Amylin analogs for the treatment of diabetes mellitus

INTRODUCTION — Despite advances in options for the treatment of diabetes, optimal glycemic targets are often not achieved [1]. Hypoglycemia and weight gain associated with therapy may interfere with the implementation and long-term application of "intensive" therapies [2-4]. Treatment of type 1 diabetes is directed at physiologic insulin replacement. Many patients with type 2 diabetes also ultimately require insulin therapy as a result of progressive beta cell dysfunction [5]. Starter insulin regimens (such as basal insulin monotherapy) for patients with type 2 diabetes commonly require repeated intensification over time to achieve even modest glycated hemoglobin (A1C) reductions [6]. Therefore, other therapeutic approaches are needed.

Glucose homeostasis is dependent on a complex interplay of multiple hormones that may be targets for a multifaceted treatment approach: insulin and amylin, produced by pancreatic beta cells; glucagon, produced by pancreatic alpha cells; and gastrointestinal peptides, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP; gastric inhibitory polypeptide) (figure 1) [7]. Abnormal regulation of these substances may contribute to the clinical presentation of diabetes.

The mechanism of action and therapeutic utility of amylin analogs will be reviewed here. GLP-1-based therapies and overviews of pharmacologic therapy for type 1 and type 2 diabetes are presented separately. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus" and "Management of blood glucose in adults with type 1 diabetes mellitus" and "Initial management of hyperglycemia in adults with type 2 diabetes mellitus" and "Management of persistent hyperglycemia in type 2 diabetes mellitus".)

AMYLIN — Amylin is a 37-amino acid peptide that is stored in pancreatic beta cells and is co-secreted with insulin [8]. Amylin and insulin levels rise and fall in a synchronous manner (figure 2) [7]. Amylin and insulin have complementary actions in regulating nutrient levels in the circulation. Amylin is deficient in type 1 diabetes and relatively deficient in insulin-requiring type 2 diabetes (figure 2) [7].

Amylin affects glucose control through several mechanisms, including slowed gastric emptying, regulation of postprandial glucagon, and reduction of food intake (table 1). Glucagon-like peptide 1 (GLP-1) exhibits similar properties as amylin, but amylin, unlike GLP-1, does not have insulin secretory effects. Both regulate hyperglycemia in part through amelioration of inappropriate glucagon secretion and gastric emptying. GLP-1 and amylin appear to have differing magnitudes of physiologic effects and bind to different receptors in the area postrema, the part of the brain that may be key for their effects on satiety [9,10]. In clinical practice, the effect of GLP-1 receptor agonists on gastric emptying is attenuated over time, particularly for long-acting agents. In addition, amylin agonists reduce post-meal glucagon dysregulation, while GLP-1 receptor agonists have minimal effect [11]. These complementary and potentially synergistic actions have generated interest in combination therapy with amylin- and GLP-1-based treatments, particularly for body weight management [12-14]. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".)

PRAMLINTIDE — Pramlintide is a stable, soluble, non-aggregating, equipotent amylin analog that is administered by mealtime subcutaneous injection. It is available for use for both type 1 and insulin-treated type 2 diabetes. Pramlintide reproduces the actions of amylin and lowers glucose without causing weight gain. Many questions remain unanswered regarding clinical use and long-term outcomes with this class of drug, and therefore, the exact role for amylin analogs among the myriad of other agents for diabetes management is unclear.

Mechanism of action — Pramlintide regulates post-meal blood glucose levels by slowing gastric emptying, promoting satiety, and suppressing the abnormal postprandial rise of glucagon in patients with diabetes [15-17]. Thus, endogenous (liver-derived) and exogenous (meal-derived) glucose influx are better regulated, allowing exogenous insulin therapy to more easily match physiologic needs. These effects are glucose dependent and are overridden as serum glucose levels fall [18]. Pramlintide does not cause hypoglycemia in the absence of therapies that otherwise cause hypoglycemia. Supraphysiologic doses of pramlintide do not provoke hypoglycemia in normal subjects [19], and pramlintide does not interfere with recovery from insulin-induced hypoglycemia [20,21].

Patient selection

●Type 1 diabetes – Pramlintide could be considered in motivated patients with type 1 diabetes suboptimally managed with insulin therapy alone, particularly in patients taking multiple daily injections or insulin pump therapy who gain weight despite lifestyle intervention.

