June 21-25, 2013, Chicago IL Report – Treatment Algorithms and Strategies – Draft

Executive Highlights

ADA 2013 provided both high-level and nuanced analysis on navigating the type 2 diabetes treatment paradigm. Taking a more targeted approach, Dr. Ralph DeFronzo’s study, which was presented twice during the conference, investigated whether triple therapy (metformin plus pioglitazone plus exenatide twice daily) at diagnosis provides greater glycemic control compared to the conventional step-wise method previously endorsed by the ADA (metformin followed by subsequent addition of a sulfonylurea and then basal insulin). The study showed compelling results for the triple therapy approach – an average A1c decline of 2.6% after 24 months vs. 2% in the conventional therapy arm (both from a baseline A1c of 8.6%) and supported the advantages of addressing the pathophysiological defects underlying type 2 diabetes rather than just hyperglycemia. The study also raised several questions beyond the glycemic efficacy of these two treatment approaches – i.e., how relevant are the results now that prescriptions for pioglitazone and exenatide twice daily appear to be decreasing? How can the results of the trial be replicated in a real-world setting? Should specialists and maybe even PCPs follow the deliberate titration scheme used in the study?

The buzz surrounding Dr. DeFronzo’s study also reminded us that there is really a lack of head-to-head data directly comparing different therapies and/or treatment approaches. Our hope is that future trials (e.g., the ongoing GRADE study) will continue to evaluate treatment methods and paradigms across the spectrum of type 2 diabetes, as well as the dosing needed to optimize these approaches.

Also enlightening was a current issue debate on what patients failing orals should do next – add a GLP- 1 agonist or insulin? Dr. Vivian Fonseca took the former position, emphasizing GLP-1s strong benefits on glucose control (especially low risk of hypoglycemia), cardiovascular risk markers, and body weight. He characterized insulin as a somewhat blunt instrument, with limitations that include weight gain, hypoglycemia, and challenges for older patients. His counterpart, Dr. Parresh Dandona, did not discuss the use of a GLP-1 agonist vs. basal insulin in great detail, though he commented that patients with an A1c of 8.5% and above should start on basal insulin to address elevated fasting glucose, while patients with an A1c of over 10% will not benefit much from a GLP-1 agonist. Both found a middle ground as well, noting that the combination of a basal insulin plus a GLP-1 agonist provides additional benefits beyond either alone. This was certainly a theme from the meeting given the striking results from the DUAL-1 study of IDegLira.

On the broader level, we heard further discussion of the ADA/EASD position statement by Dr. Anne Peters, as well as more commentary on the recently-released AACE comprehensive treatment algorithm by Dr. Paul Jellinger. In general, KOLs appear to agree that rather than opposing each other, the two documents serve different purposes and advantages for different types of HCPs. For more on both documents, see our previously published reports at http://www.closeconcerns.com/knowledgebase/r/4d95e564 and http://www.closeconcerns.com/knowledgebase/r/a331db88.

Treatment Algorithms and Strategies

Current Issue: In a Patient Who Is Failing Oral Antidiabetic Agent Therapy, the Next Step Is To?

ADD A GLP-1 AGONIST

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

Dr. Vivian Fonseca began his talk by discussing the disadvantages and limitations of insulin treatment for type 2 diabetes, noting that it leads to weight gain, can increase the incidence of hypoglycemia, and can be a challenge for older patients. He characterized insulin as a somewhat blunt instrument in that it exerts a constant downward pressure on glucose levels. Dr. Fonseca remarked that GLP-1 agonists are an attractive, more flexible treatment option, reviewing multiple studies that have shown the superior efficacy of once-daily and once-weekly GLP-1 agonists compared to insulin glargine. He highlighted that GLP-1 agonists act in a glucose-dependent manner, thus improving patients’ postprandial glucose levels while maintaining a low risk of hypoglycemia. Other studies indicate that GLP-1 agonists reduce biomarkers of cardiovascular risk, improve endothelial function, lower blood pressure, and reduce body weight. Dr. Fonseca further emphasized that GLP-1 agonists can also improve disposition indices and insulin sensitivity in a durable manner, thought he noted that the therapies do not induce beta cell proliferation. Speaking briefly on the currently hot topic of GLP-1 agonists and pancreatitis, Dr. Fonseca acknowledged the recent concerns, though explained that he did not believe that the current body of evidence supports an association between the two.

• Dr. Fonseca noted that the treatment paradigm for type 2 diabetes begins with lifestyle modification and metformin and proceeds to oral agents. Framing this debate, he noted that if a patient requires further glycemic control, he or she can add an injectable agent– i.e., a GLP-1 agonist or basal insulin. Dr. Fonseca noted that basal insulins increase the risk of hypoglycemia, require frequent blood glucose monitoring (which can be expensive), promote weight gain, and can be challenging for older patients. He highlighted that unlike GLP-1 agonists, basal insulin cannot correct several defects observed with diabetes, including the reduced incretin effect, as well as abnormally elevated glucagon levels.
• Both once-weekly and once-daily GLP-1 agonists have been shown to provide greater A1c reductions compared to insulin glargine. Dr. Fonseca acknowledged that some studies may have used less-than-sufficient dosages of insulin glargine, and that basal insulins generally provide greater reductions in fasting plasma glucose levels compared to GLP-1 agonists. Looking beyond just glycemic control, Dr. Fonseca pointed out that GLP-1 agonists provide the added benefit of weight loss (compared to the weight gain typically observed with insulin therapy), and appear to be particularly effective at decreasing visceral fat mass.
• Dr. Fonseca noted that GLP-1 agonists have a better safety profile than basal insulins, particularly in respect to the risk of hypoglycemia. Multiple studies show that exenatide and liraglutide produce significantly fewer episodes of hypoglycemia compared to insulin treatment. Of interest, early data appear to indicate that GLP-1 agonists can improve biomarkers of cardiovascular risk such as triglyceride levels, blood pressure, and artherosclerotic plaques. On this front, Dr. Fonseca remarked that some of this data comes from animal studies, and that the ongoing cardiovascular outcomes trials for GLP-1 agonists will provide greater clarity in the upcoming years.
• “GLP-1 agonists versus basal insulin” may not be an either-or debate. Combination of the two drug classes may provide the best results, due to their complementary effects and synergistic actions. Dr. Fonseca explained that basal insulins contribute more to the regulation of fasting glucose levels while GLP-1 agonists are particularly effective at lowering postprandial glucose excursions. Dr. Fonseca highlighted the potential of Novo Nordisk’s IDegLira (insulin degludec/liraglutide), which has demonstrated a better efficacy/safety profile than both liraglutide and insulin degludec alone (these results were presented during the oral session on GLP-1 agonists; for further details, please see page 17 of our ADA Day #2 report at https://closeconcerns.box.com/files/0/f/553426994/1/f_8826038475).

