Cardiometabolic Health Congress (CMHC) 17th Annual Conference

October 21, 2022; Boston, MA; Days #3-4 – Draft

Executive Highlights

  • Day #3 of CMHC was packed to the brim with learnings that transcended disciplines. We continue to be impressed by the panel discussions at the end of the day featuring eye-opening case studies in the management of cardiovascular disease, diabetes, and obesity – these often feature unexpected twists and turns and lead to many practical take home pearls. We look forward to the final day of the conference, which will bring cardiorenalmetabolic health together with a focus on CKD. 
  • In tech, we relished hearing from Dr. Irl Hirsch (University of Washington) on the use of CGM in type 2 diabetes. Dr. Hirsch specifically highlighted the value of professional CGM, which he said can be helpful to figure out where to “start” with a given patient for whom there might be incomplete or insightful glucose data on file, and to unveil any discordances between A1c and GMI. We were thrilled to learn that UW is following in the International Diabetes Center’s footsteps, to integrate LibreLink data directly into Epic EHR, especially in light of broader workings within the diabetes field to make CGM-EHR integration a possibility for a greater number of centers across the country. Separately, Dr. Hirsch noted that the recent FLASH-UK publication in NEJM will likely mean that is-CGM will receive “level A” evidence come December.
  • The afternoon focused on diabetes management and wow did we learn a lot! In another presentation, Dr. Hirsch shared recommendations for insulin management, specifically highlighting the use of the BeAM score (bedtime glucose – morning glucose) for basal insulin titration. He also discussed how to access affordable insulin, suggesting that clinicians consider mail-order Canadian pharmacies that accept US prescriptions for not only low-cost insulins but also low-cost GLP-1s. 
  • In a Novo Nordisk symposium on the cardiovascular benefits of GLP-1s, Drs. Marie McDonnell and Jorge Plutzky, both from Brigham and Women’s Hospital, highlighted the powerful risk reduction on a variety of MACE outcomes and offered practical tips for uptitration and safety. In addition to the incorporation of these agents into the latest ADA and EASD guidelines for cardiorenal protection, Dr. Plutzky said that neurologists are beginning to appreciate the benefits of GLP-1s for stroke reduction, citing a 2022 article published in the AHA’s Stroke journal. 
  • In obesity, we were delighted to hear Dr. Robert Eckel’s (University of Colorado) selected key publications from obesity and lifestyle medicine. Of course, his list containing seven articles included the landmark SURMOUNT-1 publication of tirzepatide in people with obesity. Dr. Eckel also highlighted an October 2022 Nature Medicine article showing the relationship between daily step counts and chronic diseases, such as obesity and diabetes. For example, as daily step count increased, the risk of diabetes significantly decreased in a non-linear fashion, reaching a maximum risk reduction at about 8,000-9,000 steps per day. We were also impressed by a case study discussion, in which Dr. Fatima Cody Stanford (Massachusetts General Hospital) presented an especially intriguing weight trajectory of one of her patients to highlight the marked heterogeneity in treatment response to anti-obesity medications.   

The Cardiometabolic Health Congress (CMHC) 2022 Fall Conference featured a terrific third day of learnings that transcended specialties. See the conference website, agenda, and our day-by-day preview for what’s to come, plus our Day #1 Highlights and Day #2 Highlights below. Keep an eye on our CMHC Fall 2022 Resource Hub for all of our conference coverage. 

Table of Contents 

Top Eight Highlights

During an early afternoon session, Dr. Irl Hirsch (University of Washington) took to the stage to tackle the question: “Why should we use CGM in patients with type 2 diabetes?” There continues to be much fanfare surrounding this juncture in diabetes care, as evidenced by the slew of conference sessions at EASD 2022, ADA 2022, and ATTD 2022 dedicated to debates, data readouts, and panels about the role of CGM for a broader population of people with diabetes beyond tech-savvy type 1s. Dr. Hirsch kicked off his presentation by highlighting the value of professional CGM in type 2s, noting that while there are several use cases for professional CGM, he most commonly uses it when he needs to figure out where to “start” with a given patient for whom there might be incomplete or insightful glucose data on file. In these cases, Dr. Hirsch emphasized the value of professional CGM to unveil any discordances between A1c and GMI – calling this area a “major research interest of his.” Diving into data, Dr. Hirsch cited his 2021 paper in DT&T unearthing that 50% of participants (n=641 office encounters) had an A1c-GMI discordance ≥0.5%, and 22% had a discordance ≥1.0%. Given that only 11% of participants had an A1c exactly matching their GMI, Dr. Hirsch emphasized that one cannot rely on just A1c to capture one’s glycemic management, thus making professional CGM an incredibly powerful tool. Additionally, Dr. Hirsch pointed to a paper in the Journal of Diabetes Science and Technology (Simonson et al. 2021) showing that professional CGM has been shown to improve A1c for type 2s (n=68) in primary care, making it clear that continuous monitoring can drive what Dr. Hirsch characterized as a “huge impact” in this patient population. We’ve had the chance to meet this remarkable innovator and we can’t wait to hear Dr. Hirsch discuss the benefits of a technology navigator. Hold on to your hats!

