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CME

Impacting Type 2 Diabetes and Optimizing Patient Outcomes With GLP-1 Receptor Agonists

  • Authors: Vivian Fonseca, MD, FACE, Moderator; Lawrence Blonde, MD, FACP, FACE; Michael A. Nauck, Professor and Head Physician
  • CME Released: 10/18/2013
  • THIS ACTIVITY HAS EXPIRED
  • Valid for credit through: 10/18/2014
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Target Audience and Goal Statement

This activity was developed for endocrinologists, internists, primary care clinicians, and other healthcare professionals who manage patients with type 2 diabetes.

Management of type 2 diabetes is shifting to new treatment modalities that offer low risks of hypoglycemia and weight gain while effectively lowering blood glucose levels. GLP-1 receptor agonists can be used alone or in combination with other agents. This case-based continuing education program will explore the relative merits of GLP-1 receptor agonist therapy across the spectrum of patients with type 2 diabetes and provide a pathophysiologic and clinical rationale for the use of these agents. Faculty will present complex cases and review the rationale for and against different therapeutic options, and present data supporting why GLP-1 receptor agonists might be appropriate as part of mono- or combination-therapy strategies. Clinical scenarios and patient complexities that may require physicians to reconsider, re-evaluate, adjust therapy, or re-affirm their clinical decisions will be posed to the faculty for their expert opinions.

Upon completion of this activity, participants should be able to:

  1. Design pharmacologic strategies that optimize the use of GLP-1 receptor agonist therapy in comprehensive care plans for patients with diabetes based on stage of disease.
  2. Select glucose-lowering strategies based on patient factors that affect treatment success and patient safety.
  3. Summarize current and future trends of GLP-1 receptor agonist-based treatment strategies based on scientific and clinical evidence that address current unmet needs.


Disclosures

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the US Food and Drug Administration (FDA). Clinical and Patient Educators Association (CPEA) and Global Directions in Medicine do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

CPEA requires instructors, planners, managers, and other individuals and their spouse/life partner who are in a position to control the content of this activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly vetted by CPEA for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:


Authors

  • Vivian Fonseca, MD, FACE, Moderator

    Professor of Medicine and Pharmacology, Tullis Tulane Alumni Chair in Diabetes, Chief, Section of Endocrinology, Tulane University Health Sciences Center, New Orleans, Louisiana

    Disclosures

    Disclosure: Investigator/Grant/Research Support to Tulane: Abbott, Eli Lilly & Company, Endo Barrier, Novo Nordisk Inc., Pan American Laboratories, Reata, Sanofi; Speaker/Consultant/Honorarium: Abbott, Astra-Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Glaxo Smith Kline, Eli Lilly & Company, Novo Nordisk Inc., sanofi aventis, Pamlabs, Takeda.

  • Lawrence Blonde, MD, FACP, FACE

    Director, Ochsner Diabetes Clinical Research Unit, Department of Endocrinology, Diabetes, and Metabolic Diseases, Ochsner Medical Center, New Orleans, Louisiana

    Disclosures

    Disclosure: Grant/Research Support to Ochsner/Investigator: Eli Lilly & Company, Novo Nordisk Inc., Sanofi; Speaker/Honorarium: Amylin Pharmaceuticals Inc., Bristol-Myers Squibb/AstraZeneca, Janssen Pharmaceuticals Inc., Johnson & Johnson Diabetes Institute LLC, Merck & Co., Novo Nordisk Inc., Sanofi, Santarus; Consultant/Honorarium: Amylin Pharmaceuticals Inc., GlaxoSmithKline, Janssen Pharmaceuticals Inc., Merck & Co. Inc., Novo Nordisk Inc., Pfizer, Sanofi, Santarus.

