Cardiometabolic Health Congress - 8th Annual Meeting

October 2-5, 2013; Boston, MA Day #3-4 Highlights - Draft

Executive Highlights

The final two days of the 2013 Cardiometabolic Health Congress delivered a series of compelling sessions on topics ranging from chronic kidney disease in clinical trials to brown fat to personalized diabetes management. The general sessions during Day #3 were dedicated to diabetes (and associated complications), while Day #4’s sessions were given to obesity and metabolic surgery.

One of the highlights of day #3 was Dr. Glenn Chertow’s (Stanford University School of Medicine, Palo Alto, CA) moving address that emphasized the need for better studies in chronic kidney disease (CKD) – he dispiritingly remarked that after the termination of the BEACON trial for bardoxolone methyl, “We are back at square one.” Dr. Chertow was very involved in BEACON, and seemed to suggest that one reason BEACON failed was that the FDA requested a change in primary outcome from the original trial design. His presentation outlined the difficulty of deciding which outcomes to use in clinical CKD research and concluded that softer quality of life measures may be more appropriate in this very sick population. We would definitely like to learn more about this as the factors behind BEACON’s failing are far from clear to most in the diabetes community; better understanding the problems could help trial design with other studies in this most important and high need area.

Dr. John Buse (University of North Carolina, Chapel Hill, NC) also spoke on day #3 on personalized diabetes management. He suggested that GLP-1 agonists should share the final spot on the ADA/EASD 2013 position statement with MDI insulin due their impressive efficacy and excellent safety profile. This would obviously be a big change! We would love to hear more about how this is moving behind the scenes with the diabeteri. He also evaluated how and where SGLT-2 inhibitors fit into the algorithm, pushing for their inclusion.

In a talk on obesity and type 2 diabetes, there was a panel discussion in which Dr. Robert Kushner was asked about adults and obesity drugs. He noted that they are most appropriate for a patients engaged in self-care, who are working to increase their physical activity, but are not able to achieve their goals, including avoiding diabetes and dyslipidemia. “What medications do is help patients better control the amount of food they take in without a sense of depravation and craving.” Quite a favorable answer from a former head of TOS!

In the keynote lecture for Day #4, Dr. Ronald Kahn (Harvard University Medical School, Boston, MA) emphasized the importance that he believes brown fat will play in the future of obesity: “No longer is this a balance of energy, but it is also a balance of fat.” Previously thought only to exist in babies and animals, brown fat has now been discovered in adult humans. Brown fat burns more energy that white fat and can increase energy expenditure, improve insulin sensitivity, and improve metabolism. Putting this into human practice is more difficult, but Dr. Kahn sees options to develop drugs from sympathomimetics, BMP-7, FGF21, and Irisin and also an option for stem cell therapy and transplantation. Combination therapy will be key; Dr. Kahn acknowledged that while brown adipose tissue was sufficient to activate and cause clinical weight loss, it would likely only be on the order of 200-400 calories per day, at the most, and would need to be coupled with other approaches. Dr. Francesco Rubino, who has now officially announced his move from Weill Cornell to King’s College London, delivered a compelling presentation on the evidence for thinking about and using metabolic surgery as more than just a weight-loss tool but also as a physiologically sound treatment for type 2 diabetes. Throughout his presentation, he made an apt analogy between metabolic surgery and aspirin – both had originally been discovered for one purpose and then serendipitously provided additional benefits that are now being harnessed. We suspect his presentation changed many audience members’ perspectives on metabolic surgery and its viability as a type 2 diabetes treatment option although there are many long-standing questions on surgery still to be answered. Dr. David Ludwig (Children’s Hospital Boston, Boston, MA) delivered a pragmatic and inspirational message on how to break the vicious cycle of transgenerational propagation of obesity.

At a Takeda-sponsored symposium, we were treated to a great deal of meaty discussion on SAVOR, EXAMINE, and CVOTs. Notably, EXAMINE principal investigator, Dr. William White (University of Connecticut, Farmington, CT), suggested that one cannot rule out chance as an explanation for the increased risk of hospitalization for heart failure in SAVOR – we look forward to AHA to hearing more about this. Finally, at a Novo Nordisk-sponsored symposium, we heard from Drs. Irl Hirsch (University of Washington, Seattle, WA) and John Buse (University of North Carolina, Chapel Hill, NC) on novel basal insulins in development and the merits of combining basal insulin and GLP-1 agonists.

 

Table of Contents 

 

Detailed Discussion and Commentary

General Sessions: Diabetes

Personalized Diabetes Management: Selecting the Right Therapy

John Buse, MD, PhD (University of North Carolina, Chapel Hill, NC)

Dr. John Buse opened Friday’s conference program with a thorough discussion of personalized diabetes management. He emphasized the importance of patient adherence to treatment, and stressed the degree to which individualized care can facilitate better adherence. This is particularly true, of course, now that there are more treatment alternatives. Dr. Buse next provided an overview and plenty of commentary on the ADA/EASD Position Statement, suggesting ways that it might be improved to account for recent developments and data. He stated that SGLT-2 inhibitors, which are approximately as effective at lowering A1c as other oral agents and also lower blood pressure, body weight, and hypoglycemia incidence, deserve to be in the algorithm. This was notable to hear since previously, many investigators have favored waiting until there is much more experience with newer agents before putting them in the algorithm. He also argued that GLP-1 agonists are approximately as effective as multiple daily doses of insulin for most patients, and that MDI and GLP-1 agonists should share the role as the final most effective treatment option on the algorithm. He questioned TZDs’ utility in long-term treatment due to their deleterious effect on bone health, and provided an assessment of sulfonylureas’ benefits – cost and short-term efficacy – as well as drawbacks, specifically hypoglycemia and acceleration of beta cell decline. He concluded by discussing recent safety concerns, referencing the EMA’s document on incretin therapies and pancreatic disease, which concluded that current data is insufficient to support a change in prescribing behaviors for incretin therapies.

  • Dr. Buse began by calling for a greater focus on the “everything else” (factors other than medication) in healthcare, quoting Harvard University researcher Dr. Ted Kaptchuk (“A Powerful Tool in the Doctor’s Toolkit,” The New York Times 2013). He pointed out that there are a multitude of extra-pharmacological factors that can have a measurable and often times significant impact on quality of care in diabetes. Studies have shown that interventions focused on improving patient-provider communication lead to better adherence, and that a poor patient-provider relationship is itself a risk factor for poor diabetes control. A number of psychological barriers threaten proper adherence in diabetes management: some patients find certain medications hard to take, some may only feel motivated while their blood sugar is high, and some may worry about certain side effects. Dr. Buse emphasized the enormous importance of adherence to therapy, citing the worrying statistic that adherence in chronic care is only 50%. Individualization of therapy through shared decision-making, in Dr. Buse’s view, can help improve adherence and thereby improve outcomes for patients. This individualization, he argued, should go beyond the management of dysglycemia and extend to the anticipation and prevention of complications, as well as quality of life issues that are not always immediately evident to HCPs.

  • Dr. Buse moved on to the ADA/EASD 2012 Position Statement, which was designed around treatment individualization. He provided some interesting ways in which the algorithm could be updated based on recent data and developments. We liked hearing this given that the individualization is often challenging for PCPs and others to know how to achieve, given limitations on time they can have with patients, etc.

    • The SGLT-2 inhibitor class, in Dr. Buse’s mind, deserves to be listed in the treatment algorithm alongside the more established drug classes. Data indicates that these agents are as effective as other oral agents at lowering A1c; additionally, they lower blood pressure, come with low hypoglycemia risk (except when taken with sulfonylureas and insulin, which are known to increase hypoglycemia incidence), and cause weight loss. The weight loss data, in Dr. Buse’s view, are particularly interesting: while the average patient loses a few kilograms, some of the patients he has seen seemed to “just melt,” in rare cases causing patients to withdrawal from SGLT-2 therapy out of concern. He acknowledged the genitourinary side effects along with the slight increases in LDL seen in phase 3 testing, but felt that the class’ overall safety profile was acceptable.

    • Currently, insulin (multiple daily injections; MDI) is listed at the end of the ADA/EASD algorithm as the most effective treatment. However, recent data demonstrate that GLP-1 agonists can be equally efficacious (Buse et al., manuscript in preparation) and it comes, of course, with a lower risk of hypoglycemia than MDI and prompts weight loss rather than weight gain. While Dr. Buse acknowledged that insulin is (theoretically) infinitely titratable, studies indicate that increasing the number of daily insulin injections has diminishing returns, and leads to substantial increases in hypoglycemia. As a result, Dr. Buse argued that GLP-1 agonists deserve to share the top spot on the algorithm with complex insulin therapy, and postulated that the optimal option may be a GLP-1 agonist/insulin combination therapy such as Novo Nordisk’s IDegLira (insulin degludec/liraglutide fixed-ratio). He referenced data from the product’s phase 3 DUAL-1 study, in which IDegLira led to an impressive 1.9% reduction in A1c, less hypoglycemia and more weight loss than insulin degludec alone, and less nausea than liraglutide alone. He also highlighted the added convenience of a combination product. While in patients with the most advanced diabetes, we are not sure GLP-1 would work as well as short-acting insulin, we can definitely understand the push to use GLP-1 before short-acting insulin. If a patient has no beta cells, we assume insulin would work better.

    • Dr. Buse mentioned the safety concerns associated with sulfonylureas, but conceded that they will likely remain clinically relevant due to their (short term) efficacy and low cost. He stated that providers who prescribe sulfonylureas will simply need to accept that, in doing so, they are modestly accelerating patients’ progress towards beta cell failure and more advanced therapy. We find this troubling from a patient perspective since there are other alternatives, albeit more expensive ones, that do not prompt beta cell burnout. It will be interesting to see data on beta cell failure that we assume will come from GRADE.

    • Dr. Buse next questioned whether TZDs should be considered as a second-line option after metformin given the class’ safety profile. He focused on the bone health risk in particular as a limiting factor to the long-term use of TZDs, at least until more conclusive evidence of cardiovascular benefit is established. We believe that even if cardiovascular benefit were established, the weight gain element that goes along with taking the therapy is a big disincentive for many patients.

  • The final portion of the presentation focused on drug safety and tolerability. Dr. Buse recognized cancer as a significant concern for diabetes patients, but stated that there is little evidence that diabetes drugs materially affect cancer risk in humans. Regarding concerns over incretin therapies and pancreatic disease, Dr. Buse praised the EMA’s document on the issue, which concluded that current data is insufficient to justify a change in prescribing behavior for incretin therapies (read our coverage of the document at http://www.closeconcerns.com/knowledgebase/r/72400858). Dr. Buse acknowledged that it is possible that incretin therapies lead to a very small increase in risk (current data cannot rule this out), but emphasized that such a small difference in such a rare event would probably not have enormous clinical relevance given the benefits. In any case, he noted, the large number of prospective outcomes trials scheduled to be completed in the next few years will likely provide better data on the issue.