  • Turning to personal CGM, Dr. Hirsch touched on the recent CMS decision to cover CGM for basal-only type 2s. Dr. Hirsch stated that >50% of his insulin-requiring type 2s and >90% of type 1s in his clinic are using a personal CGM. As for why these numbers are strong, Dr. Hirsch cited the importance of Medicaid and Medicare coverage in his state. While CMS formerly only covered CGM for type 2s on MDI, Dr. Hirsch was elated to touch on CMS’s new draft guidelines to cover CGM for basal-only type 2s. Indeed, we learned from Abbott CEO Mr. Robert Ford just this week that this CMS decision will likely be implemented in 2H23 and would expand CGM coverage to 1.5 million additional people with diabetes. Speaking of Abbott, Dr. Hirsch shared that FreeStyle Libre 3 became available as a pharmacy benefit in Seattle “last week.” This is big news for Abbott, given that company reps shared with us in July that a pharmacy launch for FreeStyle Libre 3 wouldn’t fully materialize until November or December. 

While is-CGM has a “level B” grade evidence in the ADA Standards of Care for use in people on MDI, Dr. Hirsch noted that the recent FLASH-UK publication in NEJM will likely mean that is-CGM will receive “level A” evidence come December. As a reminder, Dr. Emma Wilmot presented the FLASH-UK RCT at Diabetes UK 2022 – the study evaluated FreeStyle Libre 2 vs. BGM in people with T1D (n=156). Notably, those with A1cs ≥7.5% spent 2.1 additional hours/day in Range on Libre 2 (52% vs. 45%) and saw a 0.5% lower A1c vs. BGM at six months (7.9% vs. 8.3%). 

  • Additionally, Dr. Hirsch shared that UW is also trying to integrate LibreLink data directly into Epic EHR, just like the International Diabetes Center. As a reminder, the International Diabetes Center (IDC) easily had one of the top CGM-related sessions at ADA 2021, with Dr. Amy Criego (IDC) giving an exciting demonstration of IDC’s successful integration of Abbott LibreView data into Epic EHR. At the time, we could already tell this integration was going to be a big win for healthcare providers at IDC, as they no longer would have to navigate between multiple software platforms when reviewing data for patients using Abbott’s FreeStyle Libre CGM. It’s fantastic from our view to hear from Dr. Hirsch that UW is following in the IDC’s footsteps, especially in light of broader workings within the diabetes field to make CGM-EHR integration a possibility for a greater number of centers across the country.

Excitingly, Dr. Hirsch shared that he intends to submit an abstract to ATTD 2023 investigating the time savings and cost effectiveness of having an in-clinic tech navigator. For background, UW has a “tech navigator” that helps people with diabetes manage their technology – handling anything from data uploads, to sensor initiation and more. The concept of dedicated personnel to manage diabetes technology fascinated us when we first learned of it earlier in the year, given that we had never seen an analogous role at other centers across the US before.

  • Dr. Hirsch concluded with an overview of the non-invasive CGM landscape. While he didn’t necessarily tie this landscape to the role of CGM in type 2 diabetes, he did explain that the “future looks bright” for diabetes technology and noninvasive CGM specifically, given the recent movement from three particular players: (i) Israel-based Cnoga; (ii) Seattle-based Know Labs; and (iii) Israel-based Hagar, where Dr. Hirsch serves as a medical advisor. We appreciated getting to hear Dr. Hirsch speak at length about Hagar’s flagship product GWave at ATTD 2022. During that presentation, Dr. Hirsch shared accuracy data from GWave initial clinical trial (NCT04658082; n=5 with 45 data points each), finding that following a 75-gram oral glucose tolerance test, 98% of GWave readings fell in Zone A compared to BGM while 96% of venous glucose comparators fell in Zone A on the Clarke error grid.

2. Dr. Irl Hirsch dives into challenges for insulin management, highlighting the BeAM score for basal insulin dosing, managing insulin before procedures, and accessing affordable insulin

Dr. Irl Hirsch (University of Washington) said that one of the first things he teaches his fellows is the BeAM score as an essential tool for dosing basal insulin – it seemed to be a score most audiences members had not heard of before. The BeAM score is one’s bedtime glucose levels minus their morning (or AM) glucose levels. He explained that a positive score indicates that mean glucose trends downward overnight, and this may mean the basal dose is too high. Alternative, and far less common, a negative score indicates that mean glucose trends upward overnight and the basal dose may not be sufficient. The ideal BeAM score is zero – no change between bedtime and morning/fasting glucose. Dr. Hirsch added that people with type 2 diabetes, who have endogenous insulin production, will generally have a lower BeAM score than people with type 1 diabetes. He lamented that there is no data on the target BeAM score in type 1 diabetes, but he said from experience a BeAM score <30 mg/dL is preferred in order to minimize fasting hyperglycemia and nocturnal hypoglycemia. In type 2 diabetes, evidence suggests that nocturnal hypoglycemia begins increasingly substantially with BeAM scores >50 mg/dL.  

