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Module 2. Identifying Oral Agents Used to Treat Diabetes

Introduction

Diabetes management requires a multifaceted approach, with the goals of management to prevent complications and improve the patient’s quality of life. The progression of diabetes is associated with many comorbid conditions, including but not limited to hypertension, hypercholesterolemia, cardiovascular disease, retinopathy, diabetic kidney disease, neuropathy, non-alcoholic fatty liver disease, gum disease, hearing loss, erectile dysfunction, and depression.1

The 2 main sets of treatment guidelines are published by the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE). In 2018, the ADA released full guidelines, and AACE issued an update to the comprehensive type 2 diabetes management algorithm. Table 1-1 illustrates the glycemic targets of each guideline. It is important to note that both guidelines recommend individualized targets depending on several patient factors. A more stringent target (< 6.5%) may be recommended for individuals that have a short diabetes duration, long life expectancy, type 2 diabetes treated with lifestyle or metformin only and no significant cardiovascular complications. A less stringent target (< 8%) would be appropriate for patients that have a severe hypoglycemia history, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbidities, or long-term diabetes in whom general A1C targets are difficult to attain.2,4 As an example, an elderly individual with kidney disease and neuropathy may be prone to falls from hypoglycemia. This patient would benefit from a less stringent A1C goal of < 8%. All therapy decisions need to come from the health care team after evaluation of the patient as a whole. In general, once an agent is added to the patient’s regimen, the A1C should be re-evaluated in about 3 months. If that number is still not at goal, another agent should be added. In cases where a patient's A1C is high at diagnosis, both guidelines recommend initiating treatment with dual therapy. AACE recommends dual therapy when baseline A1C is greater than 7.5%, while ADA guidelines reserve dual therapy initiation for a baseline A1C of 9% or greater.2,4

Table 1-1: Glycemic Targets of Current ADA and AACE Guidelines2,4
  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
*Note: Goals represent appropriate goals for most nonpregnant adults. Goals should be individualized based on duration of diabetes, age/life expectancy, comorbid conditions, complications, hypoglycemia unawareness, etc.
ADA = American Diabetes Association; AACE = American Association of Clinical Endocrinologists; A1C = glycated hemoglobin

Lifestyle modification is the mainstay of diabetes management, but most patients will require pharmacotherapy as well. All patients with type 1 diabetes mellitus (T1DM) will require insulin therapy on diagnosis. Oral agents and other non-insulin pharmacotherapies are targeted at the management of type 2 diabetes mellitus (T2DM). However, many of those with T2DM will also require insulin therapy as their disease progresses.2 In general, when choosing pharmacotherapy for a specific patient, you must consider the medication’s place in treatment guidelines, potential adverse effects, contraindications, drug interactions, and ease of administration as well as the patient’s comorbid conditions. This course will explore the mechanisms of action, efficacy, adverse events, and contraindications of all major oral agents for the management of T2DM.

Principles of Drug Interactions

There are many factors to consider when selecting pharmacotherapy for a patient, including how the patient’s other medications and/or lifestyle may or may not complement a new diabetes medication. As this course progresses, you will be given specific information about drugs that may interact with each other; but it is also important to understand drug interactions, in general, so that you may identify potential interactions that are not specifically listed here. A complete review would reach beyond the scope of this activity.

Drug interactions may be classified as either pharmacodynamic or pharmacokinetic. Pharmacodynamic drug interactions occur when 2 separate drugs cause the same or opposing physiologic effects. For instance, if 2 hypoglycemic agents are given together, they will put the patient at an increased risk of experiencing clinical hypoglycemia. Conversely, if an individual receiving treatment with an oral hypoglycemic agent were to receive long-duration therapy with a corticosteroid, the corticosteroid could reduce the efficacy of the hypoglycemic agent because corticosteroid use may cause hyperglycemia.

Pharmacokinetic drug interactions occur when the presence of one drug results in increased or decreased levels of a co-administered drug. This happens when one drug affects the absorption, metabolism, distribution, or excretion of another. A common source of pharmacokinetic drug interactions is through inhibition or induction of enzymes in a drug’s metabolic pathway. For instance, sulfonylureas are metabolized through an enzyme called cytochrome P-450 (CYP) 2C9.3 Drug interactions may occur if another medication is given to a patient that inhibits or induces CYP 2C9. If CYP 2C9 is inhibited, then the sulfonylurea will be metabolized more slowly, leading to elevated levels of the sulfonylurea in the patient’s blood. This interaction may happen quickly. Conversely, if CYP 2C9 is induced, then the sulfonylurea will be metabolized more rapidly, leading to reduced levels of the sulfonylurea in the patient’s blood. This interaction usually takes a couple of weeks of simultaneous administration to occur because new enzymes must be transcribed and translated to increase the number of CYP 2C9 enzymes present in the patient’s body. As you proceed through this course, pay close attention to the metabolic pathways of each drug so that you may better predict which other medications may cause adverse drug interactions when co-administered.