Table 1: Cardiovascular outcomes trials for diabetes drugs in order of estimated completion

Compound

Trial name (CT.gov ID)

Enrollment

Primary Endpoint*

Comparator

Est. Primary Completion

Lyxumia (lixisenatide)

ELIXA (NCT01147250)

6,000

MACE+

Placebo

Aug 2014

Januvia (sitagliptin)

TECOS (NCT00790205)

14,000

MACE+

Placebo

Dec 2014

Victoza (liraglutide)

LEADER (NCT01179048)

9,340

MACE

Placebo

Jan 2016

Bydureon (exenatide once-weekly)

EXSCEL (NCT01144338)

9,500

MACE

Placebo

Mar 2017

MK-3102

No acronym (NCT01703208)

4,000

MACE+

Placebo

Oct 2017

Invokana (canagliflozin)

CANVAS (NCT01032629

4,414

MACE

Placebo

Jun 2018

Tradjenta (linagliptin)

CAROLINA (NCT01243424)

6,000

MACE+

Glimepiride

Sep 2018

Forxiga (dapagliflozin)

DECLARE-TIMI58 (NCT01730534)

17,150

CV death, MI, or ischemic stroke

Placebo

Apr 2019

Dulaglutide

REWIND (NCT01394952)

9,622

MACE

Placebo

Apr 2019

Tresiba (insulin degludec)

TBD

TBD

MACE

Insulin glargine

TBD

 

CKD Endpoints in Clinical Trials: Guidance for Clinical Practice

Glenn Chertow, MD, MPH (Stanford University School of Medicine, Palo Alto, CA)

Dr. Glenn Chertow, a chief investigator of bardoxolone methyl’s BEACON trial, delivered quite powerful opening remarks, emphasizing, “End stage renal disease is a malignant scourge. It’s miserable. […] So much so that we can give [ESRD patients] a cocktail of poisons that give them diabetes, that make them susceptible to infection, malignancy, and it’s the best day of their lives when they receive a kidney transplant. Yet [chronic kidney disease] is in the last position in terms of the number of ongoing clinical trials.” He reviewed the paucity of data from major clinical trials in CKD and touched upon the relevance of different endpoints used in these trials. Notably, he ended with lessons learned from the BEACON phase 3 trial for Reata’s bardoxolone methyl that was terminated for safety reasons — for more details, see http://www.closeconcerns.com/knowledgebase/r/6c6ed7ef. As background, the nephrology community had high, high hopes for this compound because a phase 2 trial had shown that in patients with type 2 diabetes and mostly stage 3 CKD bardoxolone produced an increase in GFR – not just stabilization but actually an increase. Dr. Chertow stated that, given these promising results, the FDA was unhappy with the idea of using typical CKD endpoints like death, dialysis, or doubling of serum creatinine in phase 3 and asked Reata to aim higher. So instead, BEACON set out with a primary composite endpoint of CV death or onset of ESRD – Dr. Chertow suggested that this choice of endpoints was what ultimately killed BEACON since the trial was terminated after accruing <50% of events when the treatment arm demonstrated an overabundance of heart failure and other CV events. This is the first time we have heard this argument – Dr. Chertow used this as an example for the broader message that endpoints in CKD trials are notoriously hard to choose. He concluded that we may need to move to intermediate composite outcomes that take into account how patients feel rather than using mortality or disease progression outcomes; he does not believe we will have the capacity to make a significant impact there any time soon. We continue to want to learn far more about this trial, particularly given that one trial design may have left us with a very different future for this compound once perceived as quite, quite promising.

 

Insulin Therapy: The State-of-the-Science

Irl Hirsch, MD (University of Washington, Seattle, WA)

Dr. Irl Hirsch’s presentation on the latest in insulin therapy focused on a number of issues, including the “lag time” in prandial insulin action and the rise in popularity of more concentrated insulin formulations. Regarding the former issue, Dr. Hirsch cited a German study (Müller et al., Diabetes Care 2013) that showed that increased injection-to-meal interval had only a modest effect on A1c in type 2 diabetes patients, and pointed out that the study enrolled well-controlled patients and used regular insulin rather than more rapid-acting analogs. Dr. Hirsch next discussed patients with large daily insulin needs, noting that increasing doses of Lantus (insulin glargine) beyond 1 unit/kg extends the dose’s duration of action but has diminishing returns in terms of additional glucose-lowering efficacy. He noted that NPH seems to be more effective in patients with high insulin needs (although he said that more data is needed to confirm this finding); ultimately, Dr. Hirsch thinks more concentrated insulin formulations are the more likely answer for such patients. The literature on concentrated insulin usage in type 2 diabetes patients is limited, he emphasized, but a meta-analysis of early trials has shown that Humulin U-500 led to a quite substantial additional A1c reduction of 1.6% over U-100, along with an increase in weight likely attributable to this improved control. Wow! He concluded by expressing enthusiasm over the idea of utilizing GLP-1 agonists along with basal insulin (instead of adding prandial insulin), a paradigm that showed promise in the 4B Study.

  • Dr. Hirsch began by discussing the potential benefits of injection-to-meal intervals (IMIs), or the “lag time” between prandial insulin injections and eating. Studies indicate that IMIs significantly reduce postprandial glucose spikes in type 1 patients, but Dr. Hirsch noted that there is not much data on IMIs in type 2 patients. One recent crossover study in Germany (Müller et al., Diabetes Care 2013) investigated the issue; it enrolled 100 type 2 diabetes patients with a mean A1c of 7% and average diabetes duration of 12.5 years, and randomized them to either a 20-minute IMI versus no pre-meal interval. Notably, the study used regular insulin rather than a rapid-acting analog. The IMI group had a statistically significant but very modest (~0.1%) improvement in A1c; disappointing but somewhat unsurprising given that the study enrolled well-controlled patients and used regular insulin. Dr. Hirsch hypothesized that a similar study that enrolled patients with a higher baseline A1c and utilized rapid-acting analogs, the difference may have been greater.

  • The number of diabetes patients requiring daily doses of insulin larger than 200 units has been growing rapidly, according to Dr. Hirsch. Dr. Hirsch cited data from a dose-response study demonstrating that increases in patients’ daily dose of Lantus (insulin glargine) beyond 1 unit/kg/day had diminishing returns in terms of glucose-lowering efficacy (Wang et al., Diabetes Care 2010). He suggested that NPH insulin, despite its less consistent PD/PK profile, may be more suitable for patients with elevated daily insulin needs (and is also substantially more affordable than analogs). On the whole, however, he noted that the current trend is to move to more concentrated insulin formulations such as Lilly’s Humulin U-500. Dr. Hirsch pointed out that the use of U-500 insulin by endocrinologists nearly doubled between 2008 and 2010, as it allows patients to avoid the pain and inconsistency that can be associated with larger injection volumes. A meta-analysis of retrospective studies (total n = 310) indicated that U-500 insulin led to an additional A1c reduction of 1.6% over U-100 formulations, along with a 52-unit increase in daily insulin dosage and upwards of 4 kg of weight gain (likely attributable to improved control, Dr. Hirsch said). A meta-analysis of studies in which the insulins were administrated via pumps found a similar A1c reduction and slight weight gain, but here daily insulin dose dropped 14 units, likely due to insulin in pumps being viewed as more “efficient” and physiologic. There was no significant increase in hypoglycemia in either analysis.

    • Dr. Hirsch noted that Humulin U-500 used to have a cost advantage as well, but that Lilly (“understandably”) decided to price match per unit, and as a result a vial of U-500 can run upwards of $880 per vial (at drugstore.com). He also noted the large variations in the cash prices of U-500 insulin — the highest he found in his hometown of Seattle was a whopping $1,250 per vial. We are very glad that Dr. Hirsch included these facts in his presentation, given that HCPs are often times insulated from (or unaware of) the rising cash costs of insulin. 

  • Dr. Hirsch sees “Glipulin” (GLP-1 agonist/basal insulin combination) as the potential “gold standard” of future insulin therapy. Given that GLP-1 agonists are associated with less glycemic variability and hypoglycemia than prandial insulin, he suggested that in many cases it may make sense to add a GLP-1 agonist in a patient on basal insulin who otherwise would progress to multiple daily injections of mealtime insulin. This was similar to Dr. Buse’s call in the ADA/EASD guidelines to make this combination a standard. Dr. Hirsch highlighted promising evidence for the “Glipulin” approach from the 4B Study presented at ADA, which compared Lantus/Byetta and Lantus/Lispro combination therapies in 657 type 2 diabetes patients (for our coverage of the 4B presentation, see 70-OR in our ADA 2013 Incretin Report at http://www.closeconcerns.com/knowledgebase/r/6001b62d). The study found no significant difference in A1c reduction (~1.1%) but better weight loss, systolic blood pressure, waist circumference, and daytime hypoglycemia with Byetta.

 

T1DM 2013 — Translating the Latest Advances Into Clinical Practice

Microvascular Complications

Jay Skyler, MD (University of Miami, Miami, FL)

Dr. Jay Skyler spoke on microvascular complications in type 1 diabetes, drawing heavily from the findings of the DCCT/EDIC, Pittsburgh EDC, and FinnDiane studies. He began by emphasizing the significant burden that diabetic microvascular complications place on patients: in the US, diabetic retinopathy is the #1 cause of blindness in working-age adults, diabetic nephropathy is the #1 cause of end-stage renal disease, and diabetic amputations are the #1 cause of non-traumatic lower extremity amputations. He cited data from the Wisconsin Epidemiological Study of Diabetic Retinopathy indicating that upwards of 50% of type 1 diabetes patients have retinopathy 10 years post-diagnosis, and that at 20 years post-diagnosis a majority of patients had proliferative retinopathy. The FinnDiane study found that women appear to be at lower risk for diabetic retinopathy than men, a result that Dr. Skyler believes deserves further exploration. Throughout his presentation, Dr. Skyler noted how much progress has been made in the reduction of microvascular complications — in the FinnDiane study, the incidence of retinopathy 20 years post-diagnosis was 30-40% in those diagnosed before 1980, compared to 5-10% in those diagnosed since 1985. Similarly, the Pittsburgh EDC study showed that all-cause mortality was significantly lower 20 years post-diagnosis in patients diagnosed in the 1970s (<5%) compared to those diagnosed in the 1950s (~20%). Dr. Skyler next shared evidence that A1c positively correlates with the development of microalbuminuria in type 1 diabetes patients (Amin et al., BMJ 2008), and that proteinuria is linked to an increased risk of mortality. The data support the conclusion that the prevention of diabetic renal disease might reduce mortality and possibly cardiovascular disease. 

 

Macrovascular Disease

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

Dr. Robert Eckel emphasized that there are a number of unanswered questions regarding cardiovascular disease in type 1 diabetes, primarily: 1) What is the basis for the increased CVD risk in type 1 diabetes? 2) Is the natural history of atherosclerosis different in type 1 and type 2 diabetes? 3) Is the increased incidence of myocarditis seen in type 1 diabetes patients post-myocardial infarction attributable to a diabetes-specific pathophysiology? 4) Can CVD risk estimation methods or biomarkers specific to type 1 diabetes be identified/developed? 5) What is the role of noninvasive imaging techniques in picking up CVD in type 1 diabetes patients? He noted that ultrasound could have utility as an imaging tool to help determine the nature of atherosclerotic plaques in type 1 diabetes patients, and hypothesized that the plaques in type 1 patients may be more fibrotic and less lipid-laden than those seen in type 2 diabetes. Regarding the question of myocardial infarctions, hearkening back to the work of the late Dr. George Eisenbarth, Dr. Eckel theorized that in autoimmune type 1 diabetes patients, the presence of dead myocardium after a myocardial infarction could lead to the creation of new autoantibodies and the persistence of myocarditis rather than the normal healing process (a theory that he reminded the audience would need validation through further study). As background, patients without type 1 diabetes generally experience tissue death without myocarditis after an infarction. A frequent theme in Dr. Eckel’s presentation was the relative lack of data on CVD in type 1 diabetes (much more data exists on CVD in type 2 diabetes). Given that there are over 1.5 million patients with type 1 diabetes in the US alone (some estimates are even higher), Dr. Eckel noted, it would behoove the scientific and medical community to more thoroughly investigate macrovascular disease in this patient population.

 

Pediatric Obesity and Type 2 Diabetes

Pediatric Obesity and Type 2 Diabetes

David Ludwig, MD (Children’s Hospital Boston, Boston, MA)

Dr. David Ludwig delivered a pragmatic and inspirational message on how to break the vicious cycle of transgenerational propagation of obesity. He argued that conventional obesity treatments focusing on one factor (e.g., diet or physical activity) fail because a host of other toxic environmental factors overwhelm any effort to address only one aspect of obesity. Dr. Ludwig considered diet, physical activity, and parenting as examples of three areas where conventional approaches have failed in the past and suggested innovative ways of altering these approaches to break the vicious cycle of childhood and adult obesity. With regard to diet, he emphasized focusing on food quality rather than macronutrient content or calorie consumption. Dr. Ludwig’s advice on parenting approaches garnered the most interest from the audience and other speakers who noted during the panel discussion that healthcare providers (or parents for that matter) rarely receive formal training or advice on how to counsel families on such matters. Dr. Ludwig emphasized that parents should set clear and authoritative boundaries while children are young such that children adopt a healthy-living mindset and self-direct their own behavior by the time they reach adolescence and no longer listen to their parents. The audience seemed to very much appreciate the advice he offered on how to counsel parents on appropriate parenting techniques for establishing healthy habits although anyone with children probably understands how challenging this is.

