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Module 2. Drug Classes to Treat Diabetes: Oral Agents


IMPORTANT DEFINITIONS

A1C: Glycosylated hemoglobin, or hemoglobin A1C (A1C), is used to estimate how much glucose is at-tached to red blood cells. A1C is assessed with a common blood test; it is used to identify patients with diabetes mellitus and, also, to evaluate diabetes control. The result of the A1C test, which is reported as a percentage, represents the average blood glucose concentration over a 2- to 3-month period. A nor-mal result is less than 5.7%, which equates to an average blood glucose level of less than 126 mg/dL. While 5.7% is considered the upper limit of “normal,” most people with diabetes have an A1C treatment goal of less than 7.0%, although this is adjusted on the basis of individual patient factors.

Incretins: Incretins are a group of metabolic hormones produced by the body. One of their key functions is to help regulate blood glucose by increasing the amount of insulin secreted in response to a meal, de-creasing the release of insulins’ opposing hormone in the liver—glucagon, and controlling appetite by slowing gastric emptying and creating a feeling of fullness after eating.

Comorbid condition: A comorbid condition is a condition that exists simultaneously with another medical condition.


INTRODUCTION

The management of diabetes mellitus requires a multifaceted approach. Treatment is difficult, in part, because the disease has no known cure, and, therefore, the goals of management are to prevent complications and improve a patient’s quality of life. The progression of diabetes is associated with many other health issues, 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, and these must also be considered as part of diabetes management.1

Diabetes management is governed by 2 primary sets of treatment guidelines: those published by the American Diabetes Association (ADA) and those published by the American Association of Clinical Endo-crinologists (AACE). Both associations released updated guidelines in January 2016. Table 1 illustrates the glycemic targets recommended by each association. There are notable differences between the ADA and AACE guidelines, but the approaches to treatment are similar: both guidelines recommend adding medications in a stepwise manner. Treatment is largely based on glycosylated hemoglobin (also known as hemoglobin A1C [A1C]) levels and the guidelines recommend that, once an agent is added to a patient’s regimen, A1C should be evaluated after approximately 3 months. If the A1C is still not at goal, another agent should be added. In general, when choosing pharmacotherapy for a specific patient, the guidelines advise consideration of the medication’s place in the treatment guidelines, potential adverse effects, contraindications, drug interactions, and ease of administration, as well as the patient’s comorbid conditions and personal preferences. This course will explore the mechanisms of action, efficacy, adverse effects, and contraindications of single-agent oral medications for the management of type 2 diabetes mellitus (T2DM).

Table 1. Glycemic Targets Listed in 2016 American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (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
Note: Goals represent appropriate targets for most nonpregnant adults. Goals should be individualized on the basis of duration of diabetes, age/life expectancy, comorbid conditions, complications, and hypoglycemia unawareness.

A1C: glycosylated hemoglobin.

ORAL TREATMENT OPTIONS

All patients with type 1 diabetes mellitus (T1DM) will require lifelong insulin therapy. In some instances, patients with T1DM will require additional medications, including oral antidiabetic agents, to help their bodies use the insulin effectively, but the use of oral agents for patients with T1DM is outside the scope of this module. Lifestyle modifications are the mainstay of T2DM management, but most patients will also require oral agents and other non-insulin prescription medications to manage the disease. Moreover, since T2DM is a progressive disease, it is likely that patients will require additional or more intensive pharmacotherapy as the disease progresses. Many patients with T2DM will also eventually require insu-lin therapy.2

Biguanides

Metformin (Fortamet, Glucophage, Glucophage XR, Glumetza, Riomet) is the only medication in the biguanide class. It is the preferred first-line therapeutic option for the treatment of patients with T2DM in both the ADA and AACE guidelines.2,3 Metformin works primarily to reduce blood glucose levels by decreasing the formation of glucose in the liver and increasing glucose uptake by muscle and fat tissue.4 Treatment with metformin can result in an A1C reduction of 1% to 1.5%.5 Metformin use also has the added benefit of reducing low-density lipoprotein cholesterol and triglyceride levels and may even increase high-density lipoprotein (HDL) levels.6 Metformin has also been shown to reduce the risk of colorectal cancer in patients with T2DM. Further research is being conducted to determine whether met-formin reduces risks of other types of cancers for patients with diabetes.7

