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Module 2. Drug Classes to Treat Diabetes: Oral Agents

DEFINITIONS

A1C: Abbreviation for hemoglobin A1C or glycosylated hemoglobin, an estimate of the average blood glucose concentration over a 2- to 3-month period. A blood test for A1C can be used to diagnose diabetes and to evaluate control of diabetes. A normal A1C is less than 5.7%; prediabetes is an A1C of 5.7 to 6.4%; diabetes is diagnosed when repeated A1C measures are greater than 6.5%.

DKA: Abbreviation for diabetic ketoacidosis. When the body does not product enough insulin, it breaks down fat as fuel. This produces a buildup of acids called ketones in the bloodstream leading to ketoacidosis. Symptoms include thirst, frequent urination, nausea, vomiting, abdominal pain, weakness, fatigue, shortness of breath, fruity-scented breath, and confusion.

Hypoglycemia: Low blood sugar, typically a glucose level less than 70 mg/dL. If left untreated, severe hypoglycemia can lead to fainting, coma, and even death. Symptoms include dizziness, confusion, hunger, thirst, nausea, sweating, and rapid heartbeat. Some diabetes patients show no symptoms of hypoglycemia, a condition called hypoglycemia unawareness.

Lifestyle management: Nonpharmacologic interventions to lower blood glucose and prevent diabetes complications. Lifestyle management includes nutrition education, physical activity, smoking cessation, and psychosocial interventions.

INTRODUCTION

Diabetes management requires a multifaceted approach. With no known cure, the goals of diabetes management are to prevent complications and improve the patient’s quality of life. The progression of diabetes is associated with many conditions, including hypertension, hypercholesterolemia, cardiovascular disease, retinopathy, diabetic kidney disease, neuropathy, non-alcoholic fatty liver disease, gum disease, hearing loss, erectile dysfunction, and depression.1

The main diabetes treatment guidelines are published by the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE). Both sets of guidelines are updated regularly.2,3 Table 1-1 illustrates the glycemic targets of each guideline. Despite these general goals of therapy, the guidelines recommend individualized targets based on several patient factors. A more stringent A1C target (< 6.5%) may be recommended for individuals that have a short diabetes duration, long life expectancy, type 2 diabetes treated with lifestyle management or metformin only, and no significant cardiovascular complications. A less stringent A1C target (< 8%) would be appropriate for patients who have a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbidities, or long-term diabetes in whom general A1C targets are difficult to attain.2,3 In general, A1C is reevaluated about 3 months after each change in therapy. If the A1C is not at goal, another agent is added. In cases where a patient's A1C is high at diagnosis, both guidelines recommend initiating treatment with dual therapy, using two medications rather than one.2,3

Table 1-1: Glycemic Targets of ADA and AACE Guidelines2,3
ADA AACE  
A1C < 7% ≤ 6.5%
Fasting plasma glucose 80 – 130 mg/dL < 110 mg/dL
2-h postprandial glucose < 180 mg/dL < 140 mg/dL

Lifestyle management is the mainstay of diabetes management, but most patients also require medication. All patients with type 1 diabetes mellitus (T1DM) require insulin therapy. In some instances, patients with T1DM use additional medications, including oral agents, to help their bodies use insulin effectively. The use of oral agents for patients with T1DM is outside the scope of this module. Oral agents and other non-insulin pharmacotherapies are primarily targeted at the management of type 2 diabetes mellitus (T2DM). However, many of those with T2DM will require insulin therapy as their disease progresses.2 This course will explore the mechanisms of action, efficacy, adverse events, and contraindications of all major oral agents for the management of T2DM.

BIGUANIDES

Metformin (Fortamet, Glucophage, Glucophage XR, Glumetza, Riomet) is the only biguanide on the market and is the preferred first-line therapeutic option for the treatment of patients with T2DM in both the ADA and AACE guidelines.2,3 Studies show that metformin reduces all-cause mortality and cardiovascular complications independent of its effect on hyperglycemia.4 Metformin works primarily to reduce blood glucose concentrations by decreasing the production of glucose by the liver and increasing the uptake of glucose by muscle and adipose tissue.5 Metformin typically reduces A1C by 1% to 1.5%.6

The usual maintenance dose of metformin is 500 to 1000 mg twice daily.7 To minimize side effects, metformin is initiated at either 500 mg twice daily or 850 mg once daily with food. Lower initial doses may be used if adverse gastrointestinal (GI) events are a concern.8 The most common adverse effects associated with metformin include diarrhea, nausea, abdominal discomfort, metallic taste, flatulence, and anorexia.8 Patients complaining of GI effects from metformin should be referred to a pharmacist or physician, as these effects may be mitigated by use of an extended-release formulation.8 The risk of hypoglycemia with metformin is quite low when used alone.8 Metformin is contraindicated in people with severe renal impairment, a known hypersensitivity to metformin, or acute or chronic metabolic acidosis, including diabetic ketoacidosis (DKA).8

