American Diabetes Association 74th Scientific Sessions

June 13-17, 2014; San Francisco, CA – Treatment Algorithms and Strategies – Draft

Executive Highlights

This year’s ADA featured a number of presentations on treatment algorithms and strategies, perhaps the most notable of which was the ADA’s newly released position statement on type 1 diabetes. We are continually inspired and encouraged by the trail-blazing authors of this position statement, including Dr. Anne Peters (Keck School of Medicine, Los Angeles, CA) who all emphasized that this document explicitly carves out a more clearly delineated arena for type 1 diabetes in the ADA’s thinking. We applaud all those who have made this happen, and hope that it will leave a legacy to “keep moving the bar forward” for type 1 diabetes, as Dr. Peters commented at this year’s 8th Annual TCOYD/The diaTribe Foundation Forum. One major change in the position statement is an updates A1c target of 7.5% (down from 8.5%) for children with type 1 diabetes under age 18. While this updated pediatric guideline will likely garner the most attention, the position statement is designed to address the entire lifespan of the disease, including updated guidelines on lipid management and blood pressure targets.

In addition to this big picture progress in refining how we think about diabetes treatment, this category also included presentations on specific treatment strategies. In regards to early combination therapy, Dr. Lawrence Phillips (Atlanta VA Medical Center, Atlanta, GA) discussed “pattern care” as an alternative approach to current standards of type 2 diabetes therapy. Pattern care is aimed at achieving normal or near-normal fasting and postprandial glucose and an A1c in the 5.5-5.7% range through an early and intensive therapy regime. Continuing on the theme of providing enhanced care strategies, Dr. Leigh Simmons (Massachusetts General Hospital, Boston, MA) advocated for shared decision-making in diabetes care, encouraging clinicians to share autonomy in treatment choice with patients and families. Undoubtedly, this emphasis on improved communication and engagement in diabetes therapy and self-management can help improve adherence and outcomes. A similar thread was heard in Dr. William Polonsky’s (UCSD, San Diego, CA) Richard R. Rubin Award Lecture. Also highlighting physician-patient interaction, Dr. Neda Laiteerapong (University of Chicago, Chicago, IL) discussed how providers could explain the metabolic legacy effect to help motivate patients in discussions about treatment change.

Aside from these broader treatment strategies, several speakers also delved into specific drug regimens. These included discussions on the use of GLP-1 analogs and TZDs by Dr. Ralph DeFronzo (University of Texas Health Science Center at San Antonio, San Antonio, TX), SGLT2 and SGLT1/2 inhibitor therapy for type 2 diabetes by Dr. Robert Henry (UCSD, San Diego, CA), and insulin/sulfonylurea combination therapy by Dr. Vivian Fonseca (Tulane University Health Sciences Center, New Orleans, LA).

Talk titles highlighted in yellow were among our favorites from ADA 2014; titles of the presentations that were not included in our daily coverage are highlighted in blue.

Table of Contents 

Treatment Algorithms and Strategies

Symposium: Type 1 Diabetes Guidelines – Are They Enough? (Supported by a grant from The Leona M. and Harry B. Helmsley Charitable Trust)

Press Conference: New American Diabetes Association Position Statement on Type 1 Diabetes

Jane Chiang, MD (Stanford Medical Center, Los Altos, CA), Sue Kirkman, MD (University of North Carolina, Chapel Hill, NC), Lori Laffel, MD (Joslin Diabetes Center, Boston, MA), Anne Peters, MD (University of Southern California, Los Angeles, CA)

The authors of the ADA’s newly released position statement on type 1 diabetes (published in Diabetes Care) explained in their session the thinking behind the document. The panelists emphasized two crucial points, one general and one specific. The more general takeaway is that this position statement explicitly carves out a more clearly delineated arena for type 1 diabetes in the ADA’s thinking. Indeed, Dr. Jane Chiang, the ADA’s Senior Vice President for Medical and Community Affairs, noted that this position statement reflects the ADA’s effort to better recognize the distinctions between type 1 and type 2 diabetes. This acknowledgment of the unique challenges faced by the type 1 diabetes patient community has been a prevailing theme of many type 1 adults diagnosed as type 2 initially, although the speakers were hesitant to translate this recognition to specific recommendations. As Dr. Anne Peters suggested at one point, the aim of this position statement is to start a conversation about type 1 diabetes – more concrete directives on treatments and care will be left to the writers of future statements – although we do note that Dr. Peters is the co-author of the highly praised Type 1 Diabetes Sourcebook published by the ADA. Ultimately, Dr. Peters expressed hope that the document will be updated in around three years. One major concrete change in the new position statement is an updated A1c target for children with type 1 diabetes. All type 1 patients aged 18 and under should now have a target A1c of 7.5%, down from 8.5%; the adult benchmark remains 7.0%. This was notable in that children and teens are already having a challenging time meeting some of the higher guidelines; that said, the data from the T1D Exchange certainly shows that even young patients who are at higher A1cs still experience a great deal of both mild to moderate as well as severe hypoglcyemia. Historically, the justification for the higher A1c guidelines was that these levels were “safer”; the data suggests, however, that this actually isn’t true. Given that the DCCT showed significantly lower reduced long-term complications associated with every point reduction in A1c, we assume the writing group felt that higher A1c levels as targets could no longer be justified.

  • The revised pediatric target of 7.5% for pediatric type 1 diabetes patients is specifically designed to improve pediatric outcomes and is a recognition of the improved ability to prevent hyperglycemia with newer therapies. The ADA previously recommended that only adolescents aged 13-19 strive for a 7.5% A1c; children 6-12 years of age were given a target of 8.0%, while children 5 years and under could have acceptable A1c levels of up to 8.5%. The varying benchmarks were prompted by concerns over hypoglycemia – Dr. Lori Laffel characterized these as the concerns of a “distant era,” noting the wealth of new clinical data obtained in the past 10 years – as the old thinking held that the risk of hypoglycemia in very young patients significantly outweighed the risk of complications related to poor glucose control.
    • The ADA’s position statement brings its guidelines on this topic more in line with international standards. The International Society for Pediatric and Adolescent Diabetes released a statement in 2009 recommending the same 7.5% target for children with type 1 diabetes. The speakers noted that harmonizing the ADA’s A1c targets with those of other organizations was a major priority of the position statement.
  • Although the revised pediatric targets are likely to attract the most attention, the speakers emphasized that the position statement is designed to address the entire lifespan of the disease. Dr. Sue Kirkman noted that, as adult endocrinologist, it drives her crazy that people still refer to type 1 diabetes as a pediatric disease. Not only are the vast majority of people with type 1 diabetes adults, but also between a third and a half of new cases develop after the age of 18. The lifespan of people with type 1 also continues to increase, a point Dr. Kirkman illustrated by pointing to the skyrocketing number of Joslin 50-Year Medals awarded to patients in the past few years. Crucially, the position statement actively pushes against the notion that patients should be classified as pediatric, adult, or geriatric; rather, the position statement argues that the lifespan of type 1 diabetes should be viewed more as a continuum. Dr. Chiang did note one particular challenge that also serves to demarcate pediatric and adult patients: the former are generally cared for by pediatric endocrinologists, whereas the latter are often treated by primary care providers. An intention of this position statement is to smooth this transition from one type of care to the other.
  • The panel repeatedly noted that what we do know about type 1 is far outweighed by what we don’t. Dr. Chiang pointed to the American College of Cardiology/American Health Association’s newly revised guidelines on cholesterol, which effectively categorize the vast majority of people with diabetes as being at-risk for cardiovascular disease and (as a result) as good candidates for statin therapy. She said that these recommendations are based on clinical data for type 2 patients, and that it can’t really be said one way or the other whether the same recommendations should also apply to type 1 diabetes patients. Dr. Kirkman agreed that cardiovascular disease (and, indeed, all microvascular and macrovascular complications) is a source of major unanswered questions for the type 1 diabetes community. More generally, Dr. Kirkman said there is still fuzziness about how many people even have type 1, and what sort of care they receive.
  • As with the ADA/EASD’s recent position statement for type 2 diabetes, the individualization of care was highlighted as a priority. The speakers emphasized that both the adult and juvenile targets could be adjusted up or down to better fit the needs of individual patients. Dr. Laffel suggest that, if a patient’s A1c is 10.0%, then his or her short-term goal should be 9.0%, with 7.0% or 7.5% held up as a “distant goal.” She further stated that her priority with this position statement and type 1 diabetes care in general is to get everyone to shift their A1cs down, if only incrementally, and then start focusing on individuals who require more significant reductions.
  • The position statement draws on work that Dr. Peters and Dr. Laffel began with the Type 1 Diabetes Sourcebook. Dr. Peters indicated that the position statement is reflective of many of the broader points made by the approximately 60 authors who contributed to that earlier work.
  • Editor’s note: The ADA had a press conference on this subject in addition to the presentation during the Scientific Sessions; our coverage incorporates learnings from both.

Glucose Targets

Lori Laffel, MD (Joslin Diabetes Center, Boston, MA)

Dr. Lori Laffel proudly announced the ADA’s new Position Statement, “Type 1 Diabetes Through the Lifespan,” released online (Chiang et al., Diabetes Care 2014). Her presentation focused on the new guidelines’ call for a universal A1c target of <7.5% in all youth under 18 years, a change from the previous call for separate targets: <8.5% (0-6 years), <8% (7-12 years), and <7.5% (13-18 years). The general goal for adults is still <7.0%, though the statement clearly articulates individualized A1c targets for older adults who are healthy (<7.5%), complex/intermediate health status (<8%), and very complex/poor health status (<8.5%). Dr. Laffel reviewed the rationale for the new targets and associated changes, highlighting that the new pediatric A1c targets are now harmonized with other international groups like ISPAD; abolish separate targets by age (i.e., simpler!); and are much needed given the average achievement of goals in type 1 diabetes care. The remainder of her talk reviewed the rationale for targets, the current state of achieving diabetes care targets in pediatrics, and opportunities for improvement.

