April 24-27, 2019; Los Angeles, CA; Day #4 Highlights – Draft

Hello from the final day of AACE 2019! This highlights report contains our top five highlights from the last day of the meeting –including a table breaking down the top technology posters – and don’t miss our highlights from day #1, day #2, and day #3.

AACE 2019 Day #3 Highlights - Dr. Mende hypothesizes renoprotection with GLP-1, DPP-4; FreeStyle Libre product theater; Exhibit hall coverage of 10 tech + 13 therapy companies

AACE 2019 Day #2 Highlights - Insulet Dash “several weeks in” to pharmacy launch; Glycemic benefits of early CGM use in T1D, and Dr. Argento’s CGM tips; Dr. Bode optimistic about DKA management with SGLTs in type 1

AACE 2019 Day #1 Highlights - Insulet Dash Omnipod pharmacy launch under way; Dr. Grunberger’s practicum on barriers to diabetes tech clinic implementation; Dr. Handelsman calls for HF prevention

Top Six Highlights

1. “The Great Debate”: AACE (Dr. Handelsman) vs. ADA (Dr. D’Alessio) Guidelines. Duke it Out Over A1c Targets, Inclusion of Cost as a Factor (Including Analog Insulins/SMBG in T2D), Combination vs. Step Therapy, +++; Numerous Predictions (Low-Cost CGM, Analog Insulins, DM Sub-types)

Dr. George Grunberger presided over a fascinating debate – “the great debate” – over type 2 treatment guidance (algorithms/guidelines) from ADA and AACE. Arguing on behalf of the ADA was Duke’s Dr. David D’Alessio, and in AACE’s corner stood former AACE President and Metabolic Institute of America’s Dr. Yehuda Handelsman. As Dr. D’Alessio pointed out at the very beginning of his talk, the two organizations’ documents really have a lot in common, and differences will be “points of nuance and quantitative nuances.” Over the course of two hours, these nuances came down to A1c targets (ADA’s <7.0% vs. AACE’s ≤6.5%, as a general goal), the inclusion of cost as an important factor in guidance, “comprehensive” vs. glucocentric guidelines, early combination therapy vs. step therapy, the role of guidance (should they be evidence-based or expert algorithms?), and the importance of rapidly reaching targets. Attendees seemed to thoroughly enjoy (and engage with) the session, and we hope to see much more focus on harmonization of recommendations; but not before Dr. D’Alessio gets the chance to debate an ACP delegate on A1c guidelines at ADA (check out a similar debate from ENDO 2019)! Dr. D’Alessio also put a nice bow on the dialogue: “There are lots of guidelines, but at the end of the day, there’s no substitute for being a good doctor, clinical intuition, meeting the patient where they are, and identifying the type of diabetes patient you have in front of you. There’s no substitute for honest-to-god clinical skill.” This was a fantastic session, and we had three notes / perspectives to share: (i) A more head-to-head style debate could’ve led to better discussion; (ii) the session was surprisingly poorly attended; and (iii) there was no discussion at all about harmonizing guidelines, which we think is unfortunate (though it also probably is easier said than done). However, both Dr. D’Alessio and Dr. Handelsman highlighted the similarities between the two societies, including that both have three goals for A1c and both endorse combination therapy if A1c is 1.5% above goal.

• ADA/EASD guides for a target A1c ≤7.0%, while AACE recommends targeting ≤6.5%. Neither debater seemed to stick too firmly to his organization’s guns, with Dr. Handelsman concluding that “we’re splitting hairs, it’d be impossible to show an outcomes difference between the two targets. If I tell you the majority of patients should be 6.5%, and ADA says 6.9%, I’ll buy 6.7%, that’s ok as long as they don’t progress [to complications].” Dr. D’Alessio also suggested that conducting a trial to parse the difference in microvascular outcomes between the two targets would be wholly unfeasible from a time and cost perspective – in our view, there are other reasons such a trial may be valuable, such as to assess the impact on outcomes of Time in Range or glucose variability, but we concede it would not be easy to fund. Citing ADVANCE – where the intensive group (final mean A1c ~6.5%) had a 14% relative risk reduction (2% absolute) for renal disease vs. the standard care group (final mean A1c ~7.3%) – he added that a group of experts would likely be divided on the question of whether further lowering A1c was worth additional medications, side effects (including 3x hypoglycemia in ADVANCE), and cost. “The data is real, but not compelling.” We point out that ADVANCE was ages ago, and hypoglcyemia is easier to address today with the right tools (we doubt anything close to 3x would be seen if optimal tools were used) and that a lower A1c would not have to come from medications only.

