Chapter 10 Diabetes Mellitus (2024)

Ms. Parker’s Insulin

Karen Parker is a 32-year-old female who is 5 feet tall and weighs 110 lb. Her type 1 diabetes was diagnosed while she was still in high school, and since she moved to town for a new job last year, she has been coming to the pharmacy counter every month to purchase NPH and regular human insulin, along with supplies for self-monitoring of blood glucose (SMBG) and insulin syringes. Today she has a prescription for an insulin glargine pen injector and has asked to speak to the pharmacist.

Types of Insulin

The standard insulin product is regular human insulin (Humulin R, Novolin R, Afrezza), a hormone identical to that produced by the healthy human pancreas. It can be administered by the subcutaneous (SUBQ), intravenous (IV), or inhaled routes of administration. It is considered a short-acting insulin, with an onset of effect 30–60 minutes after SUBQ injection and a duration of around 3–6 hours. For many years, a large number of patients with DM have “covered” their carbohydrate intake with injections of regular insulin 30 minutes before meals.

A person who does not have diabetes, however, does not have insulin secreted only around mealtime. To maintain a constant level of circulating insulin in patients with DM, formulations with a longer duration of action have been developed over the years. While you may still hear of Lente and Ultralente insulins in this context, these have not been available since 2006. One older formulation that is still available is isophane insulin suspension (Humulin N), commonly known as NPH insulin, made by complexing insulin with zinc and protamine to form an insoluble compound. It is considered intermediate acting, with an onset of 2–4 hours after SUBQ injection (the only route by which it may be administered) and a duration of 10–24 hours. Also included in the intermediate-acting classification is regular human insulin 500 units/mL (Humulin R 500).4

With rDNA technology, pharmaceutical companies have been able to engineer insulins with slight changes in the amino acid sequences that make up the insulin molecule to give them properties that make them especially useful in the treatment of DM. Because these products are similar to insulin (but slightly different), they are known as insulin analogs.

One set of analogs is a group of rapid-acting insulins. Unlike short-acting regular insulin, which must be administered at least 20–30 minutes before a meal, these insulins begin working within 15–30 minutes of SUBQ administration and continue for only 3–4 hours. The three rapid-acting analogs are insulin lispro (Humalog), insulin aspart (Fiasp, NovoLog), and insulin glulisine (Apidra). Inhaled regular human insulin (Afrezza) is also considered rapid-acting.4

The other set of analogs are long-acting insulins, which only begin to act hours after injection but may continue their effect for up to a full day and reduce the hazards of hyperglycemia (between doses) or hypoglycemia (soon after doses). Some preparations of insulin glargine (Lantus, Basaglar) have an onset 2–4 hours after administration and last for 20–24 hours, and the U-300 insulin glargine formulation (Toujeo) begins acting about 6 hours after administration, lasting up to 36 hours.4 Insulin detemir (Levemir) begins working in about 90 minutes to 4 hours and has been shown to last 16–20 hours, depending on the dose (with higher doses having a longer action). Insulin degludec (Tresiba) starts to act about an hour after injection; its effects can last up to 42 hours. Unlike the intermediate-acting NPH insulin, which requires at least two injections daily, these analogs may be injected only once a day by many patients.

Dosing of insulin is highly individualized, depending on the type of diabetes being treated, the size and health of the patient, the daily caloric needs and exercise patterns, and patient variables like insulin sensitivity and daily schedule. All patients with type 1 diabetes and some with type 2 require a basal dose of intermediate- or long-acting insulin scheduled once or twice a day, with additional doses of short- or rapid-acting insulin to control the glycemic spikes that occur with meals and snacks. This pattern is thought to mimic the natural pattern of insulin secretion. Patients whose SMBG records show a regular pattern can often use premixed combination products containing 50%–75% (50–75 units/mL) intermediate- or long-acting insulin with 25%–50% (25–50 units/mL) short- or rapid-acting insulin. These products may be NPH/regular insulin combinations (eg, Humulin 50/50, Humulin 70/30, and Novolin 70/30). Others are insulin analog combinations, including protamine lispro with unbound lispro (eg, Humalog Mix 75/25 and Humalog Mix 50/50) and protamine aspart suspension with unbound insulin aspart (eg, NovoLog Mix 70/30) (see Medication Table 10-1).

