The Elusive Value of Symlin

As noted, I’m not so interested in the worth -– or market potential –- of this new drug from Amylin Pharmaceuticals as I am in the actual value to patients. I was initially excited and intrigued by this first new offering to help Type 1 diabetics since insulin in the 1920s. Yet after querying several doctors and a number of patients who chose to stay on Symlin after participating in a study, I must say I still don’t get it.

Apparently the main benefit is requiring less insulin. BUT these patients are now injecting yet another substance – another synthetic hormone, no less — into their bodies that could easily lead to side effects or long-term effects worse than those of insulin. So what is the real VALUE of Symlin to the patient, to offset this risk?

Two things seem to appeal: Symlin works as an appetite suppressant, so it helps people lose weight. It also reduces BG levels in the three hours after eating, so that the diabetic never hits those highs that a healthy person’s system can avoid naturally. Some patients also clearly feel that it is important to participate in clinical studies for the greater good, i.e. to “be part of the solution” doing their part working toward a cure. I totally respect this, but can’t understand why people already dealing with an insulin pump would be willing to continue the Symlin treatment, requiring multiple injections throughout the day. It seems like massive inconvenience with a lot of as-yet-unknown risk.

What’s more, the vast majority of Type 1’s are children, the way I understand it. In order to push approval of this drug, the FDA allowed the manufacturer to put off studying the drug’s effect on children until September 2007. The FDA Approval letter, of which I have a copy, lists a number of precautionary requirements, including a Surveillance Plan for hypoglycemic events, and the establishment of a 24/7 nationwide call center “to assist patients and physicians with the use of Symlin.”

Sounds like the Powers That Be have their doubts about this drug as well. Maybe the idea is to let consenting adults be the guinea pigs for the first few years (?)

If anyone knows better on Symlin, I’m all ears!



		
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17 Responses

  1. Violet
    Violet March 29, 2005 at 9:20 am | | Reply

    I don’t have any direct info about this drug–indeed, everything I know about it comes from your outstanding write-ups, thanks! It doesn’t sound like the benefits would outweigh the risks for me. But if I come to a point where I’m fighting major complications that are worsening my quality of life and potential longevity–and we all know the sad, tired laundry list of those–I sure as hell would consider taking an extra few shots and risking the lows in the hopes of improving those complications, or at least staving off further decline. For those members of the diabetic population, the equation may balance out quite differently.

    That said, I share your overall skepticism about this drug & the profit motives that obviously lie behind it. We must all be diligent in protecting ourselves from medical marketing via methods such as this blog. Keep at it, Amy!

  2. Kathleen Weaver
    Kathleen Weaver March 29, 2005 at 3:34 pm | | Reply

    There is at least one person on the insulin pump users list that participated in the clinical trial and still uses it.

    One problem with many Type 1 diabetics — is that they have massive swings from high to low. And low to high. Most of the people on that list can tell you lots of “funny” stories about what happened to them when they went too low. Many of them involve paramedic and hospital visits.

    Being a probable Type 2, I haven’t gone that low yet and haven’t generated funny stories — well there was the time I almost dropped a huge glass pickle jar on a dog, and that poor dog will won’t hang out in the kitchen when the refrigator is open.

    But there are Type 1 diabetics who would willingly add more medication and more injections to avoid those lows — and one reason they are on the pump.

    I could have seen me trying it before the pump. When I was on insulin shots, I gained 20 pounds will working my rear end off at the gym. I have too good of control with the pump though to try it. I would though if my endo suggested it.

  3. Alexis Gallisa
    Alexis Gallisa March 30, 2005 at 6:33 am | | Reply

    Weight gain seems to be a big problem for diabetics. My eating habits are almost always dictated by my blood sugar, and simply skipping meals is not an option with out some serious battles with my blood sugar. One thing that I have noticed is that my body also seems to tell me to eat when a big swing happens, regardless if its up or down. Its as if my body has been trained to treat everything with food. Lantus insulin was the first change in medication to help any of this. Its 24 hour dose helps stabalize blood sugar over a longer period.

