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Symlin: A Sleeper Drug Slowly Rises: Lessons from Two Years on the Market

Updated: 8/14/21 2:00 pmPublished: 4/30/07

Golden Pearls on Symlin Use

According to Amylin, Symlin is not intended for everyone.

Because it is used with insulin, there is an increased risk of insulin-induced severe hypoglycemia. Amylin says that when severe hypoglycemia associated with Symlin use occurs, “it is seen within three hours following a Symlin injection.

Amylin stresses that appropriate patient selection, careful patient instruction, and insulin-dose adjustments are critical elements for reducing the risk of severe hypoglycemia

Nausea was the other most commonly reported adverse event associated with Symlin use.

“The incidence of nausea was higher at the beginning of Symlin treatment and decreased with time in most patients,” says Amylin. “The incidence and severity of nausea are reduced when Symlin is gradually titrated to the recommended doses.

The consensus conference on Symlin noted: “The main safety concerns associated with pramlintide are insulin-induced hypoglycemia and nausea during initiation of therapy. These side effects can be prevented or reduced by individualizing insulin dosing and timing regimens in relation to meal intake, monitoring blood glucose frequently, and titrating pramlintide gradually."

Source: Hirsch IB, Blonde L, Buse J, Close KL, Edelman SV, Peters A, Valentine V, Wysham C, Garg S. Consensus development conference on pramlintide in the management of type 1 and type 2 diabetes. Lakeville, Conn., The Diabetes Education Group, 2006. Amylin Pharmaceuticals.

by daniel trecroci and kelly close

"First and foremost, despite all of the advancements in diabetes care such as pumps, analogs, and meters, diabetes care at the community level remains quite poor. Even for those people with access to all of the tools and experts, normalization or near normalization of the A1c is difficult, limited by hypoglycemia and weight gain. In addition, many of those with a normal A1c have severe problems with wide and unpredictable glucose swings throughout the day and night. I believe that although Pramlintide does not solve all of the above problems, it is an important piece in the puzzle of successful diabetes management … I have learned from my own experience and from my patients that once the correct balance is obtained between the Pramlintide and insulin dosages, then not only are the postprandial glucose values improved, but also the rate of delayed hypoglycemia is reduced."

--Dr. Steve Edelman, letter to the FDA in support of Pramlintide (Symlin), 2003

In March of 2005, the FDA approved Symlin (pramlintide acetate), which was hailed in some corners of the diabetes community as an important drug for insulin-dependent patients despite the fact that the A1c reductions it prompted were average, but not remarkable. Symlin reduces after-meal blood glucose levels and causes weight loss, rather than weight gain – two critical advantages, especially given that so many diabetes therapies increase body weight. That in turn makes diabetes management even more complicated, for both type 1 and type 2 patients. The tradeoffs? Symlin can initially cause nausea, and for many, it takes some time to work out optimal dosing, because patients must reduce their insulin doses when they go on Symlin and any patient knows that dosing insulin is a complicated game to begin with – especially at meals.

We believe Symlin is a “sleeper” drug, whose popularity will continue to grow as healthcare providers and patients learn more about it – and take time to see how it affects their metabolism. Some patients who characterize the drug as a welcome addition to their daily therapy said their opinions changed after only a few months on the drug (see our “Test Drive” from the last issue, where Kelly herself says she wouldn’t dream of not using it but would not have stayed on it after the first couple of months except she had been in a clinical trial.). Indeed, the reactions to Symlin have been complex: while it has already had a profound impact on the lives of many patients, its unusually potent attributes have indeed made it difficult for some patients to use. What’s more, its complexity has made it unpopular with some doctors for whom working with Symlin is too much work, given the poor reimbursement system in the US (it is not approved elsewhere). So we thought it was a good time to see in more detail what the drug is and how it works.

the science behind the story

Symlin is a synthetic analog of human amylin, a hormone formed by beta cells that regulate the timing of glucose that is released into the bloodstream. What amylin does is rather simple: it slows down the emptying of your stomach after eating. Without enough amylin, your food enters quickly – too quickly – and that causes your blood glucose level to rise. At that point, your insulin has to work overtime to even out the peaks – and often the peaks never do really even out.

By definition, the beta cells in people with insulin-dependent diabetes have been destroyed or damaged, so those patients also have a deficiency in amylin – type 1 patients make no amylin, although type 2 patients do make some. Injected insulin, of course, replaces the insulin that those patients can no longer make. Injected Symlin, on the other hand, replaces the physiologic effects of amylin. It does so in two ways.

  • Symlin slows down the movement of fluid and/or food out of the stomach and into the intestine – and thus reduces the blood glucose levels.

  • It also gives an increased sense of satiety, or feeling of fullness, earlier in meals, which decreases the appetite – thus, the appeal for those who want to lose weight.