  • In Q&A, Dr. Laffel addressed the two arguments against lowering A1c targets in pediatrics. First, some have argued against lower targets in pediatrics, given the risk of severe hypoglycemia and its associated negative cognitive outcomes. In reality, the most recent T1D Exchange data suggests there is no increased risk of severe hypoglycemia with a lower A1c – that’s in contrast to data from the DCCT, where improvements in A1c came with a major increased risk for severe hypoglycemia. Second, some have postulated that the pre-pubertal years potentially don’t affect long-term complications risk. Dr. Laffel noted that this is difficult to study, and it’s likely more important to establish low targets and good diabetes management habits early.
  • The evidence for glycemic targets is based on the DCCT; however, it is both intensity of hyperglycemia exposure and duration that matters. Dr. Laffel noted that an A1c of 10% for three years vs. an A1c of 8% for eight years have the same retinopathy risk. She framed this in a positive light, noting, “there is always an opportunity to help our patients.”
    • The DCCT had certain strengths and limitations that informed A1c targets. First, the trial was restricted to ages 13-39 at entry, meaning there were no data on young children or older adults (the new position statement is trying to fill that gap). Second, the DCCT adolescent cohort was unable to achieve the same A1c outcomes as the adults (another reason why the target was set higher) – this resulted in a loss of the protective effect of metabolic memory on complication risk in this cohort. Third, hypoglycemia risk increased as A1c decreased (as noted above, another reason for higher pediatric A1c targets).
  • Dr. Laffel shared three examples from the literature that provide evidence that a lower 7.5% target could improve things. First, a 1990 NEJM article (Larsen et al.) showed that patients improve over time simply by knowing their A1c and glycemic target (compared to those who don’t know their A1c). Meanwhile, Boot et al., Diabet Med 2013 asked patients and parents about their perceived A1c target, which was compared to their actual A1c value. Those who perceived that their target was lower in reality had a lower actual A1c. Last, a recent study from Maahs et al. (Diabetologia 2014) compared the clinical care between the T1D Exchange and the German/Austrian DPV registries. More children from DPV were meeting the recommended A1c goals vs. children from T1D Exchange (A1c <7.5%: 56% vs. 22%; <8.5%: 90% vs. 66%). The study concluded, “The greater frequency of suboptimal control in young patients in the T1D Exchange compared with the DPV is not fully explained by a less frequent use of insulin pumps and may relate to the higher A1c targets that are recommended for this age group in the USA.”
  • Dr. Laffel noted that A1c is the average of blood glucose levels over the previous two to three months, but it is weighted towards the last four weeks. She cited estimates that ~50% of an A1c level is formed in the month before the test, 25% in the month earlier, and ~25% in the month before that. Given this, of course, some questions always surround studies done that are only, for example, eight weeks in length or even shorter. .

Questions and Answers

Q: Is the ADA’s guideline now that toddlers and very young children should be under 7.5%? Is there any research to show that the pre-pubertal years have some protective mechanisms even if they are at higher A1cs?

A: The consensus that went into the previous age specific guidelines was of fear of hypoglycemia in the young, and consequent fear of neurocognitive compromise. There was also the potential possibility that those years prior to puberty may not have an impact on long-term risk. It’s a very difficult area to study. It’s unclear. Many are afraid to just say clearly those years don’t matter. You establish behaviors and preferences for certain glucose levels. It’s better to establish patients feeling better, healthier, and performing better in a target range. We cannot hang our hat on the years prior to puberty not counting.

Q: I recognize that hypoglycemia may not be as much of a fear as we once thought. But should we put lower limits on A1c targets? What about the patient that comes in with a 4.7% A1c – do we think that should raise a red flag?

A: That’s the point of individualizing care – looking at the risk for severe hypoglycemia.

Q: But the message coming across is that lower is better. To a limit that’s true..

A: What would you like it to be set at?

Comment: Well, someone who comes in with a 4% A1c makes me very nervous…

Lipid Management

Trevor Orchard, MD (University of Pittsburgh Medical Center, Pittsburgh, PA)

Dr. Trevor Orchard presented the new ADA position statement on lipid guidelines for patients with type 1 diabetes, which symposium moderator Dr. Anne Peters commented was “one of the main reasons” she created the type 1 diabetes position statement since she is “continually challenged” by payers on why she doesn’t have a patient with type 1 diabetes on a statin. The new ADA position statement recommends that people with type 1 diabetes (aged 40-75) may benefit from moderate to intensive statin therapy. For patients <40 years with <20 years of diabetes, an LDL of <100 mg/dl is suggested as an appropriate goal with statin intervention. Dr. Orchard pointed out gaps in the position statement including the lack of guidance for HDL cholesterol or triglyceride management as well as specific intervention recommendations for people with type 1 diabetes >40 years or with diabetes duration >20 years. Additionally he commented, “It’s disappointing that the major killer of those with type 1 diabetes merits less than half a page of the excellent 17 page report."

  • The 2014 ADA position statement recommends that individuals with type 1 diabetes aged 40-75 years may benefit from moderate to intensive statin therapy. If 10 year risk is >7.5%, intensive statin should be considered. Additionally, people <40 years with <20 years of duration (or >75 years of age) should be recommended on an “individual basis” to achieve LDL cholesterol <100 mg/dl as an appropriate goal with statin intervention. Additionally, the statement recognizes that adults with a 20+ year duration of diabetes have a coronary artery disease (CAD) risk justifying treatment under the AHA/ACC 2013 guidelines (7.5% 10 year risk), even if not aged 40 years.
    • Dr. Orchard highlighted several problems with the position statement, notably that while the statement recognizes the relatively high risk for adults with 20+ years diabetes duration, it does not specifically recommend intervention for these individuals. Additionally, the statement provides no guidance for HDL cholesterol or triglyceride management, which observational type 1 diabetes trials have previously evidenced are significantly correlated with increased CAD risk.
    • His recommendations included a better estimate of risk for patients with type 1 diabetes >40 years, better understanding the role of HDL metabolism in type 1 diabetes, and guidelines for the management of triglyceride elevation. In order to better estimate type 1 diabetes risk, Dr. Orchard suggested pooling existing cohort databases and new EHR databases to calculate new risk equations. Encouragingly, he noted that many studies are already underway exploring HDL metabolism in type 1 diabetes as well as the differing effects for fatal vs. non-fatal events and before and after controlling for triglycerides. Additionally, Dr. Orchard advocated for revising the current position statement to recommend that all 40-75 year-old type 1 patients (or if <40 years with 20+ years of diabetes duration) should receive moderate to intensive statin therapy.
  • The 2014 ADA standards of medical care recommend adding a statin regardless of baseline LDL cholesterol if an individual has CVD or is >40 years old with an additional risk factor. Additionally, statins can be considered if LDL cholesterol is >100 mg/dl for lower risk individuals. While the goal is <100 mg/dl, LDL cholesterol of <70 mg/dl is an option for those with CVD. Dr. Orchard noted that the care standards give goal values but do not recommend intervention for triglyceride and HDL cholesterol. Additionally these standards lack type 1 diabetes evidence but applies similar lipid goals for both type 1 and type 2 diabetes.
  • In terms of new lipid guideline observations, Dr. Orchard noted that a number of investigators are exploring the utility of Hp, a liver product protein, as a biomarker. Hp is an acute phase reactant and also acts as an antioxidant binding to hemoglobin during degradation/hemolysis. Two alleles produce three genotypes of which Hp1-1 is the most efficient antioxidant and Hp2-2 the least, with Hp2-1 being intermediary in some studies. Importantly, Hp is observed to affect outcomes only in diabetes, contributing to factors such as elevated hemoglobin levels (Conway et al. Annals Epidemiology 2008), the glycosylation of hemoglobin and reduction in monocytes expressing surface CD163 (Asleh & Levy, Vasc Health Risk Manag 2005), and incomplete blocking of LDL oxidation by glycosylated hemoglobin (Asleh et al., Circ Res 2003).
    • Additionally, early research on Cox PH models for the prediction of CAD in type 2 diabetes (n=443; 132 incident events), has shown that the genotype Hp2-2 had a dramatically increased CAD risk (HR 2.62) compared to reference genotype Hp1-1 and Hp genotype 2-1 (HR 1.83).
  • Dr. Orchard emphasized that despite these few studies, the trial evidence for lipid guidelines is “very limited.” He added that while the DCCT/EDIC clearly shows benefit of intensive therapy initiated early in the course of type 1 diabetes in youth and young adults, the data does not help guide lipid or even BP management especially in adults with longstanding childhood onset type 1 diabetes. To his knowledge, the Heart Protection Study (HPS) was the only lipid intervention trial with CVD outcomes that included patients with type 1 diabetes. HPS found that high-risk patients, regardless of baseline LDL cholesterol, benefit from statin therapy (40 mg/day). Those with type 1 diabetes had the same reduction in CAD events (22%) as those with type 2 diabetes.

Blood Pressure Targets

Bruce Perkins, MD, MPH, FRCPC (University of Toronto, Mount Sinai Hospital, Toronto, Ontario)

Dr. Bruce Perkins presented a sobering picture on the state of hypertension in type 1, calling it an “epidemic” and a problem of “enormous” magnitude. Even in type 1 pediatric patients, he noted, hypertension prevalence (BP ≥ 140/90 mmHg) reaches 10-17%. He reviewed DCCT/EDIC findings of 10% high blood pressure prevalence in 20 year-old patients, escalating to 40% prevalence in 40-50 year-old patients, and rising above 50-60% prevalence in older populations. Despite these alarming rates of hypertension prevalence (in what many consider a “healthy” and “thin” population), Dr. Perkins lamented that the current blood pressure guidelines outlined by the Eighth Joint National Committee (JNC 8) are exclusively based on data from RCTs conducted in patients with type 2 diabetes. According to Dr. Perkins, the observational research in the type 1 diabetes population is discordant from type 2 RCT data. In patients with type 1 diabetes, very low systolic blood pressure (SBP <115 mg/dl) decreased CVD risk by 40%, but this cardioprotective benefit was not seen in type 2 research. In fact, data from the Louisiana State University Prospective Database showed that SBP of 110-115 mg/dl in patients with type 2 diabetes was associated with the highest risk of heart disease and stroke, even more than risk associated with SBP >160 mg/dl. Dr. Perkins advocated for evaluation of blood pressure in a type 1 diabetes observational trial like the DCCT, which could inform the concern of lower BP thresholds. He also added, “We can fight the hypertension epidemic with novel pharmacodynamic approaches in type 1 diabetes to prevent the onset of hypertension,” noting that in addition to diet and exercise, “new agents like SGLT-2 inhibitors and GLP-1 agonists could simultaneously improve glycemia, blood pressure, and hypertension risk factors.”