Regardless of the type or mixture, the most commonly used injectable insulin products in the United States, including all those available without prescription, have a concentration of 100 units/mL. For patients who require large doses of insulin, there are a concentrated regular human insulin product of 500 units/mL, insulin degludec injectors of 200 units/mL, and insulin glargine injectors with a 300 unit/mL strength.

Another option for maintaining insulin levels is continuous insulin therapy. For outpatients, this is generally accomplished by the use of an insulin pump (Figure 10-2), which delivers a continuous SUBQ infusion of a short- or rapid-acting insulin. The rate of infusion can be varied by patient adjustment to account for meals, snacks, and exercise as they occur and also adjusted based on SMBG readings to give an immediate remedy for any high or low values encountered. At one time, only regular insulin was used in these pumps, but insulin lispro and aspart are becoming the agents of choice for insulin pumps. The other situation in which continuous insulin therapy is indicated is for hospital inpatients who have been admitted with diabetic ketoacidosis, a life-threatening condition in which blood glucose levels are extremely high and the body’s electrolyte chemistry becomes altered as well. These patients will be treated with an IV infusion of regular insulin, which can be regulated in rate depending on regularly obtained blood glucose readings until the condition has been resolved. Only insulin solutions may be administered intravenously (because the insoluble particles in NPH insulin suspensions would endanger the patient if given through a vein), and regular insulin is usually chosen (rather than lispro, aspart, or glulisine) because, when directly infused, its action is nearly as rapid and the product itself costs much less.

A rapid-acting, noninjectable human insulin inhalation for use at mealtimes, Afrezza, can relieve patients dependent on insulin from the need for injections to control the glycemic spikes often experienced after eating. This preparation must be supplemented by a basal or long-acting insulin dose in the treatment of type 1 diabetes, but, in some cases, may be the only insulin needed for type 2 diabetes therapy.

The primary adverse effect observed with insulin therapy is hypoglycemia (low blood sugar). This can result from improper dosing, fluctuations in patient meal or exercise patterns (e.g., skipping a meal or particularly heavy workouts), or poor adherence to the prescribed SMBG regimen. Hypoglycemia symptoms may include fatigue, weakness, hunger, irritability, shaking, and/or sweats, and, if untreated, may progress to unconsciousness. Hypoglycemia in conscious patients is treated by administration of a readily available source of sugar—either a dextrose gel or solution specially designed for this circ*mstance or a high-sugar food like nondiet soda or sugary candy. The unconscious patient must receive a remedy via injection, which may be a concentrated dextrose injection or glucagon (the hormone that causes the release of the body’s stored glucose into the bloodstream). Glucagon kits that include an easy-to-reconstitute vial of glucagon with a syringe for administration should be carried by patients who receive insulin injections because hypoglycemia can be a life-threatening emergency.

The other adverse effect of insulin administration, seen much less often today than in the past when insulin products were of animal origin and not as well purified as those available today, is lipodystrophy, a change in the subcutaneous fat at sites of injection. One type, lipohypertrophy, is a raised mass of fat at an injection site where too many injections have been given. It is generally advised that injection sites be rotated, so that a variety of different sites are used and the same one is not repeated too often. This both prevents lipodystrophy and contributes to consistent insulin absorption (Figure 10-3). The other type sometimes seen is lipoatrophy, the destruction of fat at the injection site, probably caused by antibodies to the insulin product.

While insulin products do not appear to be involved in any direct drug–drug interactions, many medications are known to affect glycemic control, and patients taking these medications or changing their doses may need to adjust their insulin dosing as well.

CASE?

What type of diabetes has Mr. Robinson’s physician diagnosed?

Biguanides

Recall that an issue for many patients diagnosed with type 2 diabetes is insulin resistance, a condition in which their cells no longer respond to normal levels of circulating insulin. Biguanides have several actions, including increasing the insulin sensitivity of cells in the peripheral muscle tissues, allowing effective uptake and use of blood glucose, thus decreasing glucose levels. They have no direct effect on the pancreatic beta cells and may actually decrease levels of circulating insulin because lower levels of insulin become sufficient for the needs of treated patients. The only biguanide currently marketed in the United States is metformin, available as both brand and generic products. Dosage forms, all oral, include immediate-release (tablet, solution, suspension) and extended-release (tablet) preparations, as well as fixed-dose combination products with other agents. The immediate-release products are generally dosed twice daily, and the dose can be increased weekly until either the glycemic goal or the maximum dose (850 mg three times daily with meals) is reached. Extended-release metformin (Glucophage XR and generics) is generally begun once daily and can be increased up to a single dose of 2,000 mg/day or divided doses up to 750 mg 3 times/day.

