agents that cause reductions in circulating blood glucose.
Diabetes mellitus (DM)
a disorder of metabolism that results in elevated blood glucose levels, most often related to insufficient insulin production, inability of the cells to react to circulating insulin, or a combination of both. (Diabetes mellitus—“sugar” diabetes—is not to be confused with diabetes insipidus, a condition associated with lack of the pituitary hormone vasopressin.)
Estimated average glucose (eAG)
an estimate of blood glucose levels over an 8–12-week period that is calculated from the percentage value of hemoglobin A1C, but reported in the same units (mg/dL) as most regularly recorded blood glucose readings.
Fasting plasma glucose level (FPG)
concentration of glucose (sugar) in the bloodstream 8 or more hours after the last meal or snack. Levels <100 mg/dL are considered “normal,” while two recorded levels >126 support a diagnosis of diabetes mellitus.
impaired glucose metabolism related to pregnancy.
related to blood glucose levels.
blood protein used as an indicator of average blood sugar levels over the preceding 8–12 weeks. Frequently referred to simply as “A1C,” levels are reported as a percent.
higher than normal levels of circulating glucose (sugar) in the bloodstream.
lower than normal levels of circulating glucose (sugar) in the bloodstream.
decrease in the ability of cells to react to circulating insulin.
Type 1 diabetes
disease resulting from the cessation of insulin production, most often caused by the destruction of the pancreatic beta cells by a process in which the patient’s own immune system reacts against them.
Type 2 diabetes
form of diabetes in which patients generally still produce some insulin, but it is insufficient to regulate their blood sugar levels, either because they are producing smaller amounts, or because their cells have developed an insensitivity to this hormone (or even a combination of reduced production and reduced sensitivity).
After completing this chapter, you should be able to
Define the following:
Diabetes mellitus, type 1 and type 2
Outline the physiology of normal carbohydrate metabolism and the role of pancreatic hormones.
List the causes and results of diabetes mellitus.
Describe nonpharmacologic treatments for diabetes mellitus.
Review the therapeutic effects of insulin and other medications used in the treatment of diabetes and list their most common side effects and adverse reactions.
State the brand and generic names of the medications most widely used to treat diabetes, along with their routes of administration and dosage forms.
Recognize common regimens for the treatment of diabetes mellitus.
All human body processes require energy. Most of the energy used in these processes comes from the metabolism of glucose, a sugar. To function properly, the human body requires a constant level of glucose in the tissues and bloodstream—high enough to provide for the energy needs of the cells but below the level where unwanted effects will occur.
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.
The pancreas, illustrated in Figure 10-1, is a body organ with endocrine (hormone-secreting) functions. Among its major hormones are insulin and glucagon, both of which are important in glucose metabolism. Insulin, produced by the beta cells in sections of the pancreas known as the islets of Langerhans, is the hormone that allows glucose to enter body cells to be used for the energy to power cell processes. When levels of circulating glucose are too high, insulin promotes storage of the excess as glycogen. Insulin also promotes the synthesis of proteins, the building blocks of many body tissues. Glucagon is produced in the alpha cells of the islets of Langerhans. In contrast to insulin, glucagon promotes the release of glucose from stored glycogen and enables the body to produce energy from other resources. Together, these two pancreatic hormones (insulin and glucagon) are responsible for normal carbohydrate metabolism and blood glucose levels, and the body depends on the balance and interaction between them. Another pancreatic hormone, amylin, also affects blood glucose levels by inhibiting the release of glucagon, slowing stomach emptying (delaying the absorption of dietary carbohydrates) and causing feelings of fullness (inhibiting additional food intake).
Diabetes Mellitus: A Group of Metabolic Disorders
Diabetes mellitus (often abbreviated DM) is a disorder of metabolism that results in elevated blood glucose levels, usually related to insufficient insulin production, inability of the cells to react to circulating insulin, or a combination of both. It results in abnormal metabolism not only of carbohydrates but fats and proteins as well, and its most characteristic sign is increased levels of circulating glucose (sugar), known as hyperglycemia.
