ADA publishes 2018 Standards of Care – December 15, 2017

Executive Highlights

  • ADA’s treatment algorithm now recommends earlier use of cardioprotective diabetes drugs for patients with CV disease – as first-line for people with ASCVD and A1c ≥9% (in combination with lifestyle + metformin), and as second-line for people with ASCVD and A1c <9%. The 2018 Standards of Care feature much more detail than past versions on the CV effects of all available drugs, divided into MACE effects and heart failure effects. Notably, SGLT-2 inhibitors are recognized for their heart failure benefit.
  • In technology, the Standards of Care are notably conservative around CGM and AID – for now. On a positive note, ADA did expand the adult recommendation for CGM to 18+ years (from the prior 25-year threshold), and while overall, we are disappointed by the low number of mentions of CGM and AID and the cautious/restricted tone that accompanies most of them, we believe this will change over time as CGM comes more into the mainstream, as it surely has over the last year. ADA took a more modest stance on the value of AID (“may have” advantages over SAP) and FreeStyle Libre (ADA wants to see more discussion). Compared to adults, there was stronger acknowledgment of the benefits of CGM/AID in adolescents/children. Given the positive CGM comments in this month’s Diabetes Care, and comments of the editorial team and leadership, along with the special emphasis on past issues of Diabetes Care on AID, the ADA has confirmed that it will continue to advance its endorsement in this technology moving forward.
  • The ADA provided a table classifying level 1 hypoglycemia as “≤” 70 mg/dl, instead of the now-agreed-on “<” 70 mg/dl threshold. However, it is recognized that the ADA was certainly (!) part of the new consensus published nearly simultaneously by the major diabetes organizations in the December issue of Diabetes Care. The ADA confirmed that although incorporation of the new findings into the Standards of Care was not possible due to this close timing of the manuscripts, the field can expect to see this updated moving forward. We are very positive on this point, particularly considering the two major consensus statements were just published in ADA’s own journal, Diabetes Care.
  • A major change in 2018 to the Standards of Care process is that the “ADA will be updating and revising the online version of the Standards of Care throughout the year with necessary annotations if new evidence or regulatory changes merit immediate incorporation. The Standards of Care will also be available as an app (said to be designed to be user-friendly and interactive) for both web and mobile devices in the spring of 2018. The app will allow clinicians to access the most up-to-date information conveniently and will include valuable clinical tools such as a diabetes risk calculator and treatment algorithm.  

Late last week, the ADA published its official Standards of Medical Care in Diabetes for 2018 in Diabetes Care. Here, we review and contextualize the most notable updates made to the 2017 Standards of Care, broken down by topic.