  4. Amy Tenderich
    Amy Tenderich March 30, 2005 at 8:06 am | | Reply

    Remember, I’m also a Type 1, and have experienced my share of swings! I certainly would consider an extra drug if I got desperate, but what concerns me is the Commercial Push on new drugs, i.e. the “encouragement” to doctors to prescribe, prescribe, prescribe! (See my posting on FDA Approval)

  5. Shannon Lewis
    Shannon Lewis March 30, 2005 at 2:39 pm | | Reply

    I read the medicinal description on the Symlin website and a BIG factor is risk of severe lows. Extra vigilance in checking BG’s is required. As for pump users using Symlin, you take it during meals, so the effort isn’t that much. Although I’m not diabetic I am the parent of a diabetic child who does 90% of the care while my husband does the other 10%, so the effort wouldn’t bother me. Being that kids are prone to really fast drops, I wouldn’t allow my son to use it though.

    I guess it’s all a matter of how much effort one would want to put into their care. If your A1C’s are good, Symlin may not be worth the extra effort. If your A1C’s are not so hot, then I would certainly consider using it although one cannot slack on their BG checks, and insulin and diet requirements.

    Much to consider!
    Shannon

  6. Bill
    Bill April 11, 2005 at 9:19 am | | Reply

    I think I’m on the other side of this..I’m a highly insulin resistant Type 2 and I’ve seen a very sharp decrease in required insulin and both better A1C numbers and a cut in the peaks after meals with Symlin.

    I’d agree that the extra injections are a pain, but better control is the name of the game, and I’ve found this to be another tool to achieve this.

  7. Amy Tenderich
    Amy Tenderich April 11, 2005 at 2:18 pm | | Reply

    Thanks for the note, Bill. None of the Symlin users I spoke with previously were able to “quantify” the value of the drug. They sort of thought it was helping, but couldn’t really tell if their better control was simply due to being more diligent with their care since they were part of an important clinical study. So I’m very glad to hear from you!

  8. Terry
    Terry April 23, 2005 at 9:11 am | | Reply

    This Yahoo! MB has some valuable information ( as well as plenty of crap)Exptwtness and martyhah posts are most informative- you can do an author search for past posts

    http://finance.messages.yahoo.com/bbs?.mm=FN&action=m&board=7076553&tid=amln&sid=7076553&mid=114412

  9. linda
    linda April 23, 2005 at 7:13 pm | | Reply

    Understanding Symlin

    Amazed, was my reaction to your blog on Symlin.

    Some of the blog comments seems to imply a profit motive for the introduction of Symlin- this is clearly silly.
    The main backer’s daughter is on Symlin,and yes he is now a rich man,but richer still, as his daughters
    disease(16 year old Symlin T1 user) is much more in control.

    “Apparently the main benefit is requiring less insulin”.
    There are many benefits ,and yes many have insulin reductions when using symlin.(average 20-25%) is my informed opinion

    My opinion is that Symlin greatest benefits is reducing excursions post meal and stabilizing HbA1c
    You may see the label which some have termed “dangerous”.No this is a powerful drug that needs proper therapy introduction,which is why only endos introduce the drug.
    The label at Symlin.com shows the magnitude and speed of Postprandial Blood Glucose Fluctuations with insulin alone and insulin+symlin(in a nutshell most insulin only users sugars+50% in the next hr and a half,I+S- a 15% decline.The swings is blood sugars and the complications should be understood well here by diabetics

    posted
    ” requiring multiple injections throughout the day. It seems like massive inconvenience with a lot of as-yet-unknown risk.”

    Inconvience? ask those diabetic who have been “injecting” themselves for years(my husband for one)- diabetic complications are greatly reduced because of the above. The unknown risk you speak of is very well known , once there is a proper iniation of therapy(4 weeks or less) ,INSULIN induced hypoglcemia – events are very rare.

    posted
    “In order to push approval of this drug, the FDA allowed the manufacturer to put off studying the drug’s effect on children until September 2007.”