The defects of metabolism associated with diabetes mellitus can lead to serious, chronic complications if not controlled. These are grouped in two main categories: microvascular (affecting the small blood vessels) and macrovascular (affecting the major blood vessels). Damage to the eye is a major microvascular complication. The Centers for Disease Control and Prevention reports that diabetic retinopathy (damage to the retina, a major structure of the eye) is “the leading cause of blindness among U.S. working-aged adults aged 20–74 years.”1 Another serious microvascular complication is nephropathy, or kidney damage. About one in three adults with diabetes in the United States may have chronic kidney disease, which can lead to end-stage renal disease (ESRD) requiring chronic dialysis or kidney transplant for survival.2 A third microvascular complication is neuropathy (nerve damage), which can result in pain or defective sensation, especially in the hands and feet, as well as digestive problems. These nerve problems can even lead to more serious conditions requiring amputation, especially of the lower extremities (feet and legs).
Macrovascular complications of diabetes can be life threatening. These include hypertension, coronary heart disease, and stroke, the primary causes of death in patients with diabetes. (These conditions are addressed in detail in Chapters 15 and 16.) The progression of many complications of diabetes, especially those classified as microvascular, is very closely linked to blood sugar control and can be avoided or slowed by careful regulation of the levels of glucose in the blood. Patients with diabetes are frequently instructed to monitor blood sugar levels before and after meals, which, when tracked over time, can provide an idea of how well their therapy is working. An even better indicator of this, however, is the level of a blood protein, hemoglobin A1C (usually abbreviated A1C). Levels of A1C indicate average blood sugar levels over the preceding 8–12 weeks and have been correlated with both the control and the level of complications of diabetes.
If Ms. Parker’s diabetes is not treated adequately, what kinds of health problems might she encounter as a result?
Most cases of diabetes mellitus are classified as either type 1 or type 2. About 5%–10% of patients with diabetes have type 1 (once known as juvenile diabetes), which is characterized by a complete lack of insulin production.3 It is thought to be caused by the destruction of the pancreatic beta cells by a process in which the patient’s own immune system reacts against them. Although it generally develops in children and young adults, type 1 diabetes can occur at any age, and may develop over several years. Hyperglycemia does not become evident until more than 80% of the beta cells are destroyed. Because their bodies are unable to produce any insulin of their own, people with type 1 diabetes must be treated with external insulin preparations to avoid or delay the complications associated with their disease.
Type 2 diabetes is the most common form of diabetes and its incidence rises with age. It is, however, increasingly being diagnosed in adolescents and younger adults.3 Patients with this form of disease generally still produce some insulin, but it is insufficient to regulate their blood sugar levels, either because they are producing smaller amounts or because their cells have developed an insensitivity to this hormone (or even a combination of reduced production and reduced sensitivity). Insulin therapy may still be useful or even necessary in type 2 diabetes, but many patients are helped by lifestyle modifications such as diet and exercise. Frequently, patients with type 2 diabetes are treated with agents to either increase insulin production or help the body respond appropriately to circulating insulin. Often, a combination of therapies is used, reflecting the combination of factors contributing to the processes involved in this disorder.
Less-common forms of diabetes account for fewer than 2% of patients diagnosed. Gestational diabetes (sometimes abbreviated GDM) is a complication of pregnancy, and the initial therapy is generally a dietary adjustment. Insulin may be used if necessary, but the oral drugs used in type 2 diabetes are not currently approved for use during pregnancy. There are other types of diabetes, caused by hormone abnormalities and imbalances, adverse drug reactions, pancreatitis, and rare genetic defects, but they are encountered even less often than gestational diabetes.
Treatment of Diabetes
While diabetes has different causes (eg, autoimmune disease, insulin resistance, pregnancy), the treatment goals for all types are a decrease in the dangerous complications described earlier and a reduction in symptoms. Macrovascular complications (hypertension, coronary heart disease, and stroke) are best addressed by managing risk factors for these conditions and treating them with both drug and nondrug therapies (see Chapters 14 and 15). The development of microvascular complications (damage to the eye, kidneys, and nerves), however, can be diminished or slowed by regulating blood sugar to keep levels consistently within normal range. These are the therapies that will be discussed in this chapter.