Biguanides

Metformin, the only biguanide on the market, is the preferred first-line therapeutic option for the treatment of patients with T2DM in both the ADA and AACE guidelines.2,4 This is because there are positive data showing a reduction in all-cause mortality with metformin as well as vascular complications independent of its effect on glycemia.5 Metformin works primarily to reduce blood glucose concentrations by decreasing hepatic gluconeogenesis and increasing glucose uptake by muscle and adipose tissue.6 This is primarily accomplished through activation of the 5’-adenosine monophosphate-activated protein kinase (AMPK) pathway,7 which can result in an A1C reduction of 1% to 1.5%.8 Metformin use also has the added benefit of reducing cholesterol and triglyceride levels and may even increase high-density lipoprotein (HDL) levels.9

 Although not approved for the prevention of diabetes, metformin is listed in both ADA and AACE guidelines as a potential adjunct to lifestyle modification for patients with prediabetes.2,4 The Diabetes Prevention Program studies demonstrated that metformin reduced the development of diabetes by over 31% and resulted in an average weight loss of 4.6 lb in prediabetes patients. Weight reductions persisted for up to 10 years in patients taking metformin with minimal safety and tolerability issues.10

To minimize side effects, metformin is generally initiated at either 500 mg twice daily or 850 mg once daily to be taken with food; even lower initial doses may be warranted if adverse gastrointestinal (GI) events are a concern.9 The usual maintenance dose is 500 to 1000 mg twice daily.11 Renal function should be assessed prior to and periodically during metformin therapy. Inititiation of therapy is not recommended for patients with a baseline estimated glomerular filtratration rate (eGFR) of 30-45 mL/min/1.73 m2. If a patient's eGFR falls below 45 mL/min/1.73 m2 during therapy, an assessment of metformin's risks and benefits is warranted. Metformin is contraindicated in patients with an eGFR below 30 mL/minute/1.73 m2 at any time.9 These renal function guidelines reflect a 2016 update to the FDA-approved labeling for metformin as a result of research that indicated the drug was safer than previously thought in mild to moderate renal impairment.9,12 The changes have expanded the population of patients who are eligible for metformin therapy. 

Metformin carries a black box warning related to the risk of lactic acidosis, though a Cochrane review of 347 studies found no difference in risk between metformin therapy and either placebo or non-biguanide therapies.13 Although lactic acidosis is rare with metformin,  renal impairment, advanced age, radiological contrast dye, hypoxic states (e.g., acute congestive heart failure), hepatic impairment, and excessive alcohol increases this risk. Metformin is also known to interact with other commonly used medications such as loop diuretics and calcium channel blockers. Furosemide and nifedipine both lead to increased levels of metformin that will increase risk of side effects and cause unexpected therapeutic changes. Co-administration with cationic agents, such as dofetilide may result in altered levels of either drug.9

The most common adverse effects associated with metformin use include diarrhea, nausea, abdominal discomfort, metallic taste, flatulence, and anorexia. Diarrhea is the most common complaint and may be avoided by using an extended-release formulation. Metformin may also decrease the absorption of vitamin B12, so it may be wise to monitor B12 levels for certain patients on metformin therapy and to add vitamin supplementation to the individual’s regimen, if necessary. The risk of hypoglycemia with metformin is quite low when used as monotherapy, but the risk rises when utilized in combination with hypoglycemic agents.9 Metformin is contraindicated in people with severe renal impairment (eGFR below 30 mL/min/1.73 m2), a known hypersensitivity to metformin, or acute or chronic metabolic acidosis, including diabetic ketoacidosis (DKA).9

Sulfonylureas

Medications in this class 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 encompass glyburide (Diabeta, Glynase PresTab), glimepiride (Amaryl), and glipizide (Glucotrol). The ADA guidelines include sulfonylureas as an option in dual- or triple-therapy regimens. 4 The AACE guidelines rank sulfonylureas at the bottom of the list of included agents, suggesting caution when considering the use of such medications.2