The most common side effects of metformin involve the gastrointestinal system. Up to 30% of patients treated experience diarrhea, stomach upset, and/or abdominal discomfort, but it is usually mild and can be minimized by beginning with a low dose and slowly increasing it, taking the drug with or immediately after meals and/or using the extended-release form. Less common adverse effects include a metallic taste and vitamin B-12 deficiency. Rare, but more dangerous, is a condition called lactic acidosis, a serious electrolyte disturbance that can occur with the accumulation of metformin in the bloodstream, particularly the sustained-release dosage form. The most significant interactions reported have been with medications that may increase serum concentrations of metformin and could result in lactic acidosis. These include cimetidine and dolutegravir.

Metformin therapy can lower A1C by 1.5%–2% and fasting glucose by 60–80 mg/dL (even if they are extremely high). It has also been shown to reduce triglycerides and low density lipoprotein (LDL) cholesterol, and therapy often leads to modest weight reduction. For these reasons, along with its relatively low cost and usually tolerable side effects, metformin is usually the first medication prescribed in the treatment of type 2 diabetes.6 If glycemic targets (A1C and fasting blood glucose) have not been met in 3 months, another agent (sulfonylurea and insulin have the best validation) may be added to the treatment regimen. Sometimes metformin is added as the second drug when treatment with a sulfonylurea or thiazolidinedione (next sections) alone has been unsuccessful in meeting the target goals. For patients taking common fixed dosages of metformin with other diabetes therapies, products containing two drugs in the same tablet may be convenient. Some of these combinations are included in Medication Table 10-2.

Sulfonylureas

Medications in this group were the earliest agents devised for the oral treatment of type 2 diabetes (see Medication Table 10-2). They work mainly by increasing pancreatic insulin secretion. (They are, thus, ineffective for type 1 diabetes, a condition in which the pancreatic cells responsible for insulin production have been destroyed by an autoimmune reaction.) Sometimes these drugs are subclassified as first-generation and second-generation sulfonylureas, reflecting both the order in which they were brought to market and the increased potency (and corresponding lower dosage) of the newer agents. The first-generation agents are chlorpropamide, tolazamide, and tolbutamide. Seldom prescribed in the United States, they are generic products, and all are oral tablets. Second-generation agents include glipizide (Glucotrol), glyburide (Glynase), and glimepiride (Amaryl). These are available as both brand name and generic oral tablets, although not all products can be interchanged, especially those in extended-release (glipizide) or micronized (low-dose glyburide) forms.

Most patients treated with these drugs are able to take the full daily dose in the morning with breakfast or the first main meal of the day (although glipizide is almost always scheduled before breakfast). Doses are started low and then titrated upward every 1–2 weeks based on patient response, until either the glycemic goal or the maximum effective dose is reached. Older patients and those with decreased liver or kidney function generally receive lower doses.

As with insulin, the most common adverse effect of the sulfonylureas is hypoglycemia. This occurs more frequently in patients whose initial fasting plasma glucose is lower and in patients who lose weight, skip meals, or exercise heavily. Treatment for sulfonylurea-induced hypoglycemia is the same as that for hypoglycemia related to insulin use. Another common side effect of sulfonylurea therapy is weight gain in patients who are treated without reducing their dietary intake. The enhanced blood glucose control resulting from therapy comes from the body storing the excess glucose, and weight gain can result. Other less-common side effects of sulfonylureas include hyponatremia (decreased sodium), skin rash, hemolytic anemia (destruction of red blood cells), and gastrointestinal upset. A disulfiram reaction, resulting in nausea, vomiting, and flushing, may occur if alcohol is consumed, especially in patients taking first-generation sulfonylureas.

In general, when dosed at equivalent levels (higher doses for less potent drugs), all the drugs in the sulfonylurea class can have an equal effect on blood glucose levels, lowering A1C by 1.5%–2% and fasting glucose by 60–70 mg/dL.6 (Remember, the goals for sulfonylureas are A1C <7 and fasting glucose <130 mg/dL.) Because this is not usually enough of a reduction for most patients (who may start with an A1C of 10% or more and fasting glucose levels >250 mg/dL), few will be controlled sufficiently on a sulfonylurea alone. The drugs in this class, however, all act in the same way, so there is no reason to add an additional sulfonylurea if the patient is already taking one; instead, a drug from a different class will be added. The second-generation sulfonylureas are also available in fixed-dose combinations with other types of antihyperglycemic agents (metformin or a thiazolidinedione) for patient convenience in a multi-drug treatment regimen. (See Medication Table 10-2.)