• With that primary agreement in mind, both speakers did share some rationale behind their respective targets. Dr. D’Alessio argued that 7.0% is a good target because: (i) intervention studies (DCCT and UKPDS, “incomplete” data sets as they may be) suggest that targeting A1c of ≤7.0% results in lower complication incidence; (ii) pulling again from DCCT/UKPDS, A1c ≤7.0% is “safely on the flat part” of the curvilinear A1c vs. microvascular disease curve; (iii) f0r many patients, A1c ≤7.0% is achievable with one or two oral agents; and (iv) for insulin-requiring patients, a 7.0% A1c “stays at the edge of the [severe] hypoglycemia inflection point of the DCCT.” Looking at the curve, however, Dr. D’Alessio noted that perception of whether 6.5% is worse than 7.0% in terms of hypoglycemia is “sort of a matter of what you had for dinner last night and which side of the bed you woke up on.” (We agree and also point out that there are many other ways of avoiding severe hypoglcyemia – it’s a real risk, but we’re hoping most clinicians are not using the DCCT curves to assess risk.)

• In the one case study of the session, Dr. D’Alessio gave a nod to practicality, saying that he is happy with a 55 year-old type 2 getting down to an A1c of 6.8% on metformin and pioglitazone, and that distinction is the crux of the target debate; more pharmacotherapy would add cost (and reimbursement fights), side effects, and diminishing glycemic returns (we aren’t sure about this point as we had thought there was no lower threshold of benefit). On the other side, Dr. Handelsman stressed repeatedly the importance of lowering glucose early and keeping it down in order to prevent both microvascular and macrovascular complications. CHF risk, he said, rises as A1c climbs from 5.5% to 6.5%, and then levels off, and 70% of beta cell mass is already dead at an A1c of 6.5%. One of his most compelling arguments for 6.5% came in the form of ACCORD commentary, where he made the point that A1c goal is not equal to intensive treatment: “We saw that in ACCORD, we tried to get people to lower goals. Then in the intensive therapy arm, all of a sudden, 50 of them died, so they stopped the trial. The conclusion was that an A1c of 6.5% was too low. But those were not the people who died! The people who died were those who couldn’t get their A1c below 7%, so they started to bombard them with more insulin, 7 injections per day, 14 medications, just to get them to goal. But on the day that the intensive group was stopped, there was already a 10.5% reduction in non-fatal MI.” This was an important point in our view – ACCORD has long been misunderstood.

• ADA/EASD’s guideline includes specific recommendations for patients in which cost is a major issue; AACE’s does not, and includes a line saying that “safety and efficacy should be given higher priority than medication acquisition cost.” The reality of this will be very challenging for any patient watching their expenses carefully. Dr. D’Alessio called the “cost is a major issue” column “Diabetes treatment for the have-nots – and that’s the bulk of people worldwide, not a small amount of people in US. Those lining up for patient assistance programs are no longer just homeless people, now there are also lots on Medicare.” Again, there wasn’t actually much friction here: Dr. D’Alessio referred to acquisition cost as the “ultimate arbiter of what you can do” and shared that his clinic calls out of pocket cost per month the fifth vital sign, and Dr. Handelsman agreed that AACE “needs to look at the way the phrase about cost was written, as the intent was to examine the total cost of the disease, including hypoglycemia, emergency room visits, etc. when using less expensive medications causing hypoglycemia.” The line referenced by Dr. D’Alessio was intended to drive providers to look at the total cost of disease (hypo, ER visits, aka considering the cost of not giving a patient a certain medication). Dr. D’Alessio also quoted a startling health economics statistic from UCLA: 20% of Medicare beneficiaries spend >20% of their disposable income on pills – “no wonder people skip, scrimp, and save medications. But what we see is poor diabetes control.” Despite acknowledging that cost is an unfortunate but important issue, Dr. Handelsman still pushed back a little on the idea that it should be hardwired into a guideline. He pointed out that the ADA/EASD approach to managing the ~20% of patients with type 2 and established CVD became obsolete practically when it was published, as (i) DECLARE results were released shortly after; (ii) the updated EMA label for Invokana allows the potential for primary prevention with canagliflozin; and (iii) topline REWIND results for Trulicity were published. In Dr. Handelsman’s interpretation, all patients with DM regardless of A1C should be on either a GLP-1 or an SGLT-2. He also reminded the audience that GLP-1s (liraglutide), DPP-4 (sitagliptin), and SGLT-2s (dapaglflozin) are all going generic in the next few years, Hence their position in the guidelines shouldn’t change because the science isn’t changing. The AACE recommendations are not “hard directives” but rather a point of negotiation that should incorporate the shared decision between the physician and the patient, the availability of the medications on the patients formulary, etc. As an example of where factoring cost in goes wrong, Dr. Handelsman noted that Amgen slashed the cost of PCSK9 inhibitor Repatha by 60% just a month after ACC published lipid guidelines, flipping the recommendation on its head. In fact, Dr. Handelsman predicts that soon, “every person with diabetes will have to be on either GLP-1 or SGLT-2 regardless of glucose level. And for people with diabetes and CKD (eGFR 15-60), canagliflozin should be added regardless of glucose level. ” Sticking on the theme of cost, Dr. D’Alessio had specific thoughts on the use of SMBG in non-intensively managed type 2s and analog insulin in type 2s (whose physiology doesn’t resemble type 1):

