Treatments for Diabetes

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Overview

Type 2 diabetes is a chronic, lifelong condition characterized by elevated blood glucose. If high blood glucose is left untreated and remains high for long periods of time, it can lead to serious health complications, including cardiovascular disease, kidney disease, vision problems, and nerve problems. Due to the serious health risk posed by uncontrolled diabetes, an effective, well-considered treatment plan is essential for every person who has the disease. Lifestyle modification, including healthy eating and regular physical activity, play an important role in your diabetes care plan. However, very few people with type 2 diabetes can control their condition with lifestyle modifications alone.

General approach to drug treatment in type 1 and type 2 diabetes

In type 2 diabetes, the body loses the ability to use the insulin it produces effectively (this is called “insulin resistance”). We know that being overweight starts the process of events inside the body that leads to the development of insulin resistance. In addition to insulin resistance, loss of the ability to produce insulin also plays a role in elevated blood glucose in type 2 diabetes. In fact, by the time that most people are diagnosed with type 2 diabetes, they have already lost over 50% of their ability to make the insulin they need. In addition to a deficiency in insulin, abnormalities with the other hormones involved in glucose control can also contribute to type 2 diabetes.1,2

Drug treatment options for type 2 diabetes


When you are diagnosed with type 2 diabetes you will immediately start a program of lifestyle modifications to control your elevated blood glucose. This will include healthy eating, a weight-loss program (if you are overweight or obese), and regular physical activity. Healthy eating, weight loss, and physical activity are crucial parts of every diabetes care plan and they can make an immediate difference in blood glucose levels, with an expected decrease in hemoglobin A1C of 1% to 2%.

At the time you are diagnosed with type 2 diabetes or shortly thereafter, your healthcare provider may recommend that you start on an oral diabetes medication in combination with lifestyle modifications for control of blood glucose. If your blood glucose is extremely high (A1C of 10% to 12%), your provider may start you on insulin alone or in combination with another diabetes medication.

Many people who are diagnosed with type 2 diabetes will be started on an oral medication (take as a pill) called metformin (brand names: Glucophage, Gumetza, Riomet, Fortamet). Metformin is an insulin sensitizer. This means it helps the liver and the muscle use excess glucose. By sensitizing your tissues, metformin helps your body make better use of the insulin you continue to make. If the maximal dose of a single medication is not sufficient to lower blood glucose, your healthcare provider may suggest you add another medication to metformin. There are many different kinds of medications, both oral and injectable, to help you control blood glucose.3

Adding additional diabetes medications. When it comes to medications to control type 2 diabetes, the ADA recommends using an approach of adding medications (including insulin) in a stepwise fashion as needed to achieve blood glucose control. As mentioned, most people will start with the drug metformin. If this drug is insufficient for blood glucose control after a 3-month period, another oral or injectable diabetes medication or insulin is added to treatment. If this combination is insufficient for blood glucose control after a 3-month period, then another medication or insulin is added. Finally, if a three-drug combination is not sufficient, your provider may recommend a more intensive program of insulin treatment, with or without other diabetes medications.3

Additional medication choices. A commonly recommended second medication choice to add to metformin is a short-acting sulfonylurea, such as glipizide. This is the oldest class of diabetes medications and works by helping your body increase insulin production. Sulfonylureas can lower blood glucose by 20% and A1C by 1-2%. One important limitation with sulfonylureas is that they become less effective over time. The most common side effect associated with sulfonylureas is hypoglycemia. Short-acting agents are less likely to cause severe hypoglycemia.3

There are a number of sulfonylureas available, including Diabinese, Orinase, Glucotrol, Diabeta, Micronase, Glynase, and Amaryl. They have similar effectiveness but vary in cost and availability.4

For people with type 2 diabetes who cannot take a sulfonylureas or metformin or who have other medical conditions that dictate the choice of another medication, there are other classes of diabetes medications, including thiazolidinediones (pioglitazone), meglitinides (Prandin, Starlix), alpha-glucosidase inhibitors (Precose, Glyset), glucagon-like peptide-1 (GLP-1) agonists (Victoza, Bydureon, Byetta), dipeptidyl peptidase-4 (DPP-4) inhibitors (Januvia, Onglyza, Tradjenta), a sodium-glucose co-transporter 2 (SGLT2) inhibitor (Invokana), and a human amylin analog (Symlin).4-22

Medications for the treatment of type 2 diabetes4-22

Drug

Maker

Dosing

Key side effects

Metformin
Metformin HCl (Glucophage, Gumetza, others) Various manufacturers (generic available) Oral Gastrointestinal
Low risk for hypoglycemia
Sulfonylureas
Amaryl (glimepiride) Sanofi-Aventis(generic available) Oral Hypoglycemia
Glucotrol (glipizide) Pfizer(generic available) Oral Hypoglycemia
Other brands:

  • Diabeta
  • Micronase
  • Glynase
Various manufacturers Oral Hypoglycemia
Thiazolidinediones
Actos (pioglitazone) Takeda Pharmaceuticals America(generic available) Oral
  • Risk of liver toxicity
  • Potential cardiovascular risk
Avandia (rosiglitazone maleate) GlaxoSmithKline(no generic available) Oral
  • Risk of liver toxicity
  • Potential cardiovascular risk
Meglitinides
Prandin (repaglinide) Novo Nordisk(no generic available) Oral Hypoglycemia
Starlix (nateglinide) Novartis(generic available) Oral Hypoglycemia
Alpha-glucosidase inhibitors
Precose (acarbose) Bayer Pharmaceuticals(generic available) Oral (taken with meals) Gas, diarrhea, abdominal pain
Glyset (miglitol) Bayer Pharmaceuticals(o generic available) Oral (taken with meals) Gas, diarrhea, abdominal pain
DPP-4 inhibitors (alone and in combination with other medications)
Januvia (sitagliptin)‎* Merck and Co Oral
  • Some nausea and diarrhea
  • Low risk of hypoglycemia
Onglyza (saxagliptin) Bristol-Myers Squibb Company(no generic available) Oral
  • Some nausea and diarrhea
  • Low risk of hypoglycemia
Tradjenta (linagliptin) Boehringer Ingelheim Pharmaceuticals(no generic available) Oral
  • Some nausea and diarrhea
  • Low risk of hypoglycemia
Janumet XR (sitagliptin and metformin HCI extended-release) Merck and Co(no generic available) Oral
  • Some nausea and diarrhea
  • Low risk of hypoglycemia
Juvisync (sitagliptin and simvastatin) Merck and Co(no generic available) Oral
  • Some nausea and diarrhea
  • Low risk of hypoglycemia
Kombiglyze XR (saxagliptin and metformin HCl extended-release) Bristol-Myers Squibb Company(no generic available) Oral
  • Some nausea and diarrhea
  • Low risk of hypoglycemia
SGLT2 inhibitors
Invokana (canagliflozin) Janssen Pharmaceuticals(no generic available) Oral
  • Risk for hypoglycemia
  • Risk for kidney problems
Farxiga (dapagliflozin) AstraZeneca(no generic available) Oral
  • Risk for hypoglycemia
  • Risk for kidney problems
  • Risk for genital yeast infections
Jardiance (empagliflozin) Boehringer Ingelheim Pharmaceuticals, Eli Lilly (no generic available) Oral
  • Risk for hypoglycemia
  • Risk for kidney problems
  • Risk for genital yeast infections
GLP-1 agonists
Victoza (liraglutide [rDNA origin]) Novo Nordisk(no generic available) Once daily SC injection
  • Gastrointestinal
  • Low risk for hypoglycemia
Bydureon (exenatide extended-release AstraZeneca Pharmaceuticals(no generic available) Once weekly SC injection
  • Gastrointestinal
  • Low risk for hypoglycemia
Byetta (exenatide) Amylin Pharmaceuticals(no generic available) SC injection (before meals)
  • Gastrointestinal
  • Low risk for hypoglycemia
Amylin analog (for type 1 and 2 diabetes)
Symlin (pramlintide acetate) Amylin Pharmaceuticals(no generic available) SC injection (before meals)
  • Gastrointestinal
  • Low risk for hypoglycemia

DPP-4=dipeptidyl peptidase-4; NPH=neutral protamine hagedorn; NPL=neutral protamine lispro;

PPAR=proliferator-activated receptor; SGLT2=sodium-glucose co-transporter 2; GLP-1=Glucagon-

Like Peptide-1.

Insulin treatment for type 2 diabetes

In the past, insulin injections were only used in people with type 2 diabetes who could not successfully control their blood glucose with healthy eating and physical activity, and other kinds of type 2 diabetes medications. However, evidence is building for earlier use of insulin treatments to control blood glucose in people with type 2 diabetes. This evidence has suggested that insulin may improve overall glycemic control in people with type 2 diabetes and may also preserve the ability of the pancreas to continue to produce insulin. So, in type 2 diabetes, insulin treatment can be used alone before any other type 2 diabetes medications have been used or it can be used in combination with other medications. Your doctor will work with you to determine which approach to drug treatment is best for you.4

Types of insulin

There are two main types of insulin preparations, insulin preparations that are identical to human insulin (these are often called “human insulin preparations”) and insulin analogs.25

Human insulin preparations are synthesized (they are made in a production facility) based on the molecular structure of human insulin produced by the body. These insulin preparations are identical to naturally produced insulin.