  • In response to a patient who cannot afford insulin due to a high deductible and high co-pays, Dr. Hirsch suggested three options to access insulin: (i) on-line price reductions programs from insulin manufacturers; (ii) human insulin at Walmart or CVS; and (iii) mail-order insulin from Canada. Dr. Hirsch explained that insulin manufacturers have robust patient assistance programs, but often pharmacists, clinicians, and patients do not about them. They key here is education and time to use these programs. Since Canadian mail-order pharmacies accept US prescriptions, Dr. Hirsch also highlighted mail-order insulin from Canada as an option to receive not only low-cost insulin but also GLP-1s. He noted that not all drugs and doses that are available in the US are available in Canada. Dr. Hirsch also encouraged audience members to support elected representatives and legislation that establishes insulin co-pay caps – currently the Inflation Reduction Act caps monthly insulin co-pays at $35 but only for people on Medicare, which will take effect in 2023. 

Dr. Hirsch recommended not changing insulin degludec dosage prior to a procedure that requires not eating for several hours, depending on the BeAM score. He presented the case of a patient who asked how to manage her insulin degludec prior to an 8 am colonoscopy, and her usual degludec dose is 40 units. When asked how to adjust the patient’s degludec dose the night before her procedure, many audience respondents chose to reduce the dose by 50%, but Dr. Hirsch explained why he would generally not adjust degludec. Since degludec has a 25-hour half-life and takes four to five days to reach steady state, any small adjustment in its dose will take a few days to effect fasting glucose. Dr. Hirsch said that most people with type 2 diabetes can achieve a BeAM score <30 mg/dL, so in most patients with type 2 diabetes he would not adjust the insulin dose. However, people with a high BeAM score and bedtime hyperglycemia may experience hypoglycemia without insulin dose adjustment. Therefore, he further emphasized the importance of using the BeAM score to guide basal insulin titration.   

  • Dr. Hirsch said that there is still a role for prandial insulin in type 2 diabetes, even though GLP-1s are the first recommended injectable therapy followed by basal insulin if needed. He listed several situations that may warrant the use of mealtime insulin: (i) severe insulin deficiency, particularly with long-standing type 2 diabetes or misdiagnosed type 1 diabetes; (ii) inability to tolerate or afford GLP-1s; (iii) pregnancy or planning pregnancy; or (iv) atypical forms of diabetes, such as pancreatic diabetes, steroid diabetes, or monogenic diabetes. 

To increase the speed of insulin absorption, Dr. Hirsch suggested increasing the surface area of the insulin depot by administering multiple smaller insulin injections at different sites instead of one injection. To support this recommendation, he cited a 2013 study in Diabetes Care: “Enhanced Absorption of Insulin Aspart as the Result of a Dispersed Injection Strategy Tested in a Randomized Trial in Type 1 Diabetic Patients.” In this study, insulin aspart with dispersed injections had a quickening of its kinetics – a faster onset of action and a more rapid decline in action – compared to a single injection. Dr. Hirsch said that this technique applies to all insulins.  

3. Novo Nordisk symposium traces cardiovascular benefit of GLP-1s: From the glucose paradox to CVOT evidence to incorporation into ADA/EASD guidelines; greater recognition of stroke benefit among neurologists

In an afternoon symposium sponsored by Novo Nordisk, Drs. Marie McDonnell and Jorge Plutzky (both from Brigham and Women’s Hospital) discussed the cardiovascular benefits of GLP-1s and shared practical tips for initiating these agents. Drs. McDonnell and Plutzky highlighted that GLP-1s are potent glucose lowering agents that have been demonstrated to reduce major adverse cardiovascular events (MACE) across the class. Discussing the 2022 ADA Standards of Care and ADA/EASD consensus report on the management of type 2 diabetes, Dr. McDonnell highlighted that the guidelines now incorporate cardiorenal protection as one of the four key pillars of treatment. In other words, she said cardiorenal protection should be “at least 25% of what HCPs think about” when addressing a patient with diabetes. On the mechanistic side, Dr. Plutzky explained there are multiple sites of action of GLP-1s, including direct effects on the vasculature in the heart, allowing these agents to confer risk reduction across different facets of CVD; he said they can even influence disease states such as obstructive sleep apnea. Ultimately, Dr. Plutzky expressed that the updated ADA and EASD guidelines have ushered in a new era of diabetes management in which providers across different specialties address shared cardiorenalmetabolic endpoints, rather than saying “that’s not my disease” or “that’s not my organ.” 