  • Conventional diets have emphasized reducing caloric consumption of a single macronutrient, but have failed to cause significant weight loss. For example, Dr. Ludwig presented data showing that over the past few decades, as Americans’ fat consumption decreased, obesity prevalence has skyrocketed. In addition, the Women’s Health Initiative showed that the a low-fat diet initially caused a ~2 kg weight loss that was then quickly re-gained to nearly equal that of the control group.

    • Dr. Ludwig believes we should focus more on food quality, not macronutrient content – he used the glycemic index (GI) as an example of how food quality matters. Dr. Ludwig showed that, in comparison to low or medium GI meals (omelet or steel-cut oats, respectively), a high GI meal (instant oatmeal) will result in a higher initial postprandial spike in blood glucose followed by a drop in glucose that was statistically significantly lower than that of the other two groups after four-five hours that translated into a surge in epinephrine and corresponding surge in hunger (Ludwig, Pediatrics 1999). Brain imaging studies showed that high GI meals caused significantly more brain activity in the reward, craving, and addiction center of the brain than low or mid-GI meals. Finally, Dr. Ludwig demonstrated that glycemic load can have an effect on weight – in the Diogenes Adult Study, 773 adults were randomized to low or high protein and low or high glycemic load (GL) diets after they had achieved some weight loss. The low GL and high protein diet was the only combination that resulted in no weight regain, while the high GI and low protein diet produced the fastest weight regain.

  • With regard to physical activity, Dr. Ludwig recommended focusing on getting children to increase physical activity throughout the day rather than in intense bouts of exercise. He noted that exercise has its benefits, but by itself, is not a good way of producing weight loss.

  • What most audience members seemed to find most valuable was Dr. Ludwig’s advice on how to develop a parenting style that promotes healthy eating and living habits.  Dr. Ludwig posited that young children, born with innate preferences for sweet, salty, and fatty foods, acquire a mindset about food by watching parents, and they require clear boundaries. In contrast, older children are influenced more by peers than by parents and require autonomy. Unfortunately, the parenting style of the current generation tends to get this backwards – young children are often raised without clear guidance around food, with TV and the junk food industry infiltrating the gap in parenting. By adolescence, when children develop a weight problem parents then come in with inappropriately controlling approaches – e.g., nagging, punishment, and food restrictions. Coercive parenting at any age, Dr. Ludwig maintained, has adverse effects and produces the opposite of the intended effect. Instead, Dr. Ludwig proposed that parents should establish a parent-directed system with clear limits for young children, which will translate into a child-directed system in adolescence. He remarked that this approach works with, not against, a child’s psychological and developmental clock.

 

Development of Type 2 Diabetes in the Obese Adolescent: A Growing Challenge

Sonia Caprio, MD (Yale University School of Medicine, New Haven, CT)

Dr. Sonia Caprio spoke on the prevalence of childhood obesity and type 2 diabetes, specifically on the typical metabolic phenotype of youth onset. The prevalence of childhood obesity in the US spiked approximately three decades ago, early in the 1980s, and since this shift, there have not been any significant changes for this dramatic problem. A study at the Yale Multiethnic Cohort of Childhood Obesity followed 31 teens with impaired glucose tolerance (IGT) for about two years, none of whom were ever treated for their IGT. At mean follow-up of 21 months, one-third of the teens had glucose levels that returned to normal, one-third remained with IGT, and one-third developed diabetes. This prompted the TODAY study, led by Dr. Caprio and colleagues and funded by the NIH/NIDDK, which aimed to determine the pattern of impaired development and glycemic control of type 2 diabetes in youth using medication regimens involving metformin, rosiglitazone (GSK’s Avandia), and/or lifestyle modifications. The results indicated half of participants experienced loss of glycemic control on metformin in a median time of just 11 months. Adding rosiglitazone reduced the loss of glycemic control by 23%, with no significant difference in time to failure. Adding intensive lifestyle modifications promoted more weight loss at 6 months than did metformin, but no improvement in glycemic control was observed. As such, a clinical take-home message from the TODAY study was to ensure that insulin therapy is initiated for children and adolescents with type 2 diabetes.

 

Panel Discussion

Moderator: Jay Skyler, MD (University of Miami Miller School of Medicine, Miami, FL)
Panelists: John Buse, MD, PhD (University of North Carolina School of Medicine Irl Hirsch (University of Washington, Seattle, WA); Robert Eckel, MD (University of Colorado School of Medicine, Aurora, CO); David Ludwig (Harvard Medical School and Harvard School of Public Health, Boston, MA); Sonia Caprio, MD (Yale University School of Medicine, New Haven, CT)

Dr. Skyler: I want to open up with a question on Dr. Ludwig’s presentation. Parents do not receive much instruction on how to build a healthy environment for their children, and as physicians we do not receive much formal training in the area of communicating with parents – do you think it is our responsibility to address these kinds of issues?

Dr. Buse: I suspect in part because we don’t get enough training in this area, it’s the reason why we view some people as being incredibly gifted practitioners, but other people with the same training may be viewed as not being as gifted. It may be due to communication style more than intellect or knowledge. I do think there are aspects of this that can be trained, but maybe what we really need to do is focus on how we select people to go to medical school. The input will really have a lot to do with the output. At least at our medical school there’s a huge emphasis on scores and tests.

Dr. Ludwig: This is in a deeper cultural context. For example, Sonia’s great-grandparents probably grew up in some little Italian village where you didn’t need to have lessons on parenting. The culture around it, the village that supports the family and child, infused the healthful approaches to eating, physical activity, and the like. Because of our highly industrialized society, we have to consciously re-learn basic lifestyle practices, and I think that is an important responsibility of dieticians, physicians, nurses, psychologists. It reminds us that what may have occurred automatically in the past now needs to be consciously part of our practice.

Dr. Hirsch: Most of us didn’t have formal training on how to be parents. I want to thank David because we’re dealing with the same things, and I didn’t have any training with how to deal with food with my teenager so it’s actually quite helpful. But I as I think about it, we don’t do medical training for residents for these very complex issues where our PCPs get 8-12 minutes to do all of these things they’re supposed to do. Even more concerning is that now I’m reading that some schools are thinking of cutting medical school down to three years. I’ve become very concerned about how this going to turn out.

Q: For a patient who is post-MI would you continue to use a SFU?

Dr. Buse: I would think about not using it very specifically in the setting of people who have ongoing ischemia. Whether post- or pre-MI or people having frequent angina events, I would think about not using it or I might specifically think about not using glyburide. Perhaps long-acting glipizide or glimepiride would be acceptable options.

Q: So John, in the picture of the ADA guidelines you had an ’X’ over TZD’s and sulfonylureas. The only reason to use sulfonylureas is cost. We have a cost neutral environment, so why not ‘X’ sulfonylureas, too?

Dr. Buse: No, I think the evidence base for sulfonylurea is extreme strong on the safety end. There is evidence showing in the ADVANCE trial that it has a very strong record of safety and lowering A1c. The problem with the newer drugs, which are very popular, is that we don’t have this very strong record of safety. It’s not that they are not safe; we just don’t have the data to show it.

Dr. Hirsch: Last I checked, we still have a ‘black box’ from a study that most of us have forgotten about because we either deem it a poorly run trial or not sufficient. The black box I am specifically talking about, even though it was a short acting sulfonylurea, shows evidence of harmful effects. We know that these drugs should not be used with coronary artery disease. Should we as a group not use this information we know? This could be an issue. The question is, do we not pay attention to this information, to the ‘the black box’?

Dr. Buse: It’s a matter for shared decision making. The real benefit of sulfonylurea is the cost. If that is a major concern, use the sulfonylurea and if you get sued I will testify.

Q: Sonia, one of the things you pointed out is that there is a significant portion of people in the TODAY study who have autoimmunity. There is nothing about being obese that protects you from autoimmunity. Can children have type 2 diabetes plus autoimmunity in terms of pathophysiology?

Dr. Caprio: We tended to be extremely certain that children enrolled in the study who had type 2 diabetes were without autoimmunity. Obesity is considered a baseline inflammatory process so whether this is contributing to some extent of this autoimmunity we are seeing, I am not still clear. In my mind, this study tried to ensure just type 2 diabetes, but I don’t know if there is a pure form of type 2 diabetes in children.

Q: Does anyone know why metformin causes B12 deficiency in 30% percent of people on metformin? I am a neurologist and see a lot of people who come to me with neuropathy.

Dr. Buse: The mechanism has not been detailed but is thought to be related to absorption. One study suggests that if metformin is co-administered with calcium, then B12 deficiency doesn’t occur. We are starting to understand metformin may work in the large intestine and the hypothesis that it has to be absorbed in the blood stream is fallacious. Severe B12 deficiency occurs in about 15% people per year who are taking metformin. B12 supplementation is advised as is regularly checking B12 levels.

 

General Sessions: Obesity

Metabolic Surgery 2013: Patient Selection and Outcomes

Francesco Rubino, MD (King’s College London, London, UK)

Dr. Francesco Rubino delivered a compelling presentation on the evidence for thinking about and using metabolic surgery as more than a weight-loss tool, advocating that it should also be used as a physiologically sound treatment for type 2 diabetes. Dr. Rubino remarked upon how far the field has come since 1999 when the first protocol for an RCT comparing gastric bypass to intensive medical therapy for type 2 diabetes was submitted to an IRB and was promptly dismissed as being unthinkable. Now in 2013, four RCTs have been published on the issue, all demonstrating remarkable results such as diabetes remission (details below) and a possible reduction of cardiovascular outcomes. He emphasized that the notion of reversing or curing diabetes through surgery (this is more often characterized today as putting obesity “into remission”) had previously been nearly inconceivable. Long-term data is still scarce, but the prospective, non-randomized SOS study has demonstrated that even with now-obsolete techniques, 35-40% of patients undergoing surgery remain in remission after 10-15 years. In selecting the appropriate patient for metabolic surgery, Dr. Rubino made a number of astute observations including: 1) unfortunately, BMI is not the best criterion for selecting patients, as there is no indication that baseline weight or even weight loss after surgery predicts the effect of surgery on CV or diabetes outcomes; 2) HCPs should begin to consider “metabolic” surgery as a new application of what was previously thought of as “weight loss” surgery, meaning that the primary objective of metabolic surgery should not be seen as weight reduction, but an improvement in metabolic health – diabetes, hypertension, CVD, etc.

  • Throughout his presentation, Dr. Rubino used aspirin as an analogy for how medical therapies can be initially discovered for one purpose (aspirin as a pain killer; bariatric surgery as a tool for weight loss), and then serendipitously provide additional benefits (aspirin for CV protection, and metabolic surgery as a type 2 diabetes treatment).

  • Four randomized-controlled trials have been published to date demonstrating the superiority of various metabolic surgery procedures over standard or intensive medical therapy for remitting type 2 diabetes. For example, Mingrone et al., (NEJM 2012) showed that after two years, RYGB or biliopancreatic diversion (BPD) had remittance rates of 75% and 90%, respectively, compared to none in the medical therapy group (remission defined as A1c <6.5% for at least one year without medication). Similarly, Schauer et al.’s STAMPEDE trial (NEJM 2012) found that RYGB and sleeve gastrectomy had remittance rates of 42% and 37%, respectively compared to 12% on medical therapy (remittance defined as A1c <6.0% at one year with or without medications). Most recently, Ikramuddin et al., (JAMA 2013) showed that the composite endpoint of normalization of diabetes, hypertension, and dyslipidemia at one year was achieved by 49% of RYGB patients and 19% on medical therapy — see page 31 of our ADA 2013 Obesity Report for more information on this study: http://www.closeconcerns.com/knowledgebase/r/edfacef8. The final published RCT, Dixon et al., (NEJM 2008), was not covered in detail in the presentation. In the study, 60 obese type 2 diabetes patients were randomized to laparoscopic gastric banding surgery or lifestyle intervention: remission of diabetes was seen in 73% of the surgical group versus 13% of the lifestyle group.