ADD INSULIN

Parresh Dandona, MD (State University of New York, Buffalo, NY)

After briefly recalling the history of insulin treatment, Dr. Parresh Dandona focused the majority of his presentation dispelling commonly held misconceptions regarding the safety of insulin. He emphasized that insulin is the most potent glucose-lowering agent, and can be used any time during the natural course of diabetes. Dr. Dandona stated that insulin has no side effects other than hypoglycemia, which can be minimized with proper titration. Reviewing a number of mouse and in vitro studies, he highlighted that insulin confers profound anti-inflammatory action, cardioprotective action, potential anti-atherogenic action, and potential protection against Alzheimer’s disease. Though he did not discuss the use of a GLP-1 agonist versus basal insulin in great detail, he commented that patients with an A1c of 8.5% and above should start on basal insulin to address elevated fasting glucose, and that patients with an A1c of over 10% would not benefit much from a GLP-1 agonist because elevated fasting glucose is the main contributor to hyperglycemia at higher A1cs. Lastly, Dr. Dandona showed several CGM tracings demonstrating reductions in glucose variability in patients with type 1 diabetes when liraglutide (Novo Nordisk’s Victoza) was added on to their insulin therapy. In closing, Dr. Dandona noted that every drug has its own place, and that it is up to clinicians to make sure they use them appropriately to best help their patients achieve good glycemic control.

• Dr. Dandona stressed that insulin has a safe cardiovascular profile, and may actually be anti-atherogenic. He highlighted results from the ORIGIN trial, which showed no divergence of the incidence of cardiovascular events between those treated with insulin glargine versus standard care in the trial. In the GRACE study, a substudy of the ORIGIN trial, the maximum common cIMT and bifurcation cIMT were significantly improved with patients treated with insulin glargine versus standard care.
• Subsequently, he emphasized that there is no evidence of cancer risk in humans with insulin treatment. He noted that these concerns were drawn entirely from in vitro studies in which insulin was administered at concentrations far greater than physiologic levels, and that there is no data showing a mitogenic effect with insulin at physiologic or near physiologic concentrations. In the ORIGIN trial, the incidence of various types of cancer was balanced versus standard care, reassuring Dr. Dandona of insulin’s safety regarding cancer risk.
• Though it has been suggested that insulin causes hyperlipidemia, Dr. Dandona noted that it could actually lower lipid levels. In a review of the literature, he found no good evidence of any increase in lipid levels with insulin treatment; rather, LDL and triglycerides decreased (Chaudhuri and Dandona, DOM 2011).
• Noting the relatively high contribution of fasting hyperglycemia to total hyperglycemia in patients with high A1cs (Monnier, Diabetes Care 2003), Dr. Dandona recommended for patients with A1c of 8.5% and above to start on basal insulin to address elevated fasting glucose. He commented that using a GLP-1 agonist for a patient with an A1c over 10% would not do much, since most of the hyperglycemia is a result of elevated fasting glucose; instead, basal insulin would be able to get patients down to target, with minimal hypoglycemia if titrated properly. For those who want to minimize weight gain, Dr. Dandona advocated for the use of basal-bolus therapy versus biphasic insulin with either basal or prandial insulin, given reduced weight gain with the therapy. In addition, he noted that basal- bolus therapy provided improved control compared to sliding-scale insulin (Umpierrez et al., Diabetes Care 2007), and reduced the rates of postoperative complications for those whounderwent surgery (Umpierrez et al., Diabetes Care 2011). Dr. Dandona commented that newer insulins aren’t even necessary for good glycemic control – in the DEAN trial, regular insulin plus NPH provided similar control as insulin detemir plus insulin aspart (Umpierrez et al., JCEM 2009).

PANEL DISCUSSION

Guillermo Umpierrez, MD (Emory University, Atlanta, GA); Vivian Fonseca, MD (Tulane University School of Medicine, New Orleans, LA); Parresh Dandona, MD (State University of New York, Buffalo, NY)

Q: No study has shown that GLP-1 agonists reduce the risk of cardiovascular complications. Can you predict whether they will reduce these risks?

Dr. Fonseca: I can only say, “give me a break.” It took nine years for DCCT to show such an effect. But we all accept that glucose levels and A1c are good surrogates for cardiovascular risk. I don’t see why there would be differences between drugs in that sense.

Dr. Dandona: I agree that GLP-1 agonists haven’t been given enough time. My prediction is that these agents will be shown to reduce complications independent of glycemia.

Q: I want to raise a question around weight change being seen as an important factor in late type 2 diabetes management. I’m not aware of any study except the obesity studies that were randomized and that show a strong association with weight loss from any pharmacologic agent in type 2 diabetes reducing microvascular or macrovascular disease risk. Conversely, out of the studies that show an increased macrovascular event rate with insulin, I’m not aware of evidence saying that it’s related to weight change. Do we have enough evidence to show that weight is a therapeutic target of its own in late type 2 management?

Dr. Fonseca: It is an important question. However, let me just say that you’re not primarily using these drugs to lower weight. You’re using it for glycemic control, but weight gain is distressing for the patient who is trying to lose weight. The point I’m trying to make is that it’s against what the patient wants and what you’re telling the patient – you’re telling patients that you want them to lose weight and then you give them agents that make them gain weight? There’s no data saying that you’re causing cardiovascular disease by making them gain weight. However, weight is linked to other diseases such as sleep apnea that affect the patient. Weight gain is contrary to what the patient may desire and I think it’s an important consideration.

Q: In terms of combination therapy, when orals are failing and we decide to put patients on insulin, there are some patients on high doses of insulin who remain on sulfonylurea treatment. What are your thoughts on this?

Dr. Fonseca: In terms of sulfonylurea use in the presence of a high dose of insulin, you might get some benefit if the patient is only on basal insulin. If the patient is using prandial insulin, I’m not sure you’d get much by continuing to use a sulfonylurea.

Q: Do you have any comments on the use of GLP-1 agonists in type 1 patients?

Dr. Dandona: We’ve used this agent in a limited number of patients with type 1 diabetes, no more than 100. We’ve published two papers in this area. One was in patients with well-controlled type 1 diabetes on both a continuous subcutaneous insulin infusion system and a continuous monitoring system. They were well controlled and got better controlled. The other group was patients that had badly-controlled type 1diabetes, with an A1c around 8%, who were also obese. In that group, GLP-1 agonists worked too, and reduced A1c, body weight, and systolic blood pressure. There were spectacular falls in blood pressure. You can see that paper in Endocrine Practice. In both sets, it works. To pronounce a much more detailed sort of algorithm is still some time away; this is just the beginning of the story.

Dr. Fonseca: The issue of gastric emptying and its impact on A1c is an interesting one. I refer you to Michael Horowitz in Australia, who has done a lot of work in this area. Nutrient delivery is important in terms of glucose excursions, but I don’t know whether it affects A1c a lot.. It may affect the variability of glucose, but whether that has an impact on A1c is also highly debatable. There is no study yet showing that flattening it out has an effect on A1c.

Q: Two questions for the experts. First, when you start either basal insulin or GLP-1 agonists, what do you usually do with the dosages of sulfonylureas? Because many patients in a clinical setting will be failing on metformin and sulfonylureas when you need to move to these agents. Secondly, when you add a basal insulin, what is your view of the optimal time at which to give the basal insulin?