  • Dr. Plutzky traced the evolving understanding of the cardiovascular benefit conferred by GLP-1s. Specifically, he discussed the glucose paradox, or the finding that tighter glucose control was not shown to reduce CVD risk in studies such as ACCORD, ADVANCE, and VADT. Many possible explanations were ascribed to this finding regarding the trial methods, use of the wrong markers, wrong endpoints, wrong strategies, or wrong agents. Ultimately, this changed with the LEADER trial assessing the cardiovascular safety of liraglutide, which found a significant 13% reduction on the primary endpoint of three-point MACE (non-fatal MI, non-fatal stroke, and CV death) as well as the individual components of this endpoint. Indeed, a 2021 meta-analysis by Sattar et al. across eight trials and ~60,000 patients found a consistent benefit of GLP-1s with a significant 14% risk reduction on MACE. Dr. Plutzky also noted the increasing discussion surrounding the potential kidney benefits of GLP-1s, citing the 22% risk reduction on the composite kidney outcome (macroalbuminuria, doubling of serum creatinine, or ≥40% decline in eGFR, kidney replacement therapy, or death due to kidney disease) in this same meta-analysis. Although this reduction was not statistically significant, Dr. Plutzky said that these reductions on the kidney composite endpoint are clearly trending in the right direction.
    • We were especially intrigued to hear Dr. Plutzky highlight the powerful stroke reduction conferred by GLP-1s. In a 2019 meta-analysis by Kristensen et al., GLP-1s led to a significant 16% relative risk reduction on fatal or non-fatal stroke, which Dr. Plutsky said is very important given that patients are often more worried about stroke than other cardiovascular events. For instance, he said patients often express that someone they know had a stent placed and was discharged that same day, whereas patients are much more fearful of strokes given the often-debilitating consequences on daily living. Indeed, Dr. Plutzky said that neurologists are beginning to appreciate the benefits of GLP-1s for stroke reduction, citing a 2022 article published in the AHA’s Stroke journal, “Benefits of GLP-1 (Glucagon-Like Peptide 1) Receptor Agonists for Stroke Reduction in Type 2 Diabetes: A Call to Action for Neurologists.”
  • Addressing common cautions and concerns regarding GLP-1s, Dr. McDonnell highlighted the importance of careful patient education, screening, and suggested following a “start low, go slow” approach to titration. On safety, she distinguished between real concerns of GI intolerance, gallstone disease, and pancreatitis and not real concerns of thyroid and/or pancreatic cancer. Noting that the overall risk of pancreatitis with GLP-1s is low and is often gallstone mediated, Dr. McDonnell advised screening patients careful to ensure those at uniquely high risk of pancreatitis are not being prescribed a GLP-1. On the not real concern of thyroid cancer, she noted that this was seen in rodents but has not been observed in humans, as there are no GLP-1 receptors in the thyroid beds in humans. Likewise, multiple meta-analyses on prospectively followed patients have shown no increased risk of pancreatic cancer across all GLP-1 agents. Last but certainly not least, Dr. McDonnell touched on cost as a side effect, noting that financial concerns can prevent patients from taking their medications consistently in the same way that unpleasant side effects can also discourage patients from taking GLP-1s consistently. 

4. Dr. Joseph Saseen explores polypharmacy – the unwarranted combinations of medications – and how to reduce it, particularly in older adults with several comorbidities

Dr. Joseph Saseen (University of Colorado) said that combination therapy is vital for cardiometabolic care but it is also important to know when combinations can be unwarranted and harmful. Dr. Saseen defined polypharmacy as the unwarranted combination of medications, driven by both patient and HCP causes. On the patient side, Dr. Saseen highlighted driving factors for polypharmacy as multiple comorbidities, use of multiple providers, hospitalization, patient expectations, reluctance to stop meds, and self-medication with over-the-counter drugs. On the HCP side, Dr. Saseen point toward multiple providers and pharmacies, a lack of regular review of patients’ medication lists, reluctance to discontinue medications, and treating adverse drug reactions with other medications, leading to a prescribing cascade. Importantly, he noted that deprescribing medications is not always appropriate – deprescribing depends on the specific drug and the patients’ individual characteristics. Dr. Saseen shared eight questions to guide the de-prescription decision (see bullet below). To reduce polypharmacy in older adults, Dr. Saseen emphasizing the importance of “treating physiological age instead of numeric age,” eliminating medicines that are part of a prescribing cascade, using combination therapies, considering a topic agent, and evaluating drug-drug interactions. He also directed audience members to the Lown Institute, which has resources and projected dedicated to reducing polypharmacy in older adults, including a National Action Plan for Eliminating Medication Overload published in 2020.    