  • Michael A. Nauck, Professor and Head Physician

    Professor and Head Physician, Diabeteszentrum Bad Lauterberg, Harz, Germany

    Disclosures

    Disclosure: Investigator/Grant/Research Support -- Monocentric investigator-initiated studies: Berlin Chemie AG, Eli Lilly & Co., Merck Sharp & Dohme GmbH, Novartis Pharma AG; Multicentric clinical studies: AstraZeneca, Boehringer lngelheim, GlaxoSmithKline, Lilly Deutschland GmbH, MetaCure Inc., Roche Pharma AG, Novo Nordisk Pharma GmbH, Tolerx Inc.; Advisory Board/Membership: Amylin Pharmaceuticals Inc., Berlin Chemie AG, Boehringer lngelheim, Eli Lilly & Co., Hoffmann-La Roche Ltd., lntarcia Therapeutics Inc., Janssen Global Services LLC, Merck Sharp & Oohme GmbH, Merck Sharp & Dohme Corp., Novo Nordisk Pharma GmbH, Sanofi-Aventis Pharma, Takeda, Versartis; Consultant/Honorarium: Amylin Pharmaceuticals Inc., AstraZeneca, Berlin Chemie AG, Boehringer lngelheim, Bristol Myers Squibb EMEA, Diartis Pharmaceuticals Inc., Eli Lilly & Co., Hoffmann-La Roche Ltd., GlaxoSmithKline LLC, Lilly Deutschland GmbH, MannKind Corp., Merck Sharp & Dohme GmbH, Novartis Pharma AG, Novo Nordisk Pharma GmbH, Novo Nordisk NS, sanofi-aventis Pharma, Takeda, Wyeth Research.

The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:

Deanna N. Schuly, Global Directions in Medicine: Nothing to disclose.

Katherine Mann, PharmD, Global Directions in Medicine: Nothing to disclose.

Kelly Enders, CPEA: Nothing to disclose.

Dennis Zanella, MD, CPEA: Nothing to disclose.


Accreditation Statements

This activity is jointly sponsored by Clinical and Patient Educators Association and Global Direction in Medicine.

    For Physicians

  • This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Clinical and Patient Educators Association and Global Directions in Medicine. Clinical and Patient Educators Association is accredited by the ACCME to provide continuing medical education for physicians.

    Clinical and Patient Educators Association designates this enduring material for a maximum of 2.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

    Fee Information & Refund/Cancellation Policy:
    There is no fee to participate in this activity.

    Contact This Provider

For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]


Instructions for Participation and Credit

There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.

This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. To receive AMA PRA Category 1 Credit™, you must receive a minimum score of 75% on the post-test.

Follow these steps to earn CME/CE credit*:

  1. Read the target audience, learning objectives, and author disclosures.
  2. Study the educational content online or printed out.
  3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. In addition, you must complete the Activity Evaluation to provide feedback for future programming.

You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates from the CME/CE Tracker.

*The credit that you receive is based on your user profile.

CME

Impacting Type 2 Diabetes and Optimizing Patient Outcomes With GLP-1 Receptor Agonists

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PART 3: Treatment Intensification to Improve Glycemic Control While Minimizing Weight Gain and Hypoglycemia: Use of GLP-1 Receptor Agonists

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  • I am going to now move a little further along the natural history of type 2 diabetes and talk about intensifying therapy in the later stage, in the people on insulin, while trying to minimize weight gain and hypoglycemia.

  • Slide 1.

    Slide 1.

    (Enlarge Slide)
  • Let me start with a question. Which of the following is true with regard to the use of incretin-based therapies along with insulin? Number 1, only DPP-4 inhibitors are approved for use with insulin therapy. Number 2, use of incretin-based therapy with insulin is associated with a lower risk of weight gain. Number 3, any of the GLP-1 receptor agonists can be used with basal insulin. And number 4, both classes of drugs are associated with hypoglycemia, so this is not an ideal combination.

  • Slide 2.

    Slide 2.

    (Enlarge Slide)

Okay. We'll come back to some more questions later on.