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 of metformin. Metformin may also decrease the absorption of vitamin B12, so monitoring of B12 levels, as well as vitamin supplementation, may be necessary for patients on metformin therapy. The risk of hypoglycemia (low blood sugar) with metformin is quite low when this medication is used alone, but the risk rises when metformin is used in combination with other medications that can lower blood sugar levels.6 Metformin is contraindicated in people with renal disease or dysfunction, a known hypersensitivity to metformin, or acute or chronic metabolic acidosis, including diabetic ketoacidosis (DKA).6

Metformin is generally initiated at either 500 mg twice daily or 850 mg once daily and it is taken with food to minimize the risk of gastrointestinal (GI) side effects. Lower initial doses may be warranted if adverse GI events are a concern.6 Metformin can be titrated to a maintenance dose of 500 to 1000 mg twice daily on the basis of patient need and tolerability.8

Sulfonylureas

Sulfonylureas are one class of insulin secretagogues—medications that prompt the pancreas to secrete more insulin. Sulfonylureas are divided into first-generation and second-generation agents. First-generation sulfonylureas include chlorpropamide (Diabinese), tolazamide (Tolinase), and tolbutamide (Orinase). Second-generation agents include glyburide (Diabeta, Glynase PresTab), glimepiride (Amaryl), and glipizide (Glucotrol). Today, second-generation agents are used almost exclusively. All sulfonylureas are considered second-line therapy in the ADA guidelines, usually as an addon to metformin therapy.3 The AACE guidelines rank sulfonylureas at the bottom of the list of recommended agents and suggest caution when considering the use of sulfonylureas.2

Sulfonylureas can potentially reduce a patient’s A1C by 1% to 1.5%.5 Because these medications simply enhance the natural ability of pancreatic beta cells to secrete insulin, they become less effective as diabetes progresses and beta cell function decreases.8

The most common adverse effects associated with sulfonylureas are hypoglycemia and weight gain.4,8 Hypoglycemia is more common with this drug class than with many of the other available oral agents. Sulfonylureas should be avoided in patients with a concerning history of hypoglycemic events. This class of medications is not indicated for patients with T1DM.

In general, sulfonylureas are initiated at low doses and slowly titrated up according to effectiveness and tolerability. These medications should be taken with meals to decrease the risk of low blood sugar; gli-pizide is the only exception, and it is given 30 minutes before breakfast. Glimepiride is available as 1-mg, 2-mg, and 4-mg tablets. The usual starting dose is 1 or 2 mg once daily. The usual maintenance dose is 1 to 4 mg daily, with a maximum daily dose of 8 mg.9 The immediate-release form of glipizide is available as 5-mg and 10-mg tablets. The usual starting dose is 5 mg daily, though doses of 2.5 mg may be neces-sary to prevent hypoglycemia. The maximum daily dose is 40 mg, but this must be divided into multiple individual doses that should not exceed 15 mg.10 Glipizide is also available as an extended-release for-mulation for once-daily dosing. Glyburide is manufactured in regular and micronized formulations, and these 2 formulations are not interchangeable. Depending on the formulation used and patient tolerability, the daily dose of glyburide may range from 1.25 to 20 mg.5 The maximum daily dose for the mi-cronized formulation is 12 mg.11

Meglitinides

Meglitinides are non-sulfonylurea insulin secretagogues. This class includes repaglinide (Prandin) and nateglinide (Starlix). These agents are not included in the ADA or AACE guidelines,2,3 but they may still be prescribed by physicians on the basis of professional judgment and experience for certain patients. The drugs have a more rapid onset and a shorter duration of action than sulfonylureas. For this reason, these agents are taken at mealtime to reduce postprandial (after-meal) blood sugars.12 Meglitinides have the potential to lower A1C by 0.5% to 1%.5

Because of their rapid onset of action, meglitinides are generally taken 3 times daily, within 30 minutes of starting a meal. If a meal is skipped, then the meglitinide dose associated with that meal should also be skipped: taking a meglitinide on an empty stomach may result in hypoglycemia. Nateglinide is available as 60-mg 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 daily may be used in a patient who is close to achieving his or her A1C goal at the time the medication is initiated.12 Repaglinide is available as 0.5-mg, 1-mg, and 2-mg tablets, with the initiation dose depending on the patient’s A1C level. If the A1C is less than 8%, repaglinide is initiated at 0.5 mg 3 times daily; if the A1C is 8% or higher, it is initiated at 1 or 2 mg 3 times daily. The maximum total daily dose is 16 mg.13