Dr. Dandona: Let’s start with the basal insulin issue. In our unit, basal insulin is usually given at bedtime, but we sometimes find that patients fall asleep before they take it. If that happens, we ask them to take it at dinnertime. I’m reluctant to ask them to take it at breakfast time, because I’m not yet convinced that they act for a full day.

Dr. Fonseca: There was one study done where glargine was given in the morning or the evening, and the effect on A1c was essentially the same. To get back to your first question about sulfonylureas, there is no best option. If your A1c is high, it may be inappropriate to stop. If the A1c is low enough, because sulfonylureas have been shown to be associated with hypoglycemia, you may want to lower or stop sulfonylureas.

Q: For patients who are doing well on high-dose insulin, would they be good candidates for GLP-1 therapy? I’m thinking of people on 100 units of insulin a day.

Dr. Dandona: I don’t see why not. I personal believe – and I’ve had this hang up for decades now – that when you inject insulin, not all of it gets into your body. And therefore, in the obese patients in particular, you may be injecting a lot of insulin that’s not getting into the circulation. What is surprising is that when you give five micrograms of exenatide, it makes it to the target almost immediately. So therefore, what you just said is very, very relevant. Usually when I start these patients on a GLP-1 agonist, the insulin dose comes down and glycemic control improves.

Dr. Fonseca: There’s a lot of interest in the use of high-concentrated insulin – e.g., U300 and U500. We need to explore this area further.

Dr. Umpierrez: There was an abstract last year that looked at very high doses of insulin and compared add-on placebo to add-on GLP-1 therapy. The GLP-1 agonist resulted in significant improvements in A1c with less weight gain.

Q: For patients on both metformin and a DPP-4 inhibitor, is it worth adding a GLP-1 agonist, or would you go to basal insulin?

Dr. Fonseca: You have to have a lot of money to add a GLP-1 agonist to a DPP-4 inhibitor. There’s just no data on it at this point.

Dr. Dandona: Also, remember that these molecules that we are using are manufactured on the basis that they are resistant to degradation by DPP-4.

Q: You talked a lot about the risk of cancer with insulin, but didn’t talk about the issue with GLP-1 agonists. In the UK in the popular media, we’ve been having a debate about whether GLP-1 agonists cause pancreatic cancer.

Dr. Fonseca: I like the way you used the phrase “popular media” to refer to the BMJ. But like I said, what we need to see are proper studies, not these little anecdotal reports drawn from databases based on sub- reporting. We need to take patient level data from many randomized control trials and put it all together to see what’s going on.

Q: Can you address the issue of the 24-hour or 24-hour-plus insulin? There’s a dawn phenomenon in type 1 diabetes, which exists to some extent in type 2 diabetes. The patients that take basal insulin in the evening are accustomed to titrating the dosage according to fasting glucose level. If you get the dose down before breakfast, that’s when patients are the most insulin resistant. And some are going to run into trouble before supper, when they are less insulin resistant and still have the same amount of insulin on board. We had some patients on glargine and their fasting glucose was at goal – 90 mg/dl – and they were getting hypoglycemia before supper and we had to switch them to Levemir. Do you think this will be a problem for degludec?

Dr. Dandona. You seem to imply with confidence that Levemir has a shorter duration of action.

Dr. Umpierrez: We’ve heard a lot about long-acting insulins at this meeting, and we’ve heard a lot about long-acting GLP-1 agonists that could be dosed once weekly or longer. What do you anticipate will happen with these new insulins and GLP-1 agonists? Will we stick with what we have, or shift to using these new drugs?

Dr. Dandona: I think time will tell. I’m trying to dodge the question, because we have so much on our plate right now. The menu is so large, the choices so many. We can be brainwashed for a while into using specific preparations. And of course, degludec would come up with the idea that it is stable, with highly predictable bioavailability, pharmacodynamics, and so on, but I think only time will tell what its utility is. The reason I included your [Dr. Umpierrez’s] slide is for the simple reason that you asked the question whether we are going overboard with these novel preparations. You showed that good old regular insulin and NPH worked as well as insulin detemir and insulin aspart. I think that only time will tell with these new agents. Clinical practice will tell. We can model utopia in clinical trials, but whether this utopia gets translated is another matter.

Dr. Fonseca: Predictions are usually wrong, especially when they are about the future.

Dr. Umpierrez: Could you provide any comment about long-acting GLP-1 agonists?

Dr. Fonseca: I think it’s very attractive for patients to have a long-acting preparation, as it improves compliance. I want to point out the Intarcia product – it’s subcutaneously implanted for six months, and may even go for one year. Compliance is assured for that duration [Editor’s note: we previously reported on ITCA 650’s phase 3 trial in our March 22, 2013 Closer Look: http://www.closeconcerns.com/knowledgebase/r/ab30a6c3.

Dr. Umpierrez: If I have a patient on metformin and sulfonylurea, what would you recommend next?

Dr. Dandona: If the patient’s A1c is above 8.5%, it has to be basal insulin. If it’s less than 8.5%, you have an argument, but you need basal insulin to bring it down to that. Normally, a GLP-1 agonist will not get you down to 7% when your A1c is greater than 8.5%.

Dr. Fonseca: I totally agree with that. You may get it in an occasional patient, but what is the chance of that effect?

Oral Sessions: GLP-1 Agonists in Practice

INITIAL TRIPLE COMBINATION THERAPY IS SUPERIOR TO STEPWISE ADD-ON CONVENTIONAL THERAPY IN NEWLY DIAGNOSED T2DM (72-OR)

Muhammad Abdul-Ghani, MD, PhD (University of Texas Health Science Center, San Antonio, TX)

Most people in the GLP-1 agonist oral session remained for the last presentation, during which Dr. Muhammad Abdul-Ghani presented the results of Dr. Ralph DeFronzo’s triple therapy trial. The open label, randomized controlled trial assigned 155 drug naïve, newly-diagnosed type 2 patients to either triple therapy (metformin plus pioglitazone plus exenatide) or conventional therapy (metformin followed by the sequential addition of a SFU and then basal insulin). The drug doses were titrated to avoid hypoglycemia and to achieve an A1c <6.5%. At 24 months, those in the triple therapy arm experienced a lower average A1c (6.0%) compared to those in the conventional therapy arm (6.6%; p<0.001) from a baseline A1c of 8.6%. Compared to the conventional group, the triple therapy group had a greater proportion of participants who achieved an A1c <6% (27% vs. 60%; p<0.001) or an A1c <7% (72% vs. 92%; p<0.001). The triple therapy approach also provided greater improvements in body weight (-1.2 kg [-2.6 lbs]) compared to the conventional therapy approach (+4.1 kg [+9.0 lbs]). On the safety front, Dr. Abdul-Ghani highlighted that the triple therapy group had a lower rate of hypoglycemia compared to the conventional group (15% vs. 46%, respectively), despite having a lower average A1c. However, triple therapy was associated with a higher rate of GI side effects compared to conventional therapy (33% vs. 21%, respectively), as well as a higher rate of edema (5.3% vs. 1.3%, respectively), though Dr. Abdul-Ghani commented that no cases of heart failure were observed. Based on these results, Dr. Abdul-Ghani concluded that HCPs should “treat the disease, not the symptoms, and treat the patient, not his blood sugar.”

