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Drug Treatment of Diabetes Mellitus

By Erika F. Brutsaert, MD, Assistant Professor;Attending Physician, Albert Einstein College of Medicine;Montefiore Medical Center

(See also Diabetes Mellitus.)

Many people with diabetes require drugs to lower blood glucose levels, relieve symptoms, and prevent complications.

There are two types of diabetes mellitus, type 1 and type 2.

General treatment of type 1 diabetes requires lifestyle changes, including healthy diet and exercise. People with type 1 diabetes require insulin injections and frequent monitoring of fingerstick glucose levels.

General treatment of type 2 diabetes also requires lifestyle changes, including weight loss, healthy diet, and exercise. A few people with type 2 diabetes can control blood glucose levels with only diet and exercise, but most people require drugs to lower blood glucose levels, sometimes including insulin. People who take drugs for type 2 diabetes often need to monitor fingerstick glucose daily to several times daily.

Doctors must be careful when treating diabetes with drugs because insulin and many of the drugs given by mouth can make blood glucose levels too low (hypoglycemia).

Insulin Replacement Therapy

People with type 1 diabetes almost always require insulin therapy and will become very sick without it. Many people with type 2 diabetes require insulin as well. Usually, insulin is injected into the skin. For certain people, inhaled insulin is also available, although it is not used commonly. Insulin currently cannot be taken by mouth because insulin is destroyed in the stomach. New forms of insulin, such as forms that can be taken by mouth, are being tested.

Insulin is injected under the skin into the fat layer, usually in the arm, thigh, or abdomen. Small syringes with very thin needles make the injections nearly painless.

An insulin pen, which contains a cartridge that holds the insulin, is a convenient way for many people to carry and use insulin, especially for people who take several injections a day outside the home.

Another device is an insulin pump, which pumps insulin continuously from a reservoir through a small needle left in the skin. The rate of insulin administration can be adjusted depending on the time of day, whether the person is exercising, or other parameters. People can release additional doses of insulin as needed for meals or to correct high blood glucose levels. The pump more closely mimics the way the body normally produces insulin. Pump therapy is considered in some people who require more than three injections per day. For some people, the pump offers an added degree of control, whereas others find wearing the pump inconvenient or develop sores at the needle site.

A new device, a hybrid closed-loop insulin delivery system is now available. With this system (sometimes called an artificial pancreas), an algorithm is used to calculate and automatically deliver baseline insulin doses through an insulin pump based on input from a continuous glucose monitor. However, this device does not completely eliminate the need for people to monitor their blood glucose levels and give themselves additional insulin before meals.

Insulin forms

Insulin is available in four basic forms, divided by speed of onset and duration of action:

  • Rapid-acting insulin includes lispro, aspart, and glulisine insulins. They are the fastest of all, reaching maximum activity in about 1 hour and working for 3 to 5 hours. Rapid acting insulins are injected at the beginning of a meal.

  • Short-acting insulin, such as regular insulin, begins acting slightly more slowly and lasts longer than rapid-acting insulin. Regular insulin reaches its maximum activity in 2 to 4 hours and works for 6 to 8 hours. It is injected 30 minutes before eating a meal.

  • Intermediate-acting insulin, such as neutral protamine Hagedorn (NPH) or U-500 insulin, starts to work within 0.5 to 2 hours, reaches its maximum activity in 4 to 12 hours, and works for 13 to 26 hours depending on which intermediate-acting insulin is used. This type of insulin may be used in the morning to provide coverage for the first part of the day or in the evening to provide coverage during the night.

  • Long-acting insulin, such as insulin glargine, insulin detemir, U-300 insulin glargine or insulin degludec, has very little effect during the first few hours but provides coverage for 20 to 40 hours depending on which of these types is used.

Both rapid-acting insulin and short-acting insulin are often used by people who take several daily injections and need extra insulin for meals.

Some combinations of insulin are available already mixed. In addition, concentrated insulins are available for people who require high doses of insulin.

Inhaled insulin is available for use in some situations for people who are unable or unwilling to take insulin injections. Inhaled insulin is available as an inhaler (similar to an asthma inhaler), and people inhale the insulin into the lungs for absorption. Inhaled insulin works similar to short-acting insulin and needs to be taken several times per day. People also need to take injections of long-acting insulin. While people are using inhaled insulin, doctors check their lung function every 6 to 12 months.

Insulin preparations are stable at room temperature for up to 1 month, allowing them to be carried, brought to work, or taken on a trip. Insulin should not, however, be exposed to extreme temperatures and should be refrigerated if being stored for longer than 1 month.

Choice of insulin type and dose

The choice of insulin is complex. Doctors consider the following factors when deciding which insulin is best and how much insulin to use:

  • How well the body responds to the insulin it makes

  • How much the blood glucose level rises after meals

  • Whether other antihyperglycemic drugs can be used instead of insulin

  • How willing and able people are to monitor their blood glucose levels and adjust their insulin dosage

  • How often people are willing to inject insulin

  • How varied daily activity is

  • How likely a person is to have symptoms of hypoglycemia

Doctors sometimes have people combine two insulins—a rapid-acting and an intermediate-acting insulin—in one morning dose. A second injection of one insulin or both may be taken at dinner or at bedtime.