  • Dr. Saseen presented eight questions to consider to mitigate polypharmacy, and highlighted the concerns older patients have when choosing drugs: 
    • Is this the right drug for this illness? 
    • Is this the right drug for this patient?
    • Is this the right dose for this patient?
    • What is the appropriate duration of therapy? 
    • Is the drug causing the desired therapeutic effect? Is it causing unwanted adverse effects? 
    • Are there deprescribing opportunities? If so, use the American Geriatric Society’s Beers Criteria list of potentially inappropriate medications for older adults. 

5. Panel discussion delves into challenging obesity cases, highlighting the complexity of obesity management and the importance of taking a full weight history

During a discussion on challenging obesity cases, Dr. Fatima Cody Stanford (Massachusetts General Hospital), Dr. Michelle Look (San Diego Sports Medicine and Family Health Center), and CDCES extraordinaire Ms. Amy Hess-Fischl (University of Chicago) presented a range of case studies to illustrate the complexity of obesity management. As the obesity landscape continues to evolve, it’s important to recognize that selecting the correct intervention may not be as simple as expected, particularly given the heterogeneity in treatment response for many anti-obesity medications. Overall, presenters underscored the importance of assessing a patient’s full medication list – both to consider replacing therapies that promote weight gain and to consider optimizing and uptitrating therapies for additional weight loss and risk reduction. Together with Dr. Louis Aronne’s commentary yesterday on the importance of not giving up with obesity pharmacotherapy, this session provided a practical approach to thinking about management in a clinical setting with many take-home pearls. 

  • We were most struck by a case presented by Dr. Stanford, which emphasized the marked heterogeneity in treatment response and the importance of examining a patient’s full weight history. Dr. Stanford introduced the audience to a 57-year-old woman with history of dyslipidemia, breast cancer, hypertension, depression, and pernicious anemia. Despite following a very healthy diet, performing a considerable amount of physical activity, and sleeping eight hours each night, this woman struggled with severe obesity, presenting with an initial BMI of 56 kg/m2. Within a year, her BMI dropped steeply to 33 kg/m2. Showing the graph below without any interventions labeled, Dr. Stanford asked the audience what they thought caused this initial sizeable drop in BMI. Answers included a GLP-1, bariatric surgery, cancer, life changes, and a very low-calorie diet. Surprisingly, this sharp weight loss was caused by phentermine/topiramate (Vivus’ Qsymia), which Dr. Stanford noted exceeded the average 9% weight loss conferred by the 15 mg dose in the initial phase 3 trials. While the field awaits pharmacogenomics for anti-obesity medications, Dr. Stanford emphasized that certain patients respond better to certain treatments. 
    • Following a period of weight regain from 2005-2006, this woman saw another drop in her body weight, this time from Roux-en-Y gastric bypass surgery. While bariatric surgery is typically associated with strong weight loss of 20-30%, this patient did not have a very sizeable response to metabolic surgery, which again illustrates the heterogeneity in treatment response to weight loss interventions. She exhibited a gradual increase in her BMI over the next decade or so, followed by another sharp drop in body weight in 2016, to attain a record low BMI of 29 kg/m2. Dr. Stanford shared that this dramatic weight loss was due to re-starting phentermine/topiramate, which clearly worked very well for this particular patient. In summary, Dr. Stanford said she “didn’t re-invent the wheel” but rather listened thoroughly to the patient’s weight history, saw that phentermine/topiramate was highly effective for her, and re-introduced this therapy.   

 

  • Dr. Look presented a case of a Anne, 25-year-old woman referred to endocrinology for evaluation of elevated blood sugar. This young woman had a BMI of 26 kg/m2, and A1c of 5.6%, and migraines, major depression, and back pain. She had just finished graduate school and had gained 25 lbs over the past five years. In terms of medications, Anne was on medroxyprogesterone acetate injectable, the SSRI paroxetine, and the beta-blocker metoprolol, and also taking acetaminophen due to stress and inability to sleep. As a first step, Dr. Look suggested telling Anne that she has prediabetes, which is affecting her blood sugar and increasing her health risks, and referring her to her PCP to take a weight history. On taking weight history, Drs. Look and Stanford said that patients are often able to identify the reasons for changes in their body weight when they see a graph. Dr. Aronne chimed in, calling this one of the most “flavored cases” he’s seen and urging the provider to re-evaluate her prescription regimen, as all four of the drugs she is taking cause weight gain. In terms of treatment options, Dr. Look recommended a four-pronged approach: (i) consider changing metoprolol to topiramate for migraine prophylaxis; (ii) advise and agree on the benefits of a food and activity tracker; (iii) discuss benefits of metformin for regression to normoglycemia and prevention of type 2 diabetes; and (iv) schedule her for a follow-up appointment or refer back to her PCP to reassess weight loss, comorbidities, and medications. 