The term glycemic refers to the level of glucose (sugar) in the blood. Blood glucose is normally lowest in the fasting state, 8–12 hours after the most recent meal, generally 70–110 mg/dL. Higher levels can be expected after meals. Hypoglycemia refers to blood glucose below the normal level, and hyperglycemia is a blood glucose level higher than would be expected. Glycemic goals are based on the fact that maintaining blood glucose levels within the normal range has been shown to reduce microvascular complications. Various groups of medical practitioners have established slightly different definitions of what “normal” should be, but most agree that fasting levels of glucose should be below 125 mg/dL and that the levels obtained after meals (postprandial blood glucose) should not rise higher than 199 mg/dL.4 Most patients with diabetes engage in regimens of self-monitoring of blood glucose (SMBG) with varying frequency, as prescribed by their physicians. There is a wide array of SMBG equipment available for these patients, with choices in cost, features, and size. Most blood glucose meters produce readings on a digital display, and some have a memory to keep track of several consecutive levels. Some may be connected to a personal computer for detailed recordkeeping and printouts. Meters require various supplies (testing strips or solutions, etc.) and, as of this writing, SMBG generally involves testing an actual blood sample obtained by using a lancet (a small, sharp blade) to prick a finger or other place on the skin. A meter must be calibrated with a standard sample on a regular basis to ensure its accuracy. Researchers are studying less invasive ways to measure blood glucose without breaching the skin, and, while some devices to do this already exist, most are not yet considered reliable enough for exclusive use in an SMBG regimen.
While SMBG is a valuable tool for tracking day-to-day (and even hour-to-hour) blood glucose levels and is used to adjust insulin dosing for immediate regulation, the best indicator of overall long-term glycemic control is the blood protein known as hemoglobin A1C. As noted earlier, levels of A1C indicate average blood sugar levels over the preceding 8–12 weeks. A1C is measured as a percentage of overall hemoglobin, and the American Diabetes Association recommends a glycemic goal of less than 7% for most nonpregnant adults.5 Some physicians may set an even lower target, as may the guidelines from other organizations. Because SMBG readings are reported as a specific amount of blood glucose in a specific sample size (mg/dL) and A1C is reported as a percentage, it is sometimes difficult for patients and even clinicians to see the relationship between them. An additional measurement, estimated average glucose (eAG), correlates with A1C but uses the same units (mg/dL) as SMBG readings. While it is an “average,” it is NOT the average of the readings from the SMBG meter, but just a translation of A1C into a different type of unit that represents an average of glucose levels 24 hours per day over a longer period. Overall, A1C and eAG have the same meaning, and an A1C of 7% is equal to an eAG of 154 mg/dL.5
Nonpharmacologic (Nondrug) Therapy
Regardless of type, all patients diagnosed with diabetes mellitus should receive medical nutrition therapy. An individual diet plan formulated by a healthcare professional (preferably a licensed dietitian) will facilitate intake of balanced amounts of protein, fat, and carbohydrate, help the person reach or maintain a healthy weight, and contribute to reaching the glycemic goals described above. A planned activity regimen is also a vital tool in the treatment of diabetes. The goals of the activity regimen are weight loss, a healthy blood sugar level, and cardiovascular health, but the individual’s age, weight, current level of fitness, and other health conditions must be taken into account.
In some cases of type 2 diabetes or gestational diabetes, nonpharmacologic therapy may be the only initial treatment indicated. For others, it may be part of a treatment plan that also involves medications. For patients diagnosed with type 1 diabetes, nutrition and activity will always be coordinated with an insulin regimen to optimize health and promote glycemic control.
Pharmacologic Therapy: Insulin
Insulin is a hormone that governs the body’s use of nutrients. Diabetes mellitus is, primarily, a condition in which there is a deficiency of insulin production or a resistance to its actions, or a combination of these two factors. It is not surprising, therefore, that insulin therapy has been a major component of the therapy for DM. Originally, insulin was derived from beef or pork. Both types of animal-derived insulin are very similar to the insulin produced by the human body. Recombinant DNA (rDNA) technology now allows pharmaceutical manufacturers to engineer microorganisms (usually bacterial species) so that they can produce insulin identical to that secreted by the human pancreas. They can also produce insulins that differ slightly from that normally secreted in the human body and have characteristics (either longer or shorter in onset or duration of action) that make them advantageous in diabetes therapy. Because insulin is a protein that would be digested (and thus inactivated) in the gastrointestinal tract, it cannot be administered by the oral route. Currently, most insulin products are given by injection, but an inhalation is also available. (See Medication Table 10-1; Medication Tables are located at the end of the chapter).