CV Recommendation Added to Treatment Algorithm

  • “If the A1c target is not achieved after approximately 3 months […] For patients with ASCVD, add a second agent with evidence of cardiovascular risk reduction after consideration of drug-specific and patient factors.”
    • ADA has acknowledged that cardioprotective diabetes drugs should be used earlier in patients facing high CV risk – as first-line for people with ASCVD and A1c ≥9% (in combination with lifestyle + metformin), and as second-line for people with ASCVD and A1c <9%. This builds on last year’s Standards of Care, which recommended SGLT-2 inhibitor empagliflozin (Lilly/BI’s Jardiance) and GLP-1 agonist liraglutide (Novo Nordisk’s Victoza) based on positive data from EMPA-REG OUTCOME and LEADER, respectively. Notably, this endorsement from ADA came before the FDA approved a CV indication for Victoza, and only shortly after the label change for Jardiance. Both products now have cardioprotection on their labels, and this is noted in the 2018 Standards of Care. Currently, we believe patients mainly see agents for use in lowering glucose and we hope considerably more education is planned on this front.
    • To outline options for cardioprotective diabetes therapy, all CVOT data published to-date is reflected in table 8.1:
      • SGLT-2 inhibitors canagliflozin (J&J’s Invokana) and empagliflozin (Lilly/BI’s Jardiance) are recognized for MACE benefit as well as risk reduction for heart failure. We find this quite progressive, considering heart failure hospitalization was a secondary endpoint in CANVAS and EMPA-REG OUTCOME, not enough to support a label change from the regulatory perspective. We applaud ADA’s forward thinking here. Thought leaders have pointed out the discrepancy between the immense burden of heart failure for people with diabetes vs. the omission of heart failure from FDA’s 2008 CVOT guidance. Certainly, best practice diabetes management must address heart failure risk in addition to atherosclerotic risks, and it’s meaningful that the ADA Standards of Care acknowledge the compelling data out there on SGLT-2 inhibitors/heart failure. We look forward to much more focus on heart failure in particular in the years ahead and appreciate ADA’s focus here.
      • For GLP-1 agonist liraglutide (Novo Nordisk’s Victoza), ADA endorses a MACE benefit and a neutral impact on heart failure. Exenatide once-weekly (AZ’s Bydureon) is listed as having neutral effects on both MACE and heart failure. This isn’t entirely surprising, considering Bydureon did not meet statistical significance for CV efficacy in EXSCEL. That said, Bydureon only missed the threshold for superiority by a razor-thin margin, and we believe it’s still up for debate whether or not weekly exenatide could show cardioprotection in some patients – for instance, risk reduction did reach statistical significance for adults older than 65, and when SGLT-2 inhibitors were excluded as drop-in medications from the placebo arm of the trial. In the future, we’d like to see more agreement on how CVOTs should be designed for comparison, or up-front acknowledgement that enrollment criteria should prevent comparison.
      • DPP-4 inhibitors are considered neutral for MACE events, with a risk for heart failure attributed to saxagliptin (AZ’s Onglyza) and alogliptin (Takeda’s Nesina). The FDA has added heart failure warnings to all DPP-4 products, also including sitagliptin (Merck’s Januvia) and linagliptin (Lilly/BI’s Tradjenta), a move that many have called overly conservative. Only the SAVOR-TIMI CVOT for saxagliptin found a significant signal for heart failure hospitalizations. Results for this endpoint trended in the wrong direction in EXAMINE, favoring placebo over alogliptin, but did not reach statistical significance. The TECOS trial for sitagliptin reported a resoundingly neutral hazard ratio for heart failure hospitalization of 1.00, while CVOTs for linagliptin are still ongoing, expected to complete next year.
      • ADA points to a potential MACE benefit with pioglitazone, which has garnered support from many diabetes thought leaders since the IRIS trial, and lists increased risk for heart failure associated with the TZD class.
      • Second-gen sulfonylureas are listed as neutral for MACE and heart failure. The evidence on sulfonylureas and CV effects is mixed, with some signal for CV harm. More definitive evidence will come from the CAROLINA CVOT, comparing Lilly/BI’s DPP-4 inhibitor Tradjenta (linagliptin) head-to-head vs. SU glimepiride – topline results are anticipated in late 2018, and we believe full results could influence a future iteration of ADA’s Standards of Care (possibly 2020 or later).
  • While we’re SO happy to see this emphasis on CV risk reduction early on in diabetes care, we believe cardioprotective agents should be first-line for some with established CV disease, regardless of starting A1c. Glucose-lowering has been ruled out as a mechanism for CV benefit in most (if not all) of these trials, meaning these drugs could exert protective effects independent of the necessary A1c decline to meet glycemic targets. We’ve been hearing arguments in favor of SGLT-2 inhibitors as first-line from numerous thought leaders, most recently at IDF, and while we understand the substantial cost, we’d like to see more economic analyses incorporate the cost of the actual heart attacks, strokes, heart failure, etc that could be prevented (this rarely seems to be part of the conversation). Without a doubt, this is an important stride – the ADA Standards have global influence, and best practice diabetes care everywhere should incorporate CV risk mitigation as a central component. We also hope that this is one additional piece of leverage for manufacturers to use in garnering better payer coverage of advanced, cardioprotective therapies.
  • To navigate the choices for pharmacotherapy, ADA has created a treatment algorithm (figure 8.1) separate from the table of therapeutic properties (table 8.1). It may be slightly more cumbersome for providers to use two figures rather than one, but we’re very impressed by the amount of detail and wide range of considerations (glycemic effects, hypoglycemia, CV effects, weight effects, cost, oral/injectable administration, renal effects, and more). We can’t help but be excited by the inclusion of outcomes-based recommendations (CV, renal, hypo). ADA indicates that this change is meant to promote patient-centeredness and shared decision-making.
    • We don’t want to read too much into things, but we’re intrigued to see SGLT-2 inhibitors and GLP-1 agonists at the top of this table, just under metformin, followed by DPP-4 inhibitors, TZDs, then SUs and insulin. We’d like to think this is a tacit acknowledgement of the superiority of these two newest therapy classes, though we’d also note that SUs and insulin – the only two drugs carrying hypoglycemia risk – are grouped together at the bottom.
  • ADA continues to use ≥140 mmHg systolic as the mark of high blood pressure in Standards of Care, even though ACC/AHA released updated guidelines last month indicating that ≥130 mmHg is the new threshold for hypertension. These two guidelines are alike in their emphasis on lifestyle management up front, and ACC/AHA made clear that people with blood pressure between 130-140 mmHg systolic should start with lifestyle changes first – not necessarily anti-hypertensive drugs right off the bat – to control this key CV risk factor. Of course, diabetes is also a substantial risk factor for CV morbidity/mortality, and we’d think it’s even more important for people with diabetes to manage their blood pressure to a lower target. We would not be surprised to see change here.