Although not approved for the prevention of diabetes, metformin is listed in both the ADA and AACE guidelines as a potential adjunct to lifestyle management for patients with prediabetes.2,3

SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITORS

Medications in the SGLT2 inhibitor class are dapagliflozin (Farxiga), canagliflozin (Invokana), empagliflozin (Jardiance), and ertugliflozin (Steglatro). The ADA guidelines include SGLT2 inhibitors as an option to add to metformin in dual- and triple-therapy regimens.3 The AACE guidelines list SGLT2 inhibitors as first-line drugs and third in order of preference (after metformin and injectable GLP-1 receptor agonists).2 SGLT2 inhibitors work in the kidney to cause greater urinary excretion of glucose.9 These agents can reduce A1C by 0.5% to 1%.6 They also may promote weight loss, increase HDL (“good” cholesterol), and decrease blood pressure.10

The ADA guidelines note that canagliflozin and empagliflozin have shown a cardiovascular benefit in patients with T2DM and existing cardiovascular disease. As a result, these two medications, along with the injectable drug liraglutide, are preferred options for dual therapy with metformin in patients with both diabetes and cardiovascular disease.3

Dapagliflozin is available as 5- and 10-mg tablets, with a maximum dose of 10 mg once per day with or without food.11 Canagliflozin is available in 100- and 300-mg tablets, with a maximum dose of 300 mg once daily before the day’s first meal.12 Empagliflozin is available as 10- and 25-mg tablets, with a maximum dose of 25 mg once a day with or without food.13 Ertugliflozin is available in 5- and 15-mg tablets, with a maximum dose of 15 mg each morning with or without food.14 All SGLT-2 inhibitors require lower initiation doses and dose adjustments in renal impairment.11–14

The most commonly reported adverse effects associated with SGLT2 inhibitors are urinary tract infections (UTIs) and female genital mycotic infections.11–14 Since their initial release, multiple safety bulletins have been released related to SGLT2 inhibitors, including warnings of increased risk of DKA, serious UTIs, and acute kidney injury as well as a precaution related to bone fractures in patients with renal impairment.15–17 Canagliflozin has a warning related to increased risk of foot and leg amputations.18 Dapagliflozin has been associated with an increased risk of bladder cancer and should be avoided in people with a history of bladder cancer.11 Research related to these serious warnings is still ongoing. All SGLT2 inhibitors are contraindicated for use in patients with hypersensitivity to the product, severe renal impairment, or dialysis.11–14

DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS

DPP-4 inhibitors include sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina). These drugs are another option for dual- and triple-therapy in the ADA guidelines.3 The AACE guidelines list DPP-4 inhibitors as first-line agents and fourth in order of preference.2

These medications stop DPP-4 enzymes from breaking down incretin hormones called gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Incretins increase insulin secretion, decrease glucagon secretion, slow gastric emptying, and increase the feeling of fullness.5,19 Thus, by preventing incretin degradation, DPP-4 inhibitors improve glycemic control, with a potential reduction in A1C of 0.5% to 1%.6

Sitagliptin is available as 25-, 50-, and 100-mg tablets. The dose for most adults is 100 mg once daily.20 Saxagliptin is available as 2.5- and 5-mg tablets and is dosed once daily.21 Alogliptin is available as 6.25-, 12.5-, and 25-mg tablets, and the dose for most adults is 25 mg once daily.22 Doses of sitagliptin, saxagliptin, and alogliptin are all reduced in patients with renal impairment.20–22 Linagliptin is available in 5-mg tablets and is dosed once daily.23 It is the only medication in this class that does not require adjustment for those with renal impairment.23

All DPP-4 inhibitors can be taken with or without food. They are generally well-tolerated and do not affect weight. Adverse events may include headache, nasopharyngitis, and hypoglycemia, though the risk of hypoglycemia is relatively low.7,20–23 Rare but serious side effects of DPP-4 inhibitors include joint pain that can be severe and disabling and pancreatitis.7,24 Saxagliptin and alogliptin also carry a warning related to an increased risk of heart failure.25 The only contraindication to DPP-4 inhibitors is hypersensitivity to the product.20–23

SULFONYLUREAS

Sulfonylureas are divided into first- and second-generation agents, of which the second-generation agents are used almost exclusively. First-generation sulfonylureas include chlorpropamide (Diabinese), tolazamide (Tolinase), and tolbutamide (Orinase). Second-generation agents are glyburide (Diabeta, Glynase PresTab), glimepiride (Amaryl), and glipizide (Glucotrol). The ADA guidelines include sulfonylureas as an option in dual- or triple-therapy regimens.3 The AACE guidelines rank sulfonylureas at the bottom of the list of included agents, suggesting caution when considering their use.2