●Type 2 diabetes – Pramlintide may be considered for motivated patients with type 2 diabetes inadequately managed with prandial insulin who have overweight or experience weight gain refractory to lifestyle measures. However, glucagon-like peptide 1 (GLP-1) receptor agonists have generally replaced pramlintide in the management of type 2 diabetes, given their demonstrated glucose-lowering efficacy, cardiovascular benefit, and relative ease of administration. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".)

Efficacy — Pramlintide has been studied in randomized controlled trials in both type 1 and type 2 diabetes [22-27].

●Type 1 diabetes – In type 1 diabetes, 30 to 60 mcg of pramlintide administered subcutaneously with meals resulted in sustained, albeit modest (<1 percentage point), reductions in A1C over the 52-week trial (figure 3A-B) [22]. More than twice as many patients (25 versus 11.3 percent) achieved an A1C of less than 7 percent in the treatment group than in the placebo group, with no increase in insulin dose or incidence of severe hypoglycemia. Modest reductions in body weight (mean of 0.5 kg) were seen in the treatment group compared with weight gain in patients receiving insulin only.

Similar results were found in a second large, randomized trial evaluating pramlintide at 60 mcg three to four times per day [23]. In this study, weight loss was more prevalent in patients with obesity compared with patients with normal body weight and was independent of reports of nausea.

Pramlintide is also under investigation for use with closed-loop insulin delivery systems, which are under development for management of type 1 diabetes [28,29]. Meal challenges are one of the greatest hurdles for maintaining glucose control with the use of closed-loop control systems. Preliminary, nonrandomized data suggest that pramlintide is associated with delayed time to peak plasma glucose excursion and reduced peak postprandial rise in glucose and area under the curve when used in combination with closed-loop systems [28,29]. In a small, randomized crossover trial, the dual hormone system resulted in an increased time in range compared with a rapid-acting insulin-only system (84 versus 74 percent), without an increase in hypoglycemia [30]. In addition, a fixed-dose coformulation with insulin is under development and may eliminate the need for separate injection or infusion in the future [31]. (See "Management of blood glucose in adults with type 1 diabetes mellitus".)

●Type 2 diabetes – In patients with type 2 diabetes, pramlintide has been shown to reduce A1C and weight (figure 3A-B) [24-26,32]. When added to existing insulin therapy with or without a sulfonylurea or metformin, reductions in A1C (mean 0.62 percentage points) and weight (1.4 kg) were seen with 120 mcg, but not 90 mcg, of pramlintide given twice daily [24]. Pooled, post hoc analyses showed that reductions in insulin requirements and body weight were greatest in patients with BMI >40 kg/m² [33].

In a 24-week trial of patients with inadequately controlled type 2 diabetes, the addition of pre-meal pramlintide to basal insulin with or without oral agents had similar glycemic efficacy as the addition of pre-meal rapid-acting insulin analogs (A1C reduction of approximately 1 percentage point) [27]. Patients randomly assigned to pramlintide maintained their weight, whereas those assigned to rapid-acting insulin gained weight (mean 4.7 kg). Pramlintide was associated with fewer hypoglycemic events compared with prandial insulin.

In addition to modest reductions in A1C and body weight, pramlintide has been associated with reductions in postprandial glucose excursions [34] and in surrogate markers of cardiovascular risk and oxidative stress [35,36]. The clinical implications of these findings are unknown.

Side effects and adverse events — Mild to moderate nausea is the most commonly reported side effect and generally dissipates by four weeks. Nausea can be minimized by slow upward dose titration and is less common in patients with type 2 diabetes [24-26].

Severe hypoglycemia in type 1 diabetes was increased fourfold during the first four weeks in one study when patients were started at full doses of pramlintide at randomization without reduction in insulin dose [23]. In a subsequent study, insulin dose was reduced by 25 percent at initiation of pramlintide therapy, which was titrated to the maximum dose over a period of one to two months. With this strategy, there was no increase in hypoglycemia. Pre-meal insulin doses stabilized at an average of 17 percent lower in pramlintide-treated patients compared with placebo by study end [37]. Hypoglycemia was less frequent in studies of patients with type 2 diabetes [24-26].