  • With only 440 patients studied over the course of one-to-two years in RCTs for metabolic surgery and type 2 diabetes, Dr. Rubino acknowledged that data are limited for long-term outcomes. However, the prospective (non-randomized) SOS study suggests that benefits are still apparent at 10-15 years with 35-40% of people in the study still in diabetes remission despite the fact that some of the surgical techniques used in the SOS study are now obsolete. In terms of long-term mortality, Dr. Rubino suggested that the aggregate of case-control studies have shown that patients who have surgery live longer.

  • Neither weight at baseline nor weight loss after surgery predict CV outcomes, suggesting that the field needs a better metric than BMI as a criterion for surgery. Instead, factors such as fasting insulin levels might be better predictors of outcomes.

  • When selecting patients for surgery, Dr. Rubino encouraged audience members to now think of metabolic surgery as more than an obesity treatment – he suggested that calling it “metabolic” or “diabetes” surgery instead of “bariatric” surgery could also help patients start to see it as a treatment for metabolic diseases. Dr. Rubino recently published a paper (Annals of Surgery 2013) demonstrating that the name “bariatric surgery” attracts a disproportionate number of female patients without metabolic disease (i.e., patients more concerned about cosmetic weight issues) whereas the name “metabolic surgery” attracted a completely different patient population – a higher proportion of males with a higher prevalence of diabetes, hypertension, and CVD (i.e., patients with health concerns in mind).

 

Brown Fat: Is It Important to Body Weight and Metabolic Risk in Humans?

C. Ronald Kahn (Harvard Medical School, Boston, MA)

In response to the common perception that obesity is leveling off, Dr. Ronald Kahn opened his presentation by remarking, “Of course it is, you can’t exceed a 100% obesity rate.” Dr. Kahn’s presentation on the biology of brown versus white fat and the medical implications was a very in depth and impressive talk. To start, he explained that the previously held belief was that only animals and baby humans had brown fat, but recent research has shown this is not the case. Utilizing PET-CT scans on humans, scientists have discovered approximately 50 g of brown fat exists throughout very specific depots of the human body: neck, subclavicular, axila, paraspinal, and suprarenal regions. Brown adipose tissue can be activated by chronic mildly cold exposure or β2adrenergic stimulation. He differentiated between two types of brown adipose tissue: beige/”brite” fat tissue (inducible brown fat) and constitutive brown fat (brown fat that is always brown). Via the BMP-7 pathway, brown adipose tissue differentiation can be increased. Furthermore, FGF21 and Irisin (a muscle-secreted signaling petide, that links muscle to brown fat) can promote the browning of white adipose tissue. Another opportunity Dr. Kahn believes is in the near future is brown fat transplantation utilizing stem cells; if there is a way to take human stem cells, make them into brown fat, and transplant them back to the donor to generate brown adipose tissue, it may be possible to improve metabolism and prevent weight gain. This has already been proven to occur in mice.

  • Dr. Kahn opened by bringing to light several statistics pertaining to human lifetime food consumption: we literally eat tons of food throughout our lifetime and just a 1% error in energy balance can result in a 100+lb weight gain. The average human consumes 36 tons of food and 33 tons of liquids in his/her lifetime. The average man consumes 67 million calories and the average woman consumes 48 million calories during their lifetimes. Just a 1% error increase in energy intake over the lifetime for the average man and woman would result in a 191 lb and 137 lb weight gain, respectively. He emphasized that science needs to understand the impact of the cumulative effect and that weight loss “is a long haul game”. Dr. Kahn remarked, “No longer is this a balance of energy, but it is also a balance of fat.”

  • Just 50 g of activated brown fat can burn 300 calories per day. The average adult has 7-50+ kg of white fat and 25-150 g of brown fat. Although the brown fat by weight is much less than the white fat, it burns energy whereas the white fat stores energy.

  • Brown adipose tissue helps in thermoregulation, so in cold exposure of ~61 degrees F, it can be activated, thereby enabling detection. Brown adipose tissue is observed in 5-10% adults at room temperature. In contrast, after only two hours of cold exposure, 96% of people will have active brown fat; however, this activity is significantly lower in overweight or obese individuals.

  • Brown fat works in a very specialized way to activate the sympathetic nervous system via sensors in the brain. It releases adrenergic agents like epinephrine that act on receptors in brown adipose tissue to stimulate glucose uptake into the cell and mitochondria. Uncoupling protein 1 (UCP1) in brown adipose tissue allows it to burn glucose and lipids to generate heat, thus utilizing a lot of energy.

  • In mice there is constitutive brown adipose tissue and inducible brown adipose tissue (beige/“brite” fat). Constitutive brown adipose tissue is developmentally controlled, in discrete spots, intrascapular, age dependent, UCP1 positive, and closer developmentally to muscle. Inducible brown adipose tissue (beige/“brite”) is often mixed with white adipose tissue, more inducible, more genetically variable, and developmentally closer to white fat.

  • Brown adipose tissue contains abundant mitochondria and iron containing enzymes that give it the brownish appearance. Fat and muscle are both derived from mesodermal stem cells that then differentiate into either adipoblasts or myoadipoblasts. Constituent brown fat comes from myoadipoblasts and inducible beige/brite tissue comes from adipoblasts, but both contain UCP1 whereas white fat does not.  Most human brown fat appears to be constituent, although there is some beige/brite fat.

  • Experiments on mice have been conducted in which brown fat was transplanted (0.1 g or 0.4 g brown fat) from one mouse to another. After the transplantation, the mice were placed on a high-fat diet. No difference in weight gain was observed between the control group and the mice that received the 0.1 g brown fat transplant; however, the mice that received the 0.4 g brown fat transplant gained 10-15% less weight. Furthermore, increasing the amount of brown fat improved glucose tolerance.

  • In a study in which people were exposed to cold for several hours per day for 10 days, brown fat activity increased. Post-cold stimulation, the participants had increased BAT activity and nonshivering thermogenesis. A 20% increase in nonshivering thermogenesis was observed, with a total of 4% more energy expenditure. Dr. Kahn emphasized the significance of 4% over a long period of time—how it can be the difference between hundreds of pounds gained or lost.

  • In a second study, where participants were exposed to cold at 17 degrees C (63 degrees F) for two hours per day for six weeks, a decrease in body fat mass was observed. On average, their amount of brown fat activity nearly doubled. This shows induced thermogenesis before exposure was 100 calories and after 6 weeks it increased to 300 calories. Again, if cumulative, this could make a substantial impact.

  • Putting this into human practice is more difficult, but Dr. Kahn sees options to develop drugs from sympathomimetics, BMP-7, FGF21, and Irisin and also an option for stem cell therapy and transplantation. BMP-7 is a critical growth factor to the development of brown fat. In mice, fat cells treated withBMP-7 in culture and then injected into the mouse have developed into brown fat pads, increasing energy expenditure and weight loss. FGF21 (fibroblast growth factor 21) stimulates glucose uptake in the tissues directly in absence of insulin and thus has an insulin like effect. FGF21 stimulates browning of white fat to make beige/brite fat thereby increasing energy expenditure by about 50%, decreasing glucose and insulin levels and thus improving insulin sensitivity. Irisin is a myokine that links muscle to brown fat.

  • Exercise can also cause browning of fat tissue. In studies of athletes and mice who are chronically exercised, their energy expenditure is increased with their higher muscle mass and biopsies of fat taken from these animals show increased brown fat.

 

Look AHEAD: Interpreting the Results for Clinical Practice

David Nathan, MD (Massachusetts General Hospital/Harvard Medical School, Boston, MA)

Dr. David Nathan, who was highly involved in the Look AHEAD trial, presented the results of the study and offered his interpretation. As a reminder, Look AHEAD sought to examine wither intensive lifestyle intervention (ILI) that produced weight loss and increased physical activity could decrease CVD and morbidity/mortality in overweight and obese adults with type 2 diabetes. While significant weight loss and improvements in physical activity were improved in the ILI group compared to the control group (which received diabetes support and education [DSE]), the primary endpoint of MACE came out to be neutral (HR=0.95, 95% CI 0.83-1.09). Dr. Nathan characterized the primary outcome was extremely ambitious, saying, “The idea that you can lower CV or stroke with diet is a little nutty, in fact.” He noted that the lack of difference in CV outcomes was attributable to the existence of effective therapies such as statins, blood pressure medications, and prophylactic aspirins. Because of the effectiveness of modern CV therapies, the event rate in the trial was 1/3 of the predicted event rate at the study start, meaning the study power was lowered substantially. In addition, he noted that the DSE group had statistically significantly higher use of medications (statins, anti-hypertensives), suggesting that lifestyle intervention allowed patients to achieve the same outcomes as “drugging up” more while also experiencing better improvements in quality of life measures and several other obesity-related comorbidities compared to the DSE group.

 

Panel Discussion

I-Min Lee, MD (Harvard University School of Medicine, Boston, MA); Robert Eckel, MD (University of Colorado, Aurora, CO); C. Ronald Kahn, MD (Joslin Diabetes Center, Boston, MA); Samuel Klein, MD (Washington University School of Medicine, St. Louis, MO); Robert Kushner, MD (Northwestern University, Chicago, IL); Barbara Millen, RD (Boston University, Boston, MA); David Nathan, MD (Massachusetts General Hospital, Boston, MA); Francesco Rubino, MD (King’s College London, London, UK)

Q: Dr. Nathan, one thing I’ve seen recently in the DPP data, and I’m not sure if it’s been published yet is that in the DPP, if you use A1c rather than OGTT for assessing progress over time, the metformin effect also exists in older patients. The initial data indicated that the metformin effect was unique to younger patients. What do you think about using A1c rather than OGTT?

Dr. Nathan: What Bob’s referring to is that the outcomes we used in the DPP were predicated on fasting glucose and glucose tolerance test results. We also measured A1cs all along, and we asked what the results would look like if you looked at A1c using the current cut offs at 6.5%. Maybe not surprisingly, you don’t get the exact same results. In fact in the initial analysis, lifestyle reduced diabetes by 58% and metformin by 31%, and in the A1c analysis, metformin comes out to by about 50% and lifestyle to 55%. So this raises the general question about whether measurements of acute glycemia are as relevant as measurements of chronic glycemia. That is a continuous discussion.

Q: If ultimately you have a patient with high risk for cardiovascular disease, before starting the exercise program, what do you consider and who needs an exercise prescription?

Dr. Lee: We know to advise physical activity. Patients are more likely to take this seriously. When you talk about prescriptions for exercise, not everyone can have it. Also, I think it’s better to think of physical activity rather than exercise as a separate program. This way you can get people to make this a lifestyle more than just a one-time thing. I don’t know if this answers your question, but I think you could say something like walk more, use your car less, or find out from them if they take public transportation—things like that.

Q: Let me take this a step further. Do you use an evaluation method before prescribing a program?

Dr. Lee: In 2008, the federal guidelines concluded that it was not necessary for most people to go through official evaluation prior to starting an exercise regimen because usually we start them slowly from a low intensity regimen. The people who do need an exercise evaluation are those with cardiovascular disease and type 2 diabetes. The general health population does not need an exercise evaluation. Typically, with the patients we see, we start at a low intensity exercise regimen.

Q: How does the improvement in glycemia compare between bariatric surgery and more gradual weight loss?

Dr. Rubino: The paper shows that the immediate effect of surgery is similar to that of lower caloric intake, which isn’t surprising, because if it’s true that bariatric surgery works to reduce stimulation of the gut by food, then caloric restriction works the same way. The problem is that it’s hard to maintain the lowered caloric intake.

Comment: Bariatric surgery looks like a solution for a small number of patients, or else we would have to retrain everyone as bariatric surgeons because there would not be enough surgeons. It’s a good model to show what’s possible for the reversal of type 2 diabetes and interestingly we can achieve the same levels of glucose reduction and improvements in insulin sensitivity with the meal replacement strategy. I would strongly recommend everyone to read the Diabetes Care April 2013 paper showing that reversal of type 2 diabetes is possible with this strategy.