  • Let me present a case to you. This is Maria. A 55-year-old Latina woman who has had diabetes for 8 years. She's had the typical comorbidities of diabetes, hypertension, lipid problems, sleep apnea, past history of hypoglycemia. She's a housewife, has health insurance, smokes half a pack a day, is always tired, takes metformin and glipizide. She's been on this for 2 years. Also takes HCTZ and lisinopril, a statin and ibandronate for osteoporosis.

  • Slide 4.

    Slide 4.

    (Enlarge Slide)
  • The key points in her history and findings are she's obese with a BMI of 34. Her blood pressure is well controlled, but her lipids are not. She has an LDL of 120. Her creatinine is slightly elevated at 1.4 with an eGFR of 50. Her A1c is 8.7, and 4 months ago it was 8.6, so I've really got clinical inertia. I haven't pushed her fast enough. What to do now?

  • Slide 5.

    Slide 5.

    (Enlarge Slide)
  • I've been trying to persuade her to maybe go onto insulin. We start on a long-acting basal insulin analog, 20 units in the evening. We continue with the oral agents, and I give her instructions to titrate her dose up, increase her statin, I start aspirin, and send her for smoking cessation.

  • Slide 6.

    Slide 6.

    (Enlarge Slide)
  • She's been very good about her instructions. She up-titrated her insulin. She's up to 58 units now. Reports that she wakes up at night shaking but doesn't test her blood glucose. Her A1c has come down a little bit but not quite at goal. It's 7.8. She has unfortunately gained 6 pounds, and she's extremely unhappy with me about this. She's stopped smoking, is taking insulin, all those kind of things that contribute to weight gain.

  • Slide 7.

    Slide 7.

    (Enlarge Slide)
  • Plus, although she's not documenting it, I think she's got hypoglycemia. She has some risk factors. Now listed here are a wide range of risk factors for hypoglycemia, many of which you recognize very well so I won't repeat them, the most common being a mismatch between meals and insulin or sudden bouts of physical activity. But one important one, she has renal insufficiency, which changes the dynamics of the insulin, particularly long-acting insulin, so makes people prone to hypoglycemia.

    There is a certain degree of malnutrition associated with renal insufficiency, and they don't have renal gluconeogenesis, although that's at a later stage. One other important finding is antecedent hypoglycemia. Dr. Crier, who is a pioneer in this area, has said that hypoglycemia begets more hypoglycemia. Once you have it, you're more likely to get it. You're prone to it. You're more likely to have it in the future.

  • Slide 8.

    Slide 8.

    (Enlarge Slide)
  • Of course, hypoglycemia is very common in type 1 diabetes, particularly after you've had it for a few years and you've lost your ability to recover from hypoglycemia. Even in type 2 diabetes, and here it is after 5 years of treatment, so it's fairly early in the natural history of diabetes.

  • Slide 9.

    Slide 9.

    (Enlarge Slide)
  • Very often these episodes of hypoglycemia go unrecognized by patients. Many are asymptomatic. There are some CGMS data available that show that unrecognized hypoglycemia is very common in patients with diabetes. In one study, 63% of patients with type 1 and 47% of patients with type 2 had unrecognized hypoglycemia as measured by CGMS. CGMS was somewhat unreliable in the past. It's become a lot more reliable now, and I think we're still seeing a lot of unrecognized hypoglycemia.

    One other important thing about this is that a lot of these episodes occur at night, and when the patients do feel it, they're very vulnerable. They're very scared of what happens at night. That may well be the case with our particular patient. Very often they're unrecognized as well. Many of these, again, are nocturnal and most of them were unrecognized.

  • Slide 10.

    Slide 10.

    (Enlarge Slide)
  • Another very obvious thing is hypoglycemia unawareness is associated with a high risk of severe hypoglycemia. If you have awareness for hypoglycemia, you're more likely to intervene, have some glucose tablets of have something to eat, whereas those who do not have these symptoms and have hypoglycemia unawareness, they have a 9-fold higher rate of severe hypoglycemia because they advance so rapidly in their hypoglycemia and don't have time to intervene.