  • Dr. Perkins’ self-proclaimed alternate presentation title was: “Should we love or hate the recommendations of the JNC8?” The 8th Joint National Committee (JNC8) guidelines recommend BP target of >140/90 mm Hg in adult patients with diabetes and hypertension. However, all previous randomized controlled trials only show reduced mortality and improved CV outcomes for patients with diabetes with treatment goals of SBP <150 mm Hg. Dr. Perkins even noted that these guidelines “dismiss altogether the body of evidence” for BP guidelines for patients with diabetes. The JN8 only focused on RCTs that assessed specific BP targets, but major diabetes studies like the DCCT/EDIC wouldn’t have met this criterion.
  • Unfortunately, the JNC8 guidelines are exclusively based on data from RCTs conducted in patients with type 2 diabetes as they were the only trials that met the committee’s criterion for BP target focus. Dr. Perkins emphasized that BP thresholds from type 2 research cannot be generalized to patients with type 1 diabetes as well. In fact, the observational research in the type 1 diabetes population is discordant from type 2 RCT data.
    • In patients with type 1 diabetes, BP targets should be “not just low, but very low,” according to Dr. Perkins. In the Pittsburgh EDC trial, mortality doubled with increased SBP targets. An SBP of 110-110 mm Hg was associated with a 2.1 mortality risk whereas a target of 120-129 mm Hg increase mortality risk to 3.0 and SBP >130 mm Hg jumped to a 7.2 mortality risk. Additionally, in a regression study of microablumin in type 1 diabetes (Perkins et al., NEJM 2003), a very low systolic blood pressure (SBP <115 mg/dl) decreased CVD risk by 40%.
    • However this cardioprotective benefit of very low BP targets was not seen in type 2 research. Data from the Louisiana State University Prospective Database showed that SBP of 110-115 mg/dl in patients with type 2 diabetes was associated with the highest risk of heart disease and stroke, even more than risk associated with SBP >160 mg/dl.
  • Additionally, BP targets should have some degree of risk stratification as Dr. Perkins pointed out that aggressive BP lowering in elderly patients could be dangerous. Even with guidelines and recommendations from physician associations, he stressed that physicians must be able to make such stratification decisions in clinical decision-making. Additionally, while type 2 data can’t be generalized to type 1 diabetes, Dr. Perkins noted that certain subgroups of type 2 research, like older patients with higher risk, might lend useful data for older, high-risk type 1 patients. He added that this could potentially save billions of dollars in research that could be focused on more effective type 1 research. For example, evaluating of blood pressure in a type 1 diabetes observational trial like the DCCT could inform the concern of lower BP thresholds.

Questions and Answers

Q: Would you consider implementing ambulatory blood pressure guidelines?

A: I ran over time and I had all these other aspects I wanted to talk about and one was ambulatory blood pressure. The important thing is that guidelines must be implementable and can be disseminated into the community. Ambulatory BP monitoring at this point – until you devise an app for the iPhone – is not feasible.

Symposium: Initial Treatment of Type 2 Diabetes — New and Not-So-New Ideas

Early Combination Therapy

Lawrence Phillips, MD (Atlanta VA Medical Center, Atlanta, GA)

Dr. Lawrence Phillips gave a valuable talk to a packed audience, in which he advocated ‘pattern care’ as an alternative approach to current clinical care for people with type 2 diabetes. Pattern care is aimed at achieving normal or near-normal fasting and postprandial glucose and an A1c in the 5.5-5.7% region through an early and intensive therapy regime. He strongly believes that maintaining a low A1c early in the course of diabetes greatly reduces the risks of complications and slows the natural progression of the disease. He gave anecdotal examples of patients who had maintained excellent glucose control for over ten years using this approach. His aggressive treatment regime was centered around titrating various therapies to achieve a fasting glucose of <100 mg/dl and a post-prandial glucose <130 mg/dl. He used most oral therapies, GLP-1 agonists and insulin analogs, but notably avoided long-acting sulfonylureas and mixed insulin. We would love to see even long-term observational data of his patients on this course; we believe it would be much easier for patients to achieve these goals if they have access to glycemic dependent drugs not associated with hypoglcyemia and weight gain.

  • The “Legacy Effect” is one of the key benefits of early, intensive glucose control. Dr. Phillips showed “legacy effects” in many studies – including the DPP, (exercise/metformin), Da Qing (lifestyle), DPPOS (the DPP long-term outcomes study), and ORIGIN (glargine). He noted that compared to the natural history of diabetes, if we interrupt progress for a while (with an intervention), then afterwards diabetes continues to develop but patients that have received the intervention never do as poorly as the conventional group. 
  • The implication of these studies is that if we start early and maintain a normal glucose level, then the benefits will be large and sustained. In the Norfolk study, patients with A1cs in the range 4.5% to 6.5% showed low hazard ratios for cardiovascular disease and cancer that decreased with decreasing A1c, even down to the lowest (normal) A1cs.
  • Dr. Phillips recommended “pattern care” (a term we’ve never heard) in which early aggressive intervention with multiple drug therapies treats patients to target, rather than the current “stepped care” paradigm. In “stepped care” we screen and treat complications and then add therapies one at a time in order, once A1c has risen and patients have failed a particular step. But clinical trials of more early combination care, such as those from Rosenstock, Goldstein and DeFronzo have shown much better, sustained A1c.
  • Pattern care targets a premeal glucose <100 mg/dl, two hour postmeal glucose of 130-140mg/dl and an A1c of 5.5-5.7% using most of the pharma arsenal. Fasting glucose is treated with metformin, bedtime glipizide, or bedtime long acting insulin. Post-prandial glucose is targeted with DPP-4 inhibitors, GLP-1 analogs, pioglitazone, SGLT-2 inhibitors, nateglinide/repaglinide or rapid acting insulin. NPH insulin, premixed insulin and long-acting sulfonylureas are to be avoided.
  • Early detection plus early combination therapy aimed at keeping glucose normal or near-normal should be the new standard of care in diabetes. Dr. Phillips showed anecdotal data from patients who had succeeded in keeping their A1cs low for more than a decade on a consistent therapy regime – implying slow disease progression.

Symposium: Getting the Patient Perspective on Diabetes

Shared Decision Making With Our Patients: Models for Enhanced Diabetes Care

Leigh H. Simmons, MD (Massachusetts General Hospital, Boston, MA)

Dr. Leigh Simmons gave an impassioned talk on the value of shared decision-making in chronic disease management, strongly encouraging the individualization of treatment through the use of “decision aids” and more stringent patient and clinician training. Dr. Simmons defined shared decision-making as an interactive process between patients (and families) and clinicians that hinges on communication and reflects the goals, preferences and concerns of both parties. According to Dr. Simmons, the realm of diabetes is ideal for the implementation of this strategy, since treatment often involves “preference-sensitive care” in which the evidence and symptoms support more than one approach for therapies that often entails tradeoffs. In her view, this strategy can be broken down into six individual steps, ranging from inviting patients to participate in the decision-making process to assisting with the actual implementation of the plan. She highlighted some of the work at Massachusetts General Hospital, where around 3,000 diabetes-related decision aids have been distributed to patients. At diaTribe, we have developed a patient guide to individualizing therapy, available for download at diaTribe.org/patientguide – the one page shared decision-making guide uses the 2012 ADA/EASD position statement to help guide patients and providers to select the optimal therapy.

  • “The right treatment, the right patient, the right time.” Dr. Simmons emphasized that shared decision-making involves the development of a joint treatment plan, which results from an interactive process between patients, their families and clinicians. This strategy must involve patient self-management by incorporating a patient’s and provider’s preferences, goals, values and concerns.
  • Shared decision-making is tough. Early in her presentation, Dr. Simmons addressed the concern some clinicians may feel at relinquishing some control of treatment to patients, especially when those decisions reflect on the provider’s performance. She brought up an example of a decision faced in managing cholesterol: “Should I really push taking that statin right now? Or should I focus instead on something more pressing to the patient?” In this vein, Dr. Simmons encouraged shared decision-making even in the face of concerns regarding satisfactory performance reports, because of the value to patients.
  • Dr. Simmons laid out six steps to shared decision-making, which included (1) an invitation to participate in the process, (2) the presentation of options to patients, (3) a mutual assessment of risks and benefits, (4) eliciting patient preferences, (5) the facilitation of deliberation, and (6) assisting with implementation. The important points in her discussion of these steps are highlighted below:
    • The first step of this process, an invitation to participate in the process of decision-making, is crucial and often overlooked. Dr. Simmons noted that patients do not necessarily recognize that a decision is being made, but may believe a decision – for example, to pursue treatment with metformin – is a forgone conclusion. Clinicians are responsible for inviting a patient to participate in the process and for explaining that, “There’s a decision we need to make here.”
    • Dr. Simmons noted that facilitating the decision-making process (step #5) requires a delicate balance that is not prescriptive. She recognizes that it is a clinician’s responsibility to mediate this conversation and encouraged clinicians to ask patients specific questions that elicit their goals and worries. Examples of questions, included: “What is most important to you in a therapy? Is there something in particular you are concerned about?”
  • Videos and other interactive tools that help patients become more involved in decision-making (“Decision aids”) are essential to improving patient outcomes. These decision aids should provide information about various treatment options, offer risk versus benefit analysis, and explore patients’ personal values. However, Dr. Simmons emphasized that successful implementation of decision aids requires buy-in from hospital/practice leadership and a culture ready for “changing the conversation” with patients.
    • At Massachusetts General Hospital, around 3,000 diabetes-related decision aids have been distributed to patients. Dr. Simmons noted that the program’s popularity was driven by the simplification of the distribution process, in which clinicians can actually “prescribe” decision aids to a patient through “two clicks” on the EHR.
  • However, only 60% of patients watch decision aids given to them. Given problems with adherence, Massachusetts General Hospital developed paper tools (“choice reports”) that present the pros and cons of treatment options in a “straightforward, grid format.” Not only is this physical document thought to improve adherence, but Dr. Simmons emphasized that the choice reports are just as useful for clinicians in facilitating conversations about decision-making.
  • Shared decision-making requires comprehensive training, not just for physicians, but for entire care teams. In closing, Dr. Simmons recognized that current decision aid technology and utility is limited by our inexperience with these tools, but noted that there is great potential to engage patients more fully and improve outcomes if clinicians considered incorporating these tools and ideas into their practices.

Questions and Answers

Q: With regards to each individual patient and their multi-morbidities, how do you or other physicians at Massachusetts General Hospital evaluate what each patient’s multi-morbidities are? Do you use a scoring system? In sum, how do you determine what each patient’s health condition is?

A: I don’t think we’re that advanced yet. What has helped is that our EMR has allowed us to determine what things to focus on today. We haven’t used any scoring yet, but we use summaries of what things we can make clear and how to improve our performance down the road.

Q: My premise is that national clinicians, physicians and health care providers are poorly prepared in terms of risk reduction and evaluation. What is the obligation of professional societies to reteach this basic tenet and what is the role of ADA in mediating this change?

A: I couldn’t agree more. We certainly do need to develop tools that make it easy to make risk clear with our patients and ourselves. I think that is our position. However, I can’t say what the ADA should do about it.

Q: I’m just suggesting that this conversation needs to happen. Otherwise, ten years from now we are going to be facing the same thing.

A: Agreed.

Q: Significant numbers of patients have trouble with literacy and vision. Do you have any alternative formats for patients who can’t use the print format of your one-page diabetes aids?

A: Great question. When we looked at how these diabetes aids were being used, we noticed that –patients were looking at them in some cases – but the doctors were simply using them as a guide in most cases, to make sure they got through all the important questions: “What’s most important to the patient? What’s our action plan?” Also, I should say, the first question we always ask the patient is: “Do you want to read it yourself or would you like me to walk through this with you?” We give the option for exactly that reason. We started this with first-year medical residents and they found it helpful because they didn’t forget to talk about the important things.