Q: Two questions: one, with fat so prevalent in the liver, who could summarize how we should look at whether a person is in serious need of a biopsy? My second question is with respect to metabolic surgery. Can you review the 2013 data on mortality and morbidity regarding this? There is a readmission rate of 50% for complications.

Dr. Klein: To detect the fat in the liver, use an ultrasound. But for a patient who has diabetes and metabolic syndrome or fibrosis, they are much more likely to have NASH. They should consider biopsy only if planning to be treated with vitamin E and a glitazone. Otherwise, there is no need. Another thing, if you are not sure of the diagnosis and think it could be autoimmune hepatitis, this is another reason to do a biopsy.

Dr. Rubino: Bariatric surgery for more utilization of hospital care. In 2013, there was a rate below 0.3%, lower than any other surgical procedure. In terms of readmission, it depends on the procedure. There is a lot of readmission for gastric band readjusting. There are problems for gastric bypass with lung function but not a problem in the long term. Some people are saying we are spending lots of money seeing people more often because of surgery readmissions and subsequent visits instead of frequent medical care. Mortality and morbidity rates are low, about 0.3%, which is lower than for any other surgery.

Dr. Eckel: Dr. Kahn, if body fat is defended, as we know it is, is it possible that increasing energy expenditure for brown fat expenditure could also result in increased energy intake?

Dr. Kahn: Animal models don’t show any compensatory hyperphagia. On the other hand, we all know from clinical experience that people can always eat more. Even after bariatric surgery, people can find ways to eat more sometimes. We can’t rule that out, but I don’t think we have any experimental evidence for a response like that.

Q: When should the practitioner consider using weight loss medication?

Dr. Kushner: They are most appropriate for a patients who are already engaged in self-care, are working to increase their physical activity, but are not able to achieve their goals, including avoiding diabetes, improving their quality of life, dyslipidemia. What medications do is help patients better control the amount of food they take in without a sense of depravation and craving.

Q: My questions are: one, this is a terrific presentation about brown adipose tissue, but is brown adipose tissue sufficient to activate and cause clinical weight loss and two, can you comment on the potential of unintended buildup of waste products or increased oxidative stress on our system?

Dr. Kahn: First, I do think that, even with the kind of activation of brown adipose tissue that can be achieved, we are talking about 200-400 calories per day, at the most. This will be coupled with other things. I think the issue would be that the weight loss with this alone is slow and we hope people don’t compensate for the calorie deficit or move less. I view this not as sole therapy but important because, as we pointed out in many presentations this morning, people lose weight and rebound; they can’t keep it down. We need to reinforce weight loss that can occur with diet and exercise. This is a real opportunity. There are potential adverse effects as this brown tissue generates heat. Will people become hypothermic? In animals, about half a degree centigrade increase in body temperature is safe. This difference in body temperature is similar to the variation women experience in their menstrual cycles. There will be an increase in body temperature, but not hypothermia. Brown adipose tissue is metabolically active and will produce oxidative products, but there is no evidence of high risk for reactive oxygen species; however, there is no current model to test this. We need to find ways to pick up brown adipose tissue biogenetics and animal models to look up potential side effects. I think it will be tolerable with transplantations as it has been in rat models.

Q: We measure BMI, weight, waist circumference, all those metrics. But what about measuring, in a practical sense, your patients’ fitness level? We know there are metabolically healthy and unhealthy people.

Dr. Lee: So the question is how to measure a person’s fitness in an office setting? There are some simple tests you can do, for example, a step test. How many they can do in a period of time. At lower levels of fitness, you can ask them if they are able to take care of themselves. Do they go out and shop? Do they require help shopping? There’s a wide spectrum of fitness. You could be talking about basic necessities of daily living, or higher level functioning. Bob knows one thing big challenge is fitness testing for risk stratification. Currently there are not the best standards or consensus on what can be done in office visits short of doing something more involved than most PCPs are able to do.

Q: I have two questions about brown fat. First, it looks like brown fat distribution is in similar locations as acanthosis nigracans? And as far as metabolic surgery, is there any change in brown fat seen there?

Dr. Kahn: There is some overlap in locations between brown fat and acanthosis nigracans, which as background is a darkening of the skin that produces a shadowy look? I think the overlap in location is probably happenstance; I don’t think it is related to brown fat. As far as effects of surgery on brown fat, I don’t know of any studies that have looked at this and I cant think of any reasons for a link, but we need to keep in mind that bariatric surgery is not just about changes in absorption, but is also about changes in hormones. Certainly some of these changes, such as changes in bile acids that can activate brown fat, are affected by bariatric surgery. I think some of these things should be explored, since bariatric surgery is working through a number of mechanisms, not just caloric restriction.

Dr. Eckel: I think there is some data on the long-term benefits of bariatric surgery on energy expenditure. Has anyone looked into this with imaging studies?

Dr. Rubino: What I’d like to emphasize is that losing weight can involve a decrease in appetite or an increase in energy expenditure. If you look at surgery patients, they lose weight rapidly and they have a huge weight loss without lowering energy expenditure, in fact sometimes energy expenditure is increased. And satiety is still increased, in the face of extreme weight loss. Gastric bypass does something to change the balance that we don’t understand.

Q: When I checked into my hotel room, the thermostat read 65 degrees F and during your talk you spoke about temperatures of 61 degrees F increasing metabolic activity of brown fat. So, for overweight patients, is there an opportunity here?

Dr. Kahn: To address the temperature issue first, I actually have two comments that I don’t think were made clear in my presentation. To activate brown adipose tissue experimentally, the temperatures must be lowered modestly to the low 60’s; 61-63F is enough. My wife always turns the thermostat down but then wears two sweaters, so she doesn’t activate brown fat. You must stay lightly dressed in order for this to work. If you become too cold, you start to shiver to keep warm and then do not activate brown fat. So, we want to hit nonshivering thermogenesis, which for humans is in the low 60’s range and seems to be effective for a few hours per day. I do think there is very interesting epidemiological data for basal metabolic rate declining over decades from the introduction of central heating. People had high basal metabolic rates when everything was not so warm, but we need to figure out how to do this. Turning down the thermostat a little is a good start, but don’t do it enough so that you shiver.

My second point, for people in the six-week Japanese trial, their comfort index was measured for how much people complained about being cold. People get used to it over six weeks. The discomfort index significantly declines because people had been exposed to that temperature for a while. Like dabbling down on salt and sweeteners, you get used to it.

Q: I attended the symposium last night about the obesity drugs, and there was a comment about being comfortable using those medications. What role do you see these agents playing in the long-term maintenance of weight loss? Do you see them as 12-week one-time use or should they be used chronically? I was a little unclear about that.

Dr. Kushner: I consider the use of pharmacotherapy in terms of obesity not in terms of a specialty drug — I hope they become embraced by primary care. I think that it’s important that primary care doctors become comfortable with these drugs. However, less than 3% of eligible patients are on these medications. The data shows the benefit of using them in terms of improving comorbidities; obesity is a chronic disease. All the data I’m familiar with show that these medications need to be taken long-term to maintain the effect. You of course need to work on lifestyle modification to go along with the medications. What I can say is that the current data show that, when these medications are stopped, weight starts to creep back up. We know it is difficult to sustain weight loss – medication works, but only as long as you’re taking the medication.

Dr. Nathan: We don’t have many good tools other than lifestyle modification, so it’s hard to maintain weight loss. But I think that these drugs are a sign of our desperation. They’re not great drugs. I think that encouraging their use in primary care goes against the data we have.

Dr. Kushner: Well, there is no long-term outcomes data. But in the data we have, we see an improvement in risk factors, and we will get outcomes data on some of these drugs in coming years.

Dr. Nathan: I think that a drug that just produces weight loss that doesn’t have long-term security data is worrisome. 

 

Continuing Medical Education Event: CV Outcomes for Oral & Incretin-Based Therapies: Examining Cutting-Edge Data & Clinical Implications for Patient Care (Supported by Takeda)

FDA-Mandated CV Outcomes Studies for Diabetes Drugs: How Did We Get Here? And Where Do We Go Next?

Vivian Fonseca, MD (Tulane University, New Orleans, LA)

Dr. Vivian Fonseca briefly reviewed the history of diabetes safety scares to explain the rationale behind the FDA’s decision in 2008 to require CV safety assessments of all type 2 diabetes drugs. While he is a supporter of the wealth of data that the CV outcomes trials (CVOTs) will provide, he remarked that there have been numerous negative implications of the requirement: longer approval processes, more expensive drug development, and exposing high numbers of people at high risk to a drug whose safety has not been established. Dr. Fonseca thinks that the bi-directional invalidation of A1c as a target for CVD risk reduction means that we are treating people too late, saying that it is unrealistic to reverse complications after they have already been established. He suggested that there may be other ways of looking for safety concerns – for example, the FDA is piloting a “mini-sentinel” project, which is a prospective, observational cohort study to assess real-world experience with drugs. Nonetheless, the confounding and bias associated with observational studies means these will not be able to replace the role of RCTs.

 

CV Outcomes Data for Oral and Incretin-Based Therapies: Examining the Data

William White, MD (University of Connecticut, Farmington, CT)

Dr. William White presented detailed results of the SAVOR-TIMI 53 and EXAMINE cardiovascular outcomes trials for the DPP-4 inhibitors saxagliptin (BMS/AZ’s Onglyza) and alogliptin (Takeda’s Nesina) – Dr. White was the lead investigator on EXAMINE. His most interesting remarks were on the SAVOR trial. With regard to SAVOR’s finding that hypoglycemia was slightly elevated in the saxagliptin arm, Dr. White relayed that at EASD last week the investigators presented a subanalysis showing that this risk was confined to patients who had been on background SFU therapy and had baseline A1c <7% - he said that avoiding use of saxagliptin in these populations would be one way to guard against hypoglycemia. (We were extremely surprised by this; we assume avoiding SFUs would be a better way to avoid hypoglycemia. In any case, he characterized the hypoglycemia risk as very low. He expressed that SAVOR’s hypoglycemia definitions were “overkill” and likely captured too many events – namely he pointed out that one definition of minor hypoglycemia was a blood glucose reading under 55 mg/dl with no symptoms. (For us, this would be closer to severe hypoglycemia and the remark appeared to refute his own argument; we would have been less surprised to hear that a blood glucose reading under 75 or 85 mg/dl with no symptoms was “overkill”.) Regardless, Dr. White noted that in this large study with very close follow-up, there was “absolutely no evidence” of an increase in pancreatitis and actually a numerically lower risk of pancreatic cancer. With regard to the increased risk of hospitalization for heart failure, he noted that the patients at greatest risk were those already at highest risk at baseline. In Q&A, he suggested that we couldn’t exclude the possibility of it being a chance finding. He also relayed the heart failure findings from EXAMINE, stating that there was no significant difference between the alogliptin and placebo arms. He reported that EXAMINE is currently conducting biomarker analyses for the heart failure finding, like SAVOR has done, and we look forward to learning these results.

 

Panel Discussion

Moderator: George Bakris, MD (University of Chicago, Chicago, IL)
Panelists: William C. Cushman, MD (Memphis VA Medical Center, Memphis, TN); Vivian Fonseca, MD (Tulane University, New Orleans, LA); William White, MD (University of Connecticut, Farmington, CT)

Q: Why have preclinical data on incretins been so exciting, but we haven’t seen benefit in the two big DPP-4 trials?

Dr. Fonseca: Mice are not human. This is the problem with animal data. Human biology is very complex. There are lots of redundant systems that come into play when you block something. KO mice give you lots of understanding about processes but don’t give you answers for outcomes. We have to do these trials in humans before we make these recommendations. Animal data, for many things, have been misleading. They help you generate hypotheses and if your hypothesis turns out to be right, they give you explanations because it’s hard to get mechanistic answers in humans.

Q: Were the studies long enough to prove benefit vs. not?

Dr. Fonseca: That is a huge problem.