Sulfonylureas are insulin secretagogues — medications that prompt cells in the pancreas to produce more insulin. They can potentially reduce the A1C by 1% to 1.5%.6 However, because sulfonylureas rely on the natural ability of pancreas, they become less effective as diabetes progresses and pancreatic function decreases.7

Generally speaking, sulfonylureas are initiated at a low dose and slowly titrated upward. These medications should be taken with meals because administration on an empty stomach increases the risk of hypoglycemia.26,27 The exception to this is glipizide, which should be administered 30 minutes before breakfast.28 All second-generation sulfonylureas may be dosed once or twice daily.26–28 Glipizide is available in immediate-release and extended-release formulations. Glyburide is manufactured in regular and micronized formulations. Different formulations are not interchangeable, so care should be taken to ensure the correct formulation is dispensed.

The most common adverse effects associated with sulfonylureas are hypoglycemia and weight gain.5,7 Hypoglycemia is more common with this drug class than with many other oral diabetes agents. All sulfonylureas are contraindicated in patients with T1DM, DKA, or hypersensitivity to the product.26–28

MEGLITINIDES

Meglitinides are non-sulfonylurea insulin secretagogues and include repaglinide (Prandin) and nateglinide (Starlix). These agents are included primarily as an alternative to sulfonylureas in the ADA and AACE guidelines and carry the same cautions and contraindications.2,3 Meglitinides have the potential to lower A1C by 0.5% to 1%.6 Meglitinides are taken within 30 minutes of starting a meal and generally 3 times daily.7 Like sulfonylureas, the most common adverse events for meglitinides are hypoglycemia and weight gain.5

THIAZOLIDINEDIONES (TZDS)

The TZDs are pioglitazone (Actos) and rosiglitazone (Avandia). They are listed in the ADA guidelines as an option in dual- or triple-therapy regimens.3 The AACE guidelines list TZDs as first-line agents, but they are given low preference and caution is recommended in their prescribing.2

The TZDs are considered insulin sensitizers, meaning that they enhance the responsiveness of adipose and muscle tissues to the action of insulin.7 This effect can result in an A1C reduction of 1% to 1.5%, but the full effects of TZDs may not be seen for 4 to 8 weeks after initiation.6

Pioglitazone is available as 15-, 30-, and 45-mg tablets. It is typically initiated at a dose of 15 or 30 mg once daily, with a maximum daily dose of 45 mg for most patients.29 Rosiglitazone is available as 2-, 4-, and 8-mg tablets. It is typically initiated at a dose of 4 mg daily, with a maximum daily dose of 8 mg.30

The most commonly reported adverse effects associated with TZD therapy are weight gain and edema.5,7 TZDs are contraindicated in patients with moderate to severe heart failure or hypersensitivity to the product.29,30

ALPHA-GLUCOSIDASE INHIBITORS

Alpha-glucosidase inhibitors include acarbose (Precose) and miglitol (Glyset); both of which are listed as first-line agents in the AACE guidelines but given low preference.2 These drugs are not included in the ADA treatment algorithm.3 They work by inhibiting glucosidase, an enzyme in the small intestine that breaks down complex molecules into absorbable sugars such as glucose.31 Alpha-glucosidase inhibitors offer a potential A1C reduction of 0.5% to 1%.6

Both medications are available as 25-, 50-, and 100-mg tablets. They are initiated at low doses and may be increased to a maximum of 100 mg 3 times daily with meals.31,32 The most common adverse events are flatulence, diarrhea, and abdominal bloating, which may be minimized by slow dose titration.5,7 Both agents are contraindicated in those with hypersensitivity to the product, DKA, inflammatory bowel disease, or other chronic intestinal diseases.31,32 These medications are not commonly used because of the burdensome side-effect profile and relatively minor effect on A1C.

COLESEVELAM

Colesevelam (Welchol) belongs to a class of cholesterol-reducing medications called bile acid sequestrants. It is listed as a second-line agent with low preference in the AACE guidelines and is not included in the ADA treatment algorithm.2,3 In diabetes, colesevelam is thought to work by reducing hepatic glucose production, increasing incretin levels, and decreasing glucose absorption in the GI tract.5 Colesevelam reportedly lowers A1C by 0.5% to 1%.6 Colesevelam is available as 625-mg tablets or as 3.75-g packets for reconstitution as a suspension in water, fruit juice, or a soft drink. Regardless of dosage form, colesevelam should be taken with meals.33 Because colesevelam may reduce the absorption of other drugs, the manufacturer recommends taking other medications 4 hours before colesevelam.33

The most common adverse effects are constipation, nausea, and elevated triglycerides.5 The drug is contraindicated in patients with a history of bowel obstruction, serum triglycerides greater than 500 mg/dL, or a history of hypertriglyceridemia-induced pancreatitis.33 The use of colesevelam in diabetes has been quite limited.