The most common adverse effects associated with meglitinides are hypoglycemia and weight gain.4 Therefore, like sulfonylureas, these medications are not ideal choices for patients with a history of concerning hypoglycemia events or obesity. Meglitinides are contraindicated for use in patients with hypersensitivity to the product, T1DM, or DKA.12,13 Additionally, repaglinide is contraindicated for coadmin-istration with gemfibrozil.13

Thiazolidinediones

Thiazolidinediones (TZDs) are insulin sensitizers, which means that they enhance the responsiveness of adipose (fat) and muscle tissues to the action of insulin. Medications in this class are pioglitazone (Actos) and rosiglitazone (Avandia), and they are considered second-line agents in the ADA guidelines.3 The AACE guidelines list TZDs as first-line agents, but they are given low preference and the guidelines rec-ommend caution when prescribing these medications.2

Pioglitazone is available as 15-mg, 30-mg, and 45-mg tablets and it is typically initiated at a dose of 15 or 30 mg once daily. The maximum daily dose is 45 mg for most patients. Rosiglitazone is available as 2-mg, 4-mg, and 8-mg tablets and it is usually initiated at a dose of 4 mg daily. The maximum daily dose is 8 mg.14 The most commonly reported adverse effects associated with TZDs are weight gain and edema.4,8

Dipeptidyl peptidase-4 inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a relatively new class of medications that includes sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina). These agents are considered second-line drugs in the ADA guidelines.3 The AACE guidelines list DPP-4 inhibitors as first-line agents and they are fourth in order of preference.2 These medications inhibit the DPP-4 enzyme, which is responsible for the breakdown of the incretin hormones—gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). GIP and GLP-1 act to increase insulin secretion, decrease glu-cagon secretion, slow gastric emptying, and decrease hunger.4,15 DPP-4 inhibitors offer a potential A1C reduction of 0.5% to 1%.5

Sitagliptin is available as 25-mg, 50-mg, and 100-mg tablets. The initiation and maintenance dose for most adults is 100 mg once daily, but the dose should be reduced to 50 mg daily in a patient with a creatinine clearance (CrCl) of 30 to 50 mL/min and to 25 mg daily in a patient with a CrCl of less than 30 mL/min.16 Saxagliptin is available as 2.5-mg and 5-mg tablets. The initiation and maintenance dose may be either 2.5 or 5 mg once daily; the daily dose should not exceed 2.5 mg daily in a patient with a CrCl of less than 50 mL/min.17 Alogliptin is available as 6.25-mg, 12.5-mg, and 25-mg tablets. The initiation and maintenance dose for most adults is 25 mg once daily; the daily dose should be reduced to 12.5 mg daily in a patient with a CrCl of 30 to 60 mL/min and to 6.25 mg daily for a patient with a CrCl of less than 30 mL/min.18 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 patients with renal impairment.33 All DPP-4 inhibitors 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 (i.e., sulfonylureas or meglitinides), the dose of the insulin secretagogue may need to be lowered significantly to reduce the risk of hypoglycemia.16-19

DPP-4 inhibitors are generally well-tolerated, but adverse effects may include headache and nasopharyngitis. Hypoglycemia may occur with this class of agents, but the risk is relatively low with these medications.8,16-19 There have been reports of pancreatitis associated with the use of DPP-4 inhibitors, but causality has not been demonstrated.8 The only contraindication to the use of DPP-4 inhibitors is hypersensitivity to the product.16-19 These agents are weight neutral, meaning they do not cause weight loss or weight gain, which compels the use of DPP-4 inhibitors for patients who are overweight or obese.

Sodium glucose cotransporter-2 inhibitors

Sodium glucose cotransporter-2 (SGLT-2) inhibitors reduce the reabsorption of glucose in the kidney, which results in greater urinary excretion of glucose.20 Medications in this class include dapagliflozin (Farxiga), canagliflozin (Invokana), and empagliflozin (Jardiance). SGLT-2 inhibitors are considered second-line agents in the ADA guidelines;3 the AACE guidelines list SGLT-2 inhibitors as first-line drugs and they are third in order of preference.2 These agents can reduce A1C by 0.5% to 1%.8 They may also promote weight loss, increase HDL, and decrease blood pressure.21