Human insulin analogs (the word “analog” literally means “similar” or “comparable”) are made to be like human insulin, but with slight changes to their molecular structures that make them act in certain ways inside the body. For instance, because natural human insulin tends to be limited in how quickly it takes effect and how long its effect lasts, insulin analogs can be engineered to take effect rapidly or to last for a very long time.

This leads us to another important way insulins are categorized: how quickly they take effect and how long their effects last. There are four different types of insulins:

  • Rapid-acting
  • Short-acting
  • Intermediate-acting
  • Long-acting

Having a range of different insulin treatments, some that act quickly and don’t last too long and others that are slow to take action and work in a steady, predictable way for a long period of time, is useful because it allows you to mix different types of insulin treatments to better achieve your blood glucose goals. For example, many people with diabetes will take an intermediate- or long-acting insulin as what is called “basal therapy” (this just means “base therapy”) to provide general control throughout the day and then use a rapid- or short-acting insulin around mealtime to cover the boost of carbohydrates that we get with meals. This mixing and matching of insulins allow more tight control of blood glucose and can be tailored to an individual patient’s needs.25

Basal and bolus insulin. Intermediate- and long-acting insulins are generally referred to as basal insulin treatments. These are typically injected once or twice daily to achieve a steady base insulin level in the body. The goal of these insulin treatments is to suppress glucose production by the liver (the liver converts glucose stored in the form of glycogen back to glucose) and keeps blood glucose levels within the normal range between meals. Basal levels of insulin can also be achieved with continuous infusion of rapid- or short-acting insulin (as with an insulin pump), but typically basal insulin levels are maintained using intermediate- and long-acting insulin treatments. Short- and rapid-acting insulin are sometimes called bolus insulin treatments because they are given in a bolus injection (the word “bolus” just means a small amount of something) to supply quick-acting insulin you need to process carbohydrates during mealtime. Bolus insulin is typically given just before (5-30 minutes) before a meal.5

Commonly used insulin preparations25

Preparation

Onset of action

Peak effect

Duration of action

Rapid-acting

Lispro, aspart, glulisine Insulin analogs 5-15 min 45-75 min 2-4 hrs

Short-acting

Regular insulin Human insulin ~30 min 2-4 hrs 5-8 hrs

Intermediate-acting

NPH Human insulin ~2 hrs 4-12 hrs 18-28 hrs
NPL Human insulin ~2 hrs 6 hrs 15 hrs

Long-acting

Insulin glargine Insulin analog ~2 hrs No peak 20-24+ hrs
Insulin detemir Insulin analog ~2 hrs 3-9 hrs 6-24 hrs*

NPH=neutral protamine hagedorn, NPL=neutral protamine lispro.

*Depends on dose.

Adapted from McCulloch DK. General principles of insulin therapy in diabetes mellitus. Nathan

DM, Mulder JE, eds. UptoDate. Wolters Kluwer Health. Accessed at: www.uptodate.com. 2014.
Learn more about insulin treatments, including tips for injecting insulin

Biosimilar insulin products

In the near future (2015 in the US marketplace), a number of human insulin preparations and insulin analogs will come off-patent, and several biotech and pharmaceutical manufacturers will introduce what are called “biosimilar” insulin products: copies of human insulin preparations and insulin analogs. These biosimilar products may differ from the original on-patent product by the source materials and manufacturing processes used to make them. Therefore, they may have different batch-to-batch consistency and stability compared to the original insulin product. Before substituting a biosimilar insulin product for the insulin that you have been taking (when these products become available), you should be cautious and make sure that the biosimilar product will provide an equally safe and effective means of glucose control.

New diabetes drug treatments under development

There are several new diabetes medications that are in advanced stages of development for the US healthcare market (some of these have been approved for the European market). These include two GLP-1 receptor agonists dulaglutide, and lixisenatide (Lyxumia), and the ultra-long duration insulin analog Tresiba (insulin degludec).

Learn more about research in diabetes, including new treatments that are currently being developed.

