Adding to the Armamentarium for the Treatment of Diabetes Mellitus

It is now well established that improving glycemic control reduces the risk of microvascular complications, but optimal glycemic control has been elusive.

It is now well established that improving glycemic control reduces the risk of microvascular complications, but optimal glycemic control has been elusive. The average glucose level in people with diabetes in the US is above 200 milligrams per decilitre (mg/dL), with established guidelines recommending, at a minimum, less than 150mg/dL as measured by the A1C test.4 The reasons are multifactorial, including the need for multiple drugs to reach glycemic goals, adherence to recommended treatments, side effects of medications and hypoglycemia risk (real or perceived), cost of treatment and clinical inertia.The clinical shortcomings of current therapies necessitate the continued search for new medications to add to the armamentarium for treatment.

Until 1995, only sulfonylureas and insulin were available for pharmacological treatment of people with T2DM. Currently, five classes of oral agents are approved for the treatment of T2DM:

• α-glucosidase inhibitors (acarbose and miglitol);

• biguanides (metformin);

• meglitinides (nateglinide and repaglinide);

• thiazolidinediones (TZDs) (pioglitazone and rosiglitazone) or peroxisome proliferator-activated receptor γ (PPARγ) agonists; and

• sulfonylureas (multiple agents available).

Oral antidiabetic agents are often grouped according to their glucose-lowering mechanism of action. Metformin and TZDs are often categorized as insulin sensitizers, as they reduce insulin resistance, while sulfonylureas and meglitinides are often categorized as insulin secretagogues, as they enhance pancreatic betacell insulin release. In general, addition of one insulin secretagogue to another results in no further improvements in glucose control, thus there are truly only four distinct classes of oral medications to treat T2DM. New oral agents will potentially add novel mechanistic ways to improve glycemic control.Dipeptidyl Peptidase – 4 Inhibitors
The novel oral-medication class dipeptidyl peptidase-4 (DPP-4) inhibitors have been be reviewed and were approved by the US Food and Drug Administration (FDA) in October 2006. The incretin, glucagon-like peptide-1 (GLP-1), is produced from L-cells in the intestine. Circulating levels of GLP-1 rise within minutes of a meal and have several important glucose homeostasis actions including: glucose-dependent enhancement of insulin secretion from the pancreatic beta cells; reduction of inappropriately elevated glucagon postprandially; slowing of inappropriately rapid gastric emptying; and reduction in food intake. It has clearly been shown that, in T2DM, GLP-1 levels are deficient. The main limitation in developing GLP-1 for the treatment of T2DM is its short half-life (<2 minutes) due to rapid degradation by the enzyme DPP-4. Drugs have been developed that: • confer resistance to DPP-4 enzyme breakdown and mimic many of GLP-1 actions—called incretin mimetics (exenatide, marketed as Byetta); or • inhibit the DPP-4 enzyme, prolonging the half-life of endogenous GLP-1—called DPP-4 inhibitors (vildagliptin, marketed as Galvus; and sitagliptin, marketed as Januvia). Incretin mimetics and exenatide will not be covered in the scope of this article, as two comprehensive pharmacy reviews have recently been published. DPP-4 inhibitors are advantageous because of oral administration, weight neutrality and good tolerability.

A1C reductions with DPP-4 inhibitors average 0.5–1.0%, depending on baseline A1C levels. Small reductions are seen in the fasting plasma glucose (FPG), with pronounced glycemic reductions postprandially. Optimal dosing with vildagliptin or sitagliptin will likely be daily. DPP-4 inhibitors have a low incidence of mild hypoglycemia in monotherapy and are otherwise very well tolerated.Vildagliptin has shown to be weight-neutral for at least one year. DPP-4 enzyme metabolizes a wide variety of peptides, including playing an important role in T-cell activation. No adverse immunological reactions have been noted to date, but long-term safety data will better elucidate if there are any issues. A1C reductions with vildagliptin have been maintained for at least one year, potentially signalling DPP-4 inhibitors positively affecting betacell health, but more data is needed prior to any conclusions about their long-term effects. DPP-4 inhibitors are a welcome addition to the armamentarium to treat T2DM.Amylinomimetics
Pramlintide (Symlin®) is a synthetic analogue of human amylin, a hormone synthesized in pancreatic beta cells and co-secreted with insulin. Though pramlintide has been approved by the FDA for almost two years, most clinicians have limited experience in its use. In type-1 diabetes mellitus (T1DM),amylin is absolutely deficient and, in insulin-requiring T2DM, is moderately deficient. The peptide pramlintide was synthesized for formulation ease after it was found that endogenous amylin is a fairly insoluble hormone that aggregates in solution. Pramlintide helps to control postprandial glucose excursions by slowing gastric emptying, prevention of the inappropriate postprandial rise in plasma glucagon and by increasing satiety, resulting in a reduction in food intake and potential weight loss. Pramlintide, after subcutaneous (SQ) injection, peaks at about 20 minutes, and has a t1/2 of ~50 minutes, necessitating an injection prior to each meal. Pramlintide is degraded and eliminated in the kidneys and renal insufficiency did not result in accumulation.