Dr. White: They weren’t. SAVOR had an average exposure of two years; EXAMINE had 18 months. The amount of glycemic lower in both lowering was quite small. To be honest we did not expect to see any difference in glycemic control in EXAMINE. If there was going to be a benefit it would be a non-antihyperglycemic effect. It would have been pleiotropic, an endothelial benefit. The question was could that be shown in a study like this? Well we have a lot of events but there’s a lot of other things going against it. We had excellent lipid control, and at baseline blood pressure was not high. A1c was about 7.5% and antiplatelet drugs were used widely. So with so many things benefitting patients, what’s an extra 0.3% of A1c lowering to this population?

Dr. Fonseca: I just want to clarify something. I’ve heard comments from many people asking why the glucose control was not better. Well, although the control group got placebo, the investigators were instructed to adjust their other medications as per local guidance. These are not glycemic trials. They were not designed like ACCORD to look at the difference in glycemia in two groups – the assumption was that the glycemic control would actually be equal. The small difference in A1c between the two groups resulted because clinical inertia takes a long time to catch up.

Q: Do we know the reason why SAVOR showed an increase in heart failure?

Dr. White: To be honest we don’t know. All we know is what I showed you, and it was a small increase that turned out to be statistically significant and most prominent in patients who probably had heart failure at baseline. That’s pretty much all we know. As far as looking at background therapies, etc. I’m sure the team will report on that in next few months. It was a surprise finding so now we have to figure out if there was a reason for it. It’s also possible it was not a real finding. When you have nine components and eight show no difference, and one does, it could be by chance. So we have to be careful about interpreting one of many components in the composite.

 

Corporate Symposium: State-of-the-Art Advances in T2DM Management — Expert Analysis of New & Emerging GLP-1 Receptor Agonists (Sponsored by Lilly)

GLP-1 Agonists Explained: Expert Analysis of Structure, PK/PD Data, and Clinical Implications

Anne Peters, MD (University of Southern California Keck School of Medicine, Los Angeles, CA)

Dr. Anne Peters kicked off Lilly’s symposium on new and emerging GLP-1 agonists with an overview of the drug class — as a reminder, Lilly very recently announced the submission of its once-weekly GLP-1 agonist dulaglutide in the US and EU. Dr. Peters summarized that the class confers excellent A1c reductions, moderate weight loss, modest blood pressure improvements, and other potential benefits. As a result, it has been included in a number of diabetes treatment algorithms, including those by ADA/EASD, AACE, NICE, IDF, and CDA. Dr. Peters flipped to a massive slide outlining all the GLP-1 agonists in development, impressing upon the audience how much the field of drugs will likely grow in coming years. She noted that Sanofi’s Lyxumia (lixisenatide) has a relatively short half-life, but has been studied extensively as an add-on to basal insulin — she mentioned the recent withdrawal of the product’s FDA application (for more information on that decision, read our report at http://www.closeconcerns.com/knowledgebase/r/c7496472). She also gave brief overviews of GSK’s Eperzan (albiglutide; greater efficacy than Byetta [exenatide twice daily] but slightly less than Novo Nordisk’s Victoza [liraglutide]) and Lilly’s once-weekly dulaglutide (engineered to have a long duration of action, low immunogenic potential, and high solubility; superior A1c reduction to exenatide twice daily). She ended with Intarcia’s matchstick-sized subcutaneous osmotic GLP-1 agonist mini-pump (in development), which has demonstrated sustained A1c reductions of between 1% and 1.5% in clinical trials and would act up to one year after implantation. The device was discussed more during the panel discussion (see below).      

 

Short-Acting and Long-Acting GLP-1 Therapies: Evaluating the Data, Differences, and Implications for Clinical Practice

Carol Wysham, MD (University of Washington, Spokane, Washington)

Dr. Wysham discussed the glycemic efficacy, non-glycemic effects, and safety profiles of both long- and short-acting GLP-1 agonists, focusing on Byetta (exenatide twice daily), Bydureon (exenatide once weekly), and Victoza (liraglutide), which are the three drugs from the class currently on the market in the US and globally. In terms of glycemic effects, she noted that longer-acting agents (Bydureon and Victoza) led to greater A1c change and a greater suppression of fasting plasma glucose than shorter-acting agents (Byetta) in clinical studies. The DURATION-6 trial, however, demonstrated that Victoza was modestly but statistically significantly more effective than Bydureon; Dr. Wysham took this to mean that in terms of A1c-lowering efficacy, pushing duration of action beyond one day may not lead to a measurable benefit. The twice-daily Byetta, by comparison had a more pronounced effect on postprandial glucose, due to its magnified effect on gastric emptying. Dr. Wysham pointed out that there are few clinically significant differences between Byetta, Bydureon, and Victoza in terms of non-glycemic effects such as weight loss and blood pressure. The longer-acting agents seem to have a marginally greater impact on lipids, but data on the subject varies, she said. Dr. Wysham expressed interest in early data showing that GLP-1 agonists likely have anti-inflammatory effects. Regarding safety, she remarked that hypoglycemia is low with all three agents, although the LEAD-6 trial showed a slightly higher incidence of hypoglycemia with Victoza compared to Byetta (we can’t imagine that is clinically relevant). She argued that data on thyroid C-cell tumors and pancreatitis concerns are not convincing, and underscored the need for providers to educate patients on these issues (we are not sure PCPs themselves feel educated). She ended by citing evidence from treatment satisfaction studies indicating that most patients prefer longer-acting GLP-1 agonists, likely because of the added convenience and the reduced nausea seen with these options.

 

Defining the Role of GLP-1 Therapy in the T2DM Continuum of Care

Thomas Blevins, MD (Texas Diabetes & Endocrinology Center, Austin, TX)

Dr. Thomas Blevins’s presentation addressed the question of when providers should use GLP-1 agonists. He noted that the ADA/EASD Position Statement recommends the use of incretin therapies on top of metformin when the goal is to avoid hypoglycemia and weight gain, and wondered aloud when those two factors would ever not be a goal (right!). In terms of when to start patients on a GLP-1 agonist, Dr. Blevins expressed guarded optimism about Dr. Ralph DeFronzo’s triple therapy strategy (metformin, pioglitazone, and exenatide twice daily) as a way to treat diabetes more proactively and earlier in the disease’s time course. Dr. Blevins discussed data from head-to-head efficacy studies of currently available GLP-1 agonists, noting that Novo Nordisk’s Victoza (liraglutide) demonstrated a slight edge in efficacy over exenatide once weekly in DURATION-6. He noted that the old paradigm of adding basal insulin once all oral therapy options might be giving way to an approach where GLP-1 agonists are used instead of insulin. Although patients with very high baseline A1cs may require insulin therapy, multiple trials show comparable A1c reductions with GLP-1 agonists compared to basal insulin, with weight improvements and lower hypoglycemia risk. In his mind, combination products such as Novo Nordisk’s IDegLira (insulin degludec/liraglutide) and Sanofi’s LixiLan (insulin glargine/lixisenatide) can help facilitate the jump to insulin/incretin co-therapy. That’s very unfortunate for patients in the US, since IdegLira has been substantially delayed and LixiLan at least somewhat delayed. Dr. Blevins ended with a discussion of barriers to GLP-1 agonist initiation. He stated that concerns about the cost of GLP-1 agonists and GI symptoms are certainly valid and merit in-depth discussion with patients, but fear of injections can be drastically reduced with proper provider demonstrations.      

 

Panel Discussion

Thomas Blevins, MD (Texas Diabetes & Endocrinology Center, Austin, TX); Carol Wysham, MD (University of Washington, Spokane, Washington); Anne Peters, MD (University of Southern California Keck School of Medicine, Los Angeles, CA)

Q: Why are GLP-1 agonists higher than DPP-4 inhibitors in the AACE algorithm?

Dr. Blevins: They’re very close, but I think the reason was the efficacy difference. Head-to-head data shows that (Novo Nordisk’s GLP-1) liraglutide led to a greater A1c drop than (Merck’s DPP-4 inhibitor) sitagliptin.

Q: Which diabetes patients are best candidates for GLP-1 agonist therapy?

Dr. Peters: You have to make sure they don’t have any of the contraindications. If you have a lean type 2 patient, they may not be patients you may want to start on a GLP-1 agonist. But that being said, in some of those patients I’ve used the lower dose of liraglutide and it has worked well. But most patients who are on metformin and don’t have any of the contraindications are candidates. Of course some patients may have bad GI side effects or may not be responders, and in those cases they can switch. But I’d say most are good candidates.

Dr. Blevins: I agree, if anything I think we are underutilizing the class. We should be using them earlier.

Dr. Wysham: I usually go by the guidelines, and start a discussion about GLP-1 agonists especially in patients who are concerned about weight gain.

Dr. Peters: There are places where cost comes into play, and so in some systems you are required to go from metformin to a sulfonylurea and prove that doesn’t work before moving on to other agents.

Q: Does the effectiveness of the GLP-1 agonists decrease with longer duration diabetes?

Dr. Blevins: It depends a bit on residual beta cell function, but they’re not medicines that just affect beta cell function. Remember that glucagon is dysregulated in diabetes as well. We typically add GLP-1 agonists to patients that are on oral agents and failing, and in that space they work well. You might anticipate some reduction in effectiveness in patients with long duration diabetes, but that’s a very beta cell-centric viewpoint. I don’t really let duration of diabetes determine whether I start a patient on a GLP-1.

Dr. Peters: I would also add that there is data on these compounds in type 1 diabetes patients, so it may not be totally dependent on beta cells. Second, I have seen patients on U-500 who are incredibly insulin resistant, and the county decided that it was cheaper for me to add liraglutide than to keep them on that much insulin. They almost all get weight loss, and many have a significant reduction in their insulin needs and can come off U-500.

Q: Dr. Peters, can you talk about the data you presented on GLP-1 agonists versus basal insulin in patients at different A1c baselines?

Dr. Peters: We wanted to see if adding in basal insulin was better than adding a GLP-1 in patients with high A1cs. We got Amylin and Novo Nordisk to give us their data on this, and we looked at it in terms of A1c quartiles. For the highest quartile, GLP-1 agonists gave you bigger reductions than basal insulin. Interestingly we didn’t necessarily get differences in hypoglycemia in that quartile, because patients were on metformin and a sulfonylurea as well. The caveat is that in someone who is markedly symptomatic, our current thinking says to add insulin.

Dr. Wysham: That really points to the fact that without clinical symptoms of hyperglycemia, you have a choice between insulin and a GLP-1.

Q: Regarding the subcutaneous pump, do you have any experience with it?

Dr. Blevins: It’s a fascinating idea to have an implant that would last a year. It’s doable, the studies are ongoing, and endocrinologists could use another procedure [laughter]. Keep watching for data, there is already some, and this idea of going to monthly or even once-a-year administration is very well accepted by patients.

Dr. Wysham: It’s fascinating, and I think there will be other agents that we will be administering that way.  

 

Corporate Symposium: Obesity Management 2013 — Expert Perspectives on the Clinical Impact of Novel & Emerging Therapies (Sponsored by Novo Nordisk)

Obesity Comorbidities and Complications: Benefits and Challenges to Tightening Waistlines

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

Dr. Robert Eckel set the stage for the rest of the symposium by reminding the audience that obesity is linked to a range of complications. He noted that both increased BMI and abdominal obesity are linked to cardiovascular disease risk, before explaining the mechanisms connecting obesity to hypertension, endothelial dysfunction, and insulin resistance. He emphasized the importance of preventing obesity in patients at risk for diabetes, and underscored that a 5-10% reduction in body weight can improve glycemia, lipid levels, blood pressure, and inflammation. He acknowledged that preventing patients from regaining weight is an enormous challenge in obesity management, as the body defends its fat stores once obesity occurs. During weight loss, the body produces less leptin and GLP-1 and more ghrelin; appetite is increased (especially for energy-dense foods) and generally physical activity decreases. These factors make sustained weight loss difficult, but represent a potential therapeutic target for obesity management medications.