    This sounds conspiratorial. Because of the compexity of iniation of therapy children are not immediately canidates
    BTW-Texas Children’s Hospital has just concluded a trial involving children and Symlin(off label)

    then there is this ?
    “Sounds like the Powers That Be have their doubts about this drug as well. Maybe the idea is to let consenting adults be the guinea pigs for the first few years”

    Symlin has a great safety profile for those that are informed.Many diabetics need to be instructed and educated on Symlin therapy.Its a powerful drugs with great results,but needs proper introduction of therapy.

    Weight loss is substantial with Symlin,so much in fact that the Company is also introducing Symlin as a weight loss drug (morbid obese)for non diabetics.If you need to know why this is important,time and space prevent it.

    I would like to know whom you have talked to (You said you querying several doctors and a number of patients who chose to stay on Symlin after participating in a study- not names but numbers ,reaction Drs or “endo”- I will respond with actual participants , since your post sounds like you “heard”).The rate of continued compliance off label was very high with symlin. Are you a T2 diabetic ?

    Linda

  10. AmyT
    AmyT April 24, 2005 at 1:00 pm | | Reply

    Hi Linda,

    Thanks for your feedback. What is your stake in Symlin? Are you a patient?

    I am a Type 1, yes, and I do think that an additional set of injections is a massive inconvenience — even for those on the pump.

    My beef with the profit motive came from the way the media handled the announcement, as noted in my post at http://amy_tenderich.typepad.com/diabetes_mine/2005/03/amylins_other_p.html. I do think the pharma industry backs drugs largely based on their money-making potential.

    Are you on the pump? Have you tried Symlin? I would love to hear about your experiences. You noted that it is “a powerful drug with great results, but needs proper introduction of therapy.” What would this entail?

    - AT

  11. linda
    linda April 26, 2005 at 8:08 am | | Reply

    Thanks to martyhah on the AMLN mb-
    Symlin explained

    A Need for Improved Evaluation of Innovative Drugs

    Lately there has been considerable concern regarding the ability of the FDA to objectively evaluate innovative drugs. The time required for the agency to evaluate drugs in general has increased, leading to delays for many classes of drugs reaching the patients who need them. This has been especially problematic with drugs that are innovative in their mode of action, structure, or both as the FDA relies on lessons learned from the traditional small molecule drugs that have historically driven the pharmaceutical industry. Many drugs that target specific pathways or are not small molecules are currently being developed as a result of exciting research in molecular biology. The FDA however has little experience in evaluating these drugs, and the conservative nature of the agency delays or stalls their approval process. Substantial changes are needed at the FDA so these drugs can be brought to the patients who need them.

    A case in point is the amylin analog, pramlintide or Symlin, developed by Amylin Pharmaceuticals. This drug has gone through extensive testing, with a series of six phase III trials involving thousands of patients. The drug is meant for use by type I diabetic patients and type II patients who use insulin. It is a peptide very similar to a portion of the native amylin hormone, that is now widely recognized as being a partner with insulin in maintaining serum glucose levels. Like insulin, amylin levels decrease in diabetic patients due to the inability of the pancreas to produce the hormone. The mode of action is to decrease the postprandial rise in serum glucose partly by delaying gastric emptying and partly by suppressing glucagon. Studies in both animals and human clearly demonstrate this activity and show that amylin only has its activity in the presence of elevated glucose. The rationale behind amylin replacement therapy is simple, this hormone performs an important function in regulating serum glucose levels, it is deficient in diabetic patients, and adding it back can help insulin do its job better.