  • Slide 11.

    Slide 11.

    (Enlarge Slide)
  • Now Maria presents to you a very common situation. The patient says she's waking up in the night. She's not testing, and she gives you this diary with very reasonable fasting glucose. She's taking insulin at night, but she's got high blood sugars at many times during the day, particularly after meals. The highest is after dinner, which is a common scenario in this country where people eat more in the evenings and perhaps less at lunchtime. This may be a pointer to those episodes during the night being hypoglycemic. She's got a reasonable fasting glucose.

  • Slide 12.

    Slide 12.

    (Enlarge Slide)
  • Her A1c is of course 7.8, and the fasting glucose is at goal. So what would you do for this patient? Number 1, add a DPP-4 inhibitor. Number 2, increase her glipizide. Number 3, add a GLP-1 receptor agonist. Number 4, add prandial insulin at breakfast.

  • Slide 13.

    Slide 13.

    (Enlarge Slide)

  • I think I wouldn't add a prandial insulin. If I were going to add it, I wouldn't add it at breakfast. I'd add it at one of the other meals, usually the main meal of the day. Or you could add a GLP-1 receptor agonist, but a DPP-4 inhibitor may not be a bad choice. Her A1c is not that high. She's getting predominant postprandial hyperglycemia, and so there is no perfect, correct answer. I wouldn't increase the glipizide dose. Once you've got to this stage of diabetes, I think incremental increases in the sulfonylurea are not going to do very much for the A1c.

  • Slide 14.

    Slide 14.

    (Enlarge Slide)
  • So you just added sitagliptin. She added 10 milligrams per day. She had some improvement in blood sugars, but 4 months later, her A1c is still 7.4. She's also gained more weight. She has now managed to stop smoking, which, as you know, causes weight gain. She's now extremely concerned and unhappy about this. She also worries about costs of medicines. Why [is she] not meeting her goal? She says, "If I were meeting goal and I was doing everything right and I was losing weight I'd be a little happier, but I'm taking all these medications and things are not right."

  • Slide 15.

    Slide 15.

    (Enlarge Slide)
  • So you make a switch. You start her on liraglutide. You stop the DPP-4 inhibitor, change to liraglutide .6 milligrams and then increase over 4 weeks and you go up to 1.8 milligrams. She has some minor nausea, no vomiting, but it occurs in the first 2 weeks and then subsides. You decide to discontinue the glipizide and reduce the insulin dose by 20% when you start the GLP-1 receptor agonist. We'll come back to this issue later on.

    Here's the issue with this patient. She has a high postdinner and bedtime glucose, near normal fasting glucose. She's getting hypoglycemia during the night. If you reduce the basal insulin, she'll get even more hypoglycemia during the day. You want to control that by something that controls the blood glucose during the day.

  • Slide 16.

    Slide 16.

    (Enlarge Slide)
  • It works. Her A1c comes down to 6.8, body weight drops 8 pounds, which has made her very happy over the next few months. She's stable with metformin 1 gram a day, liraglutide 1.8, and a basal insulin, you've manage to cut back to 45 units, which may have helped with her weight loss and has also cut back on her nocturnal hypoglycemia which she was suffering.

  • Slide 17.

    Slide 17.

    (Enlarge Slide)
  • Larry pointed out the AACE algorithm, and I want to take 1 slide from there, which is what happens when people fail on basal insulin. This is a not uncommon scenario, and you have 2 major choices here. One is to add an incretin, either a GLP-1 receptor agonist or a DPP-4, and both were tried in this case. Or you add a prandial insulin and the total daily dose could be worked out at .3 to .5 units per kilogram.

    You could give it – I tend now more to give it more at 1 meal a day, usually the main meal. Or you could add it at supper in a patient like this, because that's the time of her highest blood glucose. The basal insulin is obviously not acting at that time. You can advise her on a titration on how to adjust this insulin. Now this regimen is somewhat complex. It requires a lot more monitoring, and there's an increased risk of hypoglycemia when you add in prandial insulin.