Symposium: Bending the Curve—Behavioral Health Effects in Diabetes and Health Care Reform (with Richard R. Rubin Award Lecture)

Changing the Conversation in Behavioral Diabetes – Important Lessons My Patients Have Taught Me

William Polonsky, PhD, CDE (University of California – San Diego, San Diego, CA)

After accepting this year’s very well-deserved Richard R. Rubin Award, Dr. Polonsky shared an overview of behavioral diabetes and some of the key deficiencies in the field. Dr. Polonsky began his lecture by noting the variety of tools clinicians have at their disposal to assist patients, ranging from continuous glucose meters to insulin pumps, but emphasized that none of these tools matter if clinicians cannot convince patients to adhere to treatment. Indeed, he emphasized that the behavioral changes clinicians and patients collaboratively agree upon often cannot be sustained, partially through the fault of the provider. In this vein, Dr. Polonsky believes that clinicians are not necessarily good at providing behavioral interventions, because they are susceptible to three – what he believes are universal – traps: moving toward behavior change too quickly; focusing on only the more dramatic patient obstacles that make diabetes care difficult; and presuming that any and all selected goal behaviors are equally valuable. In addressing these issues head-on and calling out these common problems, Dr. Polonsky presented a compelling overview of the field and provided actionable solutions for change.

  • “Perhaps we are a little too in love with behavior change.” Dr. Polonsky emphasized that many of his patients will agree to lifestyle modification, only to renege on those commitments later on. In this sense, he believes that “collaborative action planning,” the idea that clinicians and patients can simply work together to establish a specific behavior plan, is often not sustainable.
  • Dr. Polonsky argued that issues with behavioral therapy can be summarized in three major themes:
    • The Importance of Taking Time – Dr. Polonsky highlighted the necessity of collaborating with patients to ensure that they believe the selected behavior change is worthwhile. However, he suggested that most clinicians rush to prescribe behavioral changes too soon, without taking the time needed to make sure that the patient is fully engaged and committed.  This is understandable, because clinicians are enthusiastic “problem-solvers” by nature and genuinely care about their patients’ health. But  clinicians often ask more of their patients than is realistic, and these overwhelming expectations can actually be harmful and undermine the behavioral changes being prescribed.
    • The Importance of the Mundane – In discussing the risks of diabetes, Dr. Polonsky argued that clinicians often focus on the wrong issues – while fear of hypoglycemia, complications, eating disorders, and depression are dramatic, he emphasized that these obstacles may not actually be that common and that some of the more mundane (and much more common) obstacles to good diabetes care (such as feelings of fatality and apathy) are not given proper attention.
      • The prevalence of “diabetes distress,” defined by Dr. Polonsky as “the sense that diabetes that is overwhelming or too difficult to handle,” is remarkably prevalent-- 39% in type 1 patients and 35% in type 2 patients. Instead of focusing on the more “dramatic” issues, the prevalence of which Dr. Polonsky argued are often unclear or lower than reported, he suggested that clinicians should emphasize the value of interventions that target diabetes distress – this effort will help patients as much as any other.
    • The Importance of ATMs (Actions That Matter) – Dr. Polonsky noted that many clinicians blindly endorse behavioral change without emphasizing that the selected action to change matters a great deal. All self-care actions are not equally valuable.  In particular, some actions, such as adhering to a medication schedule, may be more valuable than others, such as dietary restriction, and it is a clinician’s responsibility to inform the patient of these differences. Taken together, Dr. Polonsky endorsed collaboration between patient and provider to select behavioral goals that can make a real difference.  

Symposium: Legacy Effect, Metabolic Memory, and Implications of Clinical Care

Incorporating Metabolic Legacy Effect Into Clinical Decision Making

Neda Laiteerapong, MD (University of Chicago, Chicago, IL)

Dr. Neda Laiteerapong discussed how clinicians can talk to patients about the metabolic legacy effect, in light of principles from psychology and behavioral economics. She also shared data from a small survey enrolling adults with hypertension and recent-onset type 2 diabetes (n=43). These patients were asked about how their willingness to add a new diabetes medication would change if they knew that the benefits on complications risk would take 10 years to begin (lag time) but that these benefits would then persist for more than a decade (legacy effect). As Dr. Laiteerapong had expected, lag time decreased patients’ intention to start a new drug, but legacy effect increased it. She therefore suggested that clinicians explain the legacy effect when trying to motivate their patients. She also recommended that policy decisions in type 2 diabetes be based on a 20-year timeframe – longer than often used in public health discussions, she said. 

  • When clinicians talk to patients about long-term decisions, the opportunities and challenges involve ideas from psychology and behavioral economics. A patient’s adherence depends in part on factors like self-efficacy (the belief that they are able to adhere to a diabetes-conscious lifestyle), outcome expectations (their belief that these efforts will lead to desired outcomes), and ability to delay gratification – a trait that may be determined early in life, Dr. Laiteerapong said. She also noted that most people work harder to avoid losses than to make gains, so she suggested that clinicians could motivate patients by framing the legacy effect as something they will lose if their glycemic control is inadequate. She also observed that translating UKPDS data to risk-benefit decisions is challenging on an individual level, given the many uncertainties involved (e.g., difficulty of reaching glycemic targets, risk of complications, life expectancy).
  • Dr. Laiteerapong reminded the audience that “patients in general do not want to take medications.” With regard to diabetes in particular, she said that initiating drug therapy is often seen as a personal failure, and that intensifying drug therapy is equated with an increased risk of complications. We assume that this somewhat paradoxical perception contributes to therapeutic inertia.
  • Dr. Laiteerapong presented data from a survey about decision making among adults with hypertension and recently diagnosed type 2 diabetes (n=43). The patients’ mean age was 59 years old, mean A1c was 6.8%, mean duration of diagnosed type 2 diabetes was 3.3 years, mean duration of diagnosed hypertension was 10.6 years, and mean blood pressure was 134/76.
    • In an interview format, patients were first asked about their willingness to take an additional diabetes pill or to start on insulin, if their doctor recommended it. Patients rated their willingness on a scale of 10. A response of ≥7 was considered “high likelihood” of taking the additional drug. Nearly two thirds (65%) of participants were highly likely to take an additional pill, and fewer than half (44%) were highly likely to take insulin.
    • Patients were then asked how their willingness to take an additional diabetes drug would change based on lag time (no benefits for 10 years); finally, they were asked about how their willingness would change given the legacy effect (benefits persist for more than 10 years once they start). (The timelines for lag time and legacy effect were based on UKPDS.) When considering starting on an additional pill, 42% of participants said that lag time would decrease their willingness to start a new drug. However, 37% said that the legacy effect would increase their willingness. When considering insulin, lag time decreased willingness for 23% of patients, and the legacy effect increased willingness in 33% of patients. Patients were especially motivated by the prospect of performing tight control for a decade but then being allowed to stop some or all of their drug regimen.
    • Dr. Laiteerapong noted that the study had several important limitations, including its small sample size, the fact that it was conducted at only one institution, and its reliance on patients’ reported intentions rather than actual behavior. 

Questions and Answers

Q: Why is it that so many patients in the original study succeeded for 9 years to control their glycemia? They did not know there was a reward at the end. They were expected to be highly performing; there seems like this would involve a notion of scolding if they did not succeed. Perhaps this is a stronger impetus to intensive control than knowing about the legacy effect.

A: There are a lot of strategies to try to motivate to lifestyle changes. There has been a lot of good research on health coaches, peer coaches, and peer support. This study addressed another variable that might be helpful; some patients might be helped by thinking about their life course in discussions of diabetes. I think this could be an important adjunct to what we already do in practice.

Q: The flip side to the legacy effect has yet to be mentioned. There is a nihilistic attitude that can come out of this. The person who has failed to engage early on, if they decide to come on board at a later stage, they can never recapture that earlier benefit, can they? So how much of this information should we give to patients? Should we tell them that they may never get as good benefits as someone with tight control from early on?

A: Clinicians deal with this all the time; there is some information we share and some we don’t share. I am staying neutral about what we should or shouldn’t do. In this study we tried to involve people with early-onset disease so that we did not have ethical issues of providing this info to patients who were unlikely to benefit. I think that patients tend to be highly motivated.

Q: I have accumulated a lot of data in type 1 diabetes from my 30 years of private practice in the same location. Among my patients with severe hypoglycemic unawareness, there are two groups. One refuses to tighten up their control. There is another group that I would encourage to stay at around 8% after having diabetes for 3 or 4 decades [rather than the tighter goal that these patients are using for themselves].

A: This study was in type 2 diabetes. They were very interested in stopping medications. Nearly 100% of participants said they would stop their medications if their doctor said they could, though some people said they would want a second opinion before stopping.

Q: I don’t know if delayed gratification is entirely appropriate for talking about diabetes management. If patients have been symptomatic they feel better immediately; if they get A1c down that can provide short-term positive feedback. I wonder if we’re just not using right tools to motivate long-term changes.

A: I would agree that quality of life is generally improved with better glucose control. I love that you are using this to motivate patients and would like to ask what they said in response.

Q: Do you frame the effects of therapy in terms of changes in absolute risk and benefit over time? These calculations vary with patient age.

A: We can run into problems with how well patients understand numbers. We provided qualitative descriptions; if patients pressed us for numbers, we used the figures from UKPDS. We did not modify the description based on patient age, given that most people were early in their duration of diabetes.

Q: I worked in the Early Treatment Diabetic Retinopathy Study. I recently talked to a colleague about patients with severe complications who were doing well years later. I am a pediatric practitioner, and most of my patients have A1c over 10%. I think we need more subset analysis of patients who weren’t in great control early on and who have since done really well. We want to inspire hope. We want to look at who does well despite a poor legacy.

A: We work mainly with adults with type 2 diabetes, who have a shorter life expectancy than children with type 1 diabetes. I think we need to understand how early vs. late intensive glycemic control affects outcomes.

Q: We take care of kids who are diagnosed with type 1 diabetes at earlier than age 5. The targets for A1c are higher in this population. Do we aim at higher sugars because we want to avoid hypoglycemia? Are we thereby creating individuals with a bad metabolic legacy? Are legacy effects different for different types of treatment – perhaps insulin is more physiologic, and orals less physiologic?

A: I don’t think we have outcomes data for pediatric patients. We don’t know if different medicines have different legacy effects.

Oral Presentations: Improving Health Care Delivery

Provider Beliefs on Optimal Glycemic Control and Barriers to Achieving It (323-OR)

Erin LeBlanc, MD (The Center for Health Research, Wallingford, CT)

Dr. Erin LeBlanc presented results from a BMS/AZ-funded survey administered to primary care physicians at Kaiser Permanente NW – the goal was to determine whether provider attitudes about optimal glycemic control were linked to patient outcomes and delays in treatment intensification for patients not at goal. Responses to the five-item questionnaire (n=150) revealed that 77% of clinicians agreed that most patients should aim for an A1c of <7%, though (shockingly) only 62% agreed that an A1c above 9% was unacceptable for everyone. Eighty percent of respondents said that they typically waited three to six months before changing a patient’s medication regimen – one-third said they would prescribe a change after one A1c >0.5% above goal, and 55% said they would wait for two A1cs 0.5% above goal or one A1c that was one percentage point above goal. This was also pretty depressing since we assume there is some survey bias here and HCPs probably wait even longer than they say they do. Only 25% of the providers said they would intensify treatment in response to an elevated A1c for a patient already on multiple medications – also quite depressing. Overall, the study did not find a clear correlation between providers’ views on optimal A1c targets and treatment intensification and their patients’ outcomes, though Dr. LeBlanc cautioned that this was a fairly simplistic, limited study and that more research will be needed – that said, if this is what Kaiser doctors think, we’d say we’re really in trouble.