    The drug has been submitted to the FDA for approval and has received two approvable letters. The problems were two-fold. First, the standard for diabetic treatments has been decrease in HbA1c. Treatment with Symlin resulted in decreased HbA1c to an extent deemed clinically relevant in the overall treatment population. In the approximately 50% of the patients who were classified as “responders” the decrease was substantial. The advisory panel was convinced that the drug was effective in this respect, but they questioned if the benefit outweighed the risks as viewed by the medical reviewer. While the decrease in HbA1c is a benefit to patients on the drug, that is not the proper measure of the drug’s effectiveness. First, this is a measure of average glucose levels, and it cannot measure the drug’s activity of decreasing the postprandial spike in glucose that accompanies each meal of the patient. One very important outcome of this is that patients feel much better after meals; they frequently describe it as getting their lives back. But the FDA does not know how to take that into account, and said so at the drug’s review. Yet the second and more important outcome of decreasing the postprandial glucose spike is that glucose increases levels of proinflammatory cytokines (1-5) and acts as a trigger to oxidative stress (6-9). Both of these effects can cause long-term tissue damage, and diabetics are very prone to complications from the continued insults their organs suffer because of poorly controlled serum glucose. These stress markers may also play a role in sudden cardiac arrest. Indeed, there is increasing evidence in the literature that controlling postprandial glucose is important to longterm health of diabetics (10-17).
    A third benefit is that the drug promotes weight loss in patients using insulin, something that has great value in maintaining health. In addition, a statistical analysis shows a large decrease in death rates of type II patients using the drug. The death rate in type I patients was lower compared to the placebo group, but to a lesser extent. These decreased death rates, extrapolated over the potential for prescribing the drug, could mean thousands of deaths prevented each year. (These statistical analyses are my own, based on data supplied in the pramlintide NDA application.)
    This drug helps patients in ways no currently available drug can. It has important potential to lower the rates of complications in diabetics. The potential benefits in health and savings in health care costs are substantial. So why does the drug remain in the approvable, but not approved, state?

    The answer lies in a perceived problem of hypoglycemia. Patients experienced increased rates of hypoglycemia in the first four weeks of treatment, but these rates decreased to levels similar to the placebo treated patients as treatment progressed. Indeed, for the type II patients, even in the initial four weeks the increase did not achieve statistical significance. When patients were allowed to adjust their insulin dosage, and the treatment with Symlin was initiated with a titrating regimen, the incidence of hypoglycemia was alleviated. In short, this drug is effective, many patients continue in open label trials because they do not want to give up the control they now have over their lives, and the drug can be safely administered as shown by the successful titration experiments the FDA had requested. Yet the FDA still cannot judge this drug for what it is, an innovative approach to helping diabetic patients take control of their lives, and the only new treatment specifically for type I diabetics to be developed in eighty years of research.

    It is also important to note that the only other adverse event reported frequently by patients was nausea, and that like hypoglycemia this was transient. The trials demonstrated that patients and physicians working together can overcome these issues so the drug can provide its benefits.

    How does this compare with other drugs currently in use? Many of the drugs that have been approved for treating diabetes have a long list of serious side effects, and some such as phenformin and Rezulin were taken off the market after high patient death rates. Many other drugs still on the market carry warnings of life threatening side effects such as liver failure, renal failure and congestive heart failure. Thousands of patients have taken Symlin, and in contrast the issues are transient hypoglycemia and nausea. In fact, hypoglycemia and nausea are commonly reported side effects of diabetes drugs. Titration studies, as well as the continuing open label studies, have shown that patients and physicians can work together to manage these side effects during the initial phase of Symlin treatment. In doing so patients can take control of their health, with a great potential for preventing the devastating complications of diabetes.

    My training is in molecular biology, not as a physician, and I respect the dedication of those with the difficult task of reviewing applications for drug approvals. Yet, based on the evidence that I can review I can only conclude that the time has long since past for this drug to be approved. The more time passes, the more patients suffer needlessly, and many will succumb to the complications of diabetes. While the FDA rightfully acts as an adversarial body in reviewing new drugs, it has gone beyond that to become an obstruction to new approaches to bring the relief that patients desperately need.