  • Slide 18.

    Slide 18.

    (Enlarge Slide)
  • Let's now talk about what we've done in this patient. We've added an incretin therapy with basal insulin. They tend to have complementary actions. Basal insulin analogs are, they work mainly on fasting glucose. They have some risk of hypoglycemia, although it's less with some of the analogs compared to NPH. They do cause modest weight increase. You can get a lot of people to target, but not always without getting hypoglycemia.

    On the other hand, GLP-1 receptor agonists have a pronounced effect on postprandial glucose, although some of them, like long-acting preparations and liraglutide also affect fasting glucose. On their own, they do not increase the risk of hypoglycemia, but they may do so in combination with insulin or sulfonylurea. So what we did in this case was reduce the dose of insulin. That's what was done in some of the clinical trials.

    Or you can eliminate the sulfonylurea, which may also contribute to that. I think the most important advantage in this situation of adding GLP-1 receptor agonists is that you have a weight-neutral effect. You may even get some weight loss. You can get a lot of patients to target with this combination.

  • Slide 19.

    Slide 19.

    (Enlarge Slide)
  • Here are a lot of data that you've seen before, a wide range of trials of adding GLP-1 receptor agonists to 1 oral agent, 2 oral agents, various combinations of various agents. If you go and look head-to-head with adding basal insulin, they're more or less equal. Some studies, the insulin does better. Some studies, the GLP-1 agonist does better. It varies depending on the titration of the insulin and whether the patient gets hypoglycemia or not. Insulin is very titratable, but sometimes you have a problem of hypoglycemia.

  • Slide 20.

    Slide 20.

    (Enlarge Slide)
  • There's another consideration I want to point out, and that is, what are we doing to the natural history of type 2 diabetes? You know that beta cell dysfunction is a major defect in these patients as the disease progresses. This is taken from a study done in Europe where they took patients failing on oral agents and randomized them to glargine or exenatide and then looked at A1c. They were equal in both groups, the dose of insulin was somewhat lower than I would have liked to see, but that's what happened in the trial. There was weight gain with the insulin and weight loss with the GLP-1 receptor agonist. You'd expect that from the data you've seen.

    They did some interesting mechanistic substudies, or mechanistic studies here. What you see is pretreatment. This is looking at a hypoglycemic clamp looking at insulin secretion. This is C-peptide secretion, basically, because you're giving exogenous insulin, measuring insulin is not very reliable, and you don't get much of a response to hypoglycemia. However, on exenatide, you get a good response to hypoglycemia in terms of insulin secretion. You get a little bit of a response with the glargine. This has been argued.

    In the ORIGIN trial, for example, there was some improvement in beta cell function. You see a little bit of improvement, but it is clearly a big difference between what you get with exenatide and what you get with glargine. Now the question then is, what are we doing with these beta cells? Are we growing new beta cells? If you really grew new beta cells, and you stopped the therapy, shouldn't you be able to manage independently without any need for treatment?

    They stopped treatment for 4 weeks and repeated the study. You see no difference from a year ago. Nothing happened in terms of getting the pancreas to change itself completely and become independent of need for therapy with 1 year of treatment with a GLP-1 receptor agonist. They then put the patients back on therapy and followed them for 3 years. At the end of 3 years, they did this hypoglycemic clamp again, after taking the patient off therapy, and did not see a dramatic response. So again, you can't be independent of therapy at that time.

  • Slide 21.

    Slide 21.

    (Enlarge Slide)
  • However, they did some additional experiments. They looked at insulin sensitivity. They measured what is called the disposition index, which is a marker of the overall glucose metabolism. It's a product of insulin sensitivity and insulin secretion. Let me take you through this. This is pretreatment, on drug, off drug after 1 year, and then after it after 3 years with exenatide. You're looking at insulin sensitivity, not much change. Then you look at the end value results. This is insulin sensitivity. You see that you get an improvement on drug with exenatide, and a little bit with glargine, but off drug, you've lost that effect. Similarly after 3 years you don't have much of an effect.