  • The goal of this study was to determine whether clinicians’ attitudes about optimal glycemic control were correlated with their patients’ A1c levels, and whether these views contributed to delays in treatment intensification commonly seen with patients who are not reaching goal. Many patients will have an A1c above target at multiple provider appointments before their medication is adjusted, and research has shown that 50-60% of A1cs above goal don’t result in any therapy change. There is surprisingly little data on clinicians’ opinions about optimal A1c goals, and Dr. LeBlanc and her colleagues wanted to investigate whether the delays in treatment intensification were mainly a result of clinical inertia or a more legitimate clinical rationale, as well as whether providers’ attitudes about optimal A1c correlated with patient outcomes.
  • Providers at Kaiser Permanente NW completed a five-item questionnaire constructed based on qualitative interviews with other clinicians. Dr. LeBlanc and her colleagues spent 12 hours interviewing providers about their approaches to glycemic control and constructed the questionnaire based on the main issues raised in those discussions. The questionnaire was administered to all 252 primary care providers at Kaiser and 150 providers completed it (60% response rate).
  • Most of the clinicians agreed that <7% was the optimal A1c target for most of their patients, but many were hesitant to immediately intensify the treatment regimen for patients with an elevated A1c.
    • Eighty percent of respondents said that they typically waited three to six months before changing a patient’s medication regimen. One-third of the providers said they would prescribe a change after one A1c >0.5% above goal, and 55% said they would wait for two A1cs 0.5% above goal or one A1c that was one percentage point above goal. Only 25% of the providers said they would intensify treatment in response to elevated A1c for a patient already on multiple medications.
    • Three-fourths (77%) of clinicians agreed that most patients should aim for an A1c of <7%, but 37% agreed that an A1c between 7% and 8% was acceptable and only 62% agreed that an A1c above 9% was unacceptable for everyone.
    • The most common reasons physicians cited for their patients’ chronically high A1cs were psychosocial issues, resistance to lifestyle change, noncompliance, and lack of time.
  • For the most part, providers’ opinions about glycemic goals did not correlate with their patients’ A1c levels. The researchers did find a couple of links: patients cared for by the 19% of providers who agreed that research didn’t support an A1c goal of <7% had a 13% lower chance of having an A1c below 7%, and patients cared for by the 22% of providers who disagreed that some patients will inevitably have an A1c above 9% had a 16% lower chance of having an A1c above 9%. In general, though, clinicians’ beliefs and their triggers for treatment intensification did not have a significant effect on their patients’ glycemic control.
  • Dr. LeBlanc acknowledged several limitations of the study, mostly stemming from the small, homogeneous sample and the complexity of the topic. The study only analyzed responses from 150 providers who all worked at the same organization, limiting the representativeness of the findings. In addition, as several questioners from the audience pointed out, physicians at Kaiser are not paid on a fee-for-service basis as most US doctors are, and their patients are much less culturally diverse than those in many other practices. Dr. LeBlanc also suggested that the patient-provider interaction may be too complex to analyze in a five-question survey and that future studies need to take the patient perspective into account to a greater extent than this one did.

Questions and Answers

Q: I’m disturbed by the number of clinicians who felt A1c could be above 9%. But all the literature in recent years has been saying we have to individualize target goals, so it’s not surprising that we have a wide range. I don’t think anyone agrees that <7% is always optimal anymore. How do we rethink questions like the ones you addressed based on that new understanding?

A: We agreed with you, so we were careful to say “0.5% above their individual target,” etc. When people in the literature say there’s clinical inertia and no one’s at 7%, is it because people aren’t aiming for that? Did providers not think it was an appropriate goal? Lots of providers we surveyed didn’t think it was the right target for many patients, especially older patients with lots of comorbidities. (Editor’s note – from a patient perspective, rather than assuming higher targets are appropriate for patients who experience hypoglcyemia, for example, what about the option of prescribing medicines not associated with hypoglycemia? We believe this will be easier when oral fixed dose combinations of branded drugs become available that are easier to prescribe and pay for and take; as well, GLP-1 combined with basal insulin will likely be easier for some patients to take than basal insulin and multiple daily injections of mealtime insulin.)

Q: I believe the physicians you surveyed were Kaiser employees. Would it make a difference if the physicians were fee-for-service rather than employed?

A: The cost issues for providers and patients do differ in the Kaiser setting, so I agree that’s another limitation. The patient population at Kaiser is also not that diverse, so that might be why cultural issues didn’t come up. In the qualitative interviews, that was a bigger issue, and cost issues also came up in qualitative interviews at certain clinics.

Meet-the-Expert Session: Adolescent Care Transitions

Adolescent Care Transitions

Lori Laffel, MD, MPH (Joslin Diabetes Center, Boston, MA); Anne Peters, MD (USC Westside Center for Diabetes, Los Angeles, CA)

Drs. Lori Laffel and Anne Peters discussed challenges of transitioning pediatric type 1 patients to an adult model of care. According to data from T1D Exchange, adolescence is the most difficult time for achieving glycemic goals – A1c is highest in patients ages 13-17 (mean: 8.7%), closely followed by patients in the 18-25 age (mean: 8.5%). In contrast, patients 12 years and under have a mean A1c at 8.3%, and those 26 years and older have an average 7.7% A1c. Drs. Laffel and Peters attributed the sustained increase to “emerging adulthood”, a disruptive series of factors occurring in young adults. As mean ages for major life milestones increase (e.g., expected education levels, marriage, long-term jobs), the latency in transitioning to effective adult care increases as well. Often, transitions to adult care occur abruptly, leading to negative health outcomes. Data from Garvey et al. in Diabetes Care suggests that 35% of young adult patients had a lapse in care of six months or greater, and only 63% reported feeling prepared for any transition. Drs. Laffel and Peters expressed that these ineffective transitions are linked to as much as four times as many diabetes-related hospitalizations in the first two years. In order to alleviate these care transition challenges, the speakers encouraged greater autonomy and self-care for older teens, as well as innovative strategies that rely on mobile communication and support communities reinforced by social media.

Current Issues: Are the New ACC/AHA Guidelines for Lipids Appropriate for Diabetes?

Pro

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

Dr. Robert Eckel provided a somewhat defensive argument about how the ACC/AHA’s new lipid guideline is the most evidence-based assessment of how to use cholesterol-lowering drug therapy to reduce atherosclerotic cardiovascular disease (ASCVD) risk (for background on what the new guideline entails, please see bullets below). Our view by the end of his presentation was that the ACC/AHA had good intentions of very rigorously assessing the entire evidence base out there and coming up with a statement that reflects that, but delivered the message poorly in a way that is misleading many providers into thinking that ACC/AHA are actually recommending against using LDL targets or non-statin therapies.

  • Dr. Eckel heavily emphasized that guidelines are not meant to dictate and restrict, but to support and guide and that the ACC/AHA guideline does not mean that providers can no longer use LDL goals or other LDL-lowering medications besides statins, but just states that there has yet to be any evidence that these strategies are beneficial (in part because there has not been an incentive yet to design a trial to prove that using LDL targets is beneficial).
  • For background, he reminded the audience that this process began five years ago when the NHLBI set out to update the outdated ATP-III, but when the NHLBI announced it would step away from making clinical guidelines, ACC/AHA stepped up to the plate to finish the work they had started – Dr. Eckel made this statement in defense of the mounting criticism ACC/AHA have received for the new guideline, suggesting that they were simply carrying out a mission they had been charged with and that had already undergone substantial internal and external review when the NHLBI was working on it.
  • He briefly showed some of the evidence used to inform the guideline – notably the Cholesterol Treatment Trialists group has published evidence showing benefit of statin therapy independent of cholesterol level, and benefits across a wide range of patient demographics and disease types (Lancet 2010). He acknowledged that the 7.5% 10-year ASCVD risk cut off was somewhat arbitrary, but based on evidence that even a 5% risk would warrant intervention.
  • For background, the AHA/ACC guideline recommends treating people for high cholesterol using statin therapy if they fall into one of four risk categories of people most likely to benefit from statin therapy: (i) people with existing atherosclerotic cardiovascular disease (ASCVD – e.g., stroke, coronary disease, aortic aneurysm, peripheral vascular disease, etc.); (ii) LDL ≥190 mg/dl and age ≥21 years; (iii) primary prevention with diabetes, aged 40-75 years and LDL 70-189 mg/dl; (iv) primary prevention without diabetes but with 10-year risk score of ≥7.5% (using the new risk calculator), aged 40-75 years, LDL 70-189 mg/dl.
    • The guideline also states that no evidence exists for using certain LDL targets, so it simply recommends that you put patients that meet any of the above criteria on a statin and monitor for adherence. The previous LDL treatment paradigm had been centered around meeting certain LDL goals. Dr. Eckel emphasized that goal setting in clinical practice may be very useful, but there just haven’t been trials conducted to prove that.
    • Another major point of the new guideline is that non-statin therapies have not been proven to provide ASCVD risk reduction benefits or safety profiles comparable to statin therapy. Again, Dr. Eckel stated that if someone still needs residual LDL-lowering after going on a statin, it is of course good clinical practice to try another LDL-lowering drug, but the evidence just does not exist yet to show that this is beneficial.

Con

Henry N. Ginsberg, MD (Columbia University College of Physicians and Surgeons, New York, NY)

Dr. Henry Ginsberg took issue with the ACC/AHA guidelines in a number of areas, although he started by saying that he welcomed the concept of initiating treatment based on patient risk. However he was strongly derisive of ACC/AHA’s claim that these guidelines were strictly evidence based - or the implication that prior guidelines were not – and showed many examples of the use of expert opinion, rather than strict application of trial data. However, his definition of applicable trial data was the randomization of the exact risk groups, rather than meta-analyses. Meanwhile, he was disappointed by the removal of specific targets for LDL cholesterol lowering and no mention of other therapies. He showed evidence that the lower the LDL-C (by whatever means), the lower the risk of a cardiovascular event. Following this maxim, he noted that if statins are not appropriate or fail to reach goal, then there is no clear guidance on how to go further and help the patient – particularly in the case of people with diabetes.