• Dr. Abdul-Ghani discussed the rationale for evaluating a metformin/pioglitazone/exenatide triple therapy. He noted that both the ADA and EASD now recommend lowering the A1c to as close to normal as possible while avoiding hypoglycemia; however, despite this guidance, no previous study has examined the optimal therapy to achieve this goal. Dr. Abdul-Ghani’s group hypothesized “that in newly diagnosed type 2 diabetes, initiating therapy with agents that correct known pathophysiological defects will produce a greater, more durable A1c reduction while avoiding hypoglycemia compared to the currently- recommended approach of sequential addition of agents that lower plasma glucose but do not correct the underlying metabolic defects.” Dr. Abdul-Ghani highlighted that pioglitazone and exenatide were chosen because of their favorable effects on insulin resistance and progressive beta cell failure, respectively.
• The open label, randomized controlled trial assigned 155 drug naïve, newly- diagnosed type 2 patients to either triple therapy (metformin plus pioglitazone plus exenatide) or conventional therapy (metformin followed by the sequential addition of a SFU and then basal insulin to maintain A1c ≤6.5%). At baseline, participants had an average age of 46- 47 years, BMI of 36-37 kg/m², diabetes duration of 5 months, A1c of 8.6%, and fasting plasma glucose (FPG) of 190-192 mg/dl. In both arms, investigators up-titrated the drug dose to achieve an A1c of <6.5%. The primary endpoint was the difference in A1c between the triple therapy and conventional therapy groups at 24 months. The investigators also measured a range of secondary endpoints pertaining to glycemic control, body weight, and hypoglycemia.
  • Participants visited the clinic every month for the first three months, after which they had a follow-up visit every three months. At the follow-up visits, physicians would decrease the medication doses if a patient experienced hypoglycemia (blood glucose <60 mg/dl) or symptoms of hypoglycemia.
  • In the triple therapy arm, participants received metformin (1,000 mg/day, titrated to 2,000 mg/day at month one), pioglitazone (15 mg/day titrated to 30 mg/day), and exenatide (5 μg twice daily titrated to 10 μg twice daily). If the patient did not achieve an A1c <6.5% at three months, the pioglitazone dose was increased to 45 mg/day.
  • In the conventional therapy arm, patients started with metformin 1,000 mg/day; if the patient’s FPG exceed 100 mg/dl after the first month, the metformin dose was increased to 2,000 mg/day and glyburide was initiated at 5 mg/day. If the patient had a FPG >100 mg/dl or an A1c >6.5% at month two, the glyburide dose was escalated to 10 mg/day. If the patient was unable to achieve FPG <100 mg/dl or A1c <6.5% at month three, insulin glargine was initiated at 10 units/day and the dose was increased based on FPG levels.
  • Treatment failure was defined as an A1c >6.5% on two consecutive visits three months apart despite maximum dosages. The rescue therapy for the conventional therapy arm was Humalog 4-6 units before meals, with a dose escalation to maintain a two-hour post-prandial glucose level <140 mg/dl. The rescue approach in the triple therapy arm was two fold: 1) insulin glargine 10 units in the morning with dose escalation to maintain FPG <100 mg/dl and an A1c <6.5%; and 2) the initiation of Humalog after reaching the maximum glargine dose of 60 units per day.
• At 24 months, the average A1c in the triple therapy arm (6.0%) was significantly lower than the average A1c in the conventional therapy arm (6.6%; p<0.001). While both groups had a similar average A1c at six months (~6.0%) , those on triple therapy maintained the A1c reduction while those on conventional therapy experienced a rise in A1c. Median A1c levels were 5.8% and 6.4% for the triple therapy and conventional therapy groups, respectively, at 24 months.
  • Kaplan Meier curves show that roughly 50% of those who failed the triple therapy approach failed within six months; in contrast, the failure rate in the conventional therapy arm was relatively steady over the course of the 24-month study. To Dr. Abdul-Ghani, this result indicates that the triple therapy affects the course of the disease, in particular beta cell failure – i.e., the primary defect behind hyperglycemia.
  • A greater proportion of patients in the triple therapy arm achieved an A1c<6% or an A1c <7% compared to those on conventional therapy (60% vs. 27% for an A1c <6%; 92% vs. 72% for an A1c <7%; p<0.001 for both comparisons).
  • Triple therapy was associated with a 1.2 kg (2.6 lbs) weight loss while conventional therapy was associated with a 4.1 kg (9.0 lbs) weight gain.

• Dr. Abdul-Ghani highlighted that while the mean A1c with triple therapy was 0.6% lower than that observed with conventional therapy, the triple therapy arm had a much lower risk of hypoglycemia (15%, vs. 46% for conventional therapy). No serious hypoglycemia events were observed in the trial.
  • The triple therapy arm was associated with slightly higher rates of GI side effects, as well as higher rates of edema, though Dr. Abdul-Ghani noted that no cases of heart failure were observed.

* not treatment related

Questions and Answers

Moderator [Dr. Julio Rosenstock]: This controversial data is now open to discussion.

Q: The number of patients was small and the A1c range at baseline was very wide. I’m wondering if the treatment differed in people with lower vs. higher A1c levels at baseline.

A: It’s impossible to say because we don’t have the statistics to stratify response by A1c; however, anecdotally, patients with higher A1c levels at baseline did less well than those with lower A1c levels to start.

Oral Sessions: Improving Health Care Delivery

PATIENT PREFERENCES FOR ORAL ANTIHYPERGLYCEMIC THERAPY (210-OR)

A. Brett Hauber, PhD (RTI Health Solutions, Durham, NC)

In a discrete-choice experiment sponsored by Merck (n=923 people with type 2 diabetes surveyed), Dr. Brett Hauber found that out-of-pocket cost and glucose control were the first- and second-most important attributes of oral type 2 diabetes medications. Dosing frequency, weight change, and adverse event rates (including hypoglycemia, chance of mild-to-moderate “stomach problems,” and additional congestive heart failure) were moderately less important to patients though still significant. Looking more specifically at dosing frequency, Dr. Hauber found that 67% of patients, particularly those who were young (<45 years old) or treatment naïve, preferred once-weekly to daily administration. The average respondent was willing to pay $5.86 more per month for a once-weekly pill than a once-daily pill (holding all else constant) – a margin we found to be surprisingly small and potentially of import as companies decide on whether or not to invest in developing once-weekly basal insulin, DPP-4 inhibitors, etc. During Q&A, Dr. Hauber noted that people taking multiple once-daily medications might prefer to another once-daily rather than once-weekly treatment, in order to limit day-to-day changes in their medication regime. Still, Dr. Hauber hypothesized that once-weekly dosing might provide an additional incentive to initiate and adhere to a given treatment for many patients, particularly those who areyoung or drug-naive. We are curious if these sub-population findings might lead Merck to target these groups when it launches its once-weekly DPP-4 inhibitor MK-3102 (phase 3). We suspect that Merck supported this research, in part, to help develop strategies for introducing MK-3102 to the market in a manner that does not cannibalize Januvia (once-daily sitagliptin) sales. For more details on MK-3102 and Januvia, please see our Merck 1Q13 report at http://www.closeconcerns.com/knowledgebase/r/f0e5540f.