A1c Targets in Older Adults

  • “Older adults who are otherwise healthy with few coexisting chronic illnesses and intact cognitive function and functional status should have lower glycemic goals (A1c <7.5% [58 mmol/mol]), while those with multiple coexisting chronic illnesses, cognitive impairment, or functional dependence should have less stringent glycemic goals (A1c <8.0–8.5% [64–69 mmol/mol]).”
    • Three new recommendations promote individualizing treatment in older adults, by (i) simplifying medication regimens; (ii) avoiding overtreatment and hypoglycemia; and (iii) suggesting A1c target flexibility based on patient factors. The statement above offers loose guidelines for relaxing glycemic targets. While nothing is inherently wrong with this concept – indeed, we add that the disappointment of not reaching A1c goal is an extra challenge for many patients – we are wary of a potential “slippery slope” in a sweeping recommendation for less stringent glycemic goals in an older population – indeed, we’d rather see the recommendations move toward ensuring CGM and glycemic-dependent medications rather than just A1c target “flexibility,” which we worry is just fodder for HCPs to increase “relax” targets. We think it’s key to emphasize that only under very specific circumstances should A1c targets be raised – this is particularly true given that hypoglycemia risk is present at every A1c level. Indeed, “Liberating A1C goals in older adults may not protect against the risk of hypoglycemia” by Dr. Medha Munshi of the Joslin Clinic, et. al. suggests that although the work to prevent hypoglcyemia is indeed very positive, movement to relax guidelines isn’t the right direction to go. According to ADA, “this is the point of the recommendations because overtreatment holds its own concerns for more hypoglycemia” – given Dr. Munshi’s work, there is more debate on this end in our view. ADA also recommends “de-intensification” (or simplification) of complex medication regimens to reduce hypoglycemia risk, if possible to do so while maintaining an individual’s goal A1c – we wish this had simply been stated as moving toward getting access for patients for CGM and prescribing CGM along with medications less associated with hypoglcyemia (e.g., GLP-1, SGLT-2s, and insulins less associated with hypoglycemia like next-generation analogs). Frustratingly, when this debate ensues, we often hear about hypothetical 92-year-olds with 5.8 A1cs who need to “relax” their A1c targets – in such a case, of course we would agree, but we would not want to see the field move toward more wholesale “relaxation” of targets given the risk toward too much relaxation encouraged overall by HCPs not able to help patients meet A1c targets for other reasons (no CGM, the wrong individualization of therapy, etc.)