Sulfonylureas act as potassium channel blockers on the β cells of the pancreas. This causes the cells to carry a more positive membrane potential at rest, easing the ability of the cells to depolarize. This leads to enhanced β-cell sensitivity to glucose and increased insulin secretion. These agents also appear to help normalize hepatic glucose production, improve peripheral glucose disposal, and reduce glucagon levels.14 Sulfonylureas can potentially reduce the A1C by 1% to 1.5%.8 Because these medications simply enhance the natural ability of pancreatic β cells to secrete insulin, they become less effective as diabetes progresses and pancreatic β-cell function decreases.11

Generally speaking, sulfonylureas are initiated at a low dose and slowly titrated upward based on effect and tolerability. These medications should be taken with meals. Administration on an empty stomach will increase the risk of hypoglycemia. The exception to this is glipizide which should be administered one-half hour before breakfast. Glimepiride is available as 1-, 2-, and 4-mg tablets. The usual starting dose is 1 or 2 mg once daily. The usual maintenance dose is 1 to 4 mg per day, with a maximum dose of 8 mg daily.15 The immediate-release form of glipizide is available as 5- and 10-mg tablets. The usual starting dose is 5 mg daily, though doses of 2.5 mg may be necessary to prevent hypoglycemia. The maximum dose per day is 40 mg, but individual doses should not exceed 15 mg.16 Glipizide is also available as an extended-release formulation for once-daily dosing, while glyburide is manufactured in regular and micronized formulations. The two formulations are not bioequivalent and, as such, are not therapeutically interchangeable. If a patient is switched from one formulation to the other, re-titration is necessary.17 Depending on the formulation of glyburide used and patient tolerability, the dose may range from 1.25 to 20 mg a day.8 The maximum daily dose for the micronized formulation is 12 mg.17 All second-generation sulfonylureas may be dosed once or twice daily. In general, it is safer to administer these medications in divided doses once the total daily dose reaches one-half of the maximum per-day dose.

Sulfonylureas are highly protein-bound. As such, coadministration of sulfonylureas with other highly protein-bound drugs may lead to hypoglycemia.15-17 Aspirin and propranolol both may elevate levels of glimepiride.15 Ciprofloxacin could potentiate the hypoglycemic action of glyburide.3,17 Sulfonylureas are also CYP 2C9 substrates; thus, coadministration with inhibitors or inducers of CYP 2C9 will increase or decrease the levels of sulfonylureas, respectively.3

The most common adverse effects associated with sulfonylureas are hypoglycemia and weight gain.6,11 Hypoglycemia is more common with this drug class than with many of the other oral agents that are available. Sulfonylureas should be avoided in patients with a concerning history of hypoglycemic events, especially in those with hypoglycemia unawareness. Also consider that weight gain is among the most common comorbid conditions in individuals with diabetes. Given that weight management as an especially important lifestyle modification in diabetes, considering alternative agents that are weight-neutral or promote weight loss may be wise. All sulfonylureas are contraindicated in patients with hypersensitivity to the product or who have DKA.15-17

Meglitinides

Non-sulfonylurea insulin secretagogues, or meglitinides, 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. Like sulfonylureas, these medications work by blocking potassium channels on β cells in the pancreas, simplifying the depolarization of cells and, thereby, leading to increased insulin secretion. The drugs have a more rapid onset of action and a shorter duration than sulfonylureas. For this reason, these agents are taken at mealtime to reduce postprandial blood sugar.14 Meglitinides have the potential to lower A1C by 0.5% to 1%.8

Because of their rapid onset of action, meglitinides are taken within 30 minutes of starting a meal and generally 3 times daily. If a meal is skipped then that meglitinide dose should also be skipped because taking a meglitinide on an empty stomach may result in hypoglycemia. Nateglinide is available as 60- and 120-mg tablets. The usual initiation and maintenance dose of nateglinide is 120 mg 3 times daily, although a dose of 60 mg 3 times per day may be used in patients who are close to meeting their A1C goal at initiation.18 Repaglinide is available as 0.5-, 1-, and 2-mg tablets, with the initiation dose depending on the patient’s A1C. If that number is less than 8%, the initiation dose is 0.5 mg 3 times daily; if the A1C is 8% or higher, the initiation dose is 1 or 2 mg 3 times a day. The maximum total daily dose is 16 mg.19

Nateglinide is a CYP 2C9 substrate.18 Thus, coadministration of nateglinide with inhibitors or inducers of CYP 2C9 may increase or decrease levels of nateglinide, respectively. Nateglinide is also a potential CYP 2C9 inhibitor, but no interactions with CYP 2C9 substrates have been demonstrated.18 Repaglinide is a substrate of both CYP 2C8 and 3A4. Coadministration of repaglinide with gemfibrozil causes dangerously elevated levels of repaglinide. Itraconazole, ketoconazole, trimethoprim, cyclosporine, simvastatin, clarithromycin, and deferasirox also increase repaglinide levels, though not as much as gemfibrozil does. Repaglinide concentrations are decreased by coadministration with rifampin.19