Because both insulin and Symlin are injected drugs, patients who want to use them have to take an extra shot before meals. However, unlike insulin, which has different peak effects, Symlin is specifically designed to lower glucose levels after eating. That’s why it is taken only before meals with at least 30 carbs or 250 calories. (In reality, we know some patients who take it for even smaller meals and forego insulin, but this is not approved in the package labeling.) Dr. Orville Kolterman of Amylin Pharmaceuticals (Symlin’s manufacturer) says, “As expected, no one is thrilled about another injection. However, it has been my experience that when the value proposition is explained, the concern about injections melts away. In my limited experience, neither the Symlin titration or the need to ‘redo’the insulin titration have been barriers.”

Trial data underscore the advantages of Symlin. In clinical studies of over 5,300 people, taking Symlin with insulin – compared to taking just insulin -- helped patients lower after-meal blood-glucose levels, leading to less glycemic fluctuation during the day, and improved A1cs.

  • A1c dropped nearly 1 point: In type 1 patients, the average A1c fell from 7.9 to 7.2, whereas in type two patients, the average A1c dropped from 8.7 to 7.8. Units of insulin taken also fell about 20% for type 1 patients, to 35-40 units per day from 45-50 units, and to 70-75 units per day from 80-90 units per day for type 2 patients. We also believe that Symlin increases what we call the “quality of A1c” – that is, that for many patients, minimizing the peaks and valleys in glucose levels can be a major advantage, even if A1c doesn’t shift. As Dr. Steve Edelman, assistant professor of medicine at the University of California San Diego School of Medicine, wrote to the FDA in 2003 in support of Symlin, “Our country has tunnel vision in that a drug is judged on its ability to drop the A1c and is blinded to the many other important aspects that a therapeutic agent for diabetes can offer.”

  • Post-meal blood sugar drops were most impressive – type 1s typically had glucose levels of 200-350 mg/dL prior to Symlin, and after taking it, they had post-meal blood glucose levels of 130-180 mg/dL. This trend held true for type 2 patients as well, whose post-meal blood gluose levels dropped from 250-310 mg/dL to 150-180 mg/dL.

  • Perhaps most welcome of all were weight reductions of about 5% - in posted clinical trials, type 2 patients saw their weight drop, on average, from 204 to 195 pounds, whereas average type 1 weight went from 197 pounds to 188 pounds.

With increased attention on glycemic variation, Symlin’s ability to reduce fluctuations adds to its appeal. (See our first issue) As shown, on average, the patients in these studies used about 25% less mealtime insulin and also lost about 5% of weight compared to patients taking insulin alone. However, averages can mask extremes; nearly 10% of patients lost more than 10% of their weight. Who are the best patients to take Symlin? According to Dr. Kolterman, based on feedback from dozens of physicians and educators: “Type 1 and Type 2 patients who are struggling with glucose swings and/or weight gain.” For more on our personal use of Symlin (specifically, Kelly Close’s experiences), please read Test Drive from Volume 1, Issue 2 of diaTribe.

benefits to the central nervous system?

Because amylin binds to certain receptors in the central nervous system, Symlin may benefit that system as well – speculation fueled by the sudden sense of well-being sometimes experienced by patients. Some of them call Symlin the “happy drug,” though there are no reported data on the question. Dr. Andrew Young, vice president and senior research fellow at Amylin Pharmaceuticals, wrote in Advances in Pharmacotherapy (Volume 52; 2005), that in rats amylin “enhanced the uptake of certain amino acids, crossed the blood– barrier, and increased body temperature.” However, he said that the physiological significance of these responses is unclear.

What is clear, according to some clinicians who have studied and used the drug widely, is that many patients who take pramlintide feel demonstrably better. As CDE Davida Kruger told an FDA panel meeting on pramlintide, “Over the past five years I have enrolled more than 60 patients in four pramlintide trials. Despite nausea and the increased number of injections, none of our patients have withdrawn from any of our clinical trials. Why? Primarily because pramlintide has provided an improved quality of life, something that I haven't heard this panel talk much about today.” She continued, “With decreased swings in their blood sugars, decreased postprandial rises, less insulin needed, less hypoglycemia, and weight loss, they generally feel better, something that is very important to people's lives with diabetes.”

We understand there have been abstracts submitted to psychiatric meetings and that more trials are measuring emotional responses to the drug; we will keep you posted on official results. All we know now is what patients say, and though anecdotal, we do keep hearing about these positives – if you are on Symlin, go to the link here, and take our two-minute poll on this topic and we’ll report back! You will be entered into a drawing for a free Adorn bag, as seen in NewNowNext and we can share with other readers your experiences.

what we have learned two years later:

clinicians’ learning curve

Clinical use of Symlin is still in its infancy. Doctors learning how to use it can find assistance from the panel of experts (including diaTribe’s Kelly Close), who wrote a Consensus Statement on Symlin , published in 2006 by The Diabetes Education Group. The report noted that patients need a sophisticated understanding of insulin therapy to use Symlin safely and that when patients cannot reach their A1c goal, Symlin may be a “viable therapeutic option.” While the prescribing label prohibits patients with an A1c over 9 from taking Symlin, the experts disagreed – they thought patients with a higher A1c could still benefit. We agree, especially because when patients have A1cs over 9, we believe many things could benefit the patient – why count Symlin out? Of course, commitment to working out optimal dosing is a paramount element of safety.

