From Pills to Needles – OHAs and Other Medications

The key to diabetes control is insulin. This is particularly true for those who have type 1 diabetes (T1D) because insulin production in many has almost stopped. In the case of type 2 diabetes (T2D), a type of drug referred to as Oral Hypoglycemic Agents (OHA) may also be used. The reason why OHA may be applicable in the case of T2D is due to the two issues related to the disease. These are:

  1. Not enough insulin is produced
  2. Insulin resistance

As a result, it often requires 2 different classes of medication insulin: one to increase output and one to improve utilization.

Medications that Work to Increase the Output of Insulin

This group derives the name of insulin secretagogues from their function. Their function is to augment secretion of insulin in the beta cells of the islets of Langerhans in the pancreas. With each type of medication side effects are always possible. For this group of drugs the most common negative effects include: weight gain and unanticipated hypoglycemia. Furthermore, if these drugs are used extensively, they may lose their effectiveness over time.

  • Sulfonylurea group (or sulphonylurea group) – This group of drugs was the first OHAs to become publicly used. It now offers first and second generation drugs. There are several agents used here in the US and others used throughout the world:
    • Acetohexamide – first generation
    • Chlorpropamide – first generation
    • Glimepiride – second generation
    • Glipizide – second generation
    • Glyburide – second generation
    • Tolazamide – first generation
    • Tolbutamide – first generation
  • Non-sulfonylurea group – Two other drugs also act as secretagogues. They are Meglitinide and Repaglinide. They have an advantage of responding more quickly and are of shorter duration that those in the sulfonylurea group. The disadvantage of taking this type of drug is potential weight.
  • DPP-4 (dipeptidyl peptidase-4) Inhibitors – This is a relatively new class of medications with members including:
    • Linagliptin
    • Saxagliptin
    • Sitagliptin
    • Vildagliptin

This group of medication acts to reduce blood sugar in two ways: by by decreasing the secretion of glucagon, which raises the the output of insulin and by delaying gastric emptying. This group of medication is less likely to cause both hypoglycemia and weight gain than various other OHA medications. The major disadvantage is a rather weak effect.

Effect on glucose output and uptake: Biguanides

Several drugs fall into this category. Two, Phenformin and Buformin, have been removed from the marketplace. This is a result of their tendency to place individuals at risk of lactic acidosis. Only one other medication in this drug class is available – Metformin.

Metformin is available in both short and long acting forms. It is one of the most commonly used medications classified as an oral anti-diabetic. It has long been the drug of choice for many respected organizations and forms the basis of most type 2 diabetics medication regimen. It acts in the following specific ways:

  • By increasing the deployment of glucose in the muscle, which increases insulin sensitivity
  • By decreasing the development of glucose in the liver

Unlike others in this group of medications, Metformin does not come with some of the common OHA drug side effects. There is no tendency to gain weight, nor does the drug cause hypoglycemia. In addition, Metformin has a beneficial impact on several risk factors for cardiovascular health problems.[2] There are a few potential disadvantages: nausea, diarrhea and the interference with vitamin B12 formation.[3]

Medications to Help with the Reduction of Resistance to Insulin

Essentially there is one specific class of drugs designed to address the issue of insulin resistance. This involves the Thiazolidinediones (TZD’s).They are usually referred to as the glitazones to simplify terminology.[4] Their main focus is your muscles. Their purpose is to enhance the utilization of glucose in the cell, i.e. increase the cell’s sensitivity to insulin. At the same time, glitazones act on your liver to reduce the quantity of glucose produced here, but to a lesser effect than metformin.

Members of this group of drugs include:

  • Pioglitazone
  • Rosiglitazone (Avandia®)
  • Troglitazone (Rezulin®)

Potential issues of cardiovascular problems have resulted in the withdrawal from both rosiglitazone and troglitazone so great care is taken. Additional research is being conducted on this topic.

Oral Drugs Unrelated to Insulin

There is one additional category of commonly used drugs for diabetics. Its purpose is to reduce the rate of absorption of glucose in the small intestine. This is called an alpha-glucosidase inhibitor. There are two noted types: acarbose and miglitol.[5] This medication is an OHA, but it has relatively low effect on diabetes control. In addition, the major side effect seen is gastrointestinal upset to include diarrhea, which limits its utility in most patients.

Needle Administered Drugs Unrelated to Insulin

While many current medications for T2D are given orally, some of them that are not insulin are injected. Two major forms of this type of drug are:

  • GLP-1(Glucagon Like Peptide) analogues – members of this classification include Exenatide and Liraglutide. These drugs perform multiple actions. They include:[6]
    • The ability to increase insulin secretion – therefore they are secretagogues
    • The reduction of the appetite – an action accomplished by lengthening stomach emptying time
    • A decrease in glucagon production

While very effective in lowering blood sugar levels and reducing weight, they are sometimes considered to have a disadvantage in that you must give yourself the drug by injection. However, a newer form of exenatide has recently been approved by the FDA that is a once weekly injection, rather than twice daily as the original formulation was, and has shown significant promise in the treatment of diabetes. Exenatide has also been shown to help patients lose weight in several studies.

  • Pramlintide acetate – The brand name of this drug is Symlin. It is a rarity – a drug approved by the FDA to treat both types of diabetes. This is a synthetic drug that mimics the hormone amylin. Individuals who are prescribed this medication in conjunction with their insulin dose indicate the need for decreased insulin and a greater control of their blood glucose levels.

Upcoming New Drug Strategies

There are several new types of drug strategies on the horizon. Many are still being tested to assure they are efficient, easy to use, are capable of doing a thorough job and are free from side effects. These include drugs that:

  • Incretin-based therapies
  • Inhibit  kidney glucose reabsorption (SGLT2 inhibitors)
  • Are glucokinase activators

Conclusion

While insulin is essential to glucose control, there are a wide variety of ways to help your body use and secrete that insulin. In addition, there are other medications that do not directly act via insulin. Among the latter are two distinct types. One addresses the lack of insulin in the body. The other addresses insulin resistance. There are drugs you can inject and drugs you can take orally. Whether you require, or can even take these medications, will depend upon your type of diabetes, the disease stage and your body. The doctor will be put together a treatment plan ensuring you are using the correct medication effectively and efficiently.

References

[1] American Diabetes Association (2009). Type 2 Diabetes. Your Healthy Living Guide. Alexandria, VA: ADA.

[2] Krentz, CJ AJ; and Bailey (2005). “Oral Antidiabetic Agents: Current Role in Type 2 Diabetes Mellitus.” . Drugs, 65(3): 385-411(27).

[3] Masharani, U (2008). Diabetes DeMYSTiFieD. New York: McGraw Hill

[4] Warshaw, HS; and Pape, J (2009). Real-Life Guide To Diabetes. Alexandria, VA: ADA.

[5] Guthrie, DW; and Guthrie, RA (2003). The Diabetes Source Book. New York: McGraw Hill.

[6] Masharani, U (2008)

This article was originally published July 12, 2012 and last revision and update of it was 9/10/2015.