Type 2 Diabetes in Children

  • The section on type 2 diabetes in children was markedly expanded to include recommendations on screening and diagnosis, as well as lifestyle and pharmacologic management. Screening for A1c, fasting plasma glucose, or via an oral glucose tolerance test is recommended in children ≥10 years-old with a BMI in the 85th percentile or above and with at least one risk factor (family history, race/ethnicity, symptoms). Beyond lifestyle, metformin is recommended, with the potential use of insulin in more serious cases. Notably, the American Academy of Pediatrics released similar guidelines on childhood type 2 diabetes in 2013, but we’ve heard relatively little on the topic since. ADA called out this addition near the very beginning of its press release on the 2018 guidelines update, putting only the CV updates beforehand when describing the important changes that have been made. Clearly, the field can no longer ignore type 2 diabetes in youth. On the bright side, recognizing hyperglycemia in younger people and intervening more swiftly with effective care could start to make a dent in the population-level burden of diabetes – there’s a long road ahead, but this push from ADA in Standards of Care is a step in the right direction. We imagine under-diagnosis is a serious problem for type 2 in youth (currently, ~5,000 new cases are diagnosed in the US each year), and we need to see more done to promote awareness, particularly as children experience more rapid decline in beta cell function and onset of complications than adults, according to ADA.

A Fresh Outlook for Those with Renal Impairment

  • “Patients with diabetic kidney disease are at high risk of cardiovascular events […] the cardiovascular benefits of empagliflozin, canagliflozin, and liraglutide were similar among participants with and without kidney disease at baseline.”
    • This new section, “Specific Glucose-Lowering Medications,” describes “emerging evidence” that SGLT-2 inhibitors and GLP-1 agonists delay the onset and progression of chronic kidney disease (CKD). It includes language pulled from the 2017 Standards of Care – for instance, noting that DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors seem to have positive glucose-independent effects on the kidney. However, these agents have not previously had a dedicated section, and the ADA has added positive results from LEADER, CANVAS, SUSTAIN-6, and EMPA-REG OUTCOME on renal outcomes.
    • This section also points out that empagliflozin, canagliflozin, and liraglutide have demonstrated cardioprotection in trials including large numbers of people with kidney disease, meaning this patient population reaps the same CV benefits as individuals with diabetes but without renal impairment. In fact, a recent post-hoc analysis of LEADER hinted that participants with CKD may have experienced the greatest CV benefit from liraglutide. Given (i) the increased risk of CV events in patients with diabetes/kidney disease; and (ii) the difficulty HCPs face in effectively treating patients with reduced kidney function, we’re so glad to see these drug classes being promoted for their CV and renal protective effects in this population.

The Language Movement Enters Guidelines

  • “A patient-centered communication style that uses person-centered and strength-based language, active listening, elicits patient preferences and beliefs, and assesses literacy, numeracy, and potential barriers to care should be used to optimize patient health outcomes and health-related quality of life.” The “person-centered and strength-based” clause is new.
    • This isn’t a particularly surprising addition considering the recent publication of a paper in Diabetes Care (from ADA/AADE), addressing word choice and outlining language recommendations. We’re nevertheless glad to see this movement make it into the guidelines, and we fully believe in its potential to improve the lives of people with diabetes. We do think that a few more lines could have been dedicated to this topic, and that a more explicit description of what “person-centered, strength-based language” really means would have been useful for real-world HCPs. Language is a critical component of psychosocial care for people with diabetes, and both these issues are being increasingly emphasized in the field.

CGM: Fairly Conservative Stance; Expanded Age Recommendation Use in T1D Adults, Children, and Adolescents on Pumps and Injections; Small T2D Mention

  • “When used properly, continuous glucose monitoring (CGM) in conjunction with intensive insulin regimens is a useful tool to lower A1C in adults with type 1 diabetes who are not meeting glycemic targets. A
    • We’re glad to see ADA provided this recommendation for CGM use in adults with type 1 not at target, endorsing the supporting evidence with a strong “A” – the highest grade possible. That said, for someone glancing at this recommendation, they might conclude that CGM is not useful for those at their glycemic targetthis would be an unfortunate interpretation, since CGM is an essential tool for anyone with type 1 diabetes, especially those at target who might have a lot of hypoglycemia. Indeed, a later comment, “CGM may be a useful tool in those with hypoglycemia unawareness and/or frequent hypoglycemic episodes” only get an evidence grade of “C,” and the use of “may be a useful tool” is not exactly a strong vote of confidence.
    • ADA now recommends CGM use for adults 18+years, expanding from the previous 25-year-old threshold – the latter is a relic from the JDRF CGM study, published in 2008, which found those below 25 years did not benefit from CGM, as the old devices prompted lower wear time. The Standards of Care do acknowledge that the JDRF study was limited by use of older-generation sensors.
    • Also in support of CGM in MDI, the statement cites the DIaMonD trial published in JAMA in type 1 diabetes earlier this year – a nice nod to CGM’s benefits beyond pumpers. The type 2 publication in Annals of Internal Medicine is not referenced, unfortunately.
  • “Continuous glucose monitoring (CGM) also has an important role in assessing the effectiveness and safety of treatment in subgroups of patients with type 1 diabetes and in selected patients with type 2 diabetes.”
    • Interestingly, this positive mention of CGM in “selected patients with type 2 diabetes” is part of a preamble to the official recommendation section noted above. The official recommendation only focuses on type 1 diabetes. Perhaps in the 2019 edition of these guidelines, the now-published DIaMonD type 2 data will be included, along with Abbott’s REPLACE study in type 2 – ADA could really influence prescribing and payers by extolling the benefits of CGM in type 2 diabetes, including both real-time and professional CGM. Since there isn’t much data on deploying professional CGM, we’d like to see this recommended too based on expert clinical opinions. Of course, we also expect to see studies of CGM in type 2 proliferate in the coming years, which will in turn stimulate a change in the Standards of Care.
  •  “Continuous glucose monitoring should be considered in children and adolescents with type 1 diabetes, whether using injections or continuous subcutaneous insulin infusion, as an additional tool to help improve glycemic control. Benefits of continuous glucose monitoring correlate with adherence to ongoing use of the device. B
    • This recommendation for CGM use in children and adolescents is a positive update to see, endorsed with “B”-level evidence – a win for the field. It’s also refreshing to see the ADA mention both injections and pump therapy for pediatric use. Over time, we hope to see “should be considered” amplified to “is standard of care in all patients with type 1 diabetes.”
  •  “The intermittent or “flash” CGM device, very recently approved for adult use only, differs from previous CGM devices. Specifically, it does not have alarms, does not require calibration with SMBG, and does not communicate continuously (only on demand). It is reported to have a lower cost than traditional systems. A study in adults with well-controlled type 1 diabetes found that flash CGM users spent less time in hypoglycemia than those using SMBG. However, due to significant differences between flash CGM and other CGM devices, more discussion is needed on outcomes and regarding specific recommendations.”
    • This is a soft stance on FreeStyle Libre, distinguishing it as a separate category from traditional CGM devices – from our view, although it does not have alarms, it is still much more similar to “traditional” CGM than current BGM. We expect the view on Libre may well change in the future but creating yet more categories may create more confusion than anything. We agree the lack of alarms brings a different feature set than Dexcom or Medtronic CGM, but the statement that more discussion is needed may confuse some – Abbott has done two big RCTs (IMPACT, REPLACE) and now presented consistent outcomes from more than 235,000 FreeStyle Libre readers (DTM 2017).  We look to the ADA provide a stronger vote of confidence on Libre in the future and now that changes are created more than once a year, we’ll expect to see more discussion sooner than a year from now!  
  • “A meta-analysis suggests that compared with SMBG, CGM is associated with short-term A1C lowering of 0.26% in insulin-treated patients. The long- term effectiveness of CGM needs to be determined. This technology may be particularly useful in insulin-treated patients with hypoglycemia unawareness and/or frequent hypoglycemic episodes, although studies have not shown consistent reductions in severe hypoglycemia.”
    • While some may not have expected to see a call for more evidence assessing the long-term effectiveness of CGM – CGM clearly offers more therapeutic value than SMBG, and no one is arguing we need more long-term evidence on SMBG – we believe this was just a timing issue. CGM won’t be held to a different standard over the long term and we certainly see ADA’s commitment to CGM as of the latest issue of Diabetes Care - see Closer Look from December 12, 2017 “Latest Diabetes Care issue highlights CGM, including consensus statements from JDRF, ATTD; major win for Beyond A1c movement”. This was such a mark of leadership from ADA, particularly given the stirring editorial by Dr. Matthew Riddle and Dr. Will Cefalu, “Maturation of CGM and Glycemic Measurements Beyond A1c – A Turning Point in Research and Clinical Decisions.”
    • While some may be disheartened to see no acknowledgment that CGM has shown severe hypoglycemia benefits in patients with hypoglycemic unawareness, we believe this is merely a timing issue and we are thrilled that there is now a way for the Standards to change sooner than a year. We look for more discussion on certain studies and we believe more discussion among the author group is in order.
      • For instance, the robust, randomized crossover IN CONTROL trial (n=52) found CGM significantly decreased the number of severe hypoglycemic events in patients with type 1 diabetes and impaired hypoglycemia awareness. This was published over a year ago in Lancet Diabetes & Endocrinology. The reason for ADA’s assertion that “studies have not shown consistent reductions” is obvious to us: CGM studies are not powered for severe hypoglycemia endpoints, nor are they typically enriched with those at high risk of severe hypoglycemia.
      • The compelling Belgian CGM poster we saw at EASD – which showed fewer severe hypoglycemia/DKA hospitalizations with CGM in a pre- vs. post-12 months of use – was also not included, though perhaps it could be if it was published and we very much hope this will happen.
  • “Data indicate similar A1C and safety with the use of CGM compared with SMBG.”
    • We believe the assessment of this will change over time; For now, we see this as a misleading interpretation of the REPLACE-BG study, which was cited as evidence for this sentence. REPLACE-BG did not address the question of SMBG vs. CGM; instead, it looked at adjunctive CGM vs. non-adjunctive CGM (i.e., insulin dosing using CGM + confirmatory fingersticks vs. CGM without confirmatory fingersticks). While ADA gets the interpretation correct in a later detailed section, it was unfortunate to see this statement so high up in the assessment of glycemic control section – it implies (incorrectly) that CGM and SMBG are equivalent on A1c and safety, which is not the case in our view. CGM has shown superior A1c reductions in several recent studies, and we’d argue its safety is much higher than fingersticks, given the real-time trends, alarms, and greater data density to inform decision making. Real-time trend arrows are, of course, of great use to patients in helping them avoid hypoglcyemia but perhaps this has not been studied quite enough to date.
    • We hope to see more discussion on this – we believe the Closer Look on this piece is useful, from late 2016: “Adjusting insulin based on real-time CGM data – Drs. Edelman and Pettus publish recommendations for Dexcom CGM in JDST.”
  • “As people with type 1 or type 2 diabetes are living longer, healthier lives, individuals who have been successfully using CGM should have continued access to these devices after they turn 65 years of age.
    • We were elated to see ADA endorse CGM use in the Medicare population so explicitly – a very positive nod to Medicare’s decision to reimburse therapeutic CGM for type 1s and type 2s on intensive insulin therapy. Hopefully this also helps with insurance hassles if patients have problems going from private insurance to Medicare.
  • “Most patients using intensive insulin regimens (multiple-dose insulin or insulin pump therapy) should perform self-monitoring of blood glucose (SMBG) prior to meals and snacks, at bedtime, occasionally postprandially, prior to exercise, when they suspect low blood glucose, after treating low blood glucose until they are normoglycemic, and prior to critical tasks such as driving.”
    • We cringed a bit seeing ADA recommend performing SMBG only “occasionally” postprandially – aside from pre-meal, this is a critical time to take fingersticks, at least in intensive insulin users. Meals drive large glucose disturbances, and checking after meals is invaluable for patient learning and therapeutic adjustment. We hope to see this advised more than “occasionally” in future Standards of Care.”
  • A key consideration is that performing SMBG alone does not lower blood glucose levels. To be useful, the information must be integrated into clinical and self-management plans.”
    • We agree wholeheartedly and hope to see the field move faster on helping patients know what to do – numbers alone won’t improve outcomes. Companies and healthcare providers can help patients find actionable insight in their data, which not only will lead to more effective management, but also will increase the likelihood that patients continue to perform glucose monitoring on a consistent basis.
  • “A1c Testing […] Perform the A1c test at least two times a year […] For many patients, this will require [SMBG] testing 6–10 (or more) times daily,...”
    • Over time, we hope to see the language evolve from “test” to “check” or “monitor” or similar – using the word “test,” in our view, can drive stigma related to “good” and “bad” grades. Obviously, the numbers do matter, but this phrasing can impact those with diabetes negatively, even reducing the likelihood they will perform consistent monitoring. Who wants to get a “poor grade”? Check or monitor can help reframe glucose data as a helpful tool/partner, rather than a judgment to be avoided. See Adam’s recent column on this here. This is obviously nitpicking, but ADA also acknowledges separately that language matters, and we think this small change might help reduce feelings of guilt linked to blood glucose numbers.

Automated Insulin Delivery / Hybrid Closed Loop

  • Automated insulin delivery systems improve glycemic control and reduce hypoglycemia in adolescents and should be considered in adolescents with type 1 diabetes. B
    • Promisingly, the ADA came out nicely in favor of automated insulin delivery systems in the children and adolescents section, grading the evidence an encouraging “B.” We were pleasantly surprised to see the ADA take such a positive stance, as the adult section is less positive:
  • “The FDA has also approved the first hybrid closed-loop system. The safety of hybrid closed-loop systems has been supported in the literature and may have advantages over sensor-augmented pump therapy in specific populations, such as pregnant women with type 1 diabetes.”
    • This was a disappointingly soft stance on Automated Insulin Delivery, which is not even mentioned in the Recommendations part of the Glycemic Targets document. “May have advantages” over sensor-augmented pumps downplays a decade of research showing significant, proven advantages of AID over SAP. The first part of the statement above only cites the 670G JAMA publication, but no other academic studies. Further, noting the “potential advantages” only exist in “specific populations, such as pregnant women with type 1 diabetes” is unexpected – given numerous studies in major journals and conferences over the past ten years, the advantages of AID on hypoglycemia, time-in-range, and hyperglycemia extend to pediatrics, adolescents, and adults of a wide age range and in many countries. We were glad to see acknowledgement of the Cambridge team’s closed-loop study in pregnancy (NEJM 2016) – the other cited AID study in the sentences above – but obviously scores of other academic closed-loop studies were not cited in the Standards of Care.

Limitations of A1c Noted; Glycemia Best Evaluated by Combining A1c with SMBG/CGM; Unfortunate Hypoglycemia Standardization Oversight

  • The ADA provided a table classifying level 1 hypoglycemia as “≤” 70 mg/dl, instead of the now-agreed-on “<” 70 mg/dl threshold – we expect to see this changed in time. We recognize, of course, that the ADA was part of the new consensus published nearly simultaneously by the major diabetes organizations in the December, 2017 issue of Diabetes Care. The ADA shared with us that incorporation of the new findings into the Standards of Care was not possible due to this close timing of the manuscripts – while we would have loved to see the Standards delayed or a footnote on this, it’s good to know that this is expected to change shortly. Dr. Cefalu himself let us know we can expect to see this updated shortly.
  •  “A1C may underestimate or overestimate mean glucose. Thus, as suggested, a patient’s CGM profile has considerable potential for optimizing his or her glycemic management […] A1C does not provide a measure of glycemic variability or hypoglycemia. For patients prone to glycemic variability, especially patients with type 1 diabetes or type 2 diabetes with severe insulin deficiency, glycemic control is best evaluated by the combination of results from A1C and SMBG or CGM.”
    • Yes! Great to see ADA discuss the limitations of A1c, recommending supplementation with SMBG or CGM as the best way to evaluate glycemic control. ADA did reference the T1D Exchange study conducted by Dr. Roy Beck and colleagues, as well as acknowledge the importance of glycemic variability as a critical metric.
  • “In selecting glycemic goals, the long-term health benefits of achieving a lower A1C should be balanced against the risks of hypoglycemia and the developmental burdens of intensive regimens in children and youth.”
    • It’s again excellent to see the ADA acknowledge outcomes beyond A1c, noting the importance of hypoglycemia and quality of life.

Nutrition – “The role of low-carbohydrate diets in patients with diabetes remains unclear”

  • The ADA continues to take a middle-of-the-road approach to nutrition, noting, “There is not a one-size-fits-all eating pattern for individuals with diabetes, and meal planning should be individualized.” That said, the standards go on to recommend three specific “acceptable” eating patterns, leaving out low-carbohydrate approaches: “The Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and plant-based diets are all examples of healthful eating patterns that have shown positive results in research…”
    • We note, however, that ADA now includes “low carbohydrate” on its website as an example of an eating pattern that “may help people living with or at risk for diabetes” – we’re elated to see this listed just below Mediterranean and Vegetarian/Vegan on the page, and notably above low fat and DASH. This is a victory, even if the Standards of Care do not weigh in positively or negatively on low carb (see below).
  •  “The role of low-carbohydrate diets in patients with diabetes remains unclear. Part of the confusion is due to the wide range of definitions for a low-carbohydrate diet. While benefits to low-carbohydrate diets have been described, improvements tend to be in the short term and, over time, these effects are not maintained. While some studies have shown modest benefits of very low-carbohydrate or ketogenic diets (less than 50-g carbohydrate per day), this approach may only be appropriate for short-term implementation (up to 3–4 months) if desired by the patient, as there is little long-term research citing benefits or harm.”
    • Given the ADA website mention (see above), this is a disappointing take on the evidence. ADA has historically not recommended low-carbohydrate diets, and this quote in the Standards above shows the writing group did not see enough evidence to make an even slightly positive recommendation. ADA does cite studies that show clear benefits to low-carb diets, including a very positive 32-week JMIR study of low-carb vs. low-fat (RCT) published earlier this year – 55% of the participants in the low-carb group lowered their A1c to less than 6.5% vs. 0% in the low-fat diet control group (p=0.02). Virta’s six-month outcomes published in JMIR earlier this year are not cited in this section of the Standards. We’d also point out a persuasive paper, “Dietary carbohydrate restriction as the first approach in diabetes management: Critical review and evidence base” (Nutrition 2015), which has been cited more than 217 times now – it is not mentioned in the Standards either.
  • Ultimately, we’d hope to see ADA’s Standards of Medical Care more specifically mention low-carbohydrate approaches as one OPTION for people with diabetes. We also hope to see studies done to more fully answer (with CGM) one of the MOST important questions in diabetes care: what should people eat? It might be that people can get great outcomes on any diet, depending on their genetics or medication timing or other factors. Still, we see big potential in more head-to-head diet trials that utilize CGM, track insulin dosing, measure quality of life, help participants stick to the assigned diet via best practices, and follow them over time. This could be a promising area of research for the ADA to fund!
  • We were pleased to see the ADA modify an existing recommendation to include the delivery of diabetes self-management, education, and support via technology as an effective solution. An additional statement details the advantages of telemedicine, especially for rural populations or those with limited physical access to health care. In particular, the ADA endorsed interactive strategies that promote communication between patients and their care team. We see huge value in telemedicine, especially digital Diabetes Prevention Programs, which unfortunately the CMS decided not to reimburse this summer. Hopefully, this recommendation by the ADA will serve to sway some opinions.


-- by Ann Carracher, Maeve Serino, Payal Marathe, Adam Brown, and Kelly Close