    References

    1. Esposito K, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation. 2002 Oct 15;106(16):2067-72. Comment in: Circulation. 2003 Jun 10;107(22):e206-7; author reply e206-7.

    2. van Oostrom AJ, et al. Postprandial recruitment of neutrophils may contribute to endothelial dysfunction. J Lipid Res. 2003 Mar;44(3):576-83.

    3. Shanmugam N, et al. High glucose-induced expression of proinflammatory cytokine and chemokine genes in monocytic cells. Diabetes. 2003 May;52(5):1256-64.

    4. Skundric DS and Lisak RP. Role of neuropoietic cytokines in development and progression of diabetic polyneuropathy: from glucose metabolism to neurodegeneration. Exp Diabesity Res. 2003 Oct-Dec;4(4):303-12.

    5. Nappo F, et al. Postprandial endothelial activation in healthy subjects and in type 2 diabetic patients: role of fat and carbohydrate meals. J Am Coll Cardiol. 2002 Apr 3;39(7):1145-50.

    6. Ceriello A. Mechanisms of tissue damage in the postprandial state. Int J Clin Pract Suppl. 2001 Sep;(123):7-12.

    7. Ceriello A, et al. Meal-generated oxidative stress in type 2 diabetic patients. Diabetes Care. 1998 Sep;21(9):1529-33.

    8. Ceriello A, et al. Role of hyperglycemia in nitrotyrosine postprandial generation. Diabetes Care. 2002 Aug;25(8):1439-43.

    9. Lefebvre PJ and Scheen AJ. The postprandial state and risk of cardiovascular disease. Diabet Med. 1998;15 Suppl 4:S63-8.

    10. Abrahamson MJ. Optimal glycemic control in type 2 diabetes mellitus: fasting and postprandial glucose in context. Arch Intern Med. 2004 Mar 8;164(5):486-91.

    11. Bonora E. Postprandial peaks as a risk factor for cardiovascular disease: epidemiological perspectives. Int J Clin Pract Suppl. 2002 Jul;(129):5-11.

    12. Ceriello A. The possible role of postprandial hyperglycaemia in the pathogenesis of diabetic complications. Diabetologia. 2003 Mar;46 Suppl 1:M9-16.

    13. Edelman SV and Weyer C. Unresolved challenges with insulin therapy in type 1 and type 2 diabetes: potential benefit of replacing amylin, a second beta-cell hormone. Diabetes Technol Ther. 2002;4(2):175-89. Comment in: Diabetes Technol Ther. 2002;4(2):190-2.

    14. Gerich JE. Clinical significance, pathogenesis, and management of postprandial hyperglycemia. Arch Intern Med. 2003 Jun 9;163(11):1306-16.

    15. Hanefeld M and Temelkova-Kurktschiev T. Control of post-prandial hyperglycemia–an essential part of good diabetes treatment and prevention of cardiovascular complications. Nutr Metab Cardiovasc Dis. 2002 Apr;12(2):98-107.

    16. Herman ME and Moore RS. The importance of postprandial glucose to treatments and outcomes in patients with type 2 diabetes. Manag Care Interface. 2001 Nov;14(11):63-9.

    17. Paolisso G, et al., Cardiovascular risk in type 2 diabetics and pharmacological regulation of mealtime glucose excursions. Diabetes Metab. 2003 Sep;29(4 Pt 1):335-40.

  12. AmyT
    AmyT April 26, 2005 at 1:50 pm | | Reply

    Linda,
    Thanks for this. Interesting. But next time may I please ask you to post the LINK here, rather than the entire article?

    Also, I still wonder why you are so fervent about Symlin. Did it help your husband that much?