When added to current therapy, pramlintide results in an additional reduction in A1C of ~0.3%-0.6%. Pramlintide is effective at reducing postprandial glucose excursions, but has little effect on the FPG. Dosing varies on whether the patient has T1DM or T2DM, tolerability and response to the drug. In T1DM, dosing starts at 15μg prior to each meal, and can be titrated up to a maximum of 60μg. In T2DM, dosing is initiated at 60μg prior to each meal, and can be increased to 120μg. Each 2.5 units on a U-100 insulin syringe is equal to 15μg of pramlintide, but this conversion can potentially confuse healthcare professionals and patients, so adequate education is required. Pramlintide comes in a phial, allowing individualisation of titration, even outside the package insert recommended titration, based on response and gastrointestinal side effects. Common side effects include nausea, vomiting, and anorexia. Pramlintide, per se, does not cause hypoglycemia, but it is exclusively indicated in patients on insulin, thus, as an add-on therapy, it can result in hypoglycemia. Severe hypoglycemic reactions have been reported, especially with initiation of therapy, and it is imperative that the prandial insulin dose (lispro, aspart or glulisine) be reduced by 50% on initiation to minimize this risk. Mixing pramlintide with insulin in the same syringe potentially reduces the number of injections for the patient, but current pramlintide labeling does not recommend this practice. It is unlikely, though, that mixing impacts the pharmacokinetics or pharmacodynamics of the insulin or pramlintide. Further fine-tuning of both pramlintide and insulin doses will likely ensue, requiring frequent follow-up and a diligent patient.

Insulin Therapy
Insulin therapy has been the only treatment of T1DM and is a major component of treatment for T2DM. Multiple types of insulin are currently available (see Table 1) and have been used with or without oral agents, in monotherapy and in combination with other complimentary insulins to improve glycemic control. The basal-bolus concept for insulin administration is becoming widespread. A long-acting insulin, often called a basal insulin, is used to suppress excess hepatic glucose production overnight, resulting in an acceptable FPG, and prandial glycemia is matched with a short- or rapid-acting insulin with each meal (see Figure 1).The rapid-acting insulin glulisine (Apidra®) and the injectable long-acting insulin detemir (Levemir®) were launched in the US in 2004 and 2005, respectively. In addition, the novel inhaled human insulin Exubera® gained FDA approval in January 2006.

Glulisine (Apidra)
Glulisine is a rapid-acting insulin analogue with similar pharmacokinetics to lispro and aspart insulin (see Figure 2). Rapid-acting insulin, in general, has shown to have higher patient satisfaction, though an advantage for A1C or hypoglycemia versus regular insulin is questionable. Glulisine has substituted out two insulin amino acids—lysine for asparagine at B-3 and glutamic acid for lysine at B-29—to obtain its rapid action.

Clinical data has shown that glulisine is effective in T1DM and in T2DM, and has been approved for use in insulin pumps. Glulisine has several characteristics that could, if proven, differentiate it from lispro and aspart. First, glulisine may be beta-cell protective by means of less apoptosis of beta-cells. Second, glulisine appears to retain its rapid-onset kinetics slightly better than lispro in obese subjects. Unfortunately, no conclusions can currently be made about these theoretical advantages, as they were performed in cell cultures or in nondiabetic subjects. Overall, glulisine appears to be a safe, effective addition to the other currently available rapid-acting insulins.Detemir (Levemir)
Detemir is a long-acting insulin analogue. Glargine insulin, with a pH level of 4, prolongs its absorption after SQ injection by slowly leaching from the injection site after precipitation at the body’s pH level of 7.4. Detemir, in contrast, attaches a C14 fatty acid (a 14- carbon fatty acid) at the B-29 position and removes the B-30 amino acid.This allows the fatty acid side chain to bind to interstitial albumin at the SQ injection site. Also, the formulation allows stronger hexamer (six molecules of insulin associated together) associations, which prolong absorption. Once detemir dissociates from the interstitial albumin, it is free to enter a capillary, where it is again bound to albumin. It then travels to a site of action and interacts, after dissociation from albumin, with insulin receptors.