The most common adverse events are hypoglycemia and weight gain.6 Thus, like sulfonylureas, these medications would not be ideal choices for those with concerning hypoglycemia or obesity. Meglitinides are contraindicated for use in patients with hypersensitivity to the product, T1DM, or DKA.18,19 Additionally, repaglinide is contraindicated for coadministration with gemfibrozil.19

Thiazolidinediones (TZDs)

Medications in this class are pioglitazone (Actos) and rosiglitazone (Avandia), listed in the ADA guidelines as options in dual- or triple-therapy regimens. 4 The AACE guidelines list TZDs as first-line agents, but they are given low preference and the guidelines recommend caution when prescribing these medications.2

The TZDs are considered insulin sensitizers, meaning that they enhance the responsiveness of adipose and muscle tissues to the action of insulin. This is primarily facilitated by interaction of TZDs with peroxisome proliferator-activated receptor-γ (PPAR-γ). Activation of this receptor results in increased transcription of a glucose transporter called GLUT-4. The increased number of GLUT-4 transporters on the cell surface results in increased glucose uptake by these cells in response to insulin,20 which can result in an A1C reduction of 1% to 1.5%.8 Because the mechanism of action relies on the transcription of new transporters, the maximal glycemic effects of the TZDs may not be seen for 4 to 8 weeks. Interaction of these agents with the PPAR family of receptors also provides the beneficial effects of raising HDL levels and lowering triglycerides.21 This positive effect on the lipid profile became a subject for debate when it was announced that rosiglitazone was associated with an increased risk of myocardial infarction (MI).22 These findings led to the institution of a risk evaluation and mitigation strategy (REMS), which severely restricted the distribution of rosiglitazone-containing products.23 Subsequent study, however, has confirmed that there is no increased risk of MI with rosiglitazone use and the dispensing restrictions were lifted, although phase 4 monitoring was still required of the drug manufacturer and up-to-date teaching materials were still necessitated for clinician education.24 The REMS program was removed entirely in December 201525 Pioglitazone has been associated with an elevated risk of bladder cancer, though results of epidemological studies and controlled trials have been mixed. The FDA warns against use of pioglitazone in patients with active bladder cancer and advises caution in patients with a history of bladder cancer.26

Pioglitazone is available as 15-, 30-, and 45-mg tablets and is typically initiated at a dose of 15 or 30 mg once daily. The maximum dose per day is 45 mg, for most patients, or 15 mg for those taking strong CYP 2C8 inhibitors such as gemfibrozil.27 Rosiglitazone is available as 2-, 4-, and 8-mg tablets and is customarily initiated at a dose of 4 mg daily. The maximum dose per day is 8 mg.28

Both pioglitazone and rosiglitazone are substrates of CYP 2C8. Thus, coadministration of either medication with inducers (e.g., phenobarbital) or inhibitors (e.g., gemfibrozil) of CYP 2C8 will decrease or increase levels of the TZD, respectively.27,28

The most commonly reported adverse effects associated with TZD therapy are weight gain and edema.6,11,20 Consider the weight-gain potential of any drug used to treat diabetes prior to prescribing it. Weight loss and maintenance are quite important for glycemic control as well as management of many other comorbid conditions. Medications that are weight-neutral or promote weight loss should be preferable to those agents that cause weight gain in patients with diabetes. There have also been postmarketing reports linking TZD use to macular edema and an increased risk of fractures. TZDs are contraindicated in patients with New York Heart Association (NYHA) class III or IV heart failure or hypersensitivity to the product.27,28 Although these drugs are not contraindicated for use in individuals with NYHA class I or II heart failure, clinicians should carefully weigh the risks and benefits of TZDs in this patient population. Those with NYHA class I or II heart failure may still experience edema, which may be worsened by the administration of TZDs. For this reason, the manufacturer of pioglitazone recommends that the lowest possible initiation dose (15 mg) be used in these patients.27 It would be logical to extend this same precaution to rosiglitazone-containing products in people with NYHA class I or II heart failure.