• Participants (n=923) were recruited by Knowledge Networks. Knowledge Networks is a nationally representative web panel of US households. Dr. Hauber acknowledged that the diabetes sample might not be nationally representative, however. People were included if they were 18 years or older, residents of the US, and self-reported being diagnosed with type 2 diabetes by a physician. They were excluded if they were currently using either insulin or a GLP-1 receptor agonist. We think this latter exclusion could have negatively biased people’s stated concerns with GI adverse events, since people with diabetes might not be on a GLP-1 receptor agonist due to this concern.
  • The researchers invited 2,262 people to participate in the study, of which 940 eligible people consented to participate. Four people were excluded since they did not answer any choice questions and 13 were excluded because they had no variation in responses to choice questions, raising concerns about the honesty of their responses.
• The sample was not representative of age, race/ethnic identity, or insurance status. It also had slightly more women than men.

• The direct-choice experiment presented participants with pairs of hypothetical oral- agent profiles and asked them to select the drug they would prefer to take. The profiles were defined by seven attributes: dosing, cost, and five clinical endpoints. These endpoints included average glucose reduction, GI adverse event risk, weight change, and congestive heart failure risk, and hypoglycemia frequency. Implicit preference weights were determined for each treatment attribute based on a participant’s pattern of choices. Data was analyzed using a limited dependent variable model.
  • The study included four dosing frequencies (once-weekly, once-daily, two bills once a day, and one pill twice a day).
  • Values for average reduction in glucose (from a baseline of 206 mg/dl) included 20, 30, 40, 50, 60, and 70 mg/dl.
  • The chances of mild-to-moderate stomach problems included were 10%, 23%, 25%, and 30%. The frequencies of hypoglycemia tested were none, 1-2 hypos per year, 1-2 hypos per month, and more than 2 hypos per month.
  • The amount of weight change tested ranged from six pounds of weight gain to six pounds of weight loss (baseline not provided).
  • Additional chances of congestive heart failure included no additional chance, additional 1% chance, and additional 3% chance.
  • The monthly out-of-pocket cost ranged from $0 to $200.
• The most important attribute for an oral drug was its monthly out-of-pocket cost and the second most important reduction to average glucose (from a baseline of 206 mg/dl). Based on a graph displayed it appeared that people went from preferring a drug due to cost to disliking a drug due to cost, when the monthly out-of-pocket cost was more than $25 and less than $100.

• Overall, 67% of the cohort preferred once-weekly to daily treatment (either one or two pills a day). People who were drug naïve were more likely than their on-treatment counterparts to prefer once-weekly treatment to daily treatment (75% vs. 65%; p=0.012). Similarly, people who were younger than 45 years old were more likely than those 45-64 years old or at least 65 years old to prefer a once-weekly treatment to a daily option (78% vs. 66% vs. 66%). However, the variation in preference by age was not statistically significant (p=0.065 for the comparison of <45 years to 45-64 years, and p=0.074 for the comparison of <45 years to ≥65 years). Dr. Hauber believed this insignificance was because of the low enrollment of younger people. People who had been diagnosed within three years had essentially same preference for a once-weekly treatment as those who had diabetes for at least three years (66% vs. 67%).
• People’s willingness to pay was greatest for the transition from a two-pill once-a-day dosing schedule to a one-pill once-a-week option ($13.88 a month). The least financially valued dosing change was going from one-pill twice a day to one-pill once a day ($3.34).

• Dr. Hauber did not detail his findings for parameters other than dosing frequency. He did, however, mention that a 13-percentage point reduction in GI risk (from a baseline risk of 23%) was about equally important to the cohort as a two-percentage point reduction in cardiovascular heart failure risk (from a baseline risk of 3%). Not particularly surprising was his finding that a 13 percentage point reduction in GI risk (from a baseline of 23% risk) was more preferred by the cohort than a five percentage point reduction (from 30% risk). 

Questions and Answers

Q: Do you have any information on these patients? For example do you know what they were treated with at baseline? Their prior experiences undoubtedly impact how they view these questions.

A: We do not know the specific drugs that they were on. In a previous study we did, we found that people who had a relatively high pill burden placed little value on lowering the frequency with which they took one medication. We probably could look at the same thing here; we have that data. We often find that serious events that impact you in some major way (such as severe hypoglycemia) tend to impact your preferences over that event. The smaller events you learn how to adjust to.

Q: Is there any information on the preferences of patients on vitamin D? Vitamin D can be given once a day to once a month. In my anecdotal experience, it is much less likely that they will take it once a month vs. taking some amount of vitamin D every day.

A: That is correct. I do not know about vitamin D in particular but there is evidence that gets exactly to that point. From my reading what I see is that people prefer for it to be a part of a regular routine – daily is obviously the easiest for that, weekly is possible, monthly is also possible. Every other day does not appear to work. Monday, Wednesday, and Friday appears to work but every other day doesn't.

Q: Why do some people not prefer daily dosing?

A: I think that the previously raised point gets to the idea that it is not unambiguously better to take a pill once weekly than once daily. People who are already taking something once a day might want to just add another once a day drug than to do something different once a week. That is a hypothesis on my part.

DETERMINANTS OF NON-ADHERENCE TO DIABETES MEDICATIONS (209-OR)

Ronald Aubert, PhD (Research and Evaluation Analytics, Ann Arbor, MI)

In individuals with chronic health conditions, lack of medication adherence represents a major barrier to achieving treatment goals and is associated with poorer health outcomes. Dr. Aubert presented a study that sought to identify factors associated with medication adherence and non-adherence. Using the Large Pharmacy Claims Database, a cohort was developed of 300,755 individuals who had diabetes, were greater than 20 years of age, were on less than three diabetes medications, and had two or more claims for a non-insulin diabetes medication. The modified metric for adherence used in this study was defined as either a medication possession ratio (MPR; a measure of the percentage of time a patient has access to medication) of greater than or equal to 0.8 or an MPR of less than 0.8 if a patient switched therapies. Less than 80% coverage was considered non-adherent. A variety of patient, medication, and prescriber factors were assessed using logistic regression analysis to determine their independent association with non-adherence. In the total sample, 24% of patients met criteria for non-adherence. Risk for non-adherence to diabetes medications was found to be highest in younger patients, women, patients using retail pharmacies (vs. mail order), patients new to diabetes therapies, and patients prescribed fewer total medications. Those who were adherent tended to be older patients with higher income and education levels. Interestingly, being prescribed medications by a diabetes specialist was associated with greater adherence. While these data are certainly intriguing, we feel it may also be beneficial to address the environmental, sociocultural, and personal determinants underlying medication adherence. In order to effectively increase rates of treatment compliance, a more in-depth analysis of the contextual factors influencing adherence may be necessary.

Questions and Answers

Q: One of the concerns we’ve often had is that with the advent of Wal-Mart type $4 formularies, people tend to pay out of pocket with cash because it’s cheaper than a co-pay. How did you deal with that in your analysis?

