Symlin (pramlintide)

Symlin (pramlintide) is a antihyperglycemic agent. It is designed to mimic the activity of the naturally occurring hormone amylin, which is secreted together with insulin and is involved in post-prandial glucose control.

Symlin is specifically indicated for the mealtime treatment of Type I and Type II diabetes in combination with standard insulin therapy, in patients who have failed to achieve adequate glucose control on insulin monotherapy. It can be administered to type II diabetics also on metformin or sulfonylurea therapy.

Symlin is supplied as a clear sterile solution designed for subcutaneous injection. Recommended dosing varies depending on whether a patient has Type I or Type II diabetes: for Type I patients, initial recommended dosing is 15 mcg, which should be titrated at 15 mcg increments to a maintenance dose of 30 mcg or 60 mcg as tolerated. For Type II patients, initial dose should be 60 mcg, with a single increment increase to 120 mcg as tolerated. NOTE: Initiation of Symlin therapy may require adjustments to insulin dosing schedules, and should be performed under the close supervision of a healthcare professional.

FDA Approval
Approval of Symlin was supported by a number of clinical trials, investigating the drug in both Type I and Type II diabetic in both short- and long-term controlled trials, long term uncontrolled trials, and an open label study.

Type I Diabetes
Symlin was evaluated for the treatment of Type I diabetics (n=1717) in 3 long-term randomized, double-blind, placebo-controlled studies. Patients received 30 mcg or 60 mcg Symlin in addition to standard insulin therapy; in 2 of the trials, only minimal insulin dose adjustment was allowed, in order to isolate Symlin's efficacy; in the third, insulin dose was adjusted per standard medical practices. Symlin administration was seen to produce significant improvements in a number of measures at 6 months, including: change in HbA1c levels vs. baseline (-0.43%); placebo-subtracted HbA1c levels (-0.33%); change in total body weight (-1.1 kg); and placebo-subtracted total body weight (-1.7 kg).

The drug was also investigated for the treatment of Type I diabetes in a dose titration study. This randomized, double-blind, placebo-controlled study enrolled patients with relatively good glycemic control (mean HbA1c = 8.1%). In addition to maintained standard insulin regimens, subjects received an initial dose of 15 mcg Symlin or placebo, which was titrated in 15 mcg intervals to 30 mcg or 60 mcg, based on whether subjects experienced significant nausea. Insulin dosing was reduced 30-50% during titration to reduce potential incidence of hypoglycemia. At 6 months, subjects receiving Symlin plus insulin achieved similar reductions in mean HbA1C levels, compared to subjects receiving placebo-plus-insulin (-0.47 +/- 0.07 % vs. -0.49 +/- 0.07 %, respectively), while using a significantly lower total and fast-acting insulin dose (-11.7%, -22.8% from baseline). Symlin also produced weight loss relative to both baseline (-1.33) and placebo-plus-insulin (-2.6 kg)

Finally, Symlin was studied in the treatment of Type I diabetes in an open-label clinical practice setting. Using a flexible dose regimen of insulin, the study enrolled Type I diabetics unable to achieve glycemic control on insulin alone. The addition of Symlin to this regimen significantly reduced mean HbA1c levels (-0.18%) and body weight (-3.0 kg) at 6 months, and reduced total, short-acting, and long-acting insulin (-12.0 +/- 1.36, -21.7 +/- 2.81, and -0.4 +/- 1.59 %, respectively), all relative to baseline.

Type II Diabetes
Symlin was investigated for the treatment of Type II diabetes in a pair of long-term randomized, double-blind, placebo-controlled studies. Patients received Symlin or placebo, in addition to the patients existing regimens of fixed dose insulin with or without metformin and/or sulfonylurea. Symlin was found to produce significantly superior improvements in reduction in HbA1c levels (-.57 %), placebo-subtracted HbA1c levels (-0.40 %), body weight (-1.5 kg), placebo-subtracted body weight (-1.7 kg), % change in rapid-acting insulin dose (-3.0 %), and % change in long-acting insulin dose (-0.2 %), at 6 months.

Symlin was also investigated in an open-label clinical practice study in the treatment of Type II diabetics whose disease was inadequately controlled by insulin therapy. The trial enrolled 166 patients, who received 120 mcg Symlin in addition to a standard flexible-dose insulin regimen. Results indicated that the drug produced reductions from baseline in mean HbA1c levels (-0.56 +/- 0.15%) and mean body weight (-2.76 +/- 0.34 kg). Symlin administration also reduced necessary doses of total, short-acting and long-acting insulin (-6.4 +/- 2.66 %, -10.3 +/- 4.84 %, and -4.20 +/- 2.42 %, respectively).

Ongoing Study Commitments

• A study of Symlin in adolescents ages 12 to less than or equal to 17 years with type 1 and type 2 diabetes to evaluate the pharmacokinetics and relevant pharmacodynamic effects of different subcutaneous doses of the drug.
  Final Report Submission: September 30, 2007
• A multi-center, open-label, observational study to prospectively collect data that characterize the use of Symlin following introduction into the marketplace. This study will include non-targeted prescribers in the same approximate proportion as targeted prescribers.
  Protocol Submission: April 30, 2005
  Study Start: September 30, 2005
  Final Report Submission: September 30, 2008

Adverse events associated with the use of Symlin may include, but are not limited to, the following:

• Nausea
• Headache
• Anorexia
• Vomiting
• Abdominal Pain
• Fatigue
• Dizziness
• Coughing

In addition, because of Symlin's effect on the rate of gastric emptying, the drug should not be used in combination with drugs that alter gastric motility, and should not be administered simultaneously with orally-delivered drugs, as Symlin may produce changes in drug absorption rates. Further, administration of the drug without adjustment to insulin dosing levels can produce hypoglycemic events: both insulin and Symlin dosing schedules should be carefully monitored under the supervision of a healthcare professional.

Symlin is an amlyinomimetic, a functional analog of the naturally occurring pancreatic hormone amylin. Amylin has activity in a number of gastrointestinal and glucodynamic systems, and by mimicking its activity, Symlin acts to improve glycemic control through modulation of the rate of gastric emptying, prevention of post-prandial rise in glucagon levels, and by increasing sensations of satiety, thereby reducing caloric intake and potentiating weight loss.

Amiel SA, Heller SR, Macdonald IA, Schwartz SL, Klaff LJ, Ruggles JA, Weyer C, Kolterman OG, Maggs DG. The effect of pramlintide on hormonal, metabolic or symptomatic responses to insulin-induced hypoglycaemia in patients with type 1 diabetes. Diabetes, Obesity & Metabolism 2005 Sep;7(5):504-16

Ratner R, Whitehouse F, Fineman MS, Strobel S, Shen L, Maggs DG, Kolterman OG, Weyer C. Adjunctive therapy with pramlintide lowers HbA1c without concomitant weight gain and increased risk of severe hypoglycemia in patients with type 1 diabetes approaching glycemic targets. Experimental Clinical Endocrinological Diabetes 2005 Apr;113(4):199-204

Ceriello A, Piconi L, Quagliaro L, Wang Y, Schnabel CA, Ruggles JA, Gloster MA, Maggs DG, Weyer C. Effects of pramlintide on postprandial glucose excursions and measures of oxidative stress in patients with type 1 diabetes. Diabetes Care 2005 Mar;28(3):632-7

Ratner RE, Dickey R, Fineman M, Maggs DG, Shen L, Strobel SA, Weyer C, Kolterman OG. Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus: a 1-year, randomized controlled trial. Diabetic Medicine 2004 Nov;21(11):1204-12

For additional information regarding Symlin or diabetes, please visit the Symlin web page.