  • Dr. D’Alessio laid out his SMBG use case, which, for such a small piece of the session, precipitated a hefty amount of debate during Q&A:  (i) SMBG is essential for type 1s and type 2s on adjustable insulin regimens; (ii) SMBG is useful to titrate basal insulin; (iii) but it’s expensive, costing the $10 billion per year in the US (“test strips are a goldmine for someone” – our model doesn’t have the aggregate at anything close to $10 billion though we acknowledge there are many companies now impossible to track); (iv) No evidence that SMBG affects adherence (“compliance” was the word used), glucose control, or patient satisfaction in type 2s on orals (see UNC’s study; “I think it’s a complete waste of time” – we believe there is a lot of diverse thought on this depending on the patients); and (v) “There’s little evidence that CGM has a meaningful impact in most patients with type 2 diabetes. Those that look like type 1 are probably going to benefit. We need more data before we start hanging these on everyone, which will make $10 billion per year look fairly trivial.” (We’d note that no one is suggesting “hanging CGM on everyone” and we’re not sure of the value of these commnets.) During Q&A, Dr. D’Alessio’s opinions proved controversial: Dr. Grunberger noted that structured CGM in type 2s is effective (we would reference the SMBG study, showing benefit); a GP in the audience shared that having his non-insulin type 2s assess whether their blood glucose is >140 mg/dl two hours post-meal, and not eating that meal again if the answer is ‘yes,’ is a very effective strategy; and Dr. Handelsman predicted that within “three years or so” there will be very inexpensive, disposable CGMs that will cost $30-$50 (presumably per month).

  • Dr. D’Alessio: “Who should get analog insulins? Type 1s and type 2s that look like type 1s. If you’re taking a unit per kg, really? I’m giving you a bolus of 35 units of Humalog before a meal and you think we’ll really see that sharp up and down PK? I don’t think so.” Citing decade-old meta-analyses from Mannucci et al. (rapid-acting analogs vs. Human R insulin in type 2s) and Monami et al. (basal analogs vs. Human N insulin in type 2s), Dr. D’Alessio noted that there is no difference in efficacy between basal analogs and NPH, and ~0.4% A1c advantage between prandial analogs and regular insulin. “But the cost difference is enormous.” We’ve heard similar arguments from the likes of Dr. Irl Hirsch. As for mealtime insulin, Dr. D’Alessio believes that the basal-bolus theory, the notion that we should dose insulin in type 2 like we do in type 1 in an effort to mimic physiology, is “probably a little wrong, at least for some patients – those with high BMI and insulin resistance, basal-bolus is not entirely necessary.” Dr. Handelsman doesn’t think analog will remain expensive, but the solution won’t necessarily be related to legislation: “10 years ago, someone from an insulin company asked me how to sell more rapid-acting analog. I told them to stop making Regular insulin, the analog will be cheaper, and then give it to everyone. Commercially, long-term, this makes more sense – it’ll happen, maybe in 2-3 years. It costs the same to manufacture.” We had not heard before that it costs the same to manufacture and are doing some checks on this.