Studies on the kinetics of detemir reveal that the onset is consistently ~2 hours, but the peak and duration are dependent on the dose. At low dose (0.2 units per kilogram (units/kg)), the peak is ~6 hours, and the duration of action is 12–14 hours. In contrast, at a higher dose (0.8 units/kg), the peak is at ~9 hours, and the duration of action is ~23 hours (see Figure 2). It is likely that, in T1DM, detemir will have to be dosed twice daily and, in T2DM,dosed once or twice daily for glycemic control.

Clinically, detemir has shown to be equally efficacious to Neutral Protamine Hagedorn (NPH) for FPG control and A1C reduction. In addition, it appears to cause less weight gain and hypoglycemia when compared with NPH. Twice-daily detemir was compared with bedtime glargine in conjunction with prandial coverage by aspart insulin in people with T1DM. A1C reduction was similar between the two groups and no difference was seen in within-subject variation or overall shape of nine-point plasma glucose profile. The overall risk of hypoglycemic reactions was similar between the two groups, but detemir had a lower risk of nocturnal and major hypoglycemia. Detemir should not be mixed with any other insulin and unopened or opened bottles or cartridges kept at room temperature are fit for use for 42 days. Detemir is a welcome addition to long- acting insulins, with more choices allowing clinicians and patients to fine-tune their diabetes control.Human Insulin Inhalation Powder (Exubera)
Human insulin inhalation powder (HIIP) is the first inhaled insulin to receive FDA approval. Unlike injectable insulin, HIIP is measured in milligrams, with 1mg equal to approximately 2.5–3 units of SQ rapidacting insulin. After inhalation, the onset of glucoselowering action is within 10 to 15 minutes, with the peak effect at approximately 60 minutes, and the duration of action being six hours. Thus, the onset and peak are similar to rapid-acting insulin, but the duration of action is between rapid-acting insulin and regular insulin (see Figure 2). HIIP will be used instead of prandial injectable insulin in appropriate candidates. Unsuitable candidates for HIIP currently include people with underlying lung disease; smokers, as systemic exposure could be two- to five-fold higher than in nonsmokers; those heavily exposed to passive smoke; and patients with asthma/chronic obstructive pulmonary disease, as insulin absorption is likely reduced.

The HIIP inhalation device, made by Nektar Therapeutics (see Figure 3), has been used throughout testing. A 1mg or 3mg blister pack of HIIP is placed into the inhalation device. After one pump of the handle on the device, the patient prepares the mouthpiece for inhalation and pushes the fire button to release the insulin powder into the chamber. The subject then inhales the insulin. This is repeated, if necessary, with a new insulin blister pack to obtain the full, inhaled dose of insulin.

HIIP is a prandial insulin, and should be inhaled at or just prior to a meal. Clinical efficacy has been demonstrated in T1DM and in T2DM. As with all insulin, HIIP can result in hypoglycemia. It is recommended that HIIP be started on a weight basis, but clinical judgement about the proper dose on which to start each patient is essential. Hypoglycemia early on in therapy has been noted, thus cautious titration of HIIP dosing based on carbohydrate intake and/or preand postprandial glucose readings is advised.The main concerns with HIIP are proper usage of the inhalation device and pulmonary safety, with education on both points essential. An insulin-release unit, which is part of the device,must be replaced every two weeks to avoid clogging. Replacement insulin-release units come with the blister packs. Blister packs are stored at room temperature and are fit for use for three months once the foil overwrap has been opened. Pulmonary symptoms, such as increased cough and dyspnea, have been associated with HIIP. In addition, long-term pulmonary safety studies were performed prior to FDA approval.Two-year lung-safety data has shown that early minor reductions in lung function, as measured by forced expiratory volume in one second (FEV1) or diffusing capacity of the lung for carbon monoxide, are reversible when HIIP is stopped. It is recommended that pulmonary function tests (PFTs) be performed at baseline, six months, and annually thereafter. If FEV1 declines >20% versus baseline, and the results are confirmed by a second PFT, HIIP should be stopped.

Conclusion
The prevalence of diabetes in the US continues to increase, and poor glucose control is still too common. Oral medications such as DPP-4 inhibitors are well tolerated and mechanistically novel. In addition, new hormonal therapy, such as pramlintide, is being used to improve postprandial control in people requiring insulin for glycemic control. New insulins, such as glulisine and detemir, add additional options to consider when choosing proper therapy, and the novel inhaled insulin Exubera will likely make insulin therapy less intimidating to people wit
diabetes. Advances in diabetes continue at a fast pace, foretelling a brighter future for clinicians and people with diabetes trying to control this chronic disease.