Meglitinides

Also known as short-acting insulin secretagogues, drugs in this class are similar to sulfonylureas as they work by stimulating pancreatic insulin production, although their actions are both faster in onset and shorter in duration. Like the sulfonylureas, they are ineffective in the treatment of type 1 diabetes, where pancreatic insulin production has ceased. Currently available agents in this class include nateglinide (Starlix and generics) and repaglinide (generics only, alone or with metformin) in tablet dosage form (see Medication Table 10-2).

Meglitinides are rapidly absorbed from the gastrointestinal tract and also rapidly cleared from the body. Because of this, they must be taken just before (within 30 minutes of) each meal. If a meal is low in carbohydrates or is skipped, the dose is skipped as well. Repaglinide therapy is generally begun at a low dose and may be titrated upward toward the maximum effective dose. Nateglinide is usually ordered as 120 mg before each meal with no dosage adjustments indicated.

The most common side effect of the meglitinides is hypoglycemia, but it is less of an issue than with the sulfonylureas because, when glucose levels decrease, so do the actions of the drugs. Weight gain has also been noted in patients taking these drugs, although more significantly with repaglinide. Because meglitinides are metabolized in the liver, there is a possibility of interactions with other liver-metabolized drugs, which could result in changes in the actions of either the meglitinides or of the other drugs.

When used alone, the meglitinides do not produce as much of a reduction in A1C as the sulfonylureas. Their main use is in treating patients who are near (within 1%) their glycemic goals. While the need for multiple daily doses may be a problem for many patients, meglitinides could be advantageous for those with irregular eating patterns, since they are taken immediately prior to a meal rather than on a fixed schedule. They are not used in addition to sulfonylureas when another drug must be added to the regimen because the similarity in their mechanism of action (increased insulin production) means that there will be little likelihood of additional benefit.

Thiazolidinediones

This group of drugs causes an increase in the insulin sensitivity of muscle, liver, and fat tissues (see Medication Table 10-2). Significantly, they accomplish this by an indirect action (unlike the biguanides) and require the presence of significant amounts of circulating insulin to be effective. Drugs in this class are sometimes known as glitazones. The two thiazolidinediones marketed in the United States are pioglitazone (Actos and generics) and rosiglitazone (generics only), both oral tablets. Both drugs are begun on a once-daily schedule—pioglitazone at 15–30 mg and rosiglitazone at 4 mg—and doses can be increased slowly, balancing therapeutic goals against side effects until the target goals or the maximum doses are reached. Some studies have shown a greater benefit for rosiglitazone if the maximum dose of 8 mg is divided and given as 4 mg twice daily.

The most common adverse effects associated with the thiazolidinediones are upper respiratory tract infection, headache, sinusitis, fluid retention, and hyperglycemia. Many patients treated with these drugs experience a modest weight gain. When used with another agent (such as metformin or a sulfonylurea), they may also be associated with hypoglycemia. While much less common, the fluid retention associated with pioglitazone and rosiglitazone can aggravate or even cause congestive heart failure. For this reason, these drugs are contraindicated in patients with symptomatic or advanced stages of heart failure and should be initiated at a lower dose for patients with cardiac problems less serious than advanced heart failure.

Thiazolidinediones therapy can lower A1C by 1.5% and fasting glucose by as much as 70 mg/dL.6 These effects, however, are not immediate, and the full benefit may not be seen for as long as 3–4 months after treatment begins. These medications cause increases in high density lipoprotein (HDL—“good cholesterol”) and pioglitazone usually causes beneficial decreases in plasma triglyceride levels.