• AACE advocates for early combination therapy, while ADA/EASD recommends sequential therapy. Dr. D’Alessio made the case for step-wise therapy: (i) You reduce drug exposure; (ii) it’s simpler and easier to evaluate efficacy and side effects; and (iii) there’s little evidence that lowering glycemia rapidly is important (see below). That stands, of course, so long as the patient doesn’t have an A1c ≥8.5% and isn’t catabolic, in which case insulin or combination therapy would be recommended right off the bat. Dr. Handelsman pointed out that the ADA/EASD guidelines advise combination therapy for patients with A1c 1.5% above goal and largely agreed with this approach, stating that he likes combination therapy early on (if a patient can afford it), but clinicians ought to “manage the patient the way they want, whether that’s combination or sequential, it’s what you do.” We note that many US patients would rather have one co-pay and perceive combination therapy as less hassle overall, particularly given better outcomes with combo therapy. To back up the general ADA/EASD position against early combo therapy, Dr. D’Alessio referenced Henry et al. (dapagliflozin plus metformin vs. dapagliflozin monotherapy vs. metformin monotherapy), in which the combination resulted in a ~2% A1c drop, while metformin alone was -1.4% and dapagliflozin alone was -1.2% – he seemed to be making the point that if baseline A1c is <8.5%, then monotherapy will be plenty potent to bring A1c near 7.0%. He also cited two-year data from the UT EDICT study comparing metformin/pioglitazone/exenatide triple therapy to an escalating dose of metformin followed by sequential addition of sulfonylurea and glargine insulin in patients with baseline A1c 8.6%. Three-year data is currently under analysis, but at two years, Dr. D’Alessio noted that both groups did extremely well: mean A1c in the combination and sequential therapy groups dropped to 5.8% and 6.2%, respectively. Dr. D’Alessio did critique the study for testing two different medication regimens (not isolating combo vs. step), for being unblinded, for having a fairly high ~30% dropout rate, and for measuring A1c, rather than microvascular outcomes. We’d add that clinical trial results where patients receive extensive attention from HCPs are not the same as “real life,” where this is unusual.

• AACE stresses the importance of rapidly bringing a patient to goal A1c, while ADA/EASD does not. Dr. Handelsman pointed out that in the EPIC-Norfolk study, the higher an A1c, the higher risk they have for all-cause mortality; and, as shown in EDICT, early intensive treatment results in sustained A1c goal achievement, suggesting that it may be more difficult to sustain a lower A1c if it takes longer to reach. Dr. D’Alessio endorses the exact opposite philosophy: “My view is slow and steady wins this race. I think there are some therapeutic advantages to approaching glycemic control not all at once, but steady.” He alluded to a fascinating DCCT post-hoc analysis, which showed that A1c two to three years prior had the greatest relative risk contribution to current progression of retinopathy; thus, microvascular complications develop over time, and a slower approach to A1c-lowering is appropriate. 

• ADA/EASD’s guideline limits scope to glucose-lowering, while AACE’s aims to be more comprehensive and treat comorbidities and other risk factors. In AACE’s and Dr. Handelsman’s view, it’s important to include, front and center, other metabolic risk factors in guidelines. He pointed to the STENO-2 trial, where treating LDL-C, blood pressure, and A1c reduced CV events and mortality significantly. This effect held despite only 8% of participants reaching A1c goal, since all three CV risk factors improved in everyone. “The more risk factors we reduce, the more we reduce morbidity and mortality.”  Of course, ADA wouldn’t argue that CV risk factors beyond glycemia are unimportant, and they are included in the Association’s Standards of Care. However, Dr. Handelsman asked “who reads that document?” “It’s a very good document, supports a lot of what AACE is saying, but who is reading it? Probably 20 people at pharmaceutical companies, and two people who will be writing the next guideline. It’s buried.” We note that Close Concerns reads the Standards of Care in lots of depth and we believe many others do as well, though extra translation is always needed.  

• Accepting that it’ll never be possible to conduct RCTs for every therapy permutation in every type of patient, part of the debate centered on the utility of evidence-based guidelines (ADA/EASD vs. expert-consensus algorithms (AACE). In his introduction, Dr. Grunberger took the first shot at ADA/EASD, suggesting that they didn’t have the “guts” to rank drugs like AACE did – “if you needed help, ADA’s table will tell you we don’t know what we’re doing.” Dr. D’Alessio retorted later (amicably) that the decision to not rank medications was “either honesty due to a lack of evidence, or more likely that there were strong opinions in the room, and consensus was euphemistic only, as no one was willing to give up their favorite.”

• Both sides agreed on the first-line use of metformin for treatment of type 2 diabetes. Said Dr. Handelsman, “Metformin should be the first choice. There’s no reason not to do it. We still need to manage hyperglycemia, not only heart attacks. Let’s not fall into the world cardiologists want to take us. I’ve seen cardiologists who want to stop insulin in all patients regardless.” Dr. D’Alessio shared that there was a lot of debate among the ADA/EASD writing group regarding whether or not metformin should be grandfathered in for another round, but there ended up being consensus that it should be. Why? (i) It has a long history of use, lots of data, and is safe; (ii) it’s effective at lowering blood glucose (citing early 1990s work from DeFronzo, when it induced A1c drops of 1.3%-1.4% and ~2% in people with baseline A1cs of 8.7% and 9%, respectively); (iii) it has a well-known side effect profile (while we agree with this for many doctors, we have heard from many HCPs and patients about dosing challenges); (iv) it proved beneficial in the UKPDS sub-study (“I’m convinced of benefit in new onset patients”); (v) It’s inexpensive (rather, “dirt cheap”); (vi) and it has actually been tested as a first line therapy, unlike some other therapies.