Some people take the same amount of insulin every day. Other people, especially people with type 1 diabetes, need to adjust the insulin dose, especially doses taken around mealtime, depending on their diet, exercise, and blood glucose patterns. In addition, insulin needs may change if people gain or lose weight or experience emotional stress or illness, especially infection.

One adjustable regimen involves injecting a long-acting insulin in the morning or evening along with several additional injections of rapid-acting insulin during the day with meals Adjustments are made as insulin needs change. Measuring blood glucose levels at various times during the day helps determine the adjustment. This regimen requires people to have a lot of knowledge about diabetes to pay close attention to the details of their treatment.

Hypoglycemia

The most common complication of insulin treatment is low blood glucose levels (hypoglycemia). Hypoglycemia occurs more often as people try to strictly control blood glucose levels.

Symptoms of mild or moderate hypoglycemia include headache, sweating, palpitations, light-headedness, blurred vision, agitation, and confusion. Symptoms of more severe hypoglycemia include seizures and loss of consciousness. In older people, hypoglycemia may cause stroke-like symptoms.

People who have frequent hypoglycemia may be unaware of hypoglycemic episodes because they no longer experience symptoms (hypoglycemia unawareness).

Doctors teach people how to recognize symptoms of hypoglycemia and how to treat these symptoms. Usually, a person can eat something sweet such as candy or juice to raise their blood glucose level quickly. People may also carry glucose tablets to take in the event of hypoglycemia. Because people with hypoglycemia may be too confused to recognize they are hypoglycemic, it is important for other members of their household to be familiar with signs of hypoglycemia.

Insulin antibodies

In very rare cases, the body produces antibodies to injected insulin because injected insulin is not exactly like the insulin the body manufactures. Although this reaction is less common with newer insulin preparations, these antibodies may interfere with the insulin’s activity, requiring very large doses.

Allergic reaction to insulin

Insulin injections can affect the skin and underlying tissues. An allergic reaction, which occurs rarely, causes pain and burning, followed by redness, itchiness, and swelling around the injection site for several hours. Very rarely, a person may have an anaphylactic reaction after injection of insulin.

Skin reactions to insulin

Insulin injections may cause fat deposits, making the skin look lumpy, or destroy fat, causing indentation of the skin. Although this skin reaction is not an allergic reaction, it can decrease the absorption of injected insulin. It is, therefore, important to rotate the injection sites, for example, using the thigh one day, the stomach another, and an arm the next, to avoid these problems.

Oral Antihyperglycemic Drugs

Oral antihyperglycemic drugs can often lower blood glucose levels adequately in people with type 2 diabetes. However, they are not effective in type 1 diabetes. There are several types, but oral antihyperglycemic drugs work in 4 major ways.

  • Insulin secretagogues, which stimulate the pancreas to produce more insulin

  • Insulin sensitizers, which do not affect the release of insulin but increase the body’s response to it

  • Drugs that delay absorption of glucose by the intestine

  • Drugs that increase glucose excretion in the urine

Insulin secretagogues include sulfonylureas (for example, glyburide) and meglitinides (for example, repaglinide).

Insulin sensitizers include biguanides (for example, metformin) and thiazolidinediones (for example, pioglitazone).

Drugs that delay absorption of glucose by the intestine include alpha-glucosidase inhibitors (for example, acarbose and miglitol).

Drugs that increase glucose secretion in the urine include sodium-glucose co-transporter-2 (SGLT2) inhibitors (for example, canagliflozin, dapagliflozin, and empagliflozin).

Dipeptidyl peptidase-4 (DPP 4) inhibitors (for example, sitagliptin, saxagliptin, linagliptin, and alogliptin) both stimulate the pancreas to produce more insulin and delay the absorption of glucose by the intestine. These drugs work by increasing glucagon-like peptide 1 (GLP).

People with type 2 diabetes are often prescribed oral antihyperglycemic drugs if diet and exercise fail to lower the levels of glucose in the blood adequately. The drugs are sometimes taken only once a day, in the morning, although some people need two or three doses. More than one type of oral drug, and/ or an oral drug plus insulin or an injectable glucagon-like peptide 1 (GLP-1) drug, may be used if one drug is not adequate.