A: Excellent question. We had a survey that we sent out to people as part of an adherence program, where we asked if they were filling their prescriptions at retailer chains offering $4 co-pay. We found that this accounted for only 4-10% of people of the surveyed population, so it was relatively small. For people with chronic illness, it was about 5% of the sample.

Q: Why limit the study population to patients on less than three diabetes medications?

A: It was a convenience factor for us from a computational perspective.

Q: This is more of a comment, but I think this type of analysis is a bit of a red herring. We shouldn’t be looking for the non-adherent person; in fact, this personality profiling is a bit old. We need to be spending time and effort on looking at peoples’ beliefs about their medications. I don’t think we should be looking for one type of person; instead, I think we should be studying everyone’s beliefs about their medications and identifying the points in their lives with diabetes that they are struggling with their medications.

A: I would I agree with that.

Oral Sessions: The Broad Spectrum of Diabetes Education–Strategies for Delivery

ARE WE REALLY READY TO DELIVER DIABETES SELF-MANAGEMENT SUPPORT? (308- OR)

Janice Koshinsky, RN (University of Pittsburgh, Pittsburgh, PA)

Ms. Janice Koshinsky argued for the use of diabetes self-management support (DSMS) plans in the ongoing process of imparting the knowledge, skill, and ability necessary for prediabetes and diabetes self-care, called diabetes self-management education (DSME). Studies have shown that sustained improvement in A1c requires ongoing follow-up and education. This is better achieved through DSMS, which incorporates multiple forms of on-going self-management support (such as websites and support groups), as opposed to DSME, which is directly facilitated by health professionals and lays the primary foundation of education (Norris et al., Diabetes Care 2001). In order to plan future DSMS programs, Ms. Koshinsky presented the results of a retrospective review of documentation representing 11 DSME program sites in western Pennsylvania and 2,448 DSMS plans. The most frequently identified form of DSMS was medical health (follow-up with professional healthcare workers, n=2,323) and the majority of plans included only one form of support, with less than 5% of plans containing more than two forms of support. Medical DSMS was the only form referenced in 41% of plans, with plans with two forms of support most frequently including medical/community support or medical/family or friends support, which represented 30% and 19% of plans, respectively. In the brief Q&A, Ms. Koshinsky reiterated the need for more reliance on community and social support, given the limited resources of diabetes health professionals and educators.

Questions and Answers

Q: What do you think is the best model for follow-up support?

A: I don’t know if there is one best plan. I think it needs to be individualized based on needs and resources. I think we need to think out of the box. We know that we’re referring them back to the healthcare resources, but they’re limited. We need to look at community support and social support, as well as other health workers. We have a lot to do in order to define what these different levels of support are.

Meeting the Expert Session

THE ABCS OF EVIDENCE-BASED CARE FOR YOUTH WITH TYPE 2 DIABETES

Tamara Hannon, MD (Indiana University, Indianapolis, IN)

Dr. Tamara Hannon led an interactive chalk talk on the treatment of type 2 diabetes in youth. Engaging the audience in a case study of an adolescent female recently diagnosed with type 2 diabetes, she discussed special considerations for youth, focusing on diagnosis and treatment. Overall, given the poor adherence observed in this population and the potential for deleterious downstream effects, she stressed the importance of early, aggressive, and individualized treatment plans, designed to maximize compliance.

• Dr. Hannon stressed the importance of screening for type 2 diabetes in patients with risk factors, even at an early age. A1c demonstrates poor specificity in youth, with affected patients having A1cs >6.5% only 15% of the time, and thus she recommended using the two-hour OGTT for diagnosis. She reinforced that even with increasing prevalence of type 2 diabetes, type 1 diabetes remains a common cause of glucose dysregulation in this population and therefore must be ruled out in each screened patient.
• In terms of treatment, Dr. Hannon recommended beginning with metformin, in addition to diabetes education and lifestyle change. The TODAY study showed that the disease remains progressive even in this younger population, with many youth requiring a second therapy within a few years of beginning treatment. Dr. Hannon suggested this supported the importance of early, aggressive treatment – even if only to reinforce to the family the seriousness of the disease, given the poor adherence observed in this population. Guidelines suggest a target treatment goal of <7.0%, though Dr. Hannon noted, “the lower, the better.”
• If initial therapy fails, Dr. Hannon pushed for insulin initiation. While guidelines suggest initiation at A1cs >9.0%, she recommended for an 8.0% threshold. When deciding on a regimen, she suggested individualization should guide treatment, given the wide range of health literacy and resources present in this population. With respect to other treatments, she highlighted the use of rosiglitazone in the TODAY trial but suggested concerns over cardiovascular outcomes make it difficult to justify use in youth. While currently unapproved, she looked forward to results from ongoing trials with GLP-1 agonists in this population. She also expressed enthusiasm for ongoing trials examining the effect of early insulin treatment on beta cell longevity.

Questions and Answers

Q: What are the guidelines for patients with microalbuminuria without elevated blood pressure?

A: We still recommend treatment with an ACE inhibitor.

Symposium: Exercise as Adjunct Therapy for Insulin Sensitivity and Diabetes

LIFESTYLE, DRUGS, OR SURGERY? A CLINICIAN’S PERSPECTIVE

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

Dr. Samuel Dagogo-Jack reviewed the major pros and cons of lifestyle intervention, pharmacology, and bariatric surgery before moving on to his guiding beliefs in the clinic. While he is always willing to start with lifestyle intervention (in a memorable statement, Dr. Dagogo-Jack said “Anyone with an arm and a leg is a candidate for lifestyle intervention”), he readily recognizes the difficulties of long-term adherence to any intensive lifestyle intervention program. In a very interesting series of slides on pharmacology, he documented his hypothesis that a 1% reduction in weight corresponds to a 15% reduction in the relative risk (RRR) of developing diabetes. Using this theory, Dr. Dagogo-Jack projects a 60-90% RRR for the 4-6% weight loss observed with GLP-1 receptor agonists, a 45% RRR for the 2-3% weight loss observed with SGLT-2 inhibitors, a 45% RRR for the 3% observed with locaserin, and a 100% RRR for the 8-9% weight loss observed with phentermine/topiramate (if the theory moves linearly). In an elaborate chart documenting his views on the different modalities of treatment, Dr. Dagogo-Jack identified lifestyle therapy as most effective for diabetes prevention and insulin sensitivity, drugs most effective for diabetes control, and surgery most effective for diabetes control, prevention, weight loss, blood pressure, lipids, and insulin sensitivity. Nonetheless, he still views bariatric surgery as a last resort. In the long run, he expressed concern for micronutrient deficits, hypoglycemia, and waning treatment efficacy. He aligns his clinical recommendations with the ADA, in which bariatric surgery is appropriate for those adults with BMI >35 kg/m² and type 2 diabetes, especially if the patient has associated comorbidities and has failed both lifestyle and drug interventions. Even then, patients with type 2 diabetes who have undergone bariatric surgery still require lifelong lifestyle support and medical monitoring. In closing, he underscored the ever-present need for data on the long-term benefits, cost-effectiveness and risks from well-designed RCTs with optimal medical and lifestyle arms.