• Dr. Handelsman wasn’t the only one who made predictions about diabetes care in the future. Said Dr. D’Alessio on type 2 subtypes: “When we meet in 2025, we’ll look back in some amusement that we talk about type 1 and type 2 diabetes. Like the way we look at adult and juvenile diabetes today. There’s been a lot of work to sub-stratify – and it’s very clear that patients are not all cut from same cloth, and that lumping all into ‘type 2 diabetes’ is probably specious. We’ll have better biomarkers, better stratification, and then we’ll say that different types of type 2 diabetes need different therapies and have different tolerances of different A1c levels. I think that’ll happen.”

Selected Questions and Answers

Q: Cost should be calculated as whole, not just for the drug. And for SMBG in type 2 diabetes with orals, I have very beneficial experience. I told patients that testing is not to increase the dose of insulin, but just to do two hours after a meal – if the value is above 140 mg/dl, then tomorrow don’t eat the same meal. We actually achieve control with most patients. Regarding stepwise treatment, ADA says do it. But if your A1c is 8.5%, use two drugs? Contradiction! Also, all guidelines in the states said three months, intervention, three months, intervention, repeat until you get to target. That can take 1.5 years! The Canadians are conservative – they recommend reaching target within 6-8 months even if that means you change treatment every day. The faster the better. ADA, for first time this year, added a recommendation for metformin for prediabetes. Prediabetes is an A1c 6.4%, metformin will reduce A1c to a lesser extent. But still: Faster, better, lower, better, earlier, better is the landmark for cardiovascular disease.

Dr. D’Alessio: The cost thing, that’s been my high horse. When I talk about cost, there’s cost to the system, and that’s what you’re talking about. Things like bariatric surgery, keeping people out of ER, that’s cost-effective. As specialists, we have a responsibility to lend our expertise to policy. It’s a zero-sum game in resources in medicine. On other hand, when I sit across the table from a patient, I can’t be making policy decisions. I need to do my utmost to take care of that patient. If GLP-1 is the best drug and he wants to do it, I don’t care, I’ll give it to him. Cost issues for me are concerned with what can a person afford today. If I give him an expensive regimen and he can’t make rent…these aren’t extremes anymore, this is the reality of the US in the 21^st century. A lot of people are making hard choices. Say you hit the donut hole, you’re on expensive drugs, looks like your grandkids don’t get Christmas presents this year. You can’t ethically cut costs for policy reasons, nor can you burden patient with more cost that’ll make their health worse.

Dr. Handelsman: I agree with your monitoring point – a majority of type 2 diabetes patients, they’re told every morning to check their glucose, and surprise, they’re always in range. That’s a waste of money, and it doesn’t change how we manage diabetes. You at least give them a nice way to do it. A majority of patients won’t do it after a meal. I do predict that within three years or so there will be very inexpensive CGMs that will cost $30-$50 [per month], that you put on and are disposable, so you can see the effect of what you eat all the time. In parts of Europe, Israel I know for a fact, they’re already using it for weight loss.

The most important thing – I like combination therapy early on. I put patients on a combo early on. I like that metformin is cheap, a TZD, GLP-1, maybe SGLT-2, costs a lot per month. Before I write prescription, need to know that the patient is willing to pay that instead of driving a Mercedes. That’s very important. I agree an SU shouldn’t be given when the patient has a lower A1c, unless we have to, because hyperglycemia not good. We agree.

Q: I actually was a bit surprised about the decreased need for SMBG where ADA does not want to move SUs from its location, and also recommends N and R old insulins, as the PD are so unpredictable from patient to patient. And for SMBG, the solution I found is to use a euglycemic agent, and after 6 months tell them to check blood glucose 2-3x per week to make sure there’s no major drop in blood glucose.