 

The Neurohormonal Basis of Obesity: Clinical Implications for Weight Loss

Caroline Apovian, MD (Boston University School of Medicine, Boston, MA)

Dr. Caroline Apovian described the main gut hormones that control food intake, modulate digestion and regulate the absorption of nutrients. These hormones also work as neurotransmitters within the central nervous system to control food intake. She explained that a better understanding of the role of gut hormones could offer better treatments for obesity; through controlling gut hormones and peptides, we can control satiety and hunger and thus, hopefully obesity. Today there are a known 30 gut hormones and 100 polypeptides from the gut that modulate the absorption of nutrients. The gut microbiome plays an important role as well, and Dr. Apovian noted that its composition changes after gastric bypass surgery. Looking to the future, Dr. Apovian suggested that combined action on hormonal targets may be able to achieve results similar to those seen with bariatric surgery.

  • Gut hormones are modulated by acute food ingestion and adiposity signals are modulated by short and long-term energy homeostasis. Ghrelin is an appetite stimulant, whereas peptide YY, pancreatic polypeptide, glucagon like peptide 1 and oxyntomodulin suppress appetite. Leptin and insulin help store fat long-term.

  • There is mixed evidence on the effect of the Vagus nerve on weight modulation. The gut is densely innervated by the Vagus nerve, which is a principle conduit for information passing from the gut to the brain and spinal cord. The nerve is increasingly seen as a potential target for obesity therapy. Dr. Apovian noted that early data on the role of the Vagus nerve are mixed: both stimulation and inhibition of the nerve have been proposed as ways to promote satiety.

  • Leptin secretion levels are proportional to fat mass and do not change acutely with meals. Leptin resistance may be attributable to reduced leptin receptor signal transduction or an impaired ability of blood brain barrier to transport leptin. Dr. Apovian cited the leptin regulatory system as the body’s main means of protecting its level of adiposity.

  • The Fat Trap, a study conducted in 2009, placed 50 obese men and women with mean weights 233lbs and 200lbs, respectively, on a very low calorie (500-550 cal) diet consisting of Optifast shakes and two cups of low-starch vegetables per day. The diet duration was eight weeks. Mean weight loss at week 10 was found to be 30 lbs. One year after the initiation of the study, patients regained an average of 11 lbs. Ghrelin was measured at during the study and was found to have increased at weeks 10 and 62. Other satiety hormones, peptide YY, CCK, and Amylin, were shown to have reached equilibrium.

 

Weight Loss Medications

Ken Fujioka, MD (Scripps Clinic, La Jolla, CA)

Dr. Ken Fujioka provided a methodical overview of six obesity management medications that are either on the market or that should be available in the next one to two years: phentermine, orlistat, Vivus’ Qsymia (phentermine/topiramate ER), Eisai’s Belviq (lorcaserin), Orexigen’s Contrave (bupropion/naltrexone), and Novo Nordisk’s Victoza (liraglutide).

  • Phentermine and orlistat: These two drugs are the “veteran” weight loss drugs — Dr. Fujioka acknowledged that the obesity management drug class has had a rough past. He noted that phentermine is very affordable, and that its sympathomimetic side effects are well-understood. He expressed concern that the drug is frequently prescribed at excessive doses, and that it is often dispensed directly out of HPCs’ offices (creating a financial conflict of interest). With regards to orlistat, Dr. Fujioka characterized the drug as quite safe and respectably effective, although gastrointestinal side effects are common.

  • Eisai/Arena’s Belviq (lorcaserin): The drug works through the serotonin 2C receptor to increase post-meal satiety.  Dr. Fujioka remarked that the drug demonstrates high selectivity for the 2C receptor, an important characteristic given that less selective serotonin receptor agonists such as fenfluramine are connected to cardiac valvulopathy. He remarked that the drug’s very low side effect profile is perhaps its biggest advantage. He had a very positive opinion of the non-responder rule, which dictates that patients should stop taking the medication if they do not lose 5% body weight by three months, and postulated that future weight loss medications may take a similar approach. A differentiating factor in Belviq’s phase 3 BLOOM program was that the drug was studied in type 2 diabetes patients as well as nondiabetic obese patients, and demonstrated significant reductions in A1c and fasting plasma glucose. There were also modest but statistically significant improvements in blood pressure and lipids seen. Dr. Fujioka noted that the drug was mainly tested in white nondiabetic obese females in order expedite clinical trials (that demographic is seen frequently at weight loss clinics), but he did not seem particularly concerned about the strategy.

  • Vivus’ Qsymia (phentermine/topiramate ER): Dr. Fujioka noted that while phentermine is well-understood, not much is understood about topiramate’s mechanism of action beyond the fact that it is a GABA antagonist. Dr. Fujioka stated that he is a fan of REMS programs, and found Qsymia’s program appropriate given the drug’s possible link with oral cleft palates. He characterized the drug’s efficacy as impressive, citing data from the CONQUER study indicating weight loss of approximately 15% after one year of treatment and a responder rate of around 80%. As opposed to Belviq, Qsymia was tested in obese patients with more comorbidities, such as hypertension, diabetes, and metabolic syndrome; it was also tested in patients on anti-depressants, which Dr. Fujioka cited as a differentiating factor.

  • Novo Nordisk’ Victoza (liraglutide): Dr. Fujioka highlighted the fact that GLP-1 agonists’ multiple beneficial effects on glycemia, weight, and other factors are fairly well understood. He shared data from the drugs’ weight loss clinical trials, which demonstrated a roughly 7% drop in weight loss from randomization — he found this result even more impressive given that counseling provided during run-in had already dropped patients’ mean weight by 7% from baseline. Dr. Fujioka noted that liraglutide was also shown to prevent the progression from prediabetes to diabetes, making the drug an especially strong candidate for obese patients with diabetes or prediabetes. He acknowledged that nausea is common with GLP-1 agonists such as liraglutide, but stated that the effect subsides in most patients by week six of treatment.

  • Orexigen’s Contrave (naltrexone/bupropion): Clinical trial data demonstrate an approximately 8% reduction in body weight with the 32 mg dose of Contrave, which Dr. Fujioka thought was a good result. He noted that nausea is a significant side effect, which makes the drug potentially tricky to use. He suggested that Contrave could be ideal for depressed patients, or those with food control issues. He also stated that, if Contrave is approved, it will have the advantage of data from high risk patients due to its cardiovascular outcomes trial. Contrave was recently submitted for regulatory approval in the US.

 

Panel Discussion

Ken Fujioka, MD (Scripps Clinic, La Jolla, CA); Robert Eckel, MD (University of Colorado, Aurora, CO); Caroline Apovian, MD (Boston University School of Medicine, Boston, MA)

Q: Bob, when clinicians are presented with comorbidities, how does a busy doctor balance all these problems and still promote weight loss?

Dr. Eckel: The primary responsibility of the physician is to deal with the comorbidities first, and then work on the weight loss. If a patient has uncontrolled hypertension and lipid abnormalities, then you have to handle those things first. I personally find that if I’m going to be the sole practitioner helping a patient with weight loss, I need 25 minutes with them, to explain weight loss mechanisms, to develop a strategic plan.

Q: How do you have a conversation with frustrated patients to convey to them to them that, like you said in your presentation, obesity has biological underpinnings?

Dr. Apovian: I see patients as you do who feel that it’s a matter of willpower and that they should be able to succeed with diet and exercise but can’t, and they beat themselves up. Just talking about the mechanisms with your patients in a simplistic way can help them realize that they may have a dysfunction in one of those mechanisms. You need to tell them that they’re not a failure.

Q: Ken, you talked about four medications that have been marketed or emerging. How does a physician who wants familiarity choose which medications to use? Here’s the hardest thing for me: at my clinic, some of the doctors will just not prescribe weight loss medicine even though I trained them to do so. Every now and then I get a primary care physician who is a part of a group taking charge on weight loss and I get them to try to medicate this best they can by using comorbidities to deliver where they are going.

Dr. Fujioka: That’s a tough one. Bottom line, there is no algorithm and there are no guidelines. For the first time the FDA has put a stop signal; if a patient is not responding by three months, their usage must be stopped and the physician can prescribe a different pharmacotherapy.

Q: How did the control group in Look AHEAD lose weight? Was it divine intervention, or surgery?

Dr. Eckel: As far as we know there wasn’t any proactive weight loss, so we don’t have a definite answer. Remember their A1cs kept going up? Perhaps there was an increase in glycosuria, or the initiation of diabetes that was having some effect there? But we really don’t know.

Q: How do you decide when to use a weight loss medication?

Dr. Fujioka: When I take my history, the first think I ask is if they’ve tried diet and exercise before. If I get the sense they’ve tried, then I have no problem starting then on a medication from day one alongside more diet and exercise. ACE has recommended that in obese patients with comorbidities, providers do not need to be afraid of starting with medication from day one. So I’m generally quick to move to help a patient with an appetite suppressant.

Q: Could GLP-1 agonists or Symlin help reduce cravings in extreme low calorie diets for weight loss? Also, which medications cause the greatest reduction in body fat?

Dr. Apovian: Yes, GLP-1, Symlin and bupropion combinations, and other medications could potentially reduce cravings. I assume this is about the study I presented where patients lost weight and were preoccupied with food and pathways were stimulated to enhance weight gain. I think a combination of the right targets could potentially reduce the hunger pathways and increase pathways to satiety. To determine which combination will work for each individual is an area that needs more study on the genetics of obesity. Someone could have obesity because their limbic system is involved. So, I think you are going to have to interview patients to decide which medication to use and it will be trial and error until we figure it out.

Dr. Eckel: People successfully lost weight and kept it off; the various ways people lost weight were individual to group or phone therapy. Today there is phone and online therapy. I think this will be true with drugs. I don’t think we know who responds to drugs and why yet. I find that people who eat when they are hungry respond to phentermine and if they’re not among those who eat when they are hungry, they don’t respond.

Q: If a patient is losing weight slowly, do they get the same hormonal response and drive to regain weight compared to rapid weight loss?

Dr. Apovian: We don’t know that definitively, but the same study showed that ghrelin changed more dramatically at 10 weeks and then started to calm down at 62 weeks. It could be that some of the hormones that act rapidly are more elevated after the rapid weight loss, and if you wait long enough they calm down. But we don’t know definitively.

Q: Please comment on the long term cognitive and memory deficits caused by phentermine and topiramate.

Dr. Fujioka: There are no long-term effects. Topiramate is associated with cognitive impairment as shown in the studies by Johnson & Johnson. This is not really common, but it can happen. I’ve yet to see any patient where this does not go away and it is acute if they do get it; it goes away once they stop the medication. (Editor’s note: the J&J studies were at much higher doses.)

Q: One of the goals of obesity therapy is to deal with the comorbidities and get patients off other medications. If you have someone with multiple comorbidities come in on eight medications, which medications would you be looking to stop, and which ones would you want to hold on to?

Dr. Eckel: I think you have to qualify the response to that. Someone on statins will stay on statins as long as they meet the indication for them. Regarding glycemic control, the target A1c should be individualized. During weight loss, patients’ doses of insulin or sulfonylureas will likely need to be tapered somewhat. Drugs for hypertension may need to be tweaked slightly during the weight loss period, and after.

Q: Are the neurohormonal pathways the same in children and adolescents since their brains are still developing?

Dr. Apovian: We do adolescent bariatric surgery in those adolescents who have reached 95% of their physiologic age growth potential because we want to make sure their height is preserved. But after that you know they do lose weight and lots of it. The surgery so far as I know, has had no case studies showing mortality and less morbidity than in adults. These changes can be made in adolescents and children. At this age things are different because they are growing and those pathways are affected by their growth potential. People hear as they get older that their appetite and satiety signals change because they don’t need to eat for growth so I think they are different and even having said that, we see children who are becoming obese in this environment so we feel there is damage to this neurohormonal pathway.

Q: Could you comment on naltrexone and liver toxicity?

Dr. Fujioka: When you look at naltrexone alone, if you give it to someone with alcoholism, there is the reported potential for liver toxicity. That said, the issue has been carefully studied for this drug. In the formulation used for obesity, the release mechanism is slower, which should mitigate some of the risk. Also the doses are different – as I can understand it’s not an issue as of now.

Q: Are primary care physicians prescribing new approved drugs or are only specific obesity clinics?

