Treatment Options for Diabetes

Treatment of Type 1 Diabetes

Insulin

Insulin is the only medication used to treat type 1 diabetes. The use of insulin in managing diabetes not only helps to prevent hyperglycemic emergencies, but is also the best safeguard to prevent the long-term complications of diabetes by correcting fasting and postprandial hyperglycemia.

Newer forms of insulin, known as insulin analogs, have been available since 1995, and have allowed improved control of blood glucose level. Human insulin analogs, which are manufactured by recombinant technology, allow more physiological patterns of insulin replacement. These insulins are no longer classified as "long-acting" or "short-acting", but rather are made to mimic the action of the body's natural (endogenous) insulin and are classified as basal (fasting) or bolus (mealtime) insulins. Each type of insulin has distinct advantages and disadvantages.

Providing continuous basal insulin throughout the day and night with boluses of insulin at mealtimes may be used for persons with either type 1 or type 2 diabetes. If regular insulin is used, injections are given approximately 30-45 minutes before meals. However, this often results in suboptimal control because the postprandial glucose will rise before the insulin peaks. In addition, when the insulin peaks later, hypoglycemia can ensue. Therefore, the shorter acting analogs are preferred for pre-meal administration and work better for persons who may have variable mealtimes.

Most children on insulin injections receive three injections per day. Traditional insulin regimens for children consist of two-thirds of the daily insulin dose given in the morning before breakfast and one third in the evening. The morning injection typically consists of rapid-acting and intermediate-acting insulin which covers breakfast, lunch, and the afternoon. The dinner injection consists of rapid-acting insulin to cover the evening and the bedtime injection of intermediate-acting insulin to cover hormone surges during the sleeping hours.

Most basal insulins can be mixed in the same syringe with short-acting insulins, allowing fewer injections. The notable exceptions, however, are Insulin Glargine and Insulin Detemir which cannot be mixed in the same syringe with other insulins.

Types of Insulin

  • Rapidly acting insulins - takes effect rapidly and can last 4-12 hours

    • Regular insulin - Onset 30-60 minutes; Peaks in 2-4 hours; Duration 6-8 hours

    • Insulin lispro (Humalog by Eli Lilly) - Onset 15-30 minutes; Peaks in 1-2 hours, Duration 3-5 hours

    • Aspart (Novolog by Novo Novodisk) - Onset 5-10 minutes; Peaks in 1-2 hours; Duration 3-4 hours

    • Glulisine (Apidra by Sanofil-Aventis) - Onset 10-15 minutes; Peaks in 1-1.5 hours; Duration 3-5 hours

  • Intermediate-acting insulins

    • NPH insulin - usually given twice daily (before breakfast and before dinner or at bedtime): Onset 1 hour; Peaks in 6-8 hours; Duration 12 hours

    • Lente Insulin - Onset 1-3 hours; Peaks in 6-8 hours; Duration 12-20 hours

  • Long-acting or Basal insulins - These are released slowly and can last up to 24 hours

    • Ultralente insulin - Onset 2-4 hours; Peaks in 8-14 hours; Duration 18-30 hours

    • Insulin Glargine (Lantus by Sanofi-Aventis) - Onset 1 hour; No peak; Duration: 24 hours. It is usually give once daily at bedtime, but may be given in the morning instead. Once a vial of Glargine is opened, it should be discarded after 28 days. Glargine has not been approved for use in children < 6 years of age.

    • Insulin Detemir (Levemir by Novo Nordisk) - Onset 6-8 hours; Peaks in 3-14 hours; Duration 5-24 hours

    • There are also combination insulins, which contain both a rapid acting and longer acting insulin. Examples include Humulin 50/50, Novolin 70/30 and Humalog 75/25.

Amylin Agonists

The hormone amylin is secreted from the pancreatic beta cells in addition to insulin. Amylin and insulin work together with another hormone, glucagon, to maintain normal glucose concentrations. People with decreased insulin secretion will also have decreased amylin secretion. Amylin replacement is thought to improve glycemic control in some people with diabetes. An analog, pramlintide ("SYMLIN" by Amylin Pharmaceuticals), has been developed and works to decrease postprandial glucose levels. It is administered subcutaneously (injected under the skin) before meals. It is used in Type 2 diabetes as an adjunct treatment in patients who use mealtime insulin therapy who have failed to achieve desired glucose control despite optimal insulin therapy, with or without a concurrent sulfonylurea agent and/or metformin. In type 1 diabetes, it is used as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy.

Methods of Insulin Administration

  • Injections - Insulin syringes are available in either low dose or regular dose (up to 100 units) volumes with calibrated markings for measuring insulin drawn up from a vial.

  • Insulin pens - allow the delivery of insulin without the need to fill syringes. Pens are either disposable with pre-filled insulin or take cartridges contacting 300 units. They are available for most types of insulin.

  • Insulin pumps are pager-like devices that contain a small syringe that can be filled with insulin for delivery through a small catheter placed in a subcutaneous site (under the skin). It can be programmed using a touchscreen to deliver small hourly doses of insulin (basal needs) and insulin boluses before meals. The injection site is changed every 48-72 hours, and the insulin syringe usually holds 220-350mL of an insulin analog. Individuals with an insulin pump must be willing to monitor their blood glucose 5-6 times per day and to follow a carbohydrate counting meal plan.

  • Inhaled aerosols - The FDA approved the first inhaled version of insulin called Exubera (Pfizer Inc.) in January 2006. It is approved for those over 18 years of age with diabetes, but is primarily intended for those with type 1 diabetes who require large doses of insulin, or those with Type 2 who can tolerate large doses of insulin. Exubera is a short-acting powder form of insulin that is inhaled before each meal. A long-acting insulin, however, still needs to be given each day by injection. Side effects include coughing, shortness of breath, sore throat and dry mouth. Exubera is not approved for smokers or anyone who has smoked in the last six months because of the possibility of overdose. It is also not approved for anyone with a lung disorder, such as asthma or emphysema.