Questions and Answers

Q: Adherence to lifestyle intervention is difficult. Bariatric surgery works well, but not every patient is willing or can afford. Drugs have costs and side-effects. How would you suggest we prescribe these modalities?

A: The AACE 2013 algorithm proposes a complications-centric approach. There are many overweight people whose metabolic profiles are surprisingly pristine. Targeting such a person with surgery or drugs is inappropriate. Lifestyle intervention is a foundational intervention. Then you use clinical judgment to layer on top of lifestyle while you consider pharmacology, opting to surgery as a last approach.

Symposium: Behavioral Interventions for Diabetes–Evidence From Recent Intervention Studies

FINANCIAL INCENTIVES VS. PEER MENTORING FOR DIABETES – WHAT WORKS?

Judith Long, MD (University of Pennsylvania, Philadelphia, PA)

Dr. Judith Long reviewed the evidence supporting the use of financial incentives and peer mentoring programs to promote more effective management of type 2 diabetes. In regard to peer mentoring, Dr. Long noted that peer mentors have shown an effect in improving glucose control, particularly in low income and minority communities. She explained that peer mentoring programs contribute informational and emotional support to improve attitudes towards diabetes. While group medical appointments have been shown to improve diabetes management (e.g., increasing rates of test ordering), they have failed to demonstrate consistent improvement in clinical measures such as A1c or blood pressure (Edelman et al., Ann Intern Med 2010). In contrast, a study that randomized patients with diabetes to either reciprocal peer support or nurse care management for six months demonstrated that subjects in the peer support arm experienced reductions in A1c (8.02% to 7.73%) whereas subjects in the nurse care management arm had worse control (7.93% to 8.22%). In regard to financial incentives, Dr. Long indicated that evidence is still lacking for or against their use. Evidence in patients with diabetes mostly reflects small, non-randomized studies that are short in duration, with many more studies demonstrating positive outcomes for weight loss.

Symposium: Diabetes in Older Adults (Supported by an Independent Educational Grant from Boehringer Ingelheim and Eli Lilly)

GLYCEMIC TREATMENT GOALS IN ELDERLY SUBJECTS WITH DIABETES

Dawn D. Smiley, MD, MS (Emory University School of Medicine, Atlanta, GA)

Dr. Dawn Smiley emphasized the importance of focusing on type 2 diabetes control in elderly patients. With an expected increase of 188% in the population aged >65 by 2050, glycemic control for the elderly will become increasingly important for the future of diabetes care. However, limited information is available due to lack of studies on this population, highlighting the need for future research. While recent A1c target guidelines published by the ADA, EASD, AACE, and American Geriatrics Society reflect the growing importance of individualized treatment regimens, Dr. Smiley emphasized that individualization may be particularly important in the elderly.

Corporate Symposium: Practical Strategies for Improving Outcomes in T2DM: The Expert Course (Sponsored by Sanofi)

THE NEW ADA/EASD POSITION STATEMENT

Silvio Inzucchi, MD (Yale University, New Haven, CT)

Dr. Silvio Inzucchi opened the evening with a review of the ADA/EASD guidelines for managing hyperglycemia. He noted that a dramatic rise in available anti-hyperglycemic agents since the 1990s has provided novel options for addressing the complex pathogenesis of diabetes, but has also presented new challenges for providers. New guidelines were necessary due to this increase in choices, new efficacy and safety data, new data regarding the benefits and risks of tight glycemic control, and a renewed focus on patient-centered care. Dr. Inzucchi emphasized the guidelines’ patient-centered approach, exemplified by their glycemic targets that depend on patient attitude, life expectancy, disease duration, comorbidities, vascular complications, and support systems. He also explained that in drafting the guidelines, the committee tried to emphasize intensity of approach rather than specific numeric targets. Dr. Inzucchi concluded by asserting that personalization of therapy will be achieved not only by physicians using the new guidelines, but also by their choosing add-on therapies based on anticipation of drugs’ efficacy, patient- concerns about adverse effects, and how advantages of certain drugs meet patients’ current needs (i.e. weight loss).

INSULIN THERAPY 2013: THE KEY QUESTIONS

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

Dr. Samuel Dagogo-Jack began his presentation with a question: When two oral agents fail to control type 2 diabetes, would you: 1) add a third oral anti-diabetic medication? 2) start insulin? or 3) start a GLP-1 receptor agonist? He admitted that there are no right answers, because different patients are in different stages in the evolution of the disease. Dr. Dagogo-Jack strongly encouraged the use of insulin therapy to correct the defects present in type 2 diabetes: a depletion of endogenous insulin reserves due to beta-cell failure and increasing insulin resistance. Of the three landmark trials analyzing methods of reducing microvascular complications, the DCCT, Kumamoto, and UKPDS trials, Dr. Dagogo-Jack noted that only DCCT and Kumamoto achieved lasting reductions in A1c. He attributed this distinction to the use of insulin dosing titrated by self-monitoring of blood glucose. Dr. Dagogo-Jack also reviewed the results of the ORIGIN trial to assure the audience that there is no excess risk of cancer with glargine therapy. (Notably, 79% of the audience was already convinced that there was no excess cancer risk prior to Dr. Dagogo-Jack’s review of ORIGIN.) Consequently, physicians considering initiating insulin therapy are left with five key questions:

1. When in the course of type 2 diabetes is it appropriate to routinely use insulin?
2. How do we determine that time or stage in any given patient?
3. What is the ideal initial insulinization strategy?
4. How should insulin therapy be intensified once initiated?
5. Do recent data demonstrating the efficacy and benefits of GLP-1 receptor agonists alter traditional approaches to the timing and deployment of exogenous insulin therapy?

COMBINATION PARENTERAL THERAPY: THE NEXT HORIZON?

Paresh Dandona, MD, PhD (University at Buffalo, Buffalo, NY)

Dr. Paresh Dandona noted that with the traditional three meal per day schedule, patients can spend a great deal of the day in postprandial hyperglycemia. Postprandial hyperglycemia is the major contributor to overall hyperglycemia for many patients with A1c levels below 8.5%, and thus presents an appealing therapeutic target. Dr. Dandona noted that GLP-1 agonists may help bring down postprandial glucose by restoring the incretin effect; he specifically suggested that adding GLP-1 receptor agonists to basal insulin can provide additional glycemic control without hypoglycemia, and may lead to weight loss. He then reviewed other advantages of GLP-1 agonists, including their glucose-dependent actions and their positive effects on visceral body fat. To differentiate the available GLP-1 agonists, he noted that short acting GLP-1 receptor agonists – exenatide and liraglutide – have a greater effect on postprandial glucose, while the long-acting exenatide-LAR has a greater effect on fasting plasma glucose levels. In the spirit of the symposium, Dr. Dandona suggested that these differences offer the potential for individualized therapy.