Small studies suggest that the increased incidence of hypoglycemia observed in patients with type 1 diabetes is related to mismatched timing of prandial insulin relative to peak glucose levels [38]. Pramlintide delays gastric emptying, resulting in blunted but delayed post-meal peak glucose. Thus, rapid-acting insulin analogs taken pre-meal may peak before the glucose peak occurs, increasing the risk of early hypoglycemia followed by delayed hyperglycemia. This is analogous to the pattern observed in patients with gastroparesis [39]. It is unknown whether regular human insulin or post-meal rapid acting insulin analogs ameliorate this problem.

Dose and administration — Pramlintide is only approved for use in patients with type 1 and type 2 diabetes taking prandial insulin. Pramlintide precipitates above a pH of 5.5 and must be injected separately from insulin at a different site [40]. The optimal timing for administration is immediately before a meal [41,42]. According to the approved labeling, pre-meal insulin doses (including pre-mixed insulin) should be reduced by 50 percent and should subsequently be titrated upward to achieve euglycemia once the target pramlintide dose is reached [43]. However, as noted above, most patients require a smaller reduction in prandial insulin. Patients with near-optimal glycemia on insulin pumps who utilize the extended wave bolus feature (square wave or dual wave) require minimal prandial insulin dose adjustments (<10 percent) after initiation of pramlintide [38,44].

Dosing

●Type 1 diabetes – The recommended starting dose for type 1 diabetes is 15 mcg before each meal, with increases of 15 mcg increments every three to seven days, as tolerated, to a goal of 60 mcg before each meal. Persistent nausea should prompt backward titration until resolved.

●Type 2 diabetes – The recommended initial dose for type 2 diabetes is 60 mcg, titrated upward as tolerated to 120 mcg with each meal.

Precautions — Pramlintide should not be administered to patients with severe hypoglycemia unawareness. Pramlintide should only be administered before meals that contain at least 250 calories or 30 grams of carbohydrates. Patients may need to administer their prandial insulin after meals until they become familiar with the degree of satiety and resulting reduction in carbohydrate intake that may occur due to pramlintide use. Another strategy is to substitute human regular insulin for the rapid-acting analog. This strategy may better match insulin with food.

Pramlintide slows gastric emptying and may delay the rate of absorption of oral medications. Patients with gastroparesis should not use pramlintide. Oral medications that require rapid absorption for effectiveness should be administered either one hour before or two hours after injection of pramlintide.

SUMMARY AND RECOMMENDATIONS

●Pramlintide – Pramlintide reproduces the actions of the naturally occurring peptide hormone, amylin, and controls glucose without causing weight gain. Many questions remain unanswered regarding clinical use and long-term outcomes with this class of drug, and therefore, the exact role for amylin analogs among the myriad of other agents for diabetes management is unclear [45]. (See 'Pramlintide' above.)

●Clinical use – We suggest an individualized approach to initiating pramlintide.

•Patient selection (see 'Patient selection' above and 'Efficacy' above and 'Side effects and adverse events' above):

-Type 1 diabetes – Pramlintide could be considered in motivated patients with type 1 diabetes suboptimally managed with insulin therapy alone, particularly in patients taking multiple daily injections or insulin pump therapy who gain weight despite lifestyle intervention.

-Type 2 diabetes – Pramlintide may be considered for motivated patients with type 2 diabetes inadequately managed with prandial insulin who have overweight or experience weight gain refractory to lifestyle measures. However, glucagon-like peptide 1 (GLP-1) receptor agonists have generally replaced pramlintide in the management of type 2 diabetes, given their demonstrated glucose-lowering efficacy, cardiovascular benefit, and relative ease of administration. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".)

•Administration – Pramlintide is only approved for use in patients also taking prandial insulin. However, it requires injections with each meal in the setting of type 1 diabetes and at least twice daily in type 2 diabetes. It cannot be mixed in a syringe with insulin. Pramlintide therapy requires careful patient education and monitoring to avoid severe hypoglycemia and should be instituted in collaboration with a diabetes educator experienced in its use. (See 'Dose and administration' above.)

●Uses not recommended – There are inadequate data to support the following uses of pramlintide:

•Pramlintide in patients not requiring insulin

•Pramlintide in patients with a history of severe hypoglycemia or hypoglycemia unawareness

•Combination therapy of pramlintide with exenatide or other GLP-1-based therapies