    - AT

  13. ScottS
    ScottS May 6, 2005 at 7:27 am | | Reply

    I find the skepticism a bit peculiar since the number of therapuetic options for Type 1 diabetes is so limited. Even with a pump, I find it nearly impossible to achieve consistent results. There always seems to be a piece of the puzzle that is missing. Replacing another one of the other missing hormones would seem to be a rational solution. These things obviously serve a purpose, or they wouldn’t be in the body to begin with. Perhaps someday synthetic human insulin will contain c-peptides, too, which has been proven to have protective benefits at the microvascular level (protecting small blood vessels in the eyes and kidneys from damage).

    One comment on the FDA labeling is worth noting, and that is that since the Vioxx debacle, the FDA is being much more careful about potential risks with newly approved drugs and ensuring that those risks are properly disclosed. It under those guidelines that the risks on hypoglycemia with Symlin are being disclosed, but my perspective is that the risk of hypoglycemia is probably overblown, and certainly no worse than insulin alone.

    The bigger issue seems to be the fact that the company is essentially being marketed as a Type 2 drug, which it really isn’t. But the law of big numbers is at work here: there are only about 1.1 million Type 1 patients vs. 16.5 million Type 2′s. If you were selling your company’s shares to Wall Street, wouldn’t you be promoting it as yet another treatment for Type 2 diabetes as well?

  14. Linda
    Linda May 7, 2005 at 12:36 pm | | Reply

    Scott- hypoglcemia is rarely seen in Symlin use when used properly.Since the hormone which is natural to non- diabetics,is re-introduced to diabetics,(who do not have this hormone) adjusting insulin is necessary.Symlin does not cause the hypoglycemia,Insulin does.The FDA wanted the drug under physicians use for introduction to therapy The drug is for anyone T1 or T2 using Insulin.Amylins other drug Byetta is for thos ewho are failing orals(and will be a monotherapy soon). Loose weight with both drugs.These 2 first in class drugs will be welcomed into the diabetic community when it is understood what they do.Something to chew on- Byetta is showing Beta cell regeneration in T2 that use the drug- the drug is showing first phase insulin response.I wont say cure for many,but the NIH is studing it and will release the data in 2007- a long trial,but patients I have talked to see lasting results-remarkable.

  15. Sandy
    Sandy July 17, 2005 at 11:31 am | | Reply

    I just started on Symlin this week, I’m always willing to try something that will help regulate blood sugars which is always a challenge. I’ve been diabetic for 38 years, on the pump for 15 years. For me taking the extra shots is no big deal, just one more, of many pokes into my skin. I am healthy with no complications but have always struggled with after meal highs so this sound very prominsing to me. So far it does seem to be helping but I am not on the full dose yet.

  16. Eric Feibelman
    Eric Feibelman September 2, 2005 at 3:16 pm | | Reply

    I am a type 1 diabetic for 15 years. I started symlin therapy recently and I would like to just list the benefits I’ve seen so far:

    1) More energy
    2) Better mood
    3) Tight glucose control – I used to average > 220 BG levels 2hrs post meals, now I average 130. Studies show that this will reduce my risk of long-term diabetic complications by 10x in some cases.
    4) Not as many lows because I don’t have the spike with the crash afterwards.
    5) Less insulin (not really a big deal for me, but it is a side-effect).
    6) No nausia.
    7) I feel full after meals and don’t feel hungry until time for the next meal.
    8) I seem to be able to concentrate better on the task at hand.

    An extra shot pre-meals is definitely worth it. This is truly a breakthrough in diabetic control.

    Thanks,
    Eric

  17. dyan olsen
    dyan olsen March 13, 2008 at 7:19 am | | Reply

    I have been a pump weared user for over 1 year and a symlin user for 6 months. symlin has been a gift from god for me. It helped me to lose /30 lbs. I have been type 1 for 23 years and I am now 55. I am very athletic. It is difficult when you are excercising like crazy and you don’t lose weight. Your joints start to fail and you are not eating more than you were before but gaining dangerous weight. My doctor said that it was because insulin makes you gain weight and I was becoming insulin resistant and increasing my insulin requirement. I love this stuff but I am worried that my body may become accustomed to it as it did the insulin.

    Dyan

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