PANEL DISCUSSION

Paresh Dandona, MD, PhD (University at Buffalo, Buffalo, NY); Silvio Inzucchi, MD (Yale University, New Haven, CT); Samuel Dagogo-Jack, MD (University of Tennessee Health Science Center, Memphis, TN); Davida Kruger, MSN (Henry Ford Medical Center, Detroit, MI)

Q: I don’t think you addressed patients who have uncontrolled A1c, like 13% or 14%. What strategies do you think would be good for these patients? What about a patient who failed two oral medications and has an A1c of 13? Or someone who has just failed metformin, with an A1c of 13%?

Dr. Inzucchi: The answer is different based on where we start. According to ADA/EASD guidelines, you should consider aggressive insulin strategies from the get-go. Once the A1c is 10-11%, you can consider other oral anti-diabetics, once the glucose toxicity is removed. Until glucose toxicity is eliminated, these drugs might not exert their best effect. So, in summary, I would use insulin in these patients. I would consider metformin, depending on renal activity. I don’t know if I would go on basal insulin immediately, or use a basal/bolus approach. I might use the more aggressive approach – it might take months to get anywhere near control on basal alone.

Ms. Kruger: We have to distinguish between a patient who is newly diagnosed vs. a patient who has failed metformin. If the A1c is 13%, sometimes they’ve been symptomatic long enough that they don’t even realize it anymore. But I think the basal/bolus approach is very aggressive. Once you see the glucose toxicity reduced, then you can scale back the insulin and let the beta cells rest. At that point, you can see where you are at so the orals can kick in. Sometimes patients do well on one oral agent, after a long period of time. I would still choose insulin that instance. But, I think those are different scenarios.

Dr. Dagogo-Jack: Patients are heterogeneous. Somebody’s A1c of 13% might indicate chronic undiagnosed diabetes, or it might indicate poorly managed diabetes of many years. While it’s academically very necessary to try to bring glucose toxicity down by using the most potent therapy before testing whether oral agents work, I have had push back from some newly diagnosed patients with double digit A1cs. When I suggest the “I”-word, they are terrified. But I have also had success with patients on metformin, sulfonylureas, and TZDs. I have seen as high as six point decreases of A1c, from 14 to 8%, within a couple of months. One cannot be too prescriptive in this matter.

Dr. Dandona: As you can see, this is a common enough problem at the general practice level, but it rarely arrives at the academic center level. And clearly, there are differences in opinion about how to handle it. But I think all of us agree that initially at that level, a little basal insulin would be of enormous help to get the A1c to normal levels, and the beta cells can rest, and then you can add different pieces, apart from metformin.

Q: I’d like to know if you can comment on the cost-effectiveness of GLP-1 agonists, for example in a patient with a reduction of 0.6% A1c. I’m wondering the value of a person spending up to $350 a month for an agent, and if that’s really cost-effective.

Dr. Inzucchi: Some people have criticized sulfonylureas for the risk of weight gain. But pound for pound, their ability to reduce A1c is without comparison. Physicians practice in two worlds: one where patients pay out of pocket, and one where someone else is covering the costs. We tend to prescribe differently if someone else is covering the costs. I think there are additional costs – some side effects of medications, besides hypoglycemia, so it’s a complex calculus. But I do agree that in the circumstance of patients of limited means that GLP-1 receptors are often out of reach.

Ms. Kruger: I’d also point out that if you choose insulin, and you don’t use human insulin and choose analog insulin, that two vials of analog insulin is the same cost as a GLP-1. So if you’re thinking about the benefit to the patient in terms of lack of hypoglycemia and weight loss, your average vial of insulin is $125-150 as well unless you go for human insulin, which is about $25.

Q: Could you talk about the use of GLP-1s in patients with gastroparesis?

Ms. Kruger: It’s contraindicated in gastroparesis because those patients have delayed gastric emptying, so you don’t want to further delay it. In terms of pancreatitis and cancer, the verdict is out. In Diabetes Care you’ll see articles come out – an article and a rebuttal out this week – and I think that will clear things up. The important thing is to monitor carefully, and not use them with people who have a personal family history of thyroid cancer, and that people need to be able to recognize the symptoms of pancreatitis. In the next two weeks, there will be more information to make these judgments.

Dr. Dagogo-Jack: In general, patients with mild or any form of gastroparesis will have a greater tendency to complain about the gastrointestinal effects of just about every drug that has gastrointestinal side effects. So, I would have a low threshold to divert to another class.

Dr. Inzucchi: Last week, the NIDDK and the National Cancer Institute put together a workshop, where the high level conclusion was that they could not find convincing evidence between GLP-1 receptor agonists, DPP-4s, and pancreatic cancer. However, they could find no evidence to refute this connection. Pancreatitis can occur – these cases are hard to dismiss, so there may be a low level of risk of pancreatitis. I’ve personally not seen a case. A recent paper from JAMA showed that a twofold risk was concerning, but there are other papers that don’t seem to find this link.

Dr. Dandona: I have had many patients on GLP-1s and DPP-4s over the past 8 years, and we’ve seen only one case of acute pancreatitis, which was resolved. So I don’t think the incidence in clinical practice is that high. But, only time will tell as we learn more information in patient registries.

Dr. Inzucchi: Also, large cardiovascular studies, which are beginning to close out now, or within the next few months, will show whether or not there is a real risk of pancreatitis.

Q: Quite often, I’ll have patients who are well controlled with metformin, sulfonylureas, and pioglitazones. But they’ll come to me with a press report saying that pioglitazones are banned in two countries. Do I listen to the patient’s fear of bladder cancer? Do I reduce the dose? This is a real-world question.

Dr. Inzucchi; I’ve tended to practice with the motto of “If it ain’t broke, don’t fix it.” If a patient is doing well, then I tend to not like the change. The bladder cancer issue has been eroded into the use of pioglitazone. I think we all agree that it is otherwise a well-tolerated medication. This is a very complex issue. I’ve looked at the databases that have been analyzed and I’m personally not convinced of an association. Specifically, the study that raised this question from Kaiser Permanente in California has reanalyzed their data with many more accumulated patient-years and they find no association. Unfortunately, the analysis was never published for a variety of reasons, which I’m not aware of. We know that this study will conclude with a ten-year analysis that will hopefully provide a definitive answer. But unfortunately, that won’t be published until 2014. So I think that this question still haunts this drug class. There’s a fear of edema, bone fractures, and wounds. In the end, sometimes your patient just wants a discussion with the physician, and they want to see what clinical data has been published.

Dr. Dagogo-Jack: Remember, we have an agency that oversees all food and drugs, and they have very qualified researchers. And drug companies are required to share their safety information. So I don’t think the FDA is shy to sanction a product. The current advisory of the product is to not use pioglitazone with a patient with bladder cancer family history, and to discuss the signs. As they have said, they have not made a judgment about whether there is a causal relationship. But I think its safety is responsible interim advice that we can follow. The moment that this is no longer the case, it will be taken from the market.

Dr. Dandona: Even the lowest doses are effective. I’d love to get some data about effects based on dose- response relationships. Because that’s totally missing – we’re talking about generic side effects.

-- By Adam Brown, Eric Chang, Hannah Deming, Jessica Dong, Adam Kraus, Tony Thaweethai, Manu Venkat, Katrina Verbrugge, Vincent Wu, and Kelly Close