  • Dr. Ginsberg welcomed the stratification of patients by risk when determining whether to prescribe a statin. The new ACC/AHA guidelines divide patients into four groups based on risk (clinical atherosclerotic cardiovascular disease (ASCVD), patients with LDL cholesterol (LDL-C) >190 mg/dl, people with diabetes and LDL-C between 70-189 mg/dl, but no existing ASCVD), and give guidance on the appropriate intensity of treatment with statins, but no targets for LDL-C.
  • The new ACC/AHA goals are supposed to minimize expert opinion and be fully evidence-based, but Dr. Ginsberg believes that this is not true. He presented extensive evidence (for each of the four risk groups) that the randomized controlled trials considered by the committee did not randomize patients at the specified level of risk at baseline – so the recommendation is necessarily based on meta-analyses.
  • Dr. Ginsberg gave his own recommendations for each of the four groups:
    1. For patients with existing ASCVD, we should treat them all with high intensity statins (not just the under 75).
    2. For patients with LDL-C >190 mg/dl, “common sense and integration of a large body of data from numerous sources say it is OK to treat” with statins.
    3. Diabetes is associated with higher event rates, so Dr. Ginsberg would treat with high intensity statins, since there is no evidence that high intensity statins are not just as good and their safety has been established. He stated, “I wouldn’t differentiate based on primary or secondary prevention”.
    4. Dr. Ginsberg noted that that the evidence is just as good for 5% as for 7.5%, but he was “OK with the recommendations”.
  • Since in Dr. Ginsberg’s view, there were plenty of exceptions and inconsistencies in the use of the data, he was disappointed that the Expert Panel couldn’t find evidence for the use of targets (for LDL or non-HDL). He stated, “…All the evidence we know shows that any way to lower LDL reduces cardiovascular disease, irrespective of the exact mechanism of LDL lowering”. He also went on to posit that “lowering LDL more is better than lowering LDL less” – implying that it makes sense to set goals.
  • Dr. Ginsberg also wanted guidance on what to do if high dose statins didn’t succeed in lowering LDL below 110mg/dl – presumably other drugs should be used to reach a target, but non-statins are rejected. He favors the ADA guidelines, which do set targets. He believes that there should be non-statin choices for LDL >70 mg/dl. High triglycerides and low HDL-C should be approached with diet and exercise, but the possibility of combinations to treat severe dyslipidemia should be supported (fibrates and possibly niacin).

Rebuttal

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

Dr. Robert Eckel rebutted Dr. Ginsberg’s arguments that the ACC/AHA guideline was not quite as evidence-based as it claims to be. His points boiled down to the idea that where the evidence does not yet exist, one must then exercise expert clinical judgment. For example, in response to the criticism that the ACC/AHA does not have clinical trial evidence to support the recommendation that everyone with LDL ≥190 mg/dl should be on a statin, Dr. Eckel said, “When you reach the need for a heart transplant or liver transplant, you don’t need a trial to tell you that you need the transplant,” suggesting that an LDL of ≥190 is so farcically high that it is a no brainer to treat it.

Panel Discussion – Selected Questions and Answers

Q: Are we setting ourselves up for never having data, because we can’t design the studies to answer the questions rigorously? In other words, are we going to stop using parachutes because there is no randomized controlled trial?

Dr. Henry Ginsberg, MD (Columbia University College of Physicians and Surgeons, New York, NY): There are two current trials of non-statin drugs that lower LDL. Hopefully people will be getting these drugs on top of statins, [in the trials], but if you take the strict use of the term ‘evidence-based’ there may not be extrapolation to the trials that say a lower LDL is better than a high HDL. Now the Panel has put themselves into a corner.

Dr. Robert Eckel, MD (University of Colorado, Aurora, CO): On the Panel, we were discouraged from expert opinion, since this is the current rule of the land. But the guidelines will be updated on a regular interval based on trial evidence, (although it’s not clear how they support this process). Dr. Ginsberg discards data based on the stringency of the trial design and that’s a concern. In the clinic what I recommend is that you document that the guideline has been applied to the patient and beyond that you then have a lot of room to do other things. If you are in primary care, you can get consultation about subsequent steps. In fact, 80% of the decisions we make in the clinic go beyond the current guidelines.

Q:  We have still avoided the whole problem of why people with diabetes have more atherosclerosis than others. It has been demonstrated that LDL and HDL are modified by glycation. That may be a link with atherosclerosis in the diabetic patient. Why hasn’t there been more attention to that process as opposed to just pushing the LDL-lowering lower and lower?

Dr. Ginsberg: I think we had three large trials that looked at lowering A1c, all of them I think showed difficulty of doing that in large clinical trials. Maybe they were all in patients who were irreversible but none of those trials in which A1c went from 8.3% to 7% or 7.4% to 6.4% showed benefit, and of course the ACCORD trials showed some detriment. I think glycated LDL and HDL exist and relate to control. Certainly people with very high A1cs may suffer some consequence. The in vivo applicability is still less certain than it was in mice but I think we have failed at proving in a late stage cohort of diabetics that lowering their A1c reverses their disease over the next several years. It’s been very disappointing, as you know.

Q: What happens in patients with high triglycerides. Should we use fibrates?

Dr. Ginsberg: If you look at fibrate trials, the monotherapy trials are even more positive for high triglycerides, even those trials that were negative overall.

Dr. Eckel: Imagine we have a patient with 6.9% A1c and triglycerides of 350 mg/dl, and LDL around 75-80 mg/dl on an appropriate dose of statin. For that patient I would add a fibrate and would tell her about the trial evidence. This again goes beyond the guidelines.

Q: Before I agree with Henry’s point about targets I do want to say these guidelines are tour de force of examining the evidence. I really compliment the committee. Having been on a guideline committee, my heart goes out to members of the guideline committee – it is thankless, and no matter what you come up with, it is often criticized often both ways for opposing reasons. Having said that, in Canada in 2009 when we came up with a target LDL of 2.0 mmol/L, we were totally aware it was not evidence based. There was no question about that we understood it, but it was a public health recommendation that was very easy for people to follow. Sometimes I think there can be a tyranny of evidence or evidence-based policy that actually ends up worse off. I think you could take your evidence and make it very user friendly. I think that’s one problem – the translation of the evidence to make it user friendly for the practicing clinician.

Dr. Eckel: The process wasn’t a simple one, and we kept getting reminded that trials were not designed to reach 100 mg/dl or 70 mg/dl and ultimately the committee in consensus voted for the guidelines as they stand. Practicality is problematic. I see nothing wrong with setting goals – if you want to interpret evidence to set a number. I still set goal with my patients, but keep in mind to realize that the goal is not in line with the guideline.

Q: The guidelines mention lifetime risk, but the calculators are strongly weighted to age – so should we wait for young people to get older for the risk to increase before we treat them?

Dr. Eckel: Lifetime risk is so appropriate, especially for women, and the Framingham score doesn’t look at lifetime risk.  There is never going to be a study that examines it, so we never are going to have the data. We should treat now, rather than wait in certain circumstance.

Dr. Rob Ratner, MD (American Diabetes Association, Alexandria, VA): We need to use common sense and use the guidelines as recommendations. Unfortunately we deal with organizations that don’t always apply common sense and yet pay for coverage. Have we seen denial of service for the use of lipid measurement as quality indices yet? [A few people raised their hands]. But it is recommended that we measure lipids three months after starting statins and annually. Goal setting behavior is not wrong, if you feel it’s appropriate then just include it in your note. And if decisions are going beyond the guidelines you should be fine (for reimbursement).

Q: I just want to focus on the young adult type 1 diabetic with 10-year diabetes duration. They are often ignored. We discussed this yesterday in the new ADA position statement on type 1 diabetes, and I don’t feel this is reversing now. We presented some data from the EDC and Scottish registries that show that risk for a type 1 younger than 40 years with 20 years diabetes duration is very close to that 7.5% cut-off – about 6.9% 10-year risk and after that the 7.5% cut point – statin therapy. Could you comment on whether a type 1 diabetes young adult with 20-year disease duration in their 30s really should be on moderate intensity therapy? My other question is why blood pressure trials have goals but none of the lipid trials do. I’ve never understood why blood pressure is treated so differently from lipids in terms of trial design.

Dr. Ginsberg: In type 1s, it comes down to taking a gestalt view of everything we know about atherosclerosis and multifactorial disease, but LDL cholesterol and other atherogenic lipoproteins are critical. I always talk to students about Japan 30-40 years ago when everyone’s LDL was 60 mg/dl, and everyone smoked two packs a day, etc. but there was no coronary disease. If you have other risk factors for atherosclerosis, having lower LDL is beneficial. So you have to have a leap of faith or a leap of knowledge to make some of those decisions. But should a 10-year-old with five-year disease duration be on a statin? If you did lifetime risk where would they be? I think the biggest conundrum is the 15-year-old with type 2 diabetes, and should they be on an ACE or statin? In type 1 with prolonged duration, I think they should be on a statin.

Dr. Eckel: I think the disease may be somewhat different from type 2 diabetes, and that needs careful scrutiny with ways to study it in terms of basic science and clinical trials. In type 1 I just haven’t heard. In America there are 1.5 million type 1s so it’s not a trivial disease, and we clearly need more data. In terms of numbers of hypertension and not lipids I agree; I have the same problem. I maintain numbers in my clinic because they’re useful but I defend the guideline as it stands because that’s what the committee decided was most evidence-based.

Q: In the PCSK9 trials they are going to analyze quartiles and tertiles of LDL, which might prove that targets make a difference.

Dr. Ginsberg: I imagine that there are pre-specified analyses in terms of LDL achieved, but even if that’s done, the evidence based purists wont abide because it’s not a randomized sub-group.

Q: As a foreigner, can we apply these guidelines to other ethnic groups? I know it would be great if we made or own guideline based on our own RCTs but we don’t have enough numbers of RCTs, and we can’t afford to do that.

Dr. Eckel: Part of the approach of these guidelines was to use trials that have a global population. There was no restriction of the US or North America. The entire world participated in these clinical trials. Keep in mind the recommendations for African Americans and Caucasians were based on populations in this country that were black or white. I think you can with comfort use the risk estimator for our population and just realize unfortunately there’s not enough evidence for people from certain populations – they haven’t been represented specifically enough in clinical trials. But I think you can be comfortable using the calculator for black or white and just know that it’s not that far off.

Dr. Ginsberg: I think there’s one important thing about this question – in Asians there are clearly differences in pharmacokinetics in the metabolism of statins. Much lower doses appear to be as beneficial in terms of LDL-lowering and also higher doses appear to be associated with more adverse effects, particularly myopathy and liver enzyme elevations.

Q: What is the official position of the guideline committee on follow up, success, failure, what to do?

Dr. Eckel: Follow up should be from 3-12 months to assess adherence. It is not to set goals but if you’re setting goals, you can do that. The guidelines said no assessment of lipids going forward. I was routinely measuring lipids in people every six months and getting back to them. That’s probably not necessary. You don’t see people’s lipids really change if they remain on the same dose of a statin. The problem that needs to be assessed is adherence.

Dr. Robert Ratner (Chief Scientific & Medical Officer, American Diabetes Association): Our practice committee is discussing whether to change ours to meet the standards of the ACC/AHA or continue using our target-based standards that go beyond LDL and incorporate non-HDL and triglycerides. By a show of hands, how many of you feel as though the ADA guidelines need to become consistent with the ACC/AHA [very few hands are raised]. How many of you believe that we should continue with the targets? We may modify them [majority of hands are raised].