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
No prescription is required for regular or isophane human insulin injections in the U-100 (100 units/mL) strength. The concentrated (U-500) injection and the inhalation, however, are available only when prescribed by a licensed practitioner.
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.
At the time of this writing, all analog insulins, alone or in combination, require a physician’s prescription.
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
Ms. Parker has been giving herself injections of NPH insulin twice every day. The pharmacist reminds her that she will no longer be needing the NPH insulin and notes she is only to inject the insulin glargine once daily. What is the difference between the two types of insulin?
LOOK-ALIKE/SOUND-ALIKE—Care must be exercised to avoid confusing Humalog with Humulin and NovoLog with Novolin.
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.
The insulin glargine is considerably more expensive than the NPH Ms. Parker has been using in the past and, unlike the NPH she has been purchasing, it requires a prescription from her physician. Does it have any advantages that might justify the price and inconvenience?
While insulin vials are stored in the refrigerator in the pharmacy before being dispensed, many patients keep opened vials at room temperature so they do not have to be warmed before administration. While insulin may be used until its marked expiration date if continuously refrigerated, vials stored at room temperature should not be used longer than 31 days (42 days for the Novolin products) and other dosage units (cartridges, prefilled pens, and others) are good for only 14–28 days (depending on brand and dosage form) after first use. Patients should store unopened packages in the refrigerator and carefully note the days of use printed on the packaging.
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).
Will Ms. Parker still need the regular insulin now that she will be using insulin glargine?
Many insulin mixtures have similar labels, and it is important to choose the correct vial by matching both the label names and numbers with the items and strengths ordered for the patient.
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.
Although most insulins are supplied as injections of 100 units/mL, it is important to dispense the correct strength of product for those that are available in multiple concentrations.
Patients using insulin from vials need a supply of insulin syringes to administer it. These syringes have markings that represent the dose in units (rather than a volume in milliliters).
Most insulin syringes are calibrated for use with U-100 (100 units/mL) insulin, and different ones will be needed for U-500 (500 units/mL) strength. (Insulin strengths of 200 units/mL and 300 units/mL are supplied as pen injectors and do not require syringes.)
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.
NPH insulin is a suspension and must never be chosen for IV administration.
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 circumstance 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.
Afrezza is supplied as single-dose cartridges with strengths of 4, 8, or 12 units of powder each, in perforated blister strips. The dose must be specified by the prescriber. Opened strips must be used within 3 days. The Afrezza inhaler is packaged and dispensed separately, and must be discarded and replaced with a new unit every 15 days (so patients will require at least two inhalers for a one-month supply).4
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.
Mr. Robinson’s Diabetes Medications
Stanley Robinson is a 56-year-old male who is 6 feet tall and weighs 240 lb. After a physical examination and blood tests 6 months ago, his doctor told him he has diabetes and gave him a plan for diet and exercise, along with a prescription for metformin, which he has been taking twice daily. He has lost 5 lb and today he got another blood test result showing that his A1C is 8%. He has returned to the pharmacy with a prescription for sitagliptin.
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.
Pharmacologic Therapy: Oral Agents
While injected insulin is necessary for all patients with type 1 diabetes, many people with type 2 diabetes can be treated with noninsulin medications taken by mouth if nonpharmacologic therapies (diet and exercise) are ineffective in meeting their glycemic goals. Oral diabetes medications currently available work in a variety of ways but fall into five basic categories, distinguishable by their actions, time course, and side effects.
What type of diabetes has Mr. Robinson’s physician diagnosed?
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.
While not approved by the Food and Drug Administration for any indication other than type 2 diabetes, metformin is sometimes prescribed off-label for DM type 2 prevention, gestational diabetes, and to reduce the weight gain associated with some antipsychotic agents (seeChapter 7). Its use in the treatment of women diagnosed with polycystic ovary syndrome is discussed inChapter 11.
Risk factors for lactic acidosis include renal impairment, interacting drugs, age over 65 years, radiological study with contrast, surgery, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
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.
What might be the meaning of Mr. Robinson’s A1C level of 8% after being treated with metformin for 6 months?
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.
LOOK-ALIKE/SOUND-ALIKE—Glipizide and glyburide are similar names for noninterchangeable drugs with similar dosing, and glimepiride may also be confused with these.
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.)
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.
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.
LOOK-ALIKE/SOUND-ALIKE—Actos looks and sounds like Actonel, a drug used for the treatment and prevention of osteoporosis.
