Diabetes Treatment: Oral Medications Materials

PHARMACOLOGIC APPROACHES TO DIABETES TREATMENT: ORAL MEDICATIONS

L. Austin Fredrickson, MD, FACP

L. Austin Fredrickson, MD, FACP is an assistant professor of internal medicine at Northeast Ohio Medical University, where he serves as core faculty and teaches diagnostics, therapeutics, clinical skills, and health humanities. He is board-certified in general internal medicine and practices rural primary care.

Topic Overview

Diabetes mellitus remains a major public health problem as a leading cause of death and micro- and macro-vascular morbidity. The management of diabetes continues to evolve as new research, technology, and treatments allow for enhanced patient care. It is vital for health care providers, including physicians, nurses, and pharmacists, to remain up to date with the newest diabetes care guidelines, which include updates to the pharmacologic management of diabetes mellitus. This course will compare available oral medications for diabetes, with a discussion of mechanisms of action, dosing, side effects, and contraindications. The suggested place of these various medications within a therapeutic regimen will be discussed in the context of the updated American Diabetes Association Standards of Care in Diabetes 2023 guidelines.

Accreditation Statement:

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Universal Activity Number (UAN): The ACPE Universal Activity Number assigned to this activity is 

Pharmacist  0669-0000-23-096-H01-P

Pharmacy Technician  0669-0000-23-097-H01-T

Credits: 1 hour of continuing education credit

Type of Activity: Knowledge

Media: Internet/Home study Fee Information: $4.99

Estimated time to complete activity: 1 hour, including Course Test and course evaluation

Release Date: June 24, 2023 Expiration Date: June 24, 2026

Target Audience: This educational activity is for pharmacists.

How to Earn Credit: From June 24, 2023, through June 24, 2026, participants must:

Read the “learning objectives” and “author and planning team disclosures;”

Study the section entitled “educational activity;” and

Complete the Course Test and Evaluation form. The Course Test will be graded automatically. Following successful completion of the Course Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

Credit for this course will be uploaded to CPE Monitor®.

Learning Objectives: Upon completion of this educational activity, participants should be able to:

Compare and contrast the mechanisms of action of available oral diabetes medications

Describe the side effects and contraindications of oral diabetes medications

Identify when to utilize oral diabetes medications within a therapeutic regimen for patients with Type 2 diabetes mellitus

Recall patient counseling points related to the use of oral diabetes medications

Disclosures

The following individuals were involved in the development of this activity: L. Austin Fredrickson, MD, FACP, Liz Fredrickson, PharmD, BCPS, and Pamela Sardo, PharmD, BS. Pamela Sardo, Pharm.D., B.S., was an employee of Rhythm Pharmaceuticals until March 2022 and has no conflicts of interest or relationships regarding the subject matter discussed. There are no financial relationships relevant to this activity to report or disclose by any of the individuals involved in the development of this activity.

© RxCe.com LLC 2023: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.

Introduction

The management of Type 2 diabetes mellitus (T2DM) involves a holistic, patient-centered approach that encompasses lifestyle modifications and the use of pharmacologic therapies. While current American Diabetes Association (ADA) Standards of Care 2023 guidelines highlight the benefits of injectable agents for reaching glycemic and weight loss goals and reducing cardiorenal risks, oral antidiabetic (OAD) medications still have important roles to play in the care plans of many patients. Numerous classes of OADs are available, each with its unique mechanism of action, efficacy, and safety profile. This course will compare available oral medications for diabetes with a discussion of mechanisms of action, dosing, side effects, and contraindications. The suggested place of these medications within a therapeutic regimen will be discussed in the context of the updated American Diabetes Association Standards of Care in Diabetes 2023 guidelines.

Oral Antidiabetic Medications

Metformin

In previous versions of the ADA guidelines, metformin, brand name Glucophage, was promoted as a first-line agent in managing T2DM.1 While it has fallen slightly out of favor within more recent guideline recommendations, it still offers important benefits for patients with T2DM.3

Mechanism of Action

Metformin is classified as biguanide and is unrelated pharmacologically to other classes of OAD medications.1,4 Metformin activates the enzyme adenosine monophosphate-activated protein kinase (AMPK), which leads to increased glucose uptake in skeletal muscle and suppressed hepatic glucose production.4 It also decreases the intestinal absorption of glucose and improves insulin sensitivity via increasing peripheral glucose uptake and absorption.4

Pharmacokinetics

While the onset of action of metformin occurs within a few days, the maximum effect can take up to two weeks to occur.4 Metformin has a half-life elimination of ~18 hours in the blood and a fasting bioavailability of 50-60%.4

Dosing

Metformin is available in an immediate-release tablet and extended- release tablet formulation.4 It is also available as a solution and suspension.4 Dosing for metformin is available in Table 1 below.4 Metformin should be taken with or immediately following meals.1,4 Metformin should be dosed starting at the lower end of the range, with doses titrated up slowly to minimize gastrointestinal (GI) side effects.4 If doses greater than 2 grams per day are required, it is recommended to divide the total daily dose (TDD) into three doses (if using the immediate-release formulation) or two doses (extended- release formulation) to minimize GI side effects.4 Between 5 and 10% of patients will not tolerate metformin therapy despite low and slow dose titrations.4

Table 1. Metformin Dosing4

Metformin is renally excreted and will accumulate in patients with renal impairment.1 Patients with an eGFR ≥ 60 mL/min/1.73 m2 do not require dose adjustments; however, renal function should be monitored at least annually.4 Patients with an eGFR between 45 and 60 mL/min/1.73 m2 should have increased renal monitoring but do not require dose adjustments.4 Initiation of metformin is typically not recommended for patients with an eGFR between 30 and 45 mL/min/1.73 m2.4 Patients already taking metformin should reduce the dose to 500 mg twice daily and closely monitor renal function. Metformin is contraindicated at eGFR less than 30 mL/min/1.73 m2.4

Dosing recommendations vary for patients depending on the degree of hepatic impairment.4

Child-Turcotte Pugh Class A: No dose adjustment needed

Child-Turcotte Pugh Class B: 500 mg once daily with increases of less than or equal to 500 mg per day every 30 days

Child Turcotte Pugh Class C: Avoid use Side Effects and Monitoring

The most common side effects of metformin include gastrointestinal symptoms such as nausea, diarrhea, and abdominal discomfort.4 Diarrhea is more common with the immediate-release formulation compared to the extended-release (53% vs 10%).4 Patients should be counseled that these symptoms can often be minimized by taking the medication with food, starting with a lower dose, and gradually titrating up.4 Other potential side effects include vitamin B12 deficiency and lactic acidosis.4 B12 levels should be monitored if there is a suspected deficiency and otherwise checked every 1-2 years.1,4 Cases of lactic acidosis are rare and often precipitated by acute kidney injury or severe illnesses; risk factors include renal impairment, acute congestive heart failure, hepatic impairment, and excessive alcohol consumption.1 Hemoglobin A1C (A1C) levels should be monitored twice yearly in patients with stable glycemic control and at least quarterly in those not meeting goals.5-7

Drug Interactions

Metformin has the potential to interact with a variety of different medications.

Contraindications and Warnings

Metformin is contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), acute or chronic metabolic acidosis, and/or hypersensitivity to metformin.4 Current guidelines also recommend holding metformin prior to the administration of iodinated contrast in those with acute kidney injury, severe chronic kidney disease, or risk factors for lactic acidosis.1,4 It can be resumed 48 or more hours later once normal kidney function is noted.1,4

Sulfonylureas

There are two generations of sulfonylurea medications.1 First-generation agents include chlorpropamide, tolbutamide, and tolazamide; second- generation agents include glyburide, glipizide, and glimepiride.1 Due to their side effect profiles and lower efficacy rates, first-generation agents are rarely used.1

Mechanism of Action

Sulfonylureas work by binding a sulfonylurea receptor (SUR1) and stimulating insulin release from beta cells in the pancreas.5 This reduces glucose output from the liver and increases insulin sensitivity at peripheral sites.5

Pharmacokinetics

Table 2 details the pharmacokinetic profiles of glipizide, glimepiride, and glyburide.

Table 2. Pharmacokinetic Profiles of Sulfonylureas

Dosing

The sulfonylureas are available in immediate and extended-release formulations.1 Glipizide is available as 2.5 mg, 5 mg, and 10 mg tablets.5 Glimepiride is available as 1 mg, 2 mg, and 4 mg tablets.6 Glyburide is available as conventional tablets (DiaBeta) and microionized tablets (Glynase PreTab).7 Dosing strategies for the various sulfonylureas are listed in Table 3. Glipizide should be taken 30 minutes prior to the first meal of the day.5 Glimepiride and glyburide should be taken with the first meal.6,7 Sulfonylureas are equally effective in their blood glucose lowering efficacy when given at equipotent doses.1

Table 3. Sulfonylurea Dosing5-7

Glipizide has inactive metabolites and is thus the preferred sulfonylurea in patients who have renal impairment.5 Patients with hepatic impairment should start at the 2.5 mg dose of glipizide IR or ER, and maintenance dosing should be conservative to avoid hypoglycemia.5 There are no dose adjustments recommended for glyburide in hepatic impairment.7 The following dose adjustments are recommended for sulfonylureas (Table 4).5-7

Table 4. Renal and Hepatic Dose Adjustments of Sulfonylureas

Side Effects and Monitoring

Sulfonylureas are associated with many side effects, including hypoglycemia, weight gain, and gastrointestinal disturbances, including nausea, vomiting, diarrhea, and constipation.5-7 Glyburide is associated with a higher risk of hypoglycemia due to its active metabolite.1 All patients taking sulfonylureas should be monitored for signs and symptoms of hypoglycemia (fatigue, increased hunger, sweating, numbness in extremities) and counseled on managing low blood sugars.1,5-7 Blood glucose levels, renal function, liver function, and body weight should be regularly monitored.5-7 Hemoglobin A1C (A1C) levels should be monitored twice yearly in patients with stable glycemic control and at least quarterly in those not meeting goals.5-7

Drug Interactions, Contraindications, and Warnings

Contraindications to using sulfonylureas include a history of hypersensitivity to sulfonylureas or sulfonamide derivatives, type 1 diabetes, and diabetic ketoacidosis.5-7 Sulfonylureas with active metabolites and long durations of action should be avoided in elderly patients due to the risk of hypoglycemia.1,5-7 For these patients, glipizide may be the best choice. Caution is also warranted for patients undergoing bariatric surgery and a deficiency of glucose-6-phosphate dehydrogenase (G6PD).5-7 Additionally, patients in a stress-related state (such as fever or trauma) should discontinue therapy and resume once the stress state is passed.5-7

Thiazolidinediones

The thiazolidinediones, also known as TZDs, include pioglitazone (Actos) and rosiglitazone (Avandia).8,9 Avandia has been discontinued in the United States due to cardiac complications.

Mechanism of Action

Thiazolidinediones enhance insulin sensitivity in fat, liver, and muscle tissue.1 They exert their effects via binding the peroxisome proliferator- activated receptor-gamma (PPAR gamma) in fat and vascular cells.1-8,9 Activation of these receptors increases the production of gene products involved in glucose and lipid metabolism in the liver, muscle, and adipose tissue.8,9 PPAR-gamma is also located in renal collecting tubules, which has effects on fluid retention.8,9

Pharmacokinetics

Pioglitazone has a delayed onset of action, and it can take several weeks to months before glucose control is achieved.8 This is an important counseling point for patients who may notice minimal changes to their blood glucose levels at the start of therapy.8 It is metabolized via CYP2C8 and CYP3A4 to

both active and inactive metabolites.8 Its half-life elimination is 3-7 hours for the parent drug and 16-24 hours for its metabolites.8

Dosing

Pioglitazone is available as a 15 mg, 30 mg, and 45 mg tablet.8 The initial dose is 15 to 30 mg once daily, which may be administered without regard to meals.8 This can be titrated in increments of 15 mg per day every 4-12 weeks to a maximum dose of 45 mg/day.8 In patients with mild-severe renal impairment, no dose adjustment is needed.8 Pioglitazone use should be avoided in patients with cirrhosis.8

Side Effects and Monitoring

There are several adverse reactions associated with TZDs. First, they may increase the risk of bladder carcinoma.8 This risk is both dose and time related with a delayed onset.8 Most cases occur with long-term use and high- dose exposure.8 Major risk factors include more than 2 years duration, European ethnicity, Caucasian race, and a prior history of bladder cancer.8 TZDs can also increase the risk of bone fracture.8 The absolute risk found with pioglitazone use was 1.6-4.9% absolute risk increase.8 The onset of fractures is delayed, with a greater risk after 2 years of therapy.8 The risk is also higher in elderly patients, those with prior stroke, and those with retinopathy.8

A third major adverse reaction is an increased risk of cardiac failure and dose-dependent edema.8 These symptoms are reversible after discontinuation.8 The onset is intermediate in length, typically within the first few weeks of therapy.8 Patients at greater risk include those with pedal edema or on treatment with loop diuretics, those with cardiovascular disease or hypertension, those on medications associated with fluid retention, older adults (>70 years old), history of heart failure, diabetes for more than 10 years, and chronic kidney disease.8 Finally, patients may be at risk of hepatic failure, though this risk is higher with older TZDs than pioglitazone.8 This delayed effect occurs 1-7 months after starting therapy.8

Other side effects (with associated incidences) include hypoglycemia (27%), upper respiratory tract infections (13%), headache (9%), and back pain (6%).8 Patients should be monitored closely for signs and symptoms of heart failure, including rapid weight gain, dyspnea, and edema).8 Serum glucose and A1C levels should be monitored.8 Additionally, liver enzymes (ALT, AST, and alkaline phosphatase) should be drawn prior to initiation in all patients, with routine monitoring recommended in patients with liver disease.8 TZDs may lead to the resumption of ovulation in anovulatory, pre-menopausal women.1 These individuals should be counseled on pregnancy prevention.1

Contraindications and Warnings

Thiazolidinediones should not be used in patients with heart failure (NYHA Class 3 or 4) or a history of bladder cancer.8 They are also contraindicated in patients with hypersensitivity to TZDs.8

DPP4-Inhibitors

Four Food and Drug Administration (FDA)-approved dipeptidyl peptidase-4 (DPP-4) inhibitors are sitagliptin (Januvia), alogliptin (Nesina), saxagliptin (Onglyza), and linagliptin (Trajenta).10-13 All agents have similar efficacy.1

Mechanism of Action

DDP-4 inhibitors block the dipeptidyl peptidase-4 enzyme, which results in prolonged, active incretin levels.10-13 Incretins (GLP-1 and GIP) work to regulate glucose homeostasis by increasing the synthesis of insulin and its release and are normally inactivated by the DPP-4 enzyme.10-13 Patients with T2DM are deficient in GLP-1.1 DPP-4 inhibitors also decrease glucagon secretion, which leads to decreased hepatic glucose production.10-13

Pharmacokinetics

The pharmacokinetic profiles of the DPP-4 inhibitors are presented in Table 5.

Table 5. Pharmacokinetic Profiles of the DPP-4 Inhibitors10-13

Dosing

Sitagliptin is available in 25 mg, 50 mg, and 100 mg tablets.10 Alogliptin comes in 6.25 mg, 12.5 mg, and 25 mg tablets.11 Linagliptin is available in 5 mg tablets, and saxagliptin in 2.5 mg and 5 mg tablets.12-13 The DDP-4 inhibitors can be taken without food. Dosing is provided in Table 6.

Table 6. DPP-4 Inhibitor Dosing10-13

Linagliptin does not require dose adjustments for renal or hepatic impairment, and saxagliptin does not require dose adjustments for hepatic impairment.12,13 No dose adjustments are recommended for alogliptin or sitagliptin regarding hepatic impairment, but caution is warranted.10,11 Table

6 provides renal dose adjustments recommended for other DDP-4 inhibitors.10,11

Table 7. DPP-4 Inhibitor Renal Dose Adjustments

Side Effects and Monitoring

DDP-4 inhibitors are generally well-tolerated.1 Headache and upper respiratory tract infections are possible but uncommon.1 Five major safety concerns related to DDP-4 inhibitor use include arthralgia, dermatologic reactions, heart failure, hypersensitivity reactions, and pancreatic issues.10-13

Severe cases of arthralgia have been linked to the use of DDP-4 inhibitors.10-13 The onset is varied and can occur within one day or years after treatment has started.10-13 The major risk factor is the duration of therapy; however, there is conflicting data regarding this.10-13 A second concern is the

development of dermatologic reactions, including bullous pemphigoid.10-13 Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome, have also been reported.10-13 The onset of bullous pemphigoid is typically around 6 months after starting therapy, while other delayed hypersensitivity reactions may occur days to weeks after starting a DDP-4 inhibitor.10-13 Risk factors include older age, and males may be at an increased risk.10-13

Heart failure is a potential risk associated with DDP4-inhibitor use, specifically with saxagliptin and alogliptin.10-13 Current ADA guidelines allow for the consideration of DDP-4 inhibitor use in patients with heart failure, but these agents are not preferred in this patient population.10-13 The main risk factor is pre-existing heart failure or having risk factors for heart failure.10-13

Hypersensitivity reactions, including anaphylaxis and angioedema, are possible with DDP4-inhibitor use.10-13 These are non-dose related, immunologic reactions with a varied onset of occurrence.10-13 Often, these occur within the first three months of therapy.10-13 Risk factors include the concomitant use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or p-glycoprotein inhibitors, hereditary angioedema, or a history of angioedema with another DDP-4 inhibitor.10-13

A final, major concern is the occurrence of acute pancreatitis, which includes hemorrhagic pancreatitis and necrotizing pancreatitis, and chronic pancreatitis.10-13 Patients with a history of pancreatitis, acute pancreatitis, or risk factors for pancreatitis are at a greater risk of experiencing this.10-13

Patients taking a DDP-4 inhibitor should have serum glucose levels monitored.10-13 Renal function should be evaluated prior to starting one of these agents and then periodically throughout the treatment period.10-13 Patients should be monitored for signs and symptoms of heart failure, hypersensitivity reactions, pancreatitis, and the development of blisters or erosions.10-13 A1C should be monitored based on the patient’s level of glycemic control.10-13

Contraindications and Warnings

DPP-4 inhibitors are contraindicated in patients with serious hypersensitivities to these agents.10-13 Caution should be used in patients with previous bariatric surgery.10-13

SGLT-2 Inhibitors

There are five FDA-approved sodium-glucose cotransporter 2 (SGLT-2) inhibitors, including bexagliflozin (Brenzavvy), canagliflozin (Invokana), dapagliflozin (Farxiga), empagliflozin (Jardiance), and ertugliflozin (Steglatro).14-18

Mechanism of Action

SGLT2 is a transporter responsible for the reabsorption of most glucose in the kidneys.14-18 SGLT-2 inhibitors work by blocking this transporter, thereby reducing the renal reabsorption of glucose and increasing urinary glucose excretion.14-18 This mechanism is independent of insulin and results whenever plasma fasting or postprandial glucose levels are elevated.1

Pharmacokinetics

Table 8 below details the pharmacokinetic profiles of the SGLT-2 inhibitors.14-18

Table 8. Pharmacokinetic Profiles of the SGLT-2 Inhibitors14-18

Dosing

SGLT-2 inhibitors are dosed once daily and may be taken with or without food in the morning. Dosing strategies are provided in Table 9 below.14-18

Table 9. Dosing Strategies for SGLT-2 Inhibitors14-18

Bexagliflozin is not recommended for patients with an eGFR less than 30 mL/min/1.73 m2 and is contraindicated for patients on dialysis. 14 Use is also not recommended for patients with severe hepatic impairment. 14 Canagliflozin requires a dose adjustment to 100 mg once daily at an eGFR of

30 to <60 mL/min/1.73 m2. 15 Under 30 mL/min/1.73 m2, patients with urinary albumin excretion >300 mg/day should not start therapy but may continue 100 mg daily.15 Those with ≤300 mg/day should not start therapy.15 At an eGFR <25 mL/min/1.73 m2, the manufacturer does not recommend the use of dapagliflozin.16 Empagliflozin is not recommended under an eGFR of 30 mL/min/1.73 m2.17 Ertugliflozin is not recommended under an eGFR of < 45 mL/min/1.73 m2.18

Side Effects and Monitoring

The most common side effects of SGLT-2 inhibitors are endocrine and genitourinary in nature.14-18 Patients may experience increased LDL cholesterol and increased thirst.14-18 Additionally, diuresis (including nocturia and polyuria), urinary tract infections, and vaginal mycosis are possible.1,14-18 Symptomatic hypotension may be seen in patients with a lower blood pressure at baseline or an eGFR <60 mL/min/1.73m2.1 Renal function should be closely assessed and patients should be monitored for genital mycotic infections and urinary tract infections.14-18

Other safety concerns of note include ketoacidosis, amputations, and fractures.1 The overall risk of ketoacidosis, as reported in meta-analyses, is small.1 Patients should be encouraged to remain hydrated throughout treatment.1 In a cardiovascular (CV) outcomes trial, canagliflozin was found to increase the risk of both bone fractures and lower-limb amputations; such fractures may result from falls due to orthostatic hypotension.1 Cases of Fournier gangrene have also been associated with SGLT-2 inhibitor use.1

Contraindications

SGLT-2 inhibitors are contraindicated in patients on dialysis or with any hypersensitivity