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

Medications in this class are sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina), which are another option for use in dual- and triple-therpy in the ADA guidelines.4 The AACE guidelines list DPP-4 inhibitors as first-line agents and they are fourth in order of preference.2 These medications work by inhibiting the DPP-4 enzyme that is responsible for the degradation of the endogenous incretins gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), hormones acting to increase insulin secretion, decrease glucagon secretion, slow gastric emptying, and increase satiety.6,29 The end result is a potential reduction in A1C of 0.5% to 1%.8

Sitagliptin is available as 25-, 50-, and 100-mg tablets. The initiation and maintenance dose for most adults is 100 mg once daily, but that should be reduced to 50 mg per day in patients with a creatinine clearance (CrCl) of from 30 to 50 mL/min and 25 mg daily in patients with a CrCl of less than 30 mL/min.30 Saxagliptin is available as 2.5- and 5-mg tablets. The initiation and maintenance dose may be either 2.5 or 5 mg once daily and should not exceed 2.5 mg a day in patients with a CrCl of less than 50 mL/min.31 Alogliptin is available as 6.25-, 12.5-, and 25-mg tablets. The initiation and maintenance dose for most adults is 25 mg once daily and should be reduced to 12.5 mg daily for patients with a CrCl 30 to 60 mL/min and to 6.25 mg once per day for those with a CrCl of less than 30 mL/min.32 Linagliptin is available in 5-mg tablets, with an initiation and maintenance dose of 5 mg once daily. It is the only medication in this class that does not require dose adjustment for those with renal impairment.33 All medications in this class can be taken with or without food. Importantly, if any of these agents are added to the regimen of a patient currently taking an insulin secretagogue (sulfonylurea or meglitinide), the dose of the insulin secretagogue may have to be lowered significantly to reduce the risk of hypoglycemia.30-33

Sitagliptin coadministration with digoxin results in increased digoxin levels, so monitoring of the digoxin level may be necessary.30 Saxagliptin is a substrate of CYP 3A4/5. Coadministration with strong CYP 3A4/5 inhibitors will increase the concentration of saxagliptin. It is recommended that the dose of saxagliptin be limited to 2.5 mg daily for patients taking strong CYP 3A4/5 inhibitors.31 It is also logical that strong inducers of CYP 3A4/5 would decrease saxagliptin concentrations, though specific interactions have not been identified. Linagliptin is a substrate of P-glycoprotein pumps (P-gp) and CYP 3A4. Concurrent administration with strong inducers (e.g., rifampin) will decrease levels of linagliptin.33 Also logical is that strong inhibitors of P-gp and/or CYP 3A4 tend to increase concentrations of linagliptin. No clinically meaningful drug interaction with alogliptin has been identified.32 Given the mutual effects of DPP-4 inhibitors and GLP-1 receptor antagonists on the incretin system, drugs from the two classes should not be used in combination with each other.

These agents are generally well-tolerated, but adverse events may include headache, nasopharyngitis, and hypoglycemia, though the risk of hypoglycemia is relatively low with these medications.11,30-33 There have been some reports of pancreatitis associated with the use of DPP-4 inhibitors, but causality has not been demonstrated.11 The only contraindication to employing DPP-4 inhibitors is hypersensitivity to the product.30-33 These agents are weight-neutral, making a DPP-4 inhibitor a compelling choice for patients who are overweight or obese. When considering the addition of a DPP-4 inhibitor to a person’s regimen, also give thought to the patient’s renal function as well as the anticipated A1C lowering effect.

Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2)

Medications in this class are dapagliflozin (Farxiga), canagliflozin (Invokana), and empagliflozin (Jardiance), all of which are considered options in dual- and triple-therapy regimens in the ADA guidelines.4 The AACE guidelines list SGLT2 inhibitors as first-line drugs, and they are third in order of preference.2 They work by reducing reabsorption of glucose in the kidney, which results in greater urinary excretion of glucose.34 These agents can reduce the A1C by 0.5% to 1%.8 They also may promote weight loss, increase HDL, and decrease blood pressure.35

The ADA guidelines note that canagliflozin and empagliflozin are two of three antidiabetes drugs that have shown a cardiovascular benefit in patients with T2DM and existing cardiovascular disease. As a result, these two drugs, along with GLP-1 receptor agonist liraglutide, are preferred options for dual therapy with metformin in patients with comorbid diabetes and cardiovascular disease.4

Dapagliflozin is available as 5- and 10-mg tablets, with an initiation dose of 5 mg daily in the morning, with or without food. The maximum dose is 10 mg once per day. Dapagliflozin should not be used in patients with an eGFR of less than 60 mL/min/1.73 m2 as it will not be effective.36 Canagliflozin is available in 100- and 300-mg tablets. The initiation dose is 100 mg once daily before the day’s first meal. The maximum dose is 300 mg once daily for patients with an eGFR of greater than 60 mL/min/1.73 m2 and 100 mg once a day for individuals with an eGFR of 45 to 60 mL/min/1.73 m2. This agent should not be used in patients with an eGFR of less than 45 mL/min/1.73 m2 because it will likely be ineffective.37 Empagliflozin is available as 10- and 25-mg tablets, with the initiation dose of 10 mg once daily in the morning, with or without food. The maximum dose is 25 mg once a day. Empagliflozin should not be used in patients with an eGFR of less than 45 mL/min/1.73 m2 because it will not be efficacious.38

