate new biological hypotheses. To this end, his research team has chemically analyzed urine samples from people without diabetes, people with diabetes, and people with diabetes and comorbid chronic kidney disease (CKD). They’ve found that levels of 13 different metabolites are significantly reduced in the diabetes/CKD condition relative to controls without diabetes. Twelve of these are significantly lowered relative to the diabetes/non-CKD condition, thus comprising a unique signature of DKD. Not only are these signatures helpful to identify DKD, but they can also be used to help predict an individual’s responsiveness to potential therapies. A good example of this comes from AbbVie’s phase 3 endothelin A antagonist atrasentan. The candidate showed a significant reduction in albuminuria in the phase 2 RADAR program, but a study by Dr. Sharma further revealed that 12 weeks of atrasentan treatment significantly increased the levels of four signature metabolites in the subset of participants with eGFR <60 ml/min/1.73m2, suggesting that the drug may be particularly effective in this population. Dr. Sharma noted that we are approaching a paradigm shift toward more personalized diabetes care, where we can get much more detailed insight into the efficacy of a drug before prescribing it. In addition, Dr. Sharma’s metabolomic approach provides insight into the signaling pathways underlying the pathogenesis of DKD. The majority of the metabolites he found to be reduced in people with diabetes/kidney disease are produced in the mitochondria, leading to a series of studies probing mitochondrial function in DKD. Dr. Sharma’s current hypothesis is that DKD involves breakdown of the electron transport chain, leaving mitochondria in kidney cells to rely only on the less efficient process of glycolysis to generate energy from glucose. This hypothesis explains the ability of a preclinical NOX-1/4 inhibitor to improve DKD in mice in a study published by Dr. Sharma’s group last year: The agent prevents the breakdown of NADPH, an important component of the electron transport chain. This unexpected molecule could very well represent the next addition to the diabetic nephropathy competitive landscape thanks to these innovative techniques in metabolomics. We can only imagine what the future holds with this big data approach to drug development – not only for DKD, but also for metabolic disease more broadly. Undoubtedly, there are major challenges ahead for precision medicine in diabetes care, but we’re pleased to see researchers committed to this work, however early-stage.

 

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