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.
Rosiglitazone and pioglitazone both carry boxed warnings for congestive heart failure; rosiglitazone has as boxed warning for myocardial infarction as well. A medication guide approved by the Food and Drug Administration (FDA) must be dispensed with these medications.
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.
Patients who are self-monitoring blood glucose levels may be disappointed in their initial response to pioglitazone or rosiglitazone. If they mention the possibility of discontinuing the medication “because it is not working,” it is important to refer them to the pharmacist, their physician, or a diabetes educator for counseling on the delayed effects of these drugs.
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
For patients who are stabilized on fixed doses of two agents, combination products may be convenient.Table 10-2lists some of these combination products.
Remember that the combination products described here are fixed doses, and the dose of one component cannot be adjusted without a change in the other. This is one of the reasons that the physician must be consulted before a patient’s regimen is changed from separate tablets of each drug to a combination product.
Mr. Robinson notes that the sitagliptin is more expensive than the metformin, and asks, “Is this a better drug than the one I used to take?” What should the pharmacy technician say?
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.
The following month Mr. Robinson returns for his refills. He mentions that it is inconvenient for him to carry around “all those tablets” and asks if there is an easier way to get his therapy. What might the pharmacist suggest in a phone call to the doctor?
An FDA-approved medication guide must be provided to all patients to whom DPP-4 inhibitors are dispensed, whether alone or as part of a combination product. This guide describes the dangers of pancreatitis and heart failure related to these medications.
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
An FDA-approved medication guide must be provided to all patients to whom SGLT-2 inhibitors are dispensed, whether alone or as part of a combination product. This guide describes the signs, symptoms, and dangers of dehydration and yeast infections (and, for canagliflozin, the increased risk for lower-limb amputations) associated with these products.
If Mr. Robinson’s A1C is still high after a few months of metformin and sitagliptin therapy, what changes might his physician make in his medication regimen? Might any of these be appropriate for Ms. Parker? Why or why not?
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.
If the oral medications are the right treatment for Mr. Robinson, why does Ms. Parker have to continue with her injections?
Patients who have taken an alpha-glucosidase inhibitor and then become hypoglycemic must be treated with pure glucose either orally or by injection because the drug will prevent rapid absorption of more complex sugars like the ones found in candy or beverages.
Noninsulin Injectable Therapies
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.
Pramlintide is available as a prefilled multi-dose pen injector specific to the dose a patient is prescribed. The medication must be discarded 30 days after first use, whether refrigerated or kept at room temperature.
Pramlintide carries a boxed warning for the risk of severe hypoglycemia, which can result in serious injury. An FDA-approved medication guide emphasizing this warning must be dispensed with this medication.
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.
Liraglutide is FDA approved for use in chronic weight management (see Chapter 24), but only under the Saxenda brand name. Liraglutide for the treatment of diabetes is marketed as Victoza.
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.
An FDA-approved medication guide must be dispensed with all GLP1-RAs. Several of these agents (dulaglutide, exenatide XR, liraglutide, semaglutide) carry a boxed warning regarding thyroid T cell tumors.
While all of these agents are refrigerated before dispensing, storage conditions that must be followed by patients (before and after packages are opened for use) are specific to each product and must be followed carefully. It is important to call this information to patients’ attention at the time of dispensing.
Diabetes mellitus is a disorder related to insufficient insulin production, the inability of the cells to react to circulating insulin, or a combination of both, and results in abnormal metabolism of dietary nutrients. Its most characteristic sign is increased levels of circulating glucose, which can lead to serious and life-threatening complications. The most common types of diabetes mellitus are type 1, usually diagnosed in children and young adults and characterized by the complete lack of insulin production, and type 2, most often diagnosed in adults and characterized by lower than necessary insulin production and/or decreased sensitivity to the effects of insulin. Other types of diabetes include gestational diabetes, as well as a few even less-common forms.
Type 1 diabetes must be treated with insulin, although there are a few other medications that may be added to therapy. Type 2 diabetes can be treated with diet and exercise, oral medication, insulin, some novel injections, or, more commonly, a combination of therapies. For both types of diabetes, blood glucose levels are monitored both in the short term (with blood glucose meters) and the long term (via A1C levels), and doses are adjusted to achieve glycemic control.