Thiazolidinediones may be used alone in the treatment of type 2 diabetes, but they are seldom considered first-line therapy and are usually used in combination with metformin or a sulfonylurea for patients who have been unable to meet their glycemic goals on a single agent.6

DPP-4 Inhibitors

Research has shown that, in addition to producing too little insulin and/or having insulin-resistant cells, patients with type 2 diabetes have lower than expected levels of a substance called glucagon-like peptide-1 (GLP-1). Dipeptidyl peptidase 4 (DPP-4) is an enzyme related to the natural degradation of GLP-1, so a substance that inhibits DPP-4 should cause an increase in the amount of circulating GLP-1, and, ultimately, result in an increase in insulin secretion after meals. That is the theory underlying the DPP-4 inhibitors, and, since it is specific to type 2 diabetes, these drugs should be used only to treat patients with this form of the disease. DPP-4 inhibitors available in the United States are alogliptin, linagliptin, saxagliptin, and sitagliptin (see Medication Table 10-2). As of this writing, alogliptin is the only DPP-4 inhibitor available as a generic product, so therapy with this group may be expensive for some patients.

DPP-4 inhibitors are usually taken once daily without regard to meals. Drugs from this class may be used alone (in conjunction with diet and exercise therapy), but, because by themselves they produce A1C reductions of less than 1%, they are usually prescribed in combination with another agent. Fixed-dose combination products containing DPP-4 inhibitors along with another agent are available for patient convenience (see examples in Medication Table 10-2).

Few patients experience adverse effects from DPP-4 inhibitors, with the most common being nasal congestion, upper respiratory tract infection, and occasional headaches. Severe joint pain and heart failure have been reported in some patients as well. Treatment with DPP-4 inhibitors has been associated with some cases of rare but severe (even fatal) pancreatitis and hypersensitivity reactions.

SGLT-2 Inhibitors

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduce circulating glucose by increasing urinary glucose excretion. While they are approved as single-agent therapy (in conjunction with diet and exercise) for improved glycemic control in type 2 diabetes, they are usually prescribed in combination with metformin or one of the other oral medications already discussed. There are four agents in this category currently available in the United States: canaglifozin, dapaglifozin, empagliflozin, and ertuglifozin; each is available alone and in combination with one or more other type 2 diabetes therapies. All of these products are brand-name only (no generics available as of this writing), so may be quite expensive for many patients.

SGLT-2 inhibitors as add-on therapy have advantages in several patient populations with conditions often seen along with type 2 diabetes. The increase in glucose excretion can contribute to weight loss and even some blood pressure reduction. Empagliflozin and canagliflozin have both been shown to reduce the risk of cardiovascular events, including myocardial infarction, stroke, and other related fatalities. They can be beneficial in patients unable to tolerate the first-line therapies described in earlier parts of this chapter.

Because SGLT-2 inhibitors act at the level of the kidney, they may be less effective in lowering plasma glucose for patients with significant renal impairment (although their cardiovascular benefits may still apply). The most common adverse effects are related to the increase in urinary glucose, including genital fungal infections and urinary tract infections, so patients receiving these agents must be alert to symptoms of these conditions, which are best treated early in their course. Other side effects, also related to the mechanism of action, include increased urinary frequency, dizziness, dehydration, or even hypotension.6

Alpha-Glucosidase Inhibitors

Medications in this group act in the small intestine by inhibiting the enzymes responsible for breaking complex sugars and carbohydrates down into glucose. This delays absorption of the glucose into the bloodstream and lowers the peak glucose level after meals of patients with diets high in complex carbohydrates (starches and sucrose). They have little effect on fasting glucose levels. Alpha-glucosidase inhibitors currently in use in the United States include acarbose (Precose and generics) and miglitol (generic only), both available as oral tablets (see Medication Table 10-2).

Medications in this class are begun at low doses with only one meal per day (to avoid side effects) and gradually increased to higher doses (based on patient weight) taken with every meal, ideally with the first bite of food. The most common adverse effects are gastrointestinal (bloating, flatulence, diarrhea), so alpha-glucosidase inhibitors is contraindicated in patients with gastrointestinal conditions such as inflammatory bowel disease. Because they depend on the kidneys for excretion, drugs from this class should not be administered to patients with more than mild renal dysfunction, either.

Alpha-glucosidase inhibitors are used only in type 2 diabetes, since they delay, rather than prevent, the absorption of glucose. This class of medications is of benefit mainly to patients who are near their glycemic goals (within 1% of their target A1C) with acceptable fasting blood sugar levels but higher than desirable levels after meals. They may be used alone, or to supplement other diabetes therapy.