The panel emphasized that frequent blood-glucose monitoring, pre-and post-meals and before bedtime, is critical for safe, effective use of Symlin, and reasonable precautions against hypoglycemia, such as testing before eating and driving, should be taken. The bottom line: patient education, individualized treatment, and consistent follow up were needed for effective use of Symlin.

Timing the injection of Symlin has also required some study. “We now know that Symlin is best given right at the beginning of the meal or a few minutes before,” says Dr. Edelman. “And, for most folks, between 15 and 30 minutes after injecting, we notice that they start pushing away their plate and they eat less [about 25 percent fewer calories]….It has such a dramatic effect on their satiety that they eat less than they were going to eat and they might end up in a hypoglycemic reaction. So, for that reason, we have them take their fast-acting insulin near the end of the meal once they have seen how much they have eaten.”

Dr. Edelman notes that since Symlin delays gastric emptying, the fast-acting insulin is more effective when taken toward the end of a meal anyway. In addition, because Symlin causes delayed nutrient delivery, Edelman suggests that patients on insulin pumps give their bolus over a two-hour period. We know some patients extend even further – the phrase YMMV (your mileage may vary) never seemed so apt!

dissenting voices

Not all experts agree. Some leading clinicians do not believe that data to date justifies adding Symlin to a treatment regime, particularly one for type 1 diabetics (given lower risk of hypoglycemia generally in type 2 diabetics and better tolerance of Symlin, with comparable efficacy, it is easier to “make the case” for Symlin use in type 2’s). Responding to a Nature article authored by Dr. Edelman supporting use of Symlin in type 1 treatment regimes to improve glycemic control, Dr. Louis Monnier of Lapeyronie Hospital, Montpellier, France wrote:

“…the reader is left with a very mixed impression of the overall treatment effectiveness of pramlintide. Progressive dose escalation did not ensure a better efficacy-to-safety ratio, as pramlintide-treated patients exhibited no improvement in HbA1c levels and continued to experience an increased number of hypoglycemic episodes when compared with patients treated with placebo. Quality of life could also have been impaired by the high frequency of adverse gastrointestinal events. As the positive effects of pramlintide were limited to reduced postprandial glucose excursions in the absence of reduced HbA1c levels, the long-term effectiveness of pramlintide is highly questionable. For the moment there are no evidence-based data to justify the clinical use of pramlintide (at either fixed or progressive doses) as an adjunct to insulin therapy in type 1 diabetes.”

It is clear that the most fervent supporters of Symlin are those with direct experience prescribing or taking the drug, and that throughout its development history clinical data has not been universally convincing to all practitioners.

more type 2s jumping on the symlin bandwagon

Interestingly, many type 2s have jumped on the Symlin bandwagon. According to Dr. David Kendall, executive director of medial affairs at Amylin, type 2 patients now represent half the clinical use of Symlin – so insulin-dependent type 2 patients are opting for Symlin, just as their type 1 counterparts. But that doesn’t mean that treatment for the two groups of patients is the same. “One thing we have learned is that we may need to use different doses of Symlin in type 1s and type 2s,” says Edelman.” “I always tell my patients that the perfect dose of Symlin is the dose that induced satiety but does not cause nausea.” In his experience, the nausea is not really a big issue in type 2s – this is likely because type 2s are typically still producing some amylin and so the “return” of the hormone to the system isn’t so jarring. In type 1s, however, the nausea can be acute, and Dr. Edelman follows the recommended titration schedule to reduce it.

where will we be two years from now with symlin?

Studies are now being conducted to determine if pramlintide could be used as an obesity drug. In a phase 2 study, the participants were able to tolerate higher doses of the drug than those studied in other diabetes trials, and they achieved clinically and statistically significant weight loss. Consistent with previous observations, the most common side effect for trials to date was mild, transient nausea.

We believe pramlintide could do very well as an obesity agent, particularly if used in combination, and we found data from late last year on this front. In pre-clinical (animal) models, a combination of pramlintide and leptin and PYY (other compounds owned by Amylin) prompted significant weight loss, far above the order seen with other obesity drugs used in monotherapy (single drug use). In fact, animals experienced 20% weight loss – and might have lost even more, but there was no more fat to lose! These were only animal models, but we’ll be looking for more data by the end of 2007, including news on the first human trials.

Meanwhile, the company says it’s in final stages of developing a pen device for Symlin, which could make it much easier to take. We know of positive anecdotal reports about Symlin in a pump, although there are no published studies on such use. As usual with new products, further study is recommended, but after two years, we believe it’s only a matter of time before more diabetics awaken to this sleeper drug.

As Davida Kruger said, “I've not met in the 19 years of my practice any patient that will not take an injection if it will improve the quality of their life and prevent the complications of the diabetes. It's how we as providers perceive that injection and how we present our case to the patient. As a provider diabetes care is an art, not a science necessarily. It all falls together and we need every tool available to help patients improve their outcome and improve their lives. I believe that pramlintide offers that one more tool that we need in the cadre of what we have to provide.”

What do you think?