Ms. Hess-Fischl presented the case of a 53-year-old Black woman with type 2 diabetes who had been referred for diabetes self-management education and support (DSMES). This patient had an A1c of 8.8% along with hyperlipidemia, hypertension, obstructive sleep apnea, and obesity (BMI 34 kg/m2). Medication wise, this patient was taking a high dose statin, blood pressure medications, an SGLT-2 (started on the lowest dose and never titrated), metformin, and a GLP-1 (lowest dose due to nausea when increased). In terms of where to start with this patient, Dr. Aronne advocated in favor of meal planning as a first step, also noting that her medication doses might not be optimal. Likewise, Dr. Look said that optimization of medications was the first thing that jumped out to her, stating that she would begin with meal-planning but with a short follow-up window, given how young the patient was and her relatively high A1c. Ms. Hess-Fischl also highlighted the value of food recall for this patient to understand her eating patterns and how this might be affecting her health. Lastly, Ms. Hess-Fischl underscored the importance of referring people with diabetes to DSMES at the four critical periods: at diagnosis, annually, when complicating factors arise, and when there are transitions in care and in life.

6. *NEW* Dr. Rajiv Agarwal presents a new post hoc analysis comparing effect of non-steroidal MRA finerenone and steroidal MRA spironolactone on hyperkalemia; finerenone associated with 1/5th the incidence of spironolactone in people with treatment resistant hypertension and CKD

Dr. Rajiv Agarwal (Indiana University) presented results from a soon-to-be published post-hoc analysis comparing results from spironolactone’s AMBER study to finerenone’s FIDELITY pooled analysis of FIGARO-DKD and FIDELIO-DKD. The study is titled “A comparative post hoc analysis of finerenone and spironolactone in resistant hypertension in moderate-to-advanced CKD” and is currently in press. The study aimed to determine the effect of finerenone on systolic blood pressure and serum potassium in people with treatment resistant hypertension and moderate-to-advanced CKD (eGFR between 25 and 45 mL/min/1.73 m2). As background, hyperkalemia is one of the main side effects of concerns for mineralocorticoid receptor antagonists. 295 patients from the phase 2 12-week AMBER study were matched to 624 people in the finerenone program who met the AMBER entry criteria. All patients had baseline potassium between 4.3-5.1 mmol/L. Dr. Agarwal highlighted finerenone’s remarkably lower incidence of hyperkalemia ad hyperkalemia-associated drug discontinuation, compared to spironolactone. Specifically, 12% of participants on finerenone experienced hyperkalemia versus 3% on placebo in FIDELTIY, but in the AMBER trial 64% of participants on spironolactone alone experienced hyperkalemia. Even when spironolactone was combined with a potassium binder, patiromer, 35% of participants experienced hyperkalemia. Furthermore, nearly one in four people on spironolactone stopped medication due to hyperkalemia, whereas only 0.3% of participants in FIDELTY stopped medication due to hyperkalemia. As we have heard repeatedly throughout this conference, the best medication is the medication that patients take, so this difference in treatment persistence has enormous clinical implications. Additionally, finerenone moderately lowered systolic blood pressure in patients with treatment resistant hypertension by 7 mmHg, compared to 1 mmHg on placebo, but spironolactone achieved greater reductions of about 11 mmHg.  Ultimately, Dr. Agarwal emphasized the finerenone is a safe drug to prevent kidney failure and CVD with significantly less hyperkalemia than steroidal MRAs.

  • Dr. Agarwal acknowledged there are clear limitations associated with indirect comparisons across trials, namely different study populations; for instance, AMBER enrolled people with and without diabetes, whereas FIDELTIY only included people with diabetes. Additionally, the finerenone program assessed potassium levels after about four months, whereas AMBER assessed potassium at about three months.
  • Many speakers on the conference circuit have mused about the potential additive benefits of finerenone and SGLT-2 therapy, and the phase 2 CONFIDENCE trial will directly test this. The CONFIDENCE trial, which is expected to complete in January 2024, will investigate finerenone vs. empagliflozin vs. finerenone + empagliflozin on albuminuria over six months in people with CKD and type 2 diabetes. Analyses have suggested that there will be additive benefits. In fact, an August 2022 FIDELITY analysis by Dr. Peter Rossing published in Diabetes Care showed that finerenone’s cardiorenal benefits were observed irrespective of SGLT-2 use, indicating finerenone has beneficial effects on top of SGLT-2 use. Additionally, at CMHC Fall 2021, Dr. Janet McGill (Washington University) reviewed preclinical and clinical data suggesting additive finerenone and SGLT-2 benefits. The use of an SGLT-2 with an MRA may also mitigate MRA-associated hyperkalemia, based on a small RCT presented at EASD 2022, a post-hoc analysis of the EMPEROR-Pooled trial, a post-hoc analysis of the EMPEROR-Preserved trial, and a sub-analysis of CREDENCE.
  • In response to concerns that finerenone is difficult to prescribe, Dr. Agarwal summarized three key points to remember when prescribing finerenone:
    • Do not initiate finerenone in people with eGFR <25 mL/min/1.73 m2.
    • Do not initiate finerenone if serum potassium is >5 mmol/L.
    • Do not stop finerenone use unless serum potassium is >5.5 mmol/L.