Dapagliflozin is a weak substrate of P-gp, so levels of this drug may be affected by strong inhibitors or inducers of P-gp. In addition, dapagliflozin levels may be reduced by coadministration with rifampin and increased by combining it with mefenamic acid.36 Likewise, cangliflozin levels may be lessened by coadministration with rifampin or other inducers. Canagliflozin may increase levels of digoxin, potentially leading to digoxin toxicity, so increased monitoring of digoxin levels is recommended.37 Empagliflozin has not demonstrated any meaningful pharmacokinetic drug interactions at this time.38 All SGLT2 inhibitors may reduce blood pressure (BP).36-38 Therefore, doses of BP medications, especially diuretics, may have to be decreased when an SGLT2 inhibitor is initiated.

The most commonly reported adverse effects associated with SGLT2 inhibitors are urinary tract infections (UTIs) and female genital mycotic infections caused by increased glucose in the kidneys. They are contraindicated for use in patients with hypersensitivity to the product or severe renal impairment or end-stage renal disease.36-38 Dapagliflozin has also been associated with an increased risk of bladder cancer and should be avoided in people with a history of bladder cancer.36 The U.S. Food and Drug Administration (FDA) issued a safety announcement in December 2015 warning patients and providers about an increased risk of ketoacidosis and serious, potentially life-threatening UTIs associated with SGLT2 inhibitors. Be sure to advise patients taking SGLT2 inhibitors of the symptoms of ketoacidosis and UTIs so they know when to seek medical attention. Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing. UTI symptoms include a feeling of burning when urinating, increased frequency or urgency of urination, lower abdominal or pelvic pain, fever, or blood in the urine. The FDA is now requiring that manufacturers of these medications conduct a 5-year pharmacovigilance study to collect additional information on the link between SGLT2 inhibitors and ketoacidosis.39

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. They work by inhibiting glucosidase, an enzyme located in the small intestine. This enzyme breaks down polysaccharides and disaccharides into absorbable monosaccharides such as glucose,40 resulting in potential A1C reductions of 0.5% to 1%.

Both are available as 25-, 50-, and 100-mg tablets. The recommended initiation dose for both agents is 25 mg dosed 3 times daily with meals; but patients who experience intolerable GI side effects may benefit from an even lower initiation dose of 25 mg once per day. As tolerated, and as necessary for glycemic control, the dose may be increased to a maximum of 100 mg 3 times daily with meals.40,41 The maximum dose of acarbose is lowered to 50 mg 3 times a day for individuals who weigh less than 132 lb (60 kg). This is traceable to the risk of elevated serum transaminase (AST and ALT) in these patients.40

Since these agents work by delaying the absorption of glucose, it is possible that they will also slow the absorption of other drugs during coadministration. For instance, both acarbose and miglitol have been shown to reduce levels of digoxin after they are used in tandem. Appropriate monitoring and dose adjustment of digoxin may be necessary. In addition, the effect of alpha-glucosidase inhibitors may be lessened by coadministration with adsorbents, such as charcoal or digestive enzyme preparations.40,41

The most common adverse events are flatulence, diarrhea, and abdominal bloating, which may be minimized by initiating at a low dose and titrating upward slowly.6,11 Hypoglycemia risk is low, but if it occurs in a patient taking an alpha-glucosidase inhibitor, the episode must be treated with glucose (e.g., glucose tablets), not sucrose (e.g., table sugar) because alpha-glucosidase is not available to convert other sugars to the rapidly absorbable glucose. Both agents are contraindicated in those with hypersensitivity to the product, DKA, inflammatory bowel disease, or other chronic intestinal diseases affecting digestion or absorption, or conditions that may deteriorate as the result of gas formation in the intestine.40,41 These medications are not commonly used because of the burdensome side-effect profile and relatively minor effect on A1C. Alpha-glucosidase inhibitors may still be beneficial for some patients, but consider the expected A1C reduction and weigh that against the person’s quality of life while taking the medication.