Dr. D’Alessio: The SMBG data is no hearsay. There was a beautiful trial conducted at UNC. In type 2s not on insulin, SMBG had no impact on glycemic control or patient satisfaction. I have some patients who insist that day doesn’t start until they stick their finger and have a cup of coffee, and I don’t fight with ‘em. But on fixed doses of oral agents, I tell them they can save their fingers. There’s no question that the biggest unknown in diabetes is, when you stick a needle in your skin and give insulin, the unpredictability and variability of response, it’s shocking how different it is. I’m not sure there’s that much of a difference between regular and analog insulin. I In recent studies, you see more nocturnal hypoglycemia with NPH and glargine than with degludec. With glargine vs. degludec, the difference is small, on the order of 0.5 events per 100 patients per year. If you’re that 0.5 of a guy, that’s a bad night, but it’s not like the hypoglycemia we see with type 1 or the type 2s that look like type 1s (older men on the leaner side).

Dr. Grunberger: I think SMBG is important. If the reading is actionable, there’s discussion, learning, and teaching, that’s a different story. Mindless monitoring doesn’t make a difference.

Q: I find it interesting that the first three people at the mic talked about SMBG, which was not a hyper-focus of your talks. I too want to make the point that postprandial monitoring is important for patients, and also really important for doctors. But also, what does the doctor do with it? By three months they make a treatment decision, but it doesn’t take that long to make a decision! More doctors should download data! CGM is useful, it’s a great teaching tool if the doctor uses the data. Within four to six weeks of a new medication, except maybe TZDs, you can tell if someone is responding. In a recent study, it took two to three years for doctors to start a second pill, two to three years before a third pill, and seven years before getting to insulin. Acceleration of data, understanding, communicating the data, then making changes without dragging feet should be done much more quickly.

Q: One important thing we’re not taught in a fellowship program is how to engage patients to intrinsically motivate. Use of actionable SMBG has to do not just with whether they change a medication but whether they understand cause and effect. CGM and SMBG, when they start getting idea that interval matters, getting those a-ha moments, are unbelievably impactful. And as for cost-benefit – as someone starting to work for Optum in case management, we have to start lobbying as physician organizations, saying to pharma and payers that we have to look at global costs. Yes, we’re using ridiculously overpriced molecules, but that reduces the global cost overall. I think we should be more effective lobbyists as an organization. Being silent is being complicit.

Dr. Grunberger: There’s a misconception that AACE is pushing expensive drugs. A better way to look at it, is what would it cost if you didn’t treat those patients with these drugs?

Q: I don’t see any mention of time-in-range or glycemic variability, and I think that’s an important thing to be mentioned now, especially with CGMs. Maybe we should implement something in the future regarding time-in-range and glycemic variability recommendations, especially for type 1 and insulin-requiring type 2 diabetes. (Editor’s note – presumably this would result in more therapies being prescribed.)

Dr. Grunberger: It’s coming. In San Francisco [at ADA], guidelines will be presented in an ADA-accepted abstract.

Dr. D’Alessio: A1c is what we have, but it is the one thing we have that’s linked to outcomes. I agree, it’d be really nice to have things where we didn’t have to wait three months. Part of the slow pace of diabetes management is limited by A1c. (Note – Time in Range has also been validated as an outcomes measure.)

Q: I did encounter many cases where in newly diagnosed diabetes, people are motivated, they want to get good control. In those cases, metformin alone with lifestyle can get A1c in target, even if A1c is above 8.5%. Yes, those patients at the end of the day, a year or two later, will need another agent, but at least at the beginning, we can save them the burden and cost of taking another drug. I have an issue considering dual therapy when A1c is above 8.5%. I’m not sure we have the data showing that the legacy effect changes significantly if we wait three months.

Dr. D’Alessio: There are lots of guidelines, but at the end of the day, there’s no substitute for being a good doctor, clinical intuition, meeting the patient where they are, and identifying the type of diabetes patient you have in front of you. There’s no substitute for honest-to-god clinical skill.

2. CANVAS Post-Hoc Suggests Tempered Benefit on Stroke, Hospitalization for Heart Failure in Those Taking Metformin at Baseline, in Line with Trends from EMPA-REG OUTCOME

A post-hoc analysis of the CANVAS CVOT for J&J’s SGLT-2 inhibitor Invokana (canagliflozin) revealed that benefit on fatal/nonfatal stroke as well as hospitalization for heart failure may be greater in those not on metformin at baseline (n=2,317) compared to those taking metformin (n=7,825). The p-values for heterogeneity below 0.05 seen below indicate a significant difference between the metformin and non-metformin groups. However, consistent effects between groups were observed for MI, CV death, the renal composite outcome, and all-cause mortality (p-heterogeneity >0.3 for all).