Dapagliflozin is available as 5-mg and 10-mg tablets. It is usually initiated with a dose of 5 mg once daily in the morning, with or without food. The maximum daily dose of dapagliflozin is 10 mg. Canagliflozin is available in 100-mg and 300-mg tablets. The initiation dose is 100 mg once daily before the day’s first meal. Empagliflozin is available as 10-mg and 25-mg tablets. It is usually initiated at a dose of 10 mg once daily in the morning, with or without food. The maximum daily dose of canagliflozin is 25 mg.24

The most commonly reported adverse effects associated with SGLT-2 inhibitors are urinary tract infections (UTIs) and female genital mycotic infections caused by increased glucose in the kidneys. SGLT-2 inhibitors are contraindicated for use in patients with hypersensitivity to the product, patients with severe renal impairment or end-stage renal disease, and patients on dialysis.22-24 Dapagliflozin has also been associated with an increased risk of bladder cancer and should be avoided in people with a history of bladder cancer.22 The U.S. Food and Drug Administration (FDA) issued a safety announcement in De-cember 2015 warning patients and providers about an increased risk of ketoacidosis (ketones in the blood) and serious, potentially life-threatening UTIs associated with SGLT-2 inhibitors. Patients taking SGLT-2 inhibitors should be advised 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 SGLT-2 inhibitors and ketoacidosis.25

Alpha-glucosidase inhibitors

Alpha-glucosidase inhibitors prevent the action of glucosidase, an enzyme located in the small intestine that is responsible for breaking down sugars into glucose.26 Alpha-glucosidase inhibitors—Acarbose (Precose) and miglitol (Glyset)—are listed as first-line agents in the AACE guidelines, but they are given low preference.2 These drugs are not included in the ADA guideline’s treatment algorithm.3 These agents can potentially lower A1C by 0.5% to 1%.

Acarbose and miglitol are available as 25-mg, 50-mg, and 100-mg tablets. The recommended initiation dose for both agents is 25 mg 3 times daily with meals. Patients who experience intolerable GI side ef-fects may benefit from a lower dose of 25 mg once daily. The dose may be increased to a maximum of 100 mg 3 times daily with meals, as tolerated and as necessary for glycemic control.26 The maximum dose of acarbose is lowered to 50 mg 3 times a day for individuals who weigh less than 132 lb (60 kg) due to the risk of elevated serum transaminases in these patients.26

Alpha-glucosidase inhibitors delay the absorption of glucose, so it is possible that they will also slow the absorption of other drugs if they are taken at the same time. Specifically, both acarbose and miglitol have been shown to reduce levels of digoxin if the alpha-glucosidase inhibitor is administered with digoxin; appropriate monitoring and dose adjustment of digoxin may be necessary.

The most common adverse effects of alpha-glucosidase inhibitors are flatulence, diarrhea, and ab-dominal bloating, which may be minimized by initiating the drug at a low dose and slowly titrating up.4,8 The risk of hypoglycemia is low with these drugs, but, if it occurs in a patient taking an alpha-glucosidase inhibitor, the episode must be treated with glucose (e.g., glucose tablets), not other sugars such as sucrose (e.g., table sugar), because alpha-glucosidase is not available to convert other sugars to the rapidly absorbable glucose. Both acarbose and miglitol are contraindicated in patients 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.26 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 the expected A1C reduction must be considered against a patient’s quality of life while taking the medication.

Colesevelam

Colesevelam (Welchol) is a bile acid sequestrant that is thought to work by reducing hepatic glucose production, increasing incretin levels, and decreasing glucose absorption in the GI tract.4 It is listed as a second-line agent in the AACE guidelines, but it is given low preference.2 It reportedly lowers A1C by 0.5% to 1%.5 Colesevelam is not included in the ADA guideline’s treatment algorithm,3 but it is offered as potential second-line and third-line therapy in the AACE guidelines.2 Colesevelam is available as 635-mg tablets or as 1.875-g or 3.75-g packets for reconstitution as a suspension in water, fruit juice, or a soft drink. Regardless of the dosage form, colesevelam should be taken with meals. The initiation and maintenance dose is 3.75 g daily in 1 or 2 divided doses.27

Colesevelam may reduce the absorption of some drugs, including oral hypoglycemic medications and, as such, the manufacturer recommends taking other medications 4 hours before colesevelam. The drug may cause increased levels of metformin when coadministered with extended-release formulations.27

The most common adverse effects of colesevelam are constipation, nausea, and elevated triglycerides.4 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.27 The use of colesevelam for the treatment of diabetes has been quite limited, likely because of the high pill burden, the large size of the tablets, and the comparatively minor effect on A1C.