If clinicians do this, Dr. Agarwal said, then patients can expect a 1/5th relative risk reduction in dialysis and a slightly greater relative risk reduction for HF hospitalization.

7. *NEW* Dr. George Bakris discusses the potential four pillars of therapy for diabetic kidney disease; recommends non-simultaneous initiation of therapy in DKD

Dr. George Bakris (University of Chicago) highlighted three pillars of cardiorenal risk reduction therapy: RAS blockade (i.e., ACEIs, ARBs, and ARNIs), SGLT-2s, and non-steroidal MRAs. Dr. Bakris suggested that in 2024 GLP-1s will become the fourth pillar of therapy, following the August 2024 completion of semaglutide’s FLOW trial in CKD and diabetes. Though there has been no phase 3 trial for a GLP-1 with a primary kidney outcome, there is plenty of secondary outcome data and post-hoc analyses indicating that GLP-1s provide kidney protection, as Dr. Katherine Tuttle (University of Washington) explained at CMHC Spring 2022. On SGLT-2s, Dr. Bakris emphasized the importance of prescribing the therapy and taking advantage of patient access programs, as less than 10% of patients with type 2 diabetes and CKD receive an SGLT-2. For example, BI/Lilly’s Jardiance has a $10 co-pay card for commercial insured people, and AZ’s Farxiga has a 30-day supply voucher, a program for those without insurance or with Medicare, and a $0 co-pay card for commercially insured people. Dr. Bakris briefly summarized the SGLT-2 trials with renal outcomes, highlighting the renal risk in study cohort (second image below). In doing so, Dr. Bakris emphasized the importance of measuring both GFR and albuminuria to characterize renal risk. As Dr. Bakris mentioned on CMHC Day #2, the latest SGLT-2 trial in CKD, EMPA-KIDNEY, will report out at ASN Kidney Week 2022 on Friday, November 4th at 12:15 pm (in-person and live-streamed) during a high-impact clinical trials session that starts at 10:30 am. Turning to the only available non-steroidal MRA, finerenone, Dr. Bakris explained that finerenone is not interchangeable with steroidal MRAs, spironolactone and eplerenone, due to their different half-lives, metabolites, receptor selectivity, CNS penetration, and structural properties.   

  • In response to a question about acute eGFR dips, Dr. Bakris emphasized that the acute eGFR dip associated with RAAS inhibition, SGLT-2s, and finerenone is normal and doesn’t warrant discontinuation, but he cautioned against simultaneous initiation of the three therapies. As we have heard repeatedly on the conference circuit, and in trial sub-analyses, the acute eGFR dip upon SGLT-2 initiation is not associated with safety events and is a key mechanism by which SGLT-2s provide kidney protection, as Dr. Tuttle explained at AHA 2021. Similarly ACEIs/ARBs are associated with an eGFR dip upon therapy initiation, and finerenone’s FIDELIO-DKD trial in CKD found a similar eGFR drop followed by a reduced rate of eGFR decline (see Figure S6). While the eGFR drop for each therapy is expected, does not indicate acute kidney injury, and does not warrant therapy discontinuation, Dr. Bakris cautioned against simultaneous initiation of the three therapies since that could magnify the acute eGFR drop. For that reason, Dr. Bakris suggested sequentially initiating each of the three therapies to avoid exacerbating the eGFR dip. This recommendation is in contrast to recommendations for the four pillars of HFrEF (heart failure with reduced ejection fraction) therapy, in which commentators have emphasized the value of simultaneous initiation at low doses.

8. Dr. Robert Eckel highlights seven major publications in obesity and lifestyle medicine, including an October 2022 Nature Medicine article identifying the association between daily step counts and obesity, diabetes, hypertension, and other chronic diseases

See a chart of the seven studies that Dr. Robert Eckel (University of Colorado) summarized below. While he was unable to include “Association of step counts over time with the risk of chronic disease in the All of Us Research Program” in his slides, he strongly encouraged audience members to read the paper, as it built on the interesting findings from “Daily Steps and All-Cause Mortality: A Meta-Analysis of 15 International Cohorts.”