Colesevelam

Colesevelam (Welchol) is a bile acid sequestrant that is listed as a second-line agent in the AACE guidelines, but given low preference.2 The medication is not included in the ADA treatment algorithm. It is thought to work by reducing hepatic glucose production, increasing incretin levels, and decreasing glucose absorption in the GI tract.6 This particular agent reportedly lowers A1C by 0.5% to 1%.8 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. The initiation and maintenance dose is 3.75 g once daily or in 2 divided doses.42

Colesevelam may reduce the absorption of some other drugs, including other oral hypoglycemic medications. The manufacturer recommends taking other medications 4 hours before colesevelam. The drug may also cause increased levels of metformin when coadministered with extended-release formulations.42

The most common adverse effects are constipation, nausea, and elevated triglycerides.6 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.42 The use of colesevelam for the treatment of diabetes has been quite limited, perhaps because of the high pill burden, the large size of the tablets, and the comparatively minor effect on A1C.

Bromocriptine

Bromocriptine (Cycloset) is a dopamine receptor agonist. It is listed as a second-line agent in the AACE guidelines, but it is given low preference.2 This formulation is not interchangeable with Parlodel or its generic bromocriptine formulations. The agent is not included in the ADA-guidelines treatment algorithm and it is unclear how bromocriptine improves glycemic control. The drug is thought to act centrally to regulate metabolism and increase insulin sensitivity6 and it lowers A1C by 0.5% to 1%.8 Bromocriptine is available as 0.8-mg tablets for glycemic control, with an initial dose of 0.8 mg daily. That dose is increased weekly by 1 tablet per day to the maximum tolerated dose of between 1.6 and 4.8 mg a day in the morning.43

Bromocriptine is highly protein-bound. Therefore, coadministration with other highly protein-bound drugs may result in elevated levels of those drugs. Combining this medication with ergot derivatives may reduce the effectiveness of these drugs while increasing such side effects as nausea, vomiting, and fatigue. The manufacturer recommends not using ergot derivatives within 6 hours of bromocriptine, which is metabolized by CYP 3A4. Thusly, coadministration with inducers or inhibitors of CYP 3A4 will decrease or increase levels of bromocriptine, respectively. In addition, the concurrent taking of bromocriptine with sympathomimetic drugs may result in hypertension and tachycardia, so simultaneous use should be limited and not exceed 10 days’ duration.43

The most common negative side effects are dizziness, syncope, and nausea.6 Bromocriptine should be recommended with food to help reduce the adverse GI events. The agent is contraindicated in patients with hypersensitivity to the product or syncopal migraines, as well as in women who are nursing.43 In practice, the use of bromocriptine to improve glycemic control is very limited because there are many more effective options available.

Conclusion

There are many oral agents currently available in the U.S. marketplace to help manage diabetes. Choosing the appropriate therapy for a specific patient may feel like a daunting task, but there are 2 major sets of treatment guidelines to turn to for help. The ADA and the AACE have both recently released updated treatment guidelines. Metformin is the first-line agent in each set of guidelines and is a good place to start for all patients with T2DM.1,2 The ADA suggests adding any one of the available agents, depending on patient and drug characteristics, in dual- and triple-therapy regimens while the AACE lists an order of preference for first-line agents as well as combinations.. Keep in mind that no matter which medications a patient may use to help manage diabetes, all of them are considered to be adjuncts to diet and exercise. Lifestyle modification is really the key to success in managing diabetes.

When choosing medication therapy for a specific patient, it is important to consider the individual as a whole. Diabetes cannot be managed in isolation from the patient’s other disease states and special consideration should be given to comorbid diabetes and cardiovascular disease. One must consider a medication’s place in the treatment guidelines, adverse effects, contraindications, drug interactions, and ease of administration as well as the patient's personal preferences. Remember that most oral agents will reduce a patient’s A1C by less than 1%; so if a person requires significant A1C reduction, combination therapy or
therapy with injectable medications may be necessary. Under the care of a multidisciplinary, collaborative treatment team, including effective counseling from pharmacists, patients can successfully manage their diabetes and prevent unnecessary complications.