Corporate Symposium: Contemporary T2DM Management (Supported by an unrestricted educational grant from AstraZeneca)

Welcome and Introductions

Zachary Bloomgarden, MD (Mount Sinai School of Medicine, New York, NY)

Dr. Zachary Bloomgarden began the symposium with a meta-analysis of different add-on therapies to metformin, comparing them in terms of efficacy, hypoglycemia, and weight gain. He highlighted that GLP-1 analogs were found to be the most efficacious and that sulfonylureas (SFUs) were associated with a marked increase in hypoglycemia. He also presented ACCORD data showing that in the intensive arm of the trial, individuals with lower on-trial mean A1c had a reduction in mortality, and individuals with baseline <8.5 had no increase in mortality, while those with A1c ≥8.5% had 1.6-fold increased mortality (p=0.044). He concluded by stating that providers must treat people for the long-term, noting that in the Da Qing prevention trial the time course of complications due to hyperglycemia runs from six years (diabetes) to 20 (retinopathy) or 23 years (cardiovascular death).  

Societies’ Practice Recommendations

Yehuda Handelsman, MD (Metabolic Institute of America, Tarzana, CA)

Starting with an example of a middle-aged, female, type 2 diabetes patient, Dr. Yehuda Handelsman presented an overview of the ADA and AACE guidelines for diabetes treatment. He emphasized the importance of individualized A1c goals: 6.5-6.9% for most; <6.5% and as close to normal for newer, younger, and healthier diabetes patients’ and less stringent goals >7% for less healthy patients, to avoid the risk of complications like hypoglycemia. Both the ADA and AACE algorithm encourage providers to individualize treatment and to intensify treatment quickly if patients are not reaching their A1c goals.

Role of GLP-1 Analogues and DPP-4 Inhibitors

Ralph DeFronzo, MD (University of Texas Health Science Center at San Antonio, San Antonio, TX)

While the topic that Dr. Ralph DeFronzo had originally been assigned was GLP-1 analogs and DPP-4 inhibitors, he focused primarily on GLP-1 analogs and TZDs per request of conference organizers (as elucidated in later conversations). Dr. DeFronzo proclaimed that GLP-1 analogs were “the most effective drugs” for diabetes. Of the positive effects of GLP-1 analogs, he focused on their ability to reduce A1c and the potential to preserve beta cell function. Besides GLP-1 analogs, he also promoted the use of TZDs due to their pleiotropic effects, including increases in insulin sensitivity and secretion and reductions in glucagon production. Importantly, Dr. DeFronzo emphasized that GLP-1 analogs and TZDs have durable A1c drops, whereas A1c levels start creeping back up with SFU use. After explaining that GLP-1 analogs and TZDs address multiple aspects of the “ominous octet” of pathophysiologic defects in type 2 diabetes, he concluded by stating that he prefers GLP-1 analogs and TZDs as his first line of treatment for type 2 diabetes patients.

  • With regard to GLP-1’s potential beta cell preservation effects, Dr. DeFronzo stated that “there is nothing else like this.” Comparing the ratio of C-peptide secretion to baseline after one year of using exenatide or insulin glargine reveals a huge difference (3.19 vs. 1.31). Also, he described a study on liraglutide (Novo Nordisk’s Victoza) that showed how a single dose restores beta cell insulin response (Chang et al., Diabetes 2003). He stated, in characteristic hyperbolic fashion, that this was “the most impressive study that’s been done.”
  • Dr. DeFronzo also addressed the concern that TZDs increase the risk of bladder cancer. He cited an eight year study analyzing the incidence of bladder cancer in 193,099 type 2 diabetes patients over forty years old on TZDs, which showed that there was no increased incidence of bladder cancer for patients with pioglitazone (Lewis et al., Diabetes Care 2011).
  • “I like GLP-1 analogs and TZDs as my first line of treatment.” He then listed the six parts of the “ominous octet” of defects in diabetes pathophysiology that GLP-1 analogs address: reduced insulin secretion, elevated hepatic glucose production, reduced glucose uptake in muscles, increased glucagon secretion, reduced incretin effect, and neurotransmitter dysfunction. TZDs correct four areas of the “ominous octet”: reduced insulin secretion, elevated hepatic glucose production, reduced glucose uptake in muscles, and increased lipolysis. Comparatively, “SFUs correct none of the abnormalities” and “metformin works on the liver, but that’s it.”

SGLT2 and SGLT1/2 Inhibitor Therapy of Type 2 Diabetes

Robert Henry, MD (University of California San Diego, San Diego, CA)

Dr. Robert Henry began his component of the symposium with an introduction to SGLT-1 and SGLT-2 inhibitors, their mechanism of action, and the differences amongst the various lead products in these categories. He highlighted the high potential this drug class holds for combination therapy due to its unique mechanism of action, and discussed several secondary effects related to SGLT-1/SGLT-2 antagonism therapy. While acknowledging some of the faults of SGLT-1/SGLT-2 inhibitors, Dr. Henry concluded his presentation by discussing two potential novel mechanisms for A1c reduction – bile acid sequestration and dopamine D2 receptor agonism.

  • Dr. Henry compared the efficacy of several SGLT-2 inhibitors in both monotherapy and in combination with metformin therapy. For monotherapy, all comparators exhibited similar reductions in A1c ranging from 0.6% to 1.0% for canagliflozin (J&J’s Invokana), dapagliflozin (AZ’s Farxiga), empagliflozin (BI/Lilly), and ipragliflozin (Astellas’ Suglat). Similar reductions took place in fasting plasma glucose as well, with a reduction of 29-65 mg/dl for the aforementioned drugs. As add-ons to metformin, further reductions in A1c were observed for all of the previously mentioned drugs, ranging from 0.5%-0.9% additional A1c reduction. Dr. Henry emphasized that the unique mechanism of these inhibitors allow them to be added to almost any therapy and yield a 0.7% to almost 1.0% reduction in A1c.
  • He noted several downsides to SGLT-2 inhibitors, and disclosed that a dapagliflozin pilot study in patients with type 1 diabetes will be published in the next few weeks in Diabetes Care. As previously noted, SGLT-2 inhibitors led to increases in LDL cholesterol of 5-10% for canagliflozin and 2-4% for dapagliflozin, with the mechanism for the increase still unknown. Dr. Henry also revealed details of a pilot study to be published soon in Diabetes Care (see our coverage of the poster on this study from ADA 2013). The 2-week randomized controlled trial studied 70 adults with type 1 diabetes on stable insulin who received one of four dapagliflozin doses. The ones on the highest dosage group of 10mg reduced their daily average blood glucose by a mean of 41.3 mg/dl. However, hypoglycemia was common across all dosage groups (60.0%-92.3% from 1-10m mg groups), although it was difficult in this pilot study to tease apart the treatment effect vs. background insulin therapy.
  • Dr. Henry touched on two novel mechanisms for combination therapy – bile acid sequestration (colesevelam) and dopamine D2 receptor agonism (bromocriptine) as potential areas for further research. Colesevelam is a non-absorbed polymer that binds bile acids in the intestine, lowering LDL cholesterol. When used in combination with metformin, SFU, or insulin therapy, there is a reduction in LDL cholesterol across all groups (p<0.001, p<0.001, p<0.05 respectively). Bromocriptine, on the other hand, is a D2 receptor agonist that increases morning dopamine receptor activity, thought to be low in type 2 diabetes. A 24-week efficacy trial of bromocriptine demonstrated A1c reduction between 0.5-1.0% versus placebo in patients groups that failed other combination therapies such as oral anti-diabetics, metformin, SFUs, and TZDs.

Do Insulin and Sulfonylureas Still Have a Role in Treatment?

Vivian Fonseca, MD (Tulane University Health Sciences Center, New Orleans, LA)

Dr. Vivian Fonseca responded to the question of whether insulin and SFUs still have a role in treatment with an emphatic “yes,” especially for economically disadvantaged patients. After acknowledging the negative side effects of insulin and SFUs, which include weight gain and hypoglycemia, he pointed out that long-term studies have shown that these agents are safe, whereas there hasn’t been time yet to study the long-term safety of newer agents. Regarding SFUs, he noted that it was necessary to be cautious about hypoglycemia, especially with A1c <7% or renal impairment. He then reviewed several trials showing the efficacy of insulin and insulin analogs. Dr. Fonseca questioned the conclusions of the recent JAMA article about delaying insulin therapy, noting that selection bias was a serious problem with retrospective analyses (see our coverage of the article here).

  • Dr. Fonseca highlighted cost as a key advantage of insulin and SFUs. While insulin analogs better mimic the physiological profile of insulin, and lower the risk of hypoglycemia, they are also more expensive. “The cost of all insulins has gone up, and that’s a problem.”
  • He cited several studies on insulin’s efficacy, especially for patients with higher A1c. One study showed that the addition of basal insulin to combination oral therapy was more effective (p <0.05) than the addition of a third oral agent for patients with A1c >9.5% (Rosenstock et al., Diabetes Care 2006).
  • Dr. Fonseca also mentioned the necessity of adjusting insulin doses more frequently and the possibility that technology can help patients reach their goals. Many times, patients stay on the same dose of insulin, even if it isn’t enough to lower their A1c. He said he was working on a fully automated algorithm that would message his patients to increase their dose if they weren’t reaching target A1c levels.
  • He also questioned the recent JAMA article about delaying insulin therapy, noting that selection bias was a serious problem with retrospective analyses (see our coverage of the article here).

Panel Discussion

The subject of the panel discussion was a case study of a middle-aged African-American woman having difficulty with following up with her doctor and maintaining glycemic control. Dr. Vivian Fonseca and Dr. Ralph DeFronzo seemed to disagree on what they believed to be the most effective first-line therapy for type 2 diabetes. Dr. Fonseca cited drug cost and patient willingness to self-inject as key considerations for prescribing metformin. Dr. DeFronzo disagreed, citing his institution’s substantial funding and his personal endorsement of combination therapy to justify prescribing a GLP-1 and pioglitazone. This disagreement and other differences in opinion led to some intriguing back and forth between all of the panelists.

Q: Recall Judith, the 54-year-old African American woman. She is probably not going to exercise, and won’t really improve her lifestyle. Her kidney function is good, and her A1c is 7.4%. Which treatment will you give to Judith? Will you start with a GLP-1 analog, a TZD, a DPP-4 inhibitor, an SFU, an SGLT-2 inhibitor, metformin, a combination of an SGLT-2 inhibitor and a DPP-4 inhibitor, a combination of a GLP-1 analog and a DPP-4 inhibitor, or a combination of a GLP-1 analog, a TZD, and metformin?

Dr. Zachary Bloomgarden, MD (Mount Sinai School of Medicine, New York, NY): Metformin. She’s at a level where with some lifestyle modification and one agent, metformin, we can expect a good initial A1c fall. I don’t see any reason for two drugs.

Dr. Vivian Fonseca, MD (Tulane University Health Sciences Center, New Orleans, LA): Metformin.