    However, when you look at disposition index, after 1 year and you stop therapy for 4 weeks, there's no change. But after 3 years, there is a bit of a change. So you're seeing some benefit on beta cell function, an early abnormality in diabetes and something responsible for the progression of the disease, as measured with the disposition index. It is different whether you've used insulin where the disease has still progressed, and some improvement when you've used a GLP-1 receptor agonist.

  • Slide 22.

    Slide 22.

    (Enlarge Slide)
  • An intriguing finding, which needs to be confirmed. We need more studies like this. We need studies to demonstrate true durability of effect over the long term, and I hope that these will be done. In summary, exenatide improved glucose and arginine stimulated C-peptide secretion, reduced body weight, and increased insulin sensitivity when compared with insulin glargine. Following cessation of therapy after 3 years, there was some improvement in the disposition index, an indicator of beneficial effect in the long term on beta cell function.

  • Slide 23.

    Slide 23.

    (Enlarge Slide)
  • What we’ve learned so far is that incretin-based therapy can work, is a good choice between incretin and insulin, but what about the combinations? Let’s now look at what it does. I mean there are some data that I’ll show you now that is effective on controlling postprandial glucose, either weight neutral with DPP-4 inhibitors, and some weight loss with GLP-1 receptor agonists with low rates of hypoglycemia.

  • Slide 24.

    Slide 24.

    (Enlarge Slide)
  • We have 3 GLP-1 receptor agonists on the market. Exenatide bid, liraglutide, and exenatide slow release, which is once a week. Now both of these have been studied in combination with insulin, and I'll show you those data, and both are a proven combination with insulin. The combination of exenatide LAR and insulin has not been well studied, and they don't currently have that indication. If you used it, it would be off-label.

    I see very little difference between the different treatment choices, although it's much, much easier to use a once-weekly preparation, it works mainly on the fasting glucose and less so on the postprandial glucose.

  • Slide 25.

    Slide 25.

    (Enlarge Slide)
  • Here is, on background therapy, reduction. This is a study by Dr. Seino et al, actually, by Dr. Buse, initially. Background therapy with glargine, metformin with or without pioglitazone, a 1% reduction in A1c when you added on exenatide. Here's another one showing a reduction of exenatide to background therapy and a 1.7% reduction in A1c. These are FDA approved. Here is using the investigational agent lixisenatide, showing a reduction. Lixisenatide is not approved in the US, so this is an off-label use.

  • Slide 26.

    Slide 26.

    (Enlarge Slide)
  • I showed you the data on her postprandial glucose being high. What is the data when you add a GLP-1 receptor agonist to insulin? This is from the Buse study where exenatide or placebo was added on to insulin therapy. You see the very substantial increases in postprandial glucose. After each meal, at baseline, and with placebo there was no change. There was a significant reduction in the postprandial glucose excursion when you added exenatide. Essentially a flat glucose curve through the day.

  • Slide 27.

    Slide 27.

    (Enlarge Slide)
  • What happened to body weight? Well, initially the insulin was reduced; the dose of insulin was reduced, and after a few weeks, they started going up again and trying to optimize the glucose control of using insulin alone. They didn't, of course, know whether they had placebo or active therapy. With insulin plus placebo, there was a weight gain of 1 kilogram; and with exenatide plus insulin, there was a weight loss of 1.8 kilograms.

  • Slide 28.

    Slide 28.

    (Enlarge Slide)
  • In addition to these randomized studies, there have been a number of observational studies in a wide variety of settings of GLP-1 receptor agonists added to insulin or insulin added to GLP-1 receptor agonists, and somewhere the sequence is not specified. All of them show an improvement in A1c with a reduction in body weight and, in many of the cases, a reduction in insulin dose.

  • Slide 29.