Dr. Apovian: Yes, they are. And we hope that primary care physicians take on the task of treating obesity as the years go by. We now have obesity certification programs that train primary care physicians to assess and treat obesity. Many primary care physicians in their practices feel they are busy and that it is difficult because it takes time to talk about diet, exercise, and medications. If we can get more primary care physicians to tackle problems, we could get more patients who are obese on regimens for exercise, diet, and anti-obesity, off diabetes medications. These people are sometimes on 20+ drugs and have a BMI > 30. Insulin usually causes about a 20 lb weight gain as do sulfonylureas. The primary care physicians need to tackle this to solve the problem.

Q: Regarding phentermine/topiramate, wouldn’t the monthly pregnancy tests be a barrier to uptake?

Dr. Fujioka: I’m not totally sure, but I think that the monthly testing is recommended but not mandatory. So I think the physician can use their judgment when it comes to that.

Q: Why ultimately are prescriptions for weight loss drugs not given to more patients? Is there a fear based on the history of weight loss drugs? Is it a cost issue? There seems to be some inertia here.

Dr. Kushner: I think there are multiple barriers or reasons why clinicians don’t use these medications. There was a 12-year gap preceding the most recent set of drugs, so there is a whole generation of physicians who do not have familiarity with the idea of using medication for weight loss. There is no training on these agents in medical school. The visit considerations are daunting, especially given how short visits are. Another factor is the bias that weight loss is something that should be done by patients through their own effort, but Carolyn spent half an hour talking about the biology of obesity and how it may not be a matter of willpower. I recommend you all to start treating with these medications, get in the game, and be part of the solution.

Dr. Apovian: I agree, from primary care clinicians to cardiologists, we all need to start treating this disease. With the million of Americans who suffer from obesity, only 2-3 % are being treated with anti-obesity agents, and an even smaller percentage go to bariatric surgery. Those are both good strategies that we’re not using enough. The AMA proclaimed obesity a disease, which was a big step forward; we need to continue moving forward.

Dr. Eckel: What would really change field is obesity drug that reduces cardiovascular disease this would change field of pharmacology.

 

Continuing Medical Education Event: Advances in Basal Insulin Therapy: Expert Analysis of Novel Formulations, Combination Therapies, & Delivery Technologies (Sponsored by Novo Nordisk)

The Next Generation of Basal Insulin Analogs: Analyzing the Clinical Data

Irl Hirsch, MD (University of Washington, Seattle, WA)

Dr. Irl Hirsch reviewed three late-stage next-generation insulin analogs in development – Sanofi’s U300 insulin glargine, Novo Nordisk’s Tresiba (insulin degludec), and Lilly’s LY2605541 (he did not mention Lilly/BI’s insulin glargine formulation, which is not surprising because little data have been publicly disclosed). For all three agents, he noted that the common theme was that all provided similar glycemic control to the current gold standard, insulin glargine, with additional benefits. He pointed out that Sanofi’s U300 and Novo Nordisk’s degludec both reduced nocturnal hypoglycemia – importantly, he remarked that he is now much more sensitive to the effects of hypoglycemia in people with type 2 diabetes than he was five years ago given what we have learned about the relationship between hypoglycemia, inflammation, and arrhythmias. With regard to Lilly’s LY2605541, he remarked that the reduction in body weight and hypoglycemia seen after only 12 weeks in a phase 2 trial was very encouraging (Bergenstal et al., Diabetes Care 2012). However, he noted that the elevations in triglycerides, and liver enzymes up to greater than three-times the upper limit of normal was not something we would expect to see with insulin. In terms of “what’s next?” and how we could improve the basal insulin experience even more, Dr. Hirsch touched upon the potential for combination with GLP-1 agonists. He presented the impressive results from Novo Nordisk’s IDegLira’s phase 3 DUAL-I trial, stating, “I am extremely excited about this” (for details on these results, please see http://www.closeconcerns.com/knowledgebase/r/6001b62d). Finally, he closed by remarking that in the ACA era, superiority will need to replace non-inferiority in our clinical trials so that there will be more value in new therapies.

 

Basal Insulin and GLP-1 Combination Therapy: Examining the Clinical Evidence

John Buse, MD, PhD (University of North Carolina School of Medicine, Chapel Hill, NC)

Dr. John Buse’s presentation extolled the benefits of combining basal insulins and GLP-1 receptor agonists. Dr. Buse reviewed the individual benefits and drawbacks of each of these individual two components and then described how combining the two could take advantage of the benefits and minimize the drawbacks. GLP-1 receptor agonists offer potential for excellent improvements in A1c, moderate weight loss, modest improvement in blood pressure, but have adverse gastrointestinal dose related events, and renal, pancreatitis, and cancer safety concerns. Basal insulin is also associated with excellent improvement in A1c, and adverse effects include dose related weight gain, and hypoglycemia. By combining GLP-1 receptor agonists and basal insulin analogs, glycemic effects were hypothesized to provide unparalleled efficacy, potential to minimize adverse effects, and to have uncertain hypoglycemia effects.  Several studies analyzing these hypotheses were reviewed throughout the presentation, including the GWCO study (exenatide and insulin glargine), LIRA-DETEMIR Study (liraglutide and insulin detemir), GetGoal-DUO 1 Study (lixisenatide and insulin glargine), and the DUAL-1 Study (liraglutide and insulin degludec [IDegLira]). Dr. Buse especially detailed the very IDegLira’s very impressive results DUAL-1 results where the degludec/liraglutide combination provided a 1.9% A1c reduction from a baseline of 8.3% with 0.5 kg weight loss (for details, please see page 4 of our ADA 2013 Incretins report at http://close.cx/ADA2013Incretin). There was no increased risk of hypoglycemia in this setting and there was greater improvement in glycemic control compared to basal insulin alone (1.4% A1c reduction with 1.5 kg weight gain). Dr. Buse believes that this product would be incredibly likely to be well tolerated and highly effective. He ended by posing an interest question – whether combining GLP-1 receptor agonists and basal insulin analogs will supplant both in treatment algorithms.

 

Overcoming Barriers to Basal Insulin Therapy: Integrating Patient Education and Novel Delivery Technologies into Clinical Practice

Luigi Meneghini, MD, MBA (University of Miami Miller School of Medicine, Miami, FL)

Dr. Luigi Meneghini reviewed barriers to insulin initiation and advised on how to address these barriers – in his presentation he noted that HCPs often perceive that patients are more worried about insulin initiation than they actually are. A major barrier to address is patients’ perception that insulin initiation represents a failure – instead, Dr. Meneghini advised that HCPs should emphasize that insulin is a tool that will help them improve their glycemic control and prevent further disease progression. He presented data suggesting that expressing empathy is actually very much under-recognized in its importance for promoting adherence to insulin therapy (Del Canale et al., Acad Med 2012)  He asked the audience how many of them had actually done a sham injection on themselves and about 50% raised their hands – he animatedly encouraged the rest to try it so that they could demonstrate on themselves in front of their patients to show them how little it actually hurts. Finally, he highlighted available tools to address barriers to insulin initiation: to reduce injections, he suggested disposable patch pumps such as Valeritas’ Vgo (he did not mention it by name); for avoiding hypoglycemia he suggested the low-glucose suspend system that the FDA has just approved; finally he recommended that patients could also download apps that help with carb counting and insulin dosing.

 

Panel Discussion

Bernard Zinman, MD (University of Toronto Institute of Medical Science, Toronto, Canada), Luigi Meneghini, MD (University of Miami Miller School of Medicine, Miami, FL); Irl Hirsch, MD (University of Washington, Seattle, WA); John Buse, MD, PhD (University of North Carolina School of Medicine, Chapel Hill, NC)

Q:  How much pediatric data is there for the new insulins?

Dr. Buse: I’m not sure there’s any data on that.

Dr. Zinman: I think it is worth noting that in registrational trials, you specifically select patients who are not having a lot of severe hypo. Those are the patients who would probably benefit the most. So I know a study is being done to look at patients who are having recurrent hypoglycemia and whether they benefit from an insulin that has a better PK profile.

Q: If you have a patient on large doses of BID glargine and large doses of rapid acting insulin, do you transition to U-500?

Dr. Hirsch: We talked about this a little this morning. I would first try the tricks we do with NPH to see if we can move the needle on glycemic control by giving NPH in multiple injections at the same time. That works sometimes. Often we have to go to U-500. That is based on what the total dose of daily insulin is. We have written all kinds of recommendations and consensus. Really we have no RCTs on it. I have the patients check their blood sugars at least four times a day, and we take it from there.

Dr. Buse: The most important thing is to have lots of conversations and make sure patients understand that when you say 150 units, that is 30 on the syringe and not 150 on the syringe. That’s the potential disaster with U-500, especially in the hospital.

Dr. Zinman:  Let’s talk about mixed insulin. What if a patient doesn’t want to take multiple injections? What about premixed insulin?

Dr. Buse: I don’t use them, but if someone won’t take the appropriate number of injections, then it is probably better to take the premixed insulin than nothing.

Dr. Hirsch: To be clear, we are talking about type 2 diabetes. In terms of beta cell failure, it works better when a patient is just starting. But for someone with longer duration of diabetes, I only use it if I have to. It is not the insulin of choice.

Q: We’re used to using GLP-1 agonists and insulin and having to adjust each of them. What do you see big advantage of mixing them?

Dr. Buse: By mixing them, the main thing is you’re titrating the GLP-1 a bit slower, so you have less nausea with it. You can “titrate” them independently, but for many patients it seems doing it together has the substantial advantage of being one injection instead of two.

Dr. Zinman: I have a little different opinion on that. I am so impressed by the IDegLira data and actually surprised. The investigators did not dose GLP-1 and then insulin independently, they just dosed based on the insulin. What I think happens in that combination, I think it makes insulin into a much better product. It’s still insulin, and it just transforms that insulin into an insulin that is effective, is associated with less hypoglycemia, and less weight again. My God, why would you use any other insulin? And you don’t have to worry about how much GLP-1 is there. On average it was 1.4 mg right? So I think that’s the secret: not to look at it as a combination but rather as, “Now I have an amazing insulin.” I think we need more studies but it looks quite remarkable.

Dr. Meneghini: We’re sure they didn’t make up the data right? [Laughter]

Q: Why does the cost of insulin increase over time? Usually the cost of things, such as iPads, goes down. Anyone want to tackle this?

Dr. Hirsch: I assume biosimilar insulin will be introduced at some point and may bring down costs.

Dr. Zinman: I think that it has to do with health care regulations. It is 1/3 of the cost in Canada.

Dr. Buse: I think we forget there is no “cost” of insulin in the US. But my guess is the VA pays 1/10 or 1/15 of the cost, so there is a different cost for everyone. In general, the pharmaceutical industry has changed the lowest and highest drug costs. This is mostly a problem because the person paying cash is paying most and the guy with insurance is getting the best insulin but at a lower price.

Dr. Hirsch: The philosophical problem is that, if I want to buy meat at the grocery store or a coat at the department store, the price can be the same no matter what, but with insulin it is controlled by something different.

Dr. Zinman: This is getting too political for me. I mean, I’m from Canada and our government works. If you need someone to lend you a government, I can lend you ours [laughter].

Q: What do you see for the direction of rapid acting inhaled insulin?

Dr. Hirsch: My initial thought is that I think it is going to happen. This is due to the fact that there was a recent trial detailed in a press release, which shows it appears to be safe according to FDA regulations. I believe there will soon be a decision. Having said that, how much will be used is hard to predict, but it may be safe to say, if it had come out five years ago it would be more exciting than it is right now.

Q: Can you comment more on the side effects of Lilly’s PEGylated-lispro?

Dr. Zinman: Larger studies are being done. What Irl reported were smaller studies, and people are looking into whether those liver effects are real and what the consequences are.

Dr. Hirsch: I feel reassured that the signal is out there in the public domain, so it’ll be looked at with a microscope going forward. Lilly is obviously very aware of the signal and still decided to move forward with phase 3, for what it’s worth, that was reassuring to me.

 

-- by Jessica Dong, Phaedra Randolph, Manu Venkat, and Kelly Close

 

Editor's note: There were some changes made to Dr. Jay Skyler's presentation on October 9, after the original publishing on October 8.