Amylin Analog

Pramlintide (Symlin) is a synthetic form of the natural human hormone amylin, normally secreted by the same pancreatic cells that produce insulin. It affects blood glucose levels by inhibiting the release of glucagon, slowing stomach emptying (delaying the absorption of dietary carbohydrates), and causing feelings of fullness. Pramlintide is used only in the treatment of patients who are using insulin (for either type 1 or type 2 diabetes) and is helpful in controlling glucose levels after meals. It has been shown to produce decreases in A1C when added to insulin therapy, and it often produces weight loss (advantageous for patients seeking this effect) probably because of a reduction in food intake (due to the feelings of fullness). Pramlintide is administered by SUBQ injection just prior to each meal, and dosages vary from 15 mcg as a beginning dose for people with type 1 diabetes to a maximum of 120 mcg before each meal for type 2 diabetes. It does not replace the premeal insulin dose, although this dose may sometimes require adjustment, especially for patients whose after-meal blood glucose was near normal on insulin alone.

The most common adverse effects of pramlintide are related to its action on the gastrointestinal tract, mainly nausea in type 2 diabetes patients and vomiting and/or loss of appetite in both type 1 and type 2 patients. Usually, these effects diminish over time and can be minimized by starting with a low dose. As with many other treatments for diabetes, hypoglycemia can also occur. Because of its effects on stomach emptying, pramlintide can delay the absorption, and, thus, action, of orally administered medications. This can be avoided by scheduling other medications 1 hour before or 2 hours after a dose.

GLP-1 Receptor Agonists

Recall from the section on DPP-4 inhibitors that patients with type 2 diabetes have lower than expected levels of a substance called glucagon-like peptide-1 (GLP-1). Naturally produced (endogenous) GLP-1 stimulates insulin secretion in response to plasma glucose levels (usually in relation to meals), limits hepatic glucose output, slows gastric emptying, and increases feelings of fullness. The synthetic GLP-1 receptor agonists (GLP1-RAs) exhibit these same actions in patients to whom they are administered, ultimately resulting in the reduction of circulating plasma glucose and body weight. They may even have a protective effect on pancreatic beta cell function,6 potentially delaying disease progression in type 2 diabetes. Pharmaceutical GLP1-RAs are more resistant to the actions of the DPP-4 enzymes (described in the earlier section of this chapter on DPP-4 inhibitors) than endogenous GLP-1, so they offer sustained blood levels and therapeutic action.

There are currently five GLP1-RAs available in the United States in seven different dosage forms (see Medication Table 10-2): dulaglutide, exenatide (regular and XR), lixisenatide, liraglutide, and semaglutide (injectable and oral). Except for the oral semaglutide (Rybelsus) tablet, they are administered as subcutaneous injections. While they all act at the body’s GLP-1 receptors, the properties of these agents vary, causing differences in dose, dosing interval, actions, and side effects. Prescribers tailor treatment to individual patient needs and responses, sometimes adapting the treatment to match affordability and insurance considerations. As of this writing, the GLP1-RAs are marketed in the United States only as brand name products, with no available generics.

Exenatide (Byetta) was the first agent of this class to be approved. Its action is relatively short, and it is administered twice daily before breakfast and dinner. Exenatide XR (Bydureon) is a longer-acting formulation dosed once weekly. They cannot be interchanged for one another.

GLP1-RAs with once daily dosing are lixisenatide (Adlyxin), and liraglutide (Victoza), administered by subcutaneous injection, and oral semaglutide (Rybelsus) tablets. Weekly dosing (by subcutaneous injection) is indicated for dulaglutide (Trulicity) and injectable semaglutide (Ozempic), in addition to exenatide XR.

GLP1-RAs used in diabetes management are seldom the sole therapy for patients being treated. The once-daily agents are also available as combination injections with long-acting insulin to reduce the number of injections patients must receive. (See Medication Table 10-2.) GLP1-RAs are not used with DPP-4 inhibitors, however, as both target increased action at the GLP-1 receptor (by increasing the agonists acting there).

Some of the GLP1-RAs have been demonstrated to reduce the risk of cardiovascular events (including myocardial infarction, stroke, and related fatalities) in patients treated with them. Ongoing research may yield additional details in this area.

The most common side effects associated with agents in this class are nausea, vomiting, and diarrhea. For many patients, these tend to be more noticeable at the start of treatment, and dose adjustment reduces them. They are contraindicated in patients with chronic pancreatitis, and in those with a history of certain types of thyroid cancer.

All of the agents in this class are supplied in proprietary injectors, some single-dose and some multiple dose. Patients must receive instructions specific to the medication and dosage form prescribed.

IV = intravenous; OTC = over the counter; SUBQ = subcutaneous.