Drugs in later stages of development for
type 1 and type 2 diabetes25-30

Drug

Maker

Administration

Indication

Drug type

Dulaglutide (LY-2189265) Eli Lilly Once weekly injection Type 2 diabetes GLP-1 receptor agonist
Lyxumia (lixisenatide) Sanofi-Aventis Once daily injection Type 2 diabetes (approved in Europe) GLP-1 receptor agonist
Tresiba (insulin degludec) (NN1250) Novo Nordisk Inc Once daily injection Diabetes (type 1 and 2) (approved in Europe) Ultra-long duration insulin analog
view references
1. Mantzoros C. Insulin resistance: Definition and clinical spectrum. Nathan DM, Mulder JE, eds. UptoDate. Wolters Kluwer Health. Accessed at: www.uptodate.com. 2013.-- 2. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364-79.-- 3. American Diabetes Association. Standards of Medical Care in Diabetes—2014. Diabetes Care 2014;37:S14-S80.-- 4. McCulloch DK. Initial management of blood glucose in adults with type 2 diabetes mellitus. Nathan DM, Mulder JE, eds. UptoDate. Wolters Kluwer Health. Accessed at: www.uptodate.com. 2013.-- 5. McCulloch DK. Patient information: Diabetes mellitus type 2: Treatment (Beyond the Basics). Nathan DM, Mulder JE, eds. UptoDate. Wolters Kluwer Health. Accessed at: www.uptodate.com. 2013.-- 6. Glucophage (metformin hydrochloride) and GLUCOPHAGE® XR (metformin hydrochloride) Extended-Release Prescribing Information. Bristol-Myers Squibb Company. Princeton, NJ. 2009.-- 7. Amaryl (glimepiride tablets) Prescribing Information. sanofi-aventis U.S. LLC. Bridgewater, NJ. 2009.-- 8.Glucotrol XR (glipizide extended-release) Prescribing Information. Pfizer Pharmaceuticals. New York, NY. October 2013.-- 9. Actos (pioglitazone) Prescribing Information. Takeda Pharmaceuticals America, Inc. Deerfield, IL. November 2013.-- 10. Avandia (rosiglitazone maleate) Prescribing Information. GlaxoSmithKline. Research Triangle Park, NC. September 2013.-- 11. Starlix (nateglinide) Prescribing Information. Novartis Pharmaceuticals Corp. East Hanover, NJ: 2013.-- 12. Glyset (miglitol) Prescribing Information. Bayer Pharmaceuticals. Manufactured by Pfizer Inc. New York, NY: 2012.-- 13. Januvia (sitagliptin)‎ Prescribing Information. Merck and Co., Inc. Whitehouse Station, NJ. 2010.-- 14. Onglyza (saxagliptin) Prescribing Information. Bristol-Myers Squibb Company. Princeton, NJ. May 2013.-- 15. Tradjenta (linagliptin) Prescribing Information. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT. June 2013.-- 16. Janumet XR (sitagliptin and metformin HCI extended-release) Prescrbing Information. Merck and Co., Inc. Whitehouse Station, NJ. 2012.-- 17. Juvisync (sitagliptin and simvastatin) Prescribing Information. Merck and Co., Inc. Whitehouse Station, NJ. 2011-2012.-- 18. Kombiglyze XR (saxagliptin and metformin hydrochloride extended-release) Prescribing Information. Bristol-Myers Squibb Company. Princeton, NJ. May 2013.-- 19. Invokana (canagliflozin) Prescribing Information. Janssen Pharmaceuticals, Inc. Titusville, NJ. 2013.-- 20. Victoza (liraglutide [rDNA origin] injection) Prescribing Information. Novo Nordisk Inc. Plainsboro, NJ. July 2013.-- 21. Bydureon (exenatide extended-release for injectable suspension) Prescribing Information. AstraZeneca Pharmaceuticals LP. Wilmington, DE. February 2014.-- 22. Byetta (exenatide) Injection Prescribing information. Amylin Pharmaceuticals, Inc. San Diego, CA. December 2011.-- 23. Symlin (pramlintide acetate) Prescribing Information. Amylin Pharmaceuticals, Inc. San Diego, CA. July 2008.-- 24. TANZEUM (albiglutide) Prescribing Information. GlaxoSmithKline. Research Triangle Park, NC. April 2014.-- 25. McCulloch DK. General principles of insulin therapy in diabetes mellitus. Nathan DM, Mulder JE, eds. UptoDate. Wolters Kluwer Health. Accessed at: www.uptodate.com. 2014.-- 26. Fonseca VA. New Developments in Diabetes Management: Medications of the 21st Century. Clin Ther 2014;1:00027-7. further reading
Rubin AL. Diabetes for Dummies. 4th ed. Hoboken, NJ: Wiley Publishing, Inc; 2012. -- American Diabetes Association Complete Guide to Diabetes: The Ultimate Home Reference from the Diabetes Experts. 5th ed. American Diabetes Association. Alexandria, VA: American Diabetes Association; 2011.
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