Updated Safety Information on Exubera

In April 2008, Pfizer informed healthcare professionals and patients of updated safety information in the WARNINGS section of prescribing information for Exubera, a short-acting insulin you breathe in through through your mouth using the Exubera inhaler, that helps to control high blood sugar in adults with diabetes. There have been 6 newly diagnosed cases of primary lung malignancy (lung cancer) in clinical trials among Exubera-treated patients, and 1 newly diagnosed case among patients in clinical trials receiving other treatments for diabetes. There has also been 1 post-marketing report of a primary lung malignancy in an Exubera-treated patient. There were too few cases, however, to determine whether the emergence of these lung cancer events is related to the use Exubera. All patients who were diagnosed with lung cancer had a prior history of cigarette smoking. Because of the limited availability of Exubera, healthcare professionals should seek alternative treatment options to maintain patients' glycemic control.

Other important safety information about Exubera includes:

  • Exubera is a rapid-acting insulin indicated for the treatment of adults with diabetes mellitus for the control of hyperglycemia (high blood sugar). In patiens with type 1 diabetes, Exubera should be used in regimens that include a longer-acting insulin. In patients with type 2 diabetes, Exubera can be used as monotherapy or in combination with oral agents or longer-acting insulins.

  • Exubera is contraindicated in patients who smoke or who have discontinued smoking less than 6 months prior to starting Exubera therapy. If a patient starts or resumes smoking, Exubera must be discontinued immediately due to the increased risk of hypoglycemia (low blood sugar) and an alternative treatment must be used.

  • Exubera is contraindicated in patients with unstable or poorly controlled lung disease because of wide variations in lung function that could affect the absorption of Exubera and increase the risk of hypoglycemia or hyperglycemia. The use of Exubera in patients with underlying lung disease, such as asthma or COPD, is not recommended because the safety and efficacy of Exubera in this patient population has not been established.

  • Hypoglycemia is the most commonly reported adverse event of insulin therapy, including Exubera.

  • In clinical trials, treatment with Exubera was associated with small, non-progressive declines in pulmonary function relative to comparator treatments. Because of the effect of Exubera on pulmonary function, all patients should have pulmonary function tests (e.g., spirometry) assessed prior to initiative therapy with Exubera, after 6 months of therapy, and annually thereafter, even in the absence of pulmonary symptoms.

  • The long-term safety and efficacy of Exubera in pediatric patients have not been established.

  • In clinical studies, respiratory adverse events included cough, which tended to occur within seconds to minutes after Exubera inhalation. The incidence of cough decreased with continued Exubera use. Other respiratory adverse events included:

    • dyspnea - shortness of breath
    • pharyngitis - inflammation of the pharynx (sore throat)
    • increase in sputum production
    • epistaxis - nosebleed

  • Non-respiratory adverse events reported in Exubera-treated patients include hypoglycemia, chest pain, and dry mouth.

Side Effects of Insulin Therapy

  • Hypoglycemia ("insulin shock") - This complication occurs if the blood glucose levels fall below normal and can be caused by insufficient intake of food, exercise, or alcohol intake. This occurs most commonly in persons using insulin and those who are attempting to achieve tight control of glucose levels. At the extreme, repeated episodes of hypoglycemia (glucose < 65mg/dL) can lead to permanent brain damage (hypoglycemia encephalopathy) or death. Symptoms of hypoglycemia include:

    • Sweating
    • Trembling
    • Headache
    • Hunger
    • Rapid heartbeat
    • Mood changes
    • Neurologic symptoms
    • Confusion and disorientation
    • Weakness
    • Combativeness
    • Coma (rare)
    • Seizures (rare)
    • Death (rare)

These symptoms should be promptly treated with juice, glucose tablets, glucose gel or another source of quick-acting carbohydrate, which should carried and available at all times. Severe hypoglycemia can be treated with glucagon, which may be injected intramuscularly or intravenously

  • Lipohypertrophy - This refers to the development of benign "tumor-like" swelling of fatty tissue at the sites of subcutaneous insulin injections. It is estimated that the prevalence of clinically significant lipohypertrophy is around 20% to 30% in patients with type 1 diabetes and 4% in patients with type 2 diabetes. Lipohypertrophy seems to be due to a cellular response of fat cells to the local effects of injected insulin. Suggested risk factors for lipohypertrophy include frequent injection at the same site, type of insulin, number of injections a day, total daily dose of insulin, reuse of needles, and use of pen devices rather than syringes. Injection into lipohypertrophied injection sites can lead to problems with glycemic control because of delay in insulin absorption. The lipohypertrophied areas can be unsightly, and the only available treatment for the condition is liposuction, although not injecting into the sites may reduce their size over time.
Interactions of Other Drugs with Insulin

Many drugs can interfere with the effectiveness of insulin and may require closer monitoring or changes in drug regimen.

Drugs that can decrease the effectiveness of insulin include:

  • Corticosteroids
  • Oral contraceptives
  • Diltiazem,
  • Epinephrine
  • Niacin
  • Thiazide diuretics

Drugs that can increase the effectiveness of insulin include:

  • Alcohol
  • Alpha-adrenergic blockers
  • Nonselective beta blockers
  • Clofibrate (lipid lowering medication)
  • MAO inhibitors (anti-depressants)
  • Pentamidine
  • Salicylate
  • Tetracycline
  • Anabolic steroids