    Slide 29.

    (Enlarge Slide)
  • What about DPP-4 inhibitor added on to insulin? There have been studies looking at sitagliptin, saxagliptin, linagliptin, and all of them are effective. The dose of insulin was kept stable during these studies just to see the effect of the study drug, unless there was a need to reduce it for hypoglycemia.

  • Slide 30.

    Slide 30.

    (Enlarge Slide)
  • You see about a .4 to .6% reduction, somewhat less than with the GLP-1 receptor agonists. There was no change in body weight.

  • Slide 31.

    Slide 31.

    (Enlarge Slide)
  • One concern has been, will you get hypoglycemia because you're suppressing glucagon. To our surprise, hypoglycemia has not been a huge problem with the DPP-4 inhibitors and also with the GLP-1 receptor agonists. Because the concern is you're not allowing the stomach to empty. You may not get the nutrient in fast enough while the insulin is working.

    There's a very interesting mechanistic study done by Bo Ahren, where he looked at glucagon response during a stepped hypoglycemic clamp on placebo or vildagliptin. You see that, with vildagliptin, glucagon is suppressed, particularly in the basal state. We know very well that DPP-4 inhibitors do this in the postprandial state. During hypoglycemia, there was a good, robust, glucagon response, so you're not compromising your ability to recover from hypoglycemia.

  • Slide 32.

    Slide 32.

    (Enlarge Slide)
  • We've talked about adding an incretin to insulin. What if it happened the other way around? Your patient is already on an incretin agent. What would happen if you added insulin?

  • Slide 33.

    Slide 33.

    (Enlarge Slide)
  • This was studied in this particular trial, when patients who were on metformin and sulfonylurea had liraglutide added, up-titrated to 1.8. A common scenario in clinical practice. Not all of them were well controlled. Some of them who remained well controlled, had an A1c less than 7. They continued on that regimen. On metformin and liraglutide. Those who had an A1c greater than 7 were randomized to either add on insulin detemir or stay on a combination of metformin and liraglutide and followed for 26 weeks.

  • Slide 34.

    Slide 34.

    (Enlarge Slide)
  • Here's what happened. Here are the responders, right down here at the bottom, who responded well to a combination of metformin and liraglutide. They came down from 7.7 to 6.4 and they stayed down for another 6 months. The other group that did not respond, they started around 8.2 or 8.3. They came down to about 7.6, not quite enough, and then were randomized to either receive detemir insulin or to carry on with metformin and liraglutide. Adding detemir gave a further reduction in A1c.

  • Slide 35.

    Slide 35.

    (Enlarge Slide)
  • You got better glycemic control, and here's the hypoglycemia rate. There was some hypoglycemia, 9.2%, whereas the control group had 1.3%, but none of the patients had major hypoglycemia.

  • Slide 36.

    Slide 36.

    (Enlarge Slide)
  • Here's the effect on body weight. The combination insulin and detemir plus liraglutide and with the background metformin therapy had some degree of weight loss as opposed to, there was no comparator, of course, of insulin alone, but liraglutide plus metformin.

  • Slide 37.

    Slide 37.

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  • When you look at safety events, as expected, all these patients had a background rate of nausea that you would expect, as well as vomiting, which is overall relatively low.

  • Slide 38.

    Slide 38.

    (Enlarge Slide)
  • Here are some data that have been very recently published with lixisenatide added on to a basal insulin. You get, again, a very similar reduction in A1c of about .8%.

  • Slide 39.

    Slide 39.

    (Enlarge Slide)
  • There's another experimental insulin, this is not available in the United States, insulin degludec. Liraglutide was added onto degludec. You see a reduction in A1c of about .7 when you add liraglutide and .3 when you add insulin aspart. This difference is statistically significant. More people met the A1c goal, and there was a weight loss with degludec plus liraglutide and weight gain when you add a short-acting insulin. This is what you would expect from what we know about rapid-acting insulin.

  • Slide 40.