BROMOCRIPTINE

Bromocriptine (Cycloset) is a dopamine receptor agonist. It is listed as a second-line agent with low preference in the AACE guidelines and is not included in the ADA treatment algorithm.2,3 The Cyclocet formulation for diabetes is not interchangeable with the anti-Parkinson agent Parlodel or its generic bromocriptine formulations. Bromocriptine lowers A1C by 0.5% to 1%, but it is unclear what mechanism results in improved glycemic control.6 Bromocriptine is available as 0.8-mg tablets for glycemic control.34

The most common side effects of bromocriptine are dizziness, syncope, and nausea.5 Bromocriptine should be taken with food to help reduce GI effects. The agent is contraindicated in patients with hypersensitivity to the product or syncopal migraines, as well as in women who are nursing.34 The use of bromocriptine in diabetes is very limited.

COMBINATION THERAPY

Given the emphasis of the ADA and AACE guidelines on dual- and triple-therapy regimens, numerous products containing fixed-dose combinations of oral diabetes medications are now available. Technicians should be aware of the individual components of each combination product.

As the first-line agent, metformin has become a common component in combination products, including metformin with alogliptin (Kazano), linagliptin (Jentadueto), saxagliptin (Kobiglyze), sitagliptin (Janumet), canagliflozin (Invokamet), dapagliflozin (Xigduo), empagliflozin (Synjardy), pioglitazone (Actoplus Met), rosiglitazone (Avandamet), glipizide, glyburide (Glucovance), or repaglinide (PrandiMet). Many of these products are also available as extended-release formulations to allow for less frequent dosing. Combinations of SGLT-2 inhibitors and DPP-4 inhibitors have also been released, including dapagliflozin/saxagliptin (Qtern), empagliflozin/linagliptin (Glyxambi), and ertugliflozin/sitagliptin (Steglujan).

CONCLUSION

There are many oral agents currently available to help manage diabetes. The ADA and AACE guidelines establish goals of therapy and guide the selection of medications based on patient-specific factors. Metformin is the first-line agent in both sets of guidelines.2,4 The ADA suggests adding any of the available agents in dual- and triple-therapy regimens, while the AACE lists an order of preference for first-line agents as well as combinations. All diabetes medications are considered adjuncts to lifestyle management. Most individual oral agents will reduce a patient’s A1C by about 0.5% to 1.5%. When significant A1C reduction is necessary, the combination of medications from different classes, including injectable medications, may be necessary for optimal control.

Pharmacy technicians can assist the pharmacist in the care of patients with diabetes by ensuring that the prescribed oral medications are correctly dispensed and by identifying patients who require referral to a physician or pharmacist for therapy adjustment, adherence assessment, or medication counseling. Asking open-ended questions can help the technician determine if a pharmacist consultation is necessary. For example:

  • What did the doctor tell you about this medication?
  • How do you feel since you began taking this medication?
  • How often do you forget or skip doses of this medication?

REFERENCES

  1. Centers for Disease Control and National diabetes statistics report, 2014: Estimates of diabetes and its burden in the United States. 2014.
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  3. American Diabetes Association. Standards of medical care in diabetes—2018. Diabetes Care. 2018;41(suppl 1):S1-S153.
  4. United Kingdom Prospective Diabetes Study Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK prospective diabetes study (UKPDS) group. Lancet. 1998;352(9131):854-865.
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  10. Monami M, Nardini C, Mannucci Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2014;16(5):457-466.
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  14. Steglatro [package insert]. Whitehouse Station, NJ: Merck and Co., Inc.; 2017.
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  16. S. Food and Drug Administration. FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). Retrieved from https://www.fda.gov/Drugs/DrugSafety/ucm505860.htm. Accessed May 19, 2018.
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  23. Tradjenta [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, ;2015.
  24. S. Food and Drug Administration. FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain. Retrieved from https://www.fda.gov/Drugs/DrugSafety/ucm459579.htm. Accessed May 19, 2018.
  25. S. Food and Drug Administration. FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin. Retrieved from https://www.fda.gov/Drugs/DrugSafety/ucm486096.htm. Accessed May 19, 2018.
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  30. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline;2014.
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  33. Welchol [package insert]. Parsippany, NJ: Daiichi Sankyo, ;2014.
  34. Cycloset [package insert]. Tiverton, RI: VeroScience, ;2015.