When combined in a meta-analysis with the corresponding data for EMPA-REG OUTCOME (the CVOT for Lilly/BI’s Jardiance – see trial appendix starting on page 47), a similar effect was observed. While both groups trended toward benefit, there were “borderline” significant differences between the metformin and no metformin groups, with those not on metformin at baseline seeing greater benefit on three-point MACE and hospitalization for heart failure.

Because this is a post-hoc analysis, it certainly can’t be concluded that cardioprotection with SGLT-2 inhibitors differs based on metformin therapy; neither CANVAS nor EMPA-REG OUTCOME was designed or powered to test this question. Indeed, the poster authors note that participants not on metformin at baseline were more likely to be older, have a longer duration of diabetes, a history of micro- or macrovascular complications, and reduced kidney function (p<0.0001 for all) – are these effects a true interaction or a function of factors in the group less likely to be on metformin? One possibility is that metformin itself is cardioprotective, thereby tempering additional cardioprotection conferred by novel agents. As we heard on day one of AACE from Dr. Dan Einhorn, metformin has “likely” CV benefit based on a reduction in left ventricular mass observed in the MET-REMODEL study, hopefully to be confirmed by the VA-IMPACT trial, an 8,000-participant CVOT of metformin in people with prediabetes and atherosclerotic CVD. On balance, however, many are hesitant to embrace metformin as a cardioprotective agent without evidence from a large-scale trial in-hand.

3. Dr. Daniel Einhorn Extolls Low-Cost, Intermittent CGM in Type 2 Diabetes and Prediabetes: “If It’s Worth Getting an A1c … It’s Worth Getting a CGM”

In a practical session on intermittent, blinded CGM in type 2, Dr. Daniel Einhorn characterized the Abbott FreeStyle Libre Pro as a low-cost ($46 for a two-week sensor in his clinic), low-risk option for both patients and clinicians to identify and correct problematic highs and lows. Dr. Einhorn uses the Libre Pro often – from diagnosing prediabetes to convincing patients they could benefit from insulin – as it makes blood glucose patterns visible and is less abstract than an A1c (and for a similar price-tag). In his words: “If it’s worth getting an A1c, by and large it’s worth getting a CGM.” Through a series of 12 case studies, he demonstrated how he uses the technology to reveal poor prandial insulin timing, nocturnal hypoglycemia caused by sulfonylureas, inaccurate SMBG test strips, and many other teachable moments for patients, though he repeatedly underscored that just seeing the data is often enough to prompt lifestyle change and improve time-in-range. Based on how the patient responds, Dr. Einhorn will then repeat the CGM exercise once or twice each year to reinforce habits and monitor progress – a similar practice to that envisioned by Abbott’s Mr. Joel Goldsmith (4x/year) as the future of diabetes management.

• Speaking to a room of clinicians, Dr. Einhorn gave reimbursement data for CGM onboarding and data interpretation in his Southern California clinic. For onboarding (CPT code 95250), he bills $244 and receives a mean reimbursement of $150 (range $0-$185; ~62%). For data interpretation (CPT code 95251), he bills $100 and receives a mean reimbursement of $80 (~80%). All in all, “not a lot of money, but not a lot to lose.” A testament to the variability of billing and reimbursement, Dr. George Grunberger shared on AACE 2019 Day #1 that his Michigan clinic bills $275 for a 95250 (receiving an average of ~$119) and $85 for a 95251 (receiving an average of $36). Worth noting, both named Blue Cross Blue Shield as a particularly difficult insurer.

4. Dr. Pratley: Limited Evidence for and Many Barriers Preventing Establishment of Optimal A1c Targets for Older Adults; Key is Personalization