Oral Antihyperglycemic Drugs

Drug

Number of Doses

Some Side Effects

Biguanides

All biguanides can cause

  • Diarrhea

  • Increased acidity of body fluids (rare

  • Liver failure (rare)

Metformin

2 to 3 per day

Extended-release metformin

1 to 2 per day

Sulfonylureas

All sulfonylureas can cause

  • Weight gain

  • Low blood glucose levels

Possibly increase the risk of death due to cardiovascular complications

Acetohexamide

1 per day

Diarrhea

Nausea

Fluid retention (edema)

Chlorpropamide

1 per day

Low sodium in blood

Glimepiride

1 per day

Dizziness

Headache

Glipizide

1 to 2 per day

Diarrhea

Nausea

Low blood count (anemia)

Glipizide, extended release

1 per day

Diarrhea

Nausea

Glyburide

1 to 2 per day

Indigestion

Micronized glyburide

1 to 2 per day

Indigestion

Tolazamide

1 to 2 per day

Nausea

Vomiting

Tolbutamide

1 to 2 per day

Headache

Low blood count

Meglitinides

All meglitinides can cause

  • Low blood glucose levels

Nateglinide

3 per day

Minimal weight gain

Repaglinide

3 per day

Thiazolidinediones

All thiazolidinediones can cause

  • Weight gain

  • Fluid retention (edema)

  • Increased risk of fractures

Pioglitazone

1 per day

Rosiglitazone

1 to 2 per day

Possible increase in heart attacks

Alpha-glucosidase inhibitors

All alpha-glucosidase inhibitors can cause

  • Diarrhea

  • Abdominal pain

  • Bloating

  • Gas

Acarbose

3 per day

Miglitol

3 per day

Dipeptidyl peptidase-4 inhibitors

All dipeptidyl peptidase-4 inhibitors can cause

  • Headache

  • Upper respiratory infection

  • Increased risk of inflammation of the pancreas (pancreatitis)

Alogliptin

1 per day

Joint pain

Linagliptin

1 per day

Diarrhea

Saxagliptin

1 per day

Joint pain

Sitagliptin

1 per day

Diarrhea

Joint pain

Sodium-glucose co-transporter-2 (SGLT2) inhibitors

All sodium-glucose co-transporter-2 (SGLT2) inhibitors can

  • Increase urination

  • Cause dizziness

  • Increase the risk of fungal infections of the genitals and urinary tract infections

SGLT2 inhibitors may possibly

Canagliflozin

1 per day

Increased risk of amputations (rare)

Dapagliflozin

1 per day

Empagliflozin

1 per day

Injectable Antihyperglycemic Drugs

Insulin is the most commonly used injectable antihyperglycemic drug. Its use is discussed above.

There are two other types of injectable antihyperglycemic drugs:

  • Glucagon-like peptide 1 (GLP-1) drugs

  • Amylin-like drugs

Injectable antihyperglycemic drugs are given together with other antihyperglycemic drugs.

Glucagon-like peptide drugs (GLP-1 drugs) work mainly by increasing insulin secretion by the pancreas. These drugs also slow the passage of food out of the stomach (which slows the rise of blood glucose), and reduce appetite and promote weight loss. GLP-1 drugs are given by injection. The most common side effects are nausea and vomiting. These drugs may increase the risk of pancreatitis (a painful inflammation of the pancreas), although the evidence is unclear. They should not be used in people with a personal or family history of medullary thyroid cancer, because studies in animals showed an increased risk of some types of thyroid tumors. So far, these types of cancers have not been shown to be increased in humans.

Amylin-like drugs mimic the action of amylin, a pancreatic hormone that helps regulate blood glucose levels after eating. Pramlintide is currently the only available amylin-like drug. It suppresses secretion of the hormone glucagon. Because glucagon increases blood glucose, pramlintide thus helps lower blood glucose. It also slows the passage of food out of the stomach and helps people feel full. It is given by injection and is used in combination with mealtime insulin in people with type 1 or type 2 diabetes.

Injectable Antihyperglycemic Drugs*

Drug

Number of Doses

Some Side Effects

Glucagon-like peptide drugs

All glucagon-like peptide drugs can cause

  • Nausea

  • Vomiting

  • Diarrhea

They may also increase the risk of inflammation of the pancreas (pancreatitis) and some types of thyroid cancer

Albiglutide

1 per week

Dulaglutide

1 per week

Exenatide

2 per day

Kidney damage (rare)

Extended release exenatide

1 per week

Injection site nodule

Liraglutide

1 per day

Amylin-like drug

Pramlintide

3 per day

Nausea

Low blood glucose levels

* Insulin is the most commonly used injectable antihyperglycemic drug.

Other Drugs Given to People With Diabetes

Because people with diabetes mellitus are at risk of complications, such as heart attacks and strokes, it is important that people take drugs to prevent or treat these complications. Unless there is a reason people cannot take one of these drugs (for example, an allergy to the drug), they may be given the following:

  • Angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs): For people with diabetes and high blood pressure or chronic kidney disease

  • Aspirin: For people with diabetes and risk factors for cardiovascular disease

  • Statins: For most people with diabetes

More Information

Resources In This Article

Drugs Mentioned In This Article

  • Generic Name
    Select Brand Names
  • No US brand name
  • AVANDIA
  • PRANDIN
  • SYMLIN
  • TANZEUM
  • GLUCOTROL
  • NESINA
  • DIABETA, GLYNASE
  • ACTOS
  • TRULICITY
  • PRECOSE
  • FARXIGA
  • ONGLYZA
  • DIABINESE
  • JANUVIA
  • TRADJENTA
  • AMARYL
  • GLYSET
  • BYETTA
  • GLUCOPHAGE
  • STARLIX
  • VICTOZA