CONCLUSION

Many single-agent oral medications are currently available in the U.S. to help manage diabetes. Choosing the appropriate therapy for a specific patient requires consideration of effectiveness, side effects, and personal preferences. Further, diabetes cannot be managed in isolation from the patient’s other disease states, and comorbid conditions are also important considerations when choosing treatments. The ADA and the AACE have both recently released updated treatment guidelines that can support clinical decision making in diabetes management. Metformin is the first-line agent in both sets of guidelines and is usually the most appropriate first oral therapy option for patients with T2DM.1,2 The ADA suggests using any one of the other available agents, depending on patient factors and drug characteristics, as second-line and third-line choices, while the AACE has a preferred algorithm for the uses of oral agents for treating diabetes. Most oral agents will reduce a patient’s A1C by less than 1%, so if a person requires significant A1C reduction, therapy with multiple oral agents or therapy with injectable medications in addition to oral agents may be necessary.

No matter which medications a patient uses to treat diabetes, all of them should be considered adjuncts to diet and exercise. Lifestyle modifications are key to managing diabetes, slowing disease progression, and preventing complications. Diabetes care should always be provided by a multidisciplinary, collabora-tive treatment team that includes effective counseling from pharmacists.

Pharmacy technicians can ask patients open-ended questions to assess adherence to diabetes management. Use questions like these to determine if a pharmacist consultation is necessary:

  • What did the doctor tell you this medication is for?
  • What method are you using to track/monitor your blood sugars?
  • How do you feel since you began taking this medication?

References

  1. Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States. 2014; Atlanta, GA. National Center for Chronic Disease Prevention and Health Promotion: Division of Diabetes Translation. Centers for Disease Control and Prevention web site. http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed November 14, 2016.
  2. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2016 executive summary. Endocr Pract. 2016;22(1):84-113.
  3. American Diabetes Association. Standards of medical care in diabetes-2016. Diabetes Care. 2016;39(Suppl 1):S1-112.
  4. O’Mara NB. Pharmacist’s Letter Detail-Document: drugs for type 2 diabetes; 2015.
  5. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a pa-tient-centered approach: position statement of the American Diabetes Association (ADA) and the Euro-pean Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364-1379.
  6. Glucophage and glucophage XR [package insert]. New York, NY: Bristol-Myers Squibb Co.; 2009.
  7. Stevens RJ, Ali R, Bankhead CR, et al. Cancer outcomes and all-cause mortality in adults allocated to metformin: systematic review and collaborative meta-analysis of randomised clinical trials. Diabetologia. 2012;55(10):2593-2603.
  8. George CM, Brujin LL, Will K, Howard-Thompson A. Management of blood glucose with noninsulin therapies in type 2 diabetes. Am Fam Physician. 2015;92(1):27-34.
  9. Amaryl [package insert]. Bridgewater, NJ: Sanofi-aventis U.S., LLC; 2009.
  10. Glucotrol [package insert]. New York, NY: Pfizer, Inc.; 2013.
  11. Glynase prestab [package insert]. New York, NY: Pfizer, Inc.; 2009.
  12. Starlix [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; 2013.
  13. Prandin [package insert]. Princeton, NJ: Novo Nordisk, Inc.; 2011.
  14. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014.
  15. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696-1705.
  16. Januvia [package insert]. Whitehouse Station, NJ: Merck and Co. Inc.; 2014.
  17. Onglyza [package insert]. New York, NY: Bristol-Myers Squibb Co.; 2014.
  18. Nesina [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2013.
  19. Tradjenta [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2015.
  20. Lajara R. The potential role of sodium glucose co-transporter 2 inhibitors in combination therapy for type 2 diabetes mellitus. Expert Opin Pharmacother. 2014;15(17):2565-2585.
  21. Monami M, Nardini C, Mannucci E. 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.
  22. Farxiga [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2015.
  23. Invokana [package insert]. Titusville, NJ: Jannsen Pharmaceuticals, Inc.; 2015.
  24. Jardiance [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2015.
  25. U.S. Food and Drug Administration. FDA drug safety communication: FDA revises labels of SGLT2 in-hibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract in-fections. FDA web site. http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm. Published 2015. Updated 2015. Accessed January 3, 2016.
  26. Precose [package insert]. Wayne, NJ: Bayer Healthcare Pharmaceuticals; 2011.
  27. Welchol [package insert]. Parsippany, NJ: Daiichi Sankyo, Inc.; 2014.

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