Study

Primary Objective

Design

Results

Comments

“Tirzepatide Once Weekly for the Treatment of Obesity” – NEJM

(presented at ADA 2022) 

Examine the efficacy and safety of tirzepatide, a novel glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist in people with obesity

RCT of tirzepatide (5 mg, 10 mg, and 15 mg) vs. placebo for 72 weeks in people with obesity or overweight with ≥1 weight-related comorbidity (n=2,539)

- Substantial and sustained weight reductions

- Up to 23% weight loss on 15 mg dose compared to 2% wight loss with placebo

- 96% of participants on 15 mg achieved ≥5% weight loss, compared to 28% on placebo

- Tirzepatide receives Fast Track designation on October 6, 2022

- Cholecystitis seen in 0.5% of participants on tirzepatide (0% in placebo), a side effect of rapid, substantial weight loss

- Nausea, vomiting, and diarrhea most common side, but mild-to-moderate and transient

“Daily Steps and All-Cause Mortality: A Meta-Analysis of 15 International Cohorts” – Lancet Public Health

Determine the association between the number of steps per day and stepping rate with all-cause mortality

-  Meta-analysis of 15 studies (seven published and eight unpublished) between 1999 and 2018 investigating the effect of daily step count on all-cause mortality in adults

- n=47,471 with 3,031 deaths and median follow-up of 7.1 years (397,837 person-years)

- Unequivocal relationship between increasing steps per day and decrease in all-cause mortality

- Benefit of increasing steps occurs regardless of age and sex

- The findings from this meta-analysis can be used to inform step guidelines for public health promotion of physical activity

- Due to the data being derived from observational studies, causal inferences cannot be made

- All studies in high income countries and participants were volunteers primarily among white populations

 

“Association of Step Counts Over Time with the Risk of Chronic Disease in the All of Us Research Program” – Nature Medicine

Examine the association between physical activity over time and incident chronic disease

- EHR data (n=6,042) from the NIH’s All of Us Resource Programand step count volumes from participants’ Fitbit devices between May 2018 to April 2021

- Higher daily step counts were associated with reduced risk of several common, chronic diseases, including diabetes, hypertension, GERD, MDD, obesity and sleep apnea

- Step intensity was significantly associated with the above incident diseases

- Provides real-world evidence for clinical guidance regarding activity levels that are necessary to reduce disease risk

- These results imply the ability for clinicians to give anticipatory physical activity guidelines

 

“Association of Bariatric Surgery with Cancer Risk and Mortality in Adults With Obesity” - JAMA

Investigate whether bariatric surgery is associated with lower cancer risk and mortality in patients with obesity

- Matched cohort study with adults with a BMI ≥35 kg/m2 who underwent bariatric surgery in the US between 2004 and 2017

- Matched 1:5 with patients who did not undergo surgery for their obesity (n=30,318)

- 17% relative risk reduction (RRR) in overall cancer incidence

- 32% RRR in obesity related cancers, defined as esophageal adenocarcinoma, renal cell carcinoma, cancers of the colon, rectum, pancreas, ovary, and endometrium

- 48% reduction in cancer related mortality over 10 years

- Among adults with obesity, bariatric surgery compared with no surgery was associated with a significantly lower incidence of obesity-associated cancer and cancer-related mortality

- Women and men demonstrated similar results, and age, BMI, race, and diabetes medication were not significant factors

 

“Calorie Restriction with or without Time-Restricted Eating in Weight Loss” - NEJM

Investigate the long-term efficacy and safety of time-restricted eating for weight loss

-  RCT in Chinese subjects with obesity randomized to time-restricted eating (eating only between 8 am and 4 pm) with calorie restriction or daily calorie restriction alone

- No substantial differences between the groups in the number of adverse events

- No difference in reduction in body weight, body fat, or metabolic risk factors than daily calorie restriction

- These findings cannot be generalized to patients with diabetes or CVD, to different periods of time-restricted eating, or to persons of other races or ethnic groups

- Physical activity was not controlled

“Effect of Sleep Extension on Objectively Assessed Energy Intake Among Adults with Overweight in Real-life Settings”– JAMA Internal Medicine

Determine the effects of a sleep extension intervention on energy intake, energy expenditure, and body weight in a real-life setting among adults with overweight who habitually curtailed their sleep duration

- Single-center RCT from 2014 to 2020 (n=80)

- Habitual sleep duration <6.4 hours per night

- Patients analyzed over a 28-day period

- Sleep extension reduced energy intake and resulted in a negative energy balance in a real-life setting (i.e., individuals ate less when they slept more)

- Improving and maintaining healthy sleep duration over long periods could be part of obesity prevention and weight loss programs

“Assessment of Calories Purchased After Calorie Labeling of Prepared Foods in a Large Supermarket Chain” – JAMA Internal Medicine

Determine if calorie labeling of prepared foods in supermarkets was associated with changes in calories purchased from prepared foods and potential packaged substances

- Controlled interrupted time series comparing sales two years before labeling implementation with sales seven months after labeling implementation (n=173 supermarkets)

- Analyzed weekly calories per transaction purchased from prepared foods

- Reduction in sales for packaged and control items

- Decrease in calories purchased from prepared bakery and deli items seven months after labeling implementation

- Results indicate that calorie labeling in supermarket chains was associated with small to moderate decreases in calories purchased

- May lead to population-level health benefits if calorie labelling translates to similar changes in food consumption

 

 

-- Ethan Litmans, April Hopcroft, Armaan Nallicheri, Ashwin Chetty, and Kelly Close