    Slide 40.

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  • This is from an abstract that has been presented. Last year at EASD, we presented a study with albiglutide. Again, you've seen a lot of abstracts on albiglutide at this meeting, added onto glargine, or lispro added onto glargine. Albiglutide is a long-acting GLP-1 receptor agonist. This group is getting 7 injections of glargine plus 1 a week, so 8 injections a week. This one is getting 3 a day of lispro. It's a lot of injections. A1c was equal in both groups, but hypoglycemia and weight gain were less in those who had albiglutide. Now that paper has been submitted for publication, so I don't have a slide to show you.

  • Slide 41.

    Slide 41.

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  • Patients with type 2 diabetes on basal insulin do well. They get better postprandial control when you add on; particularly, they seem to do better than adding prandial insulin because they get less weight gain and less hypoglycemia. Pioglitazone could be effective, but you get weight gain.

  • Slide 42.

    Slide 42.

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  • I want to draw your attention to another interesting approach, which is to have co-formulations. Mixing in 1 syringe or 1 pen a GLP-1 receptor agonist and a basal insulin and giving both together. Now this is off-label, very experimental. This is taken from the clinicaltrials.gov Web site. There are at least 3 trials, 2 with degludec and liraglutide and 1 with glargine and lixisenatide. Very limited data are available so far.

  • Slide 43.

    Slide 43.

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  • One of these papers has been presented. It got a very big drop in A1c, about a 1.9 percentage point drop down to 6.4%, with degludec plus liraglutide in the same pen injector, which was compared to degludec alone, which got a reduction to 6.9, so the difference was about .5 between the 2, and that was significant. You got a reduction in fasting glucose, as well as some weight loss on this combination, whereas if you just used up-titration of the insulin alone you got some weight gain.

  • Slide 44.

    Slide 44.

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  • Let's talk still a little bit more about Maria. She's not achieving glycemic goals with metformin, sulfonylurea, and basal insulin. You tried a DPP-4 inhibitor. She didn't quite get to goal. You then added on, and she was actually gaining weight. You added on a GLP-1 receptor agonist because she desired some weight loss, and I think we should respect the patient's wishes in this respect. She got a better reduction in A1c, as well as some degree of weight loss.

  • Slide 45.

    Slide 45.

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  • In conclusion, the use of incretin-based therapies and basal insulin is a powerful combination, reduces postprandial and fasting glucose and A1c, and can cause some degree of weight loss with GLP-1 receptor agonists, and with DPP-4 inhibitors is weight neutral. Hypoglycemia is relatively mild, not as severe as we were concerned about initially. We need to study this combination further, developing newer strategies, including some of the ongoing co-formulation trials.

  • Slide 46.

    Slide 46.

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  • Let's go back to the audience response questions. Maria's A1c was 7.8; her fasting was at goal. What would you do? Number 1, add a DPP-4 inhibitor. Number 2, increase the glipizide. Number 3, add a GLP-1 receptor agonist. And number 4, add prandial insulin at breakfast.

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    Slide 47.

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  • So 69% of you added a GLP-1 before and it went up afterwards to 89%. I think it's okay to consider DPP-4 inhibitor like we did with this patient but the A1c drop that you want of .8 or .9 may be unrealistic with a DPP-4 inhibitor in that setting.

    Let's take the other question.

  • Slide 48.

    Slide 48.

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  • Which of the following is true with regard to the use of incretin-based therapies added to insulin? Only DPP-4 inhibitors are approved for such a combination. Number 2, use of incretin-based therapy is associated with low risk of weight gain. Number 3, any of the GLP-1 receptor agonists can be used with basal insulin. And number 4, both classes of drugs are associated with hypoglycemia. So this is not an ideal combination.

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    Slide 49.

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  • The correct answer here is 2. It was a little bit of a trick question. Number 3 was put in there because LAR is currently not approved, although the off-label use is, of course, possible, but it needs to be studied more.

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    Slide 50.

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