Dr. Richard Pratley (Translational Research Institute for Metabolism and Diabetes) pushed back against the idea of a single glycemic target in older populations, advocating instead for individualized goals: “The evidence we have for optimal A1c an older people with diabetes is largely observational. It suggests an A1c of ~6%-8% is probably optimal, but we really need to personalize therapy.” Individualization is the explicit asterisk on all A1c target recommendations in every guideline and age group, Dr. Pratley explained that it’s especially important in older patients, who have: variable life expectancies, clinical heterogeneity, and functional heterogeneity. In addition, there is limited Grade A evidence for targets since older patients have been excluded from large RCTs (but CVOT evidence is starting to fill gaps – he pointed to a 2018 LEADER post hoc analysis showing that liraglutide’s CV-protective effects were more potent in adults >75 years old vs. those <75 years old). So, goals should be individualized based on the patient: diabetes duration, age/life expectancy, comorbidities, presence of CVD or advanced microvascular complications, hypoglycemia unawareness, and other considerations. Dr. Pratley shared a case to illustrate why a one-size-fits-all approach may not be optimal. An 89-year-old former Navy captain had an A1c <6.5%, so Dr. Pratley tried to wean him off of his once-weekly GLP-1 agonist. However, when the man saw his blood sugars begin to creep up, he came in “fightin’ mad,” demanding to reinitiate his GLP-1. While the “diabetes targets” moniker in the talk implied A1c, Dr. Pratley made the excellent point that hypoglycemia is particularly dangerous in the elderly, not only due to unawareness, but also because they may have impaired counterregulatory responses, their brains may be more sensitive to hypoglycemic insults. The answer is not to allow A1cs to run high – as Weinstock et al. showed in 2015, older adults in the T1D Exchange registry with A1c >8% are at the same risk of hypoglycemia as those with A1c <8%. The ATTD consensus targets for time-in-range will likely prove to be better guidance than A1c targets, as it breaks out medically frail diabetes (pushing for lower time in hypoglycemia, and therefore more time above range). These recommendations will be presented at ADA.

• “Even if we solved all heart attacks, nephropathy, neuropathy, we’re still left with dementia. That costs real money. Though there are 25% as many people with dementia as there are with diabetes, there’s almost as much spent on dementia, probably because of the need for long term care.” People with diabetes are at ~1.2x higher risk of developing dementia, “possibly related to vascular/microvascular disease associated with diabetes.”

• “Not long ago, there was a lot of therapeutic nihilism – “they’ll die of something soon anyway, so why bother treating their chronic illness?” Though the evidence for treating diabetes in older adults is “thin,” Dr. Pratley made the case, partially by pointing to data suggesting that this population has average lifespans that are “probably long enough to develop chronic complications.”

• Adults >60 years-old in the lifestyle arm of the classic NEJM DPP trial had a 71% risk reduction for progression to diabetes. Said Dr. Pratley, “We should still absolutely do lifestyle interventions.” The risk reduction profile for metformin was just 11% in this older age group. 

5. Dr. Juan Frias Assesses NAFLD/NASH Landscape: Pioglitazone and GLP-1s Today, Dual Agonists and Combination Therapies Tomorrow; Weight Loss Key

National Research Institute’s Dr. Juan Frias assessed current and future treatments for NAFLD and NASH, backing pioglitazone and GLP-1 agonists as the best options today and combination therapies/dual agonists for the future, with weight loss as the driving principle. On pioglitazone, he referenced the PIVENS study which demonstrated improvement in steatosis without worsening of fibrosis, though weight gain is a concern with TZDs. With less gusto, Dr. Frias also mentioned vitamin E as a potential option to reduce oxidative stress (one mechanism hypothesized to accelerate progression of NAFLD), based on both PIVENS as well as the TONIC study, offering the caveat that vitamin E has been associated with all-cause mortality, prostate cancer, and stroke. And while these are potential options, both of these therapies target metabolic aspects of NASH without getting at one of the major driving forces: weight gain. To this end, Dr. Frias was most excited about GLP-1s’ potential in NASH, referencing the phase 2 LEAN study for liraglutide as reason for optimism and agreeing with other GLP-1 experts Dr. Robert Eckel and Dr. Dan Drucker. Notably, Novo Nordisk is now investigating injectable semaglutide in a phase 2 study for the indication. Looking to the future, Dr. Frias highlighted Lilly’s GLP-1/GIP dual agonist tirzepatide (~25 lbs of weight loss in phase 2b for type 2, now in phase 2 for NASH) and Novo Nordisk/Gilead’s recent collaboration for a semaglutide/cilofexor/firsocostat combination trial as promising approaches – but he also urged the audience not to forget about lifestyle modification. In a 2015 study, losing ≥10% of weight with lifestyle modification conferred fibrosis regression in 45% of patients and NASH resolution in 90%. However, <10% of patients were able to sustain this weight loss for one year, presenting a potential use case for pharmacotherapies, in our opinion.

• Dr. Frias underscored the astonishing prevalence of NAFLD and NASH in the US, citing ~25% prevalence in the general adult population and up to 66% prevalence among those with type 2 diabetes. While complications are common in both populations, the risk of mortality increases substantially in the latter.

6. Top Diabetes Technology Posters: Insulet/Lilly U500 Omnipod CGM Sub-Study, Eversense Posters x3, 670G Posters x2, and Valeritas VERDICT Study

Below, read (and link to) the seven top diabetes technology posters from AACE:

-- by Ann Carracher, Martin Kurian, Brian Levine, Peter Rentzepis, and Kelly Close