Potential Counseling Tips for Pharmacists
Category Potential Counseling Tips
Disease State Knowledge
  • Diabetes is associated with many other disease states and symptoms, including eye conditions, high blood pressure, high cholesterol, heart disease, kidney disease, fatty liver disease, and gum disease, as well as weakness, numbness, or pain in the hands and feet, hearing loss, erectile dysfunction, and depression.
  • Lifestyle modifications, such as diet and exercise, are key to successfully managing diabetes.21
Proper Follow-up and Care for People With Diabetes
  • If you are started on a new diabetes medication, your glycosylated hemoglobin (A1C) should be re-evaluated in about 3 months. If your A1C is not at goal, a second medication may be added.2
The Pharmacist's Role in Diabetes Care
  • When helping a prescriber decide which diabetes medication is best for a patient, it is important to consider national treatment guidelines, potential adverse effects, contraindications (or reasons a particular drug may not be the best choice for your patient), drug interactions, and ease of use, as well as the specific comorbidities of the patient. Completing a CMR for patients with diabetes is particularly helpful when attempting to identify potential issues and when developing solutions.
Medication tips
  • Metformin should be taken with food to prevent stomach problems. Let your pharmacist know if the medication gives you adverse effects, such as diarrhea, because a change in formulation can help alleviate symptoms as they occur (e.g., to extended release).9
  • Sulfonylureas and metaglinides should generally be taken with meals to prevent low blood sugars.18
  • Maximal effects of the thiazolidinediones may not present for up to 8 weeks. Let your pharmacist know if you experience water retention while on these medications.21
  • If you are taking a drug in the SGLT-2 class, let your pharmacist or physician know if you develop a feeling of burning when urinating, increased frequency or urgency of urination, lower abdominal or pelvic pain, fever, or blood in the urine or if you have nausea, vomiting, abdominal pain, tiredness, or trouble breathing.36,37
  • If you are taking acarbose or migitol, let your pharmacist or physician know if you are experiencing flatulence, diarrhea, or abdominal bloating because these symptoms can often go away by changing the dose.41
  • Colesevelam should be taken with meals.42

Update 5/2018

SGLT-2 INHIBITORS

In late 2017, the FDA approved a new SGLT-2 inhibitor, ertugliflozin (Steglatro). Similar to other SGLT-2 inhibitors, ertugliflozin reduces A1C by 0.5% to 1%.1 The new medication is available in 5 mg and 15 mg tablets and is recommended for initiation at 5 mg once daily, taken in the morning with or without food. The dose can be increased to 15 mg as tolerated and needed for glycemic control.1

The most common adverse reactions associated with ertugliflozin are female genital mycotic infections. Other warnings include an increased risk of hypotension, ketoacidosis, acute kidney injury, lower limb amputation, and increases in LDL cholesterol. Ertugliflozin is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 and is not recommended in patients with an eGFR between 30 and 60 mL/min/1.73 m2.1

No clinically relevant drug interactions have been identified for ertugliflozin.1 As with all diabetes medications, caution should be exercised when adding ertugliflozin to any regimen containing a hypoglycemia-associated agent.

Since the initial approval of canagliflozin in 2013, the FDA has issued multiple drug safety communications related to SGLT-2 inhibitors. All now carry a warning about the increased risk of acute kidney injury. Risk factors for this adverse effect include decreased blood volume; chronic kidney insufficiency; congestive heart failure; and taking other medications that affect the kidneys (e.g., blood pressure medications and non-steroidal anti-inflammatory drugs).2 In post-marketing studies, canagliflozin has also demonstrated an increased risk of bone fractures and an increased risk of foot and leg amputation.3,4 Canagliflozin now carries a black-box warning related to amputations, and all SGLT-2 inhibitors carry a precaution related to fractures in patients with renal impairment. Studies have not yet demonstrated these adverse effects as class effects for SGLT-2 inhibitors.

DPP-4 INHIBITORS

The FDA has issued two safety communications related to DPP-4 inhibitors.5,6 All available DPP-4 inhibitors now carry a warning related to joint pain that can be severe and disabling.5 This warning was based on 33 cases of severe arthralgia reported to the FDA over a period of about 7 years as well as 7 published case reports. Reports indicated that joint pain was typically relieved in less than a month following discontinuation of the DPP-4 inhibitor.5

A warning has also been added to the labels of saxagliptin and alogliptin related to an increased risk of heart failure, particularly in patients with existing heart or kidney disease.6 The FDA reviewed two large cardiovascular outcomes trials in patients with heart disease. The saxagliptin trial found that 3.5% of patients in the saxagliptin group were hospitalized for heart failure compared to 2.8% of patients in the placebo group. Similarly, the alogliptin trial found that 3.9% of alogliptin patients were hospitalized for heart failure compared to 3.3% of placebo patients.6

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. Pharmacists should be aware of the individual components of each combination product and ensure that patients are not over-prescribed any one active ingredient.

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).

References
1. Steglatro [package insert]. Whitehouse Station, NJ: Merck and Co., Inc.; 2017.
2. U.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.
3. U.S. Food and Drug Administration. FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density. Retrieved from https://www.fda.gov/Drugs/DrugSafety/ucm461449.htm. Accessed May 19, 2018.
4. U.S. Food and Drug Administration. FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). Retrieved from https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm. Accessed May 19, 2018.
5. U.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.
6. U.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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