Dr. Robert Henry, MD (University of California San Diego, San Diego, CA): Metformin only.

Dr. Ralph DeFronzo, MD (University of Texas Health Science Center at San Antonio, San Antonio, TX): If cost is not an issue, this lady would get a GLP-1 analog and pioglitazone. But if cost were an issue, I would pick a different combination. Because of where I work, I get to decide the formulary, so cost isn’t an issue. Normally, cost is critically important; if your patients can’t afford the drug, they can’t take it.

Dr. Fonseca: I don’t think it’s a cost issue; metformin has been shown to work in the long-term. There isn’t enough data around your treatment choice.

Dr. DeFronzo: [jokingly] I can’t change, I’m too old. I’m older than Vivian.

Q: Do you think of diabetes as a progressive disease in that all beta cells must die eventually?

Dr. Fonseca: The rate of progression differs considerably. Over half of my patients remained controlled after five years on metformin. You have to see if they are responding to first-line therapy. Only with a TZD you can change the natural history.

Dr. Henry: It’s not just glucose; free fatty acids have a big role in progression along with other factors. It’s hard to argue with Dr. DeFronzo’s method because it is aggressive and addresses many contributing factors to diabetes. It’s more likely that we’re going to have less progression with multiple therapies targeting multiple mechanisms that contribute to declining beta cell function.

Q: What about directing the patient in the case study to lifestyle changes?

Dr. Fonseca: Lifestyle changes work best for prevention. The control group in UKPDS adopted lifestyle changes, but metformin was more effective. This is why the ADA chose metformin as the first choice for treatment.

Audience Comment: Age makes a difference as well.                 

Dr. DeFronzo: We understand that patients with prediabetes get results with lifestyle intervention programs, but most people regain weight within one to two years after the end of the program. 50% of the program went on to develop diabetes, despite successful weight loss. We quote lifestyle, but we have to be realistic. It’s much harder to get people at control with lifestyle. Lifestyle probably won’t get you to control.

A: The LOOK Ahead trial shows us this as well.

Q: Let’s go back to the patient. Within the first year, she improved with metformin, and didn’t return for two years. Now, her creatinine has crept up, and she’s on metformin 2,000 mg/day. She has joint pain and doesn’t sleep well, and her BMI, heart rate, and blood microalbumin have all increased. Her blood pressure is controlled. If her A1c is 7.8% and she’s already on metformin, what do you do?

Dr. Henry: I would recommend GLP-1 because she is obese and the weight loss will be beneficial. It will lower her blood pressure, as well. The added effects make it a reasonable alternative.

Dr. Fonseca: GLP-1 analogs are a good alternative, but is she willing to inject?

Dr. Bloomgarden: The most worrisome thing for me is her kidneys. Her GFR is down, and her microalbumin is up. Although the glycemic effect of SGLT2 inhibitors attenuated even in people with stage 2 chronic kidney disease, albuminuria is decreased with TZDs. If she refuses injected medicine then I would be interested in reemphasizing lifestyle and an SGLT-2 inhibitor rather than a TZD.

Dr. DeFronzo: I would prescribe a GLP-1 analog with pioglitazone if cost is not an issue. Studies suggest nephropathy protection from using TZDs. The other thing that should be pointed out is that the more weight gained with taking TZDs, the greater the drop in A1c, blood pressure, and other cofactors. Weight gain in TZD use is a cosmetic issue and not a metabolic issue. I prefer the AACE guidelines over ADA guidelines because of the emphasis on multiple therapies at a certain A1c.

Dr. Yehuda Handelsman, MD (Metabolic Institute of America, Tarzana, CA): She is a real patient, and she did decline injectable therapy, so she got a DPP-4 inhibitor. She was not willing to take other therapies. She improved initially, but I doubt she can improve her A1c in the long-term.

Dr. DeFronzo: Once you decide what the goal should be, AACE has stated that if you’re above 7.5%, you need combination therapy.

Dr. Handelsman: She was on DPP-4 inhibitors, metformin, and a sulfonylurea. I suspect that a SGLT-2 inhibitor could have been part of her triple therapy. It’s interesting to look at a combination of SGLT-2 and DPP-4 inhibitors, since they give an effect similar to a GLP-1 analog; however you don’t know the cost of that. Judith maintained her glycemic target, and didn’t come back.

Q: Imagine if another 2-year follow-up later, Judith is still not on goal, and she is now taking a sulfonylurea, a DPP-4 inhibitor, and metformin. Do you think they will worsen or improve kidney function? Which treatment is best for Judith now that she’s on triple therapy?

Dr. Fonseca: I see a lot of these patients. They first see the fancy doctors to my left [referring to the other panelists], and then they see a real doctor.

Dr. Henry: Basal insulin is a realistic therapy to add, but another combination that would be beneficial would be an SGLT-2 inhibitors with a GLP-1 analog. We’re probably going to see a lot more of that combination in the future.

Dr. DeFronzo: Would you add something else and a GLP-1 analog with insulin and/or an SGLT-2 inhibitor? I would not continue treating her with a DPP-4 inhibitor because it is costly and not as effective.

Dr. Bloomgarden: If you use DPP-4 inhibitors and switch off them, it’s essentially doing a U-turn.

Dr. Handelsman: [to the audience] Notice how none of the panelists recommended stopping all the drugs and going directly to insulin monotherapy.

Dr. Fonseca: I would stop the sulfonylureas only.

Corporate Symposium: Type 2 Diabetes Treatment for Diverse Populations: Integrating New and Emerging Agents (Supported by an educational grant from Lilly/BI)

Type 2 Diabetes Treatment for Diverse Populations: Integrating New and Emerging Agents

Vivian Fonseca, MD (Tulane University Health Sciences Center, New Orleans, LA)

Dr. Vivian Fonseca, the moderator and chair for the program, opened the symposium with a welcome and introduction. He began with an overview of the rising diabetes prevalence over time, and noted that non-white ethnic groups generally have a higher prevalence of diabetes than non-Hispanic whites. The prevalence of self-reported diagnosed diabetes in Asian-American, Hispanic, Non-Hispanic black, and Native American populations ranged from 8.4%, 11.8%, 12.6%, and 16.1% of their respective populations. In contrast, non-Hispanic white populations had a 7.1% self-reported diagnosed diabetes rate. He then turned the podium over to his fellow panelists.

Treatment Decision-Making for Diverse and Specialized Patient Populations

Joseph Betancourt, MD, MPH (Harvard Medical School, Boston, MA)

Dr. Joseph Betancourt provided an articulate overview of ways to improve diabetes care for underserved minority populations. He noted that social determinants of care shape these disparities, because minority communities are disproportionately found in relatively socioeconomically disadvantaged areas with reduced availability and quality of care. Many minority groups are more likely to be uninsured and less likely to get recommended services for their diabetes compared to white individuals. He argued that these disparities could be traced to greater rates of communication problems between minority patients and their healthcare providers, stereotyping among providers that has been studied by social cognitive theory, and greater rates of mistrust towards healthcare providers among minority patients. Finally, Dr. Betancourt proposed several strategies to address these disparities, including community-based efforts, coaches and team-based care, and utilizing health information technology and texting reminders, which have been shown to improve glycemic control across a range of race/ethnic groups.

Incretin-Based Therapies and SGLT-2 Inhibitors: Where Do They Fit With an Individualized Treatment Plan?

Samuel Dagogo-Jack, MD (University of Tennessee Health Sciences Center, Memphis, TN)

Dr. Samuel Dagogo-Jack discussed differences among DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors, and noted which agents would be suitable for different clinical scenarios. For DPP-4 inhibitors, he noted that the most notable clinical feature to be their relatively higher tolerability in comparison to GLP-1 agonists, especially with regard to GI side effects. Dr. Dagogo-Jack suggested that the adverse effect profile of SGLT-2 inhibitors has been somewhat exaggerated, especially with regard to urinary tract infections. He believes that the eGFR cutoffs for currently available SGLT-2 inhibitors were put in place due to reduced efficacy and not due to a legitimate safety concern. Dr. Dagogo-Jack concluded his presentation with an overview of GRADE, an ongoing trial attempting to elucidate the best second agent after failure on metformin monotherapy for patients with type 2 diabetes. Up to 5000 patients at A1cs of 6.8%-8.5% are begin randomized to a sulfonylurea, DPP-4 inhibitor, GLP-1 agonist, or insulin therapy in combination with metformin for seven years. The primary outcome of treatment failure, defined as A1c ≥7%, attempts to determine which types of patients responded most effectively to certain combinations of treatment.

Extraglycemic Effects of Recently Developed Pharmacotherapy

Allison Goldfine, MD (Joslin Diabetes Center, Boston, MA)

Dr. Allison Goldfine presented pooled data on the newest diabetes drug classes, focusing on their various extraglycemic effects which may help manage associated co-morbid conditions and inform clinical decision making. Beginning with weight loss, Dr. Goldfine noted that, both in monotherapy and as add-on to metformin, GLP-1 agonists and SGLT-2 inhibitors have a much more marked effect on weight reduction when compared to DPP-4 inhibitors. GLP-1 agonists and SGLT-2 inhibitors also tend to have blood pressure lowering effects, whereas DPP-4 inhibitors tend to be neutral. Studies of DPP-4 inhibitors found that the drugs have no significant effect on lipids but saw favorable effects on inflammatory conditions within three months of treatment, including increases in IL-10. In contrast, SGLT-2 inhibitors have shown to cause a modest increase in LDL-C with no documented effects on inflammatory factors. Dr. Goldfine concluded by reviewing data from the DPP-4 inhibitor cardiovascular outcomes trials EXAMINE and SAVOR-TIMI 53 (for Takeda’s Nesina and AZ’s Onglyza, respectively), which have shown that the agents are neutral from a cardiovascular point of view.

Questions and Answers

Q: There is an issue of differences between populations in cardiovascular disease and cardiovascular outcomes. Is this something biological or is it related to healthcare?

Dr. Joseph Betancourt:  There is one school of thought that says the in human genome, we are 99.9% similar as a species. That being said, the evidence is clearly telling us that that small differences between us have clinical significance. The challenge for the communities I work with is that there is a concern that if you label communities as different that can be misconstrued as “inferior” rather than having different needs. As we explore this science, we need to be able to communicate it effectively.

Q: SGLT-2 inhibition has been noted for potentially causing dehydration. Is this bad for the kidney?

Dr. Samuel Dagogo-Jack: In a study of canagliflozin and dapagliflozin, patients with eGFR as low as 45 mL/min had their creatinine levels were tracked as part of the menu of measurements. At no time did it emerge that exposure to these agents could be translated as adverse nephrotoxic effects. There is no evidence that it harms the kidney. 

 

-- by Adam Brown, Hannah Deming, Jessica Dong, Samiul Haque, Varun Iyengar, Stephanie Kahn, Emily Regier, Joseph Shivers, Jenny Tan, Alasdair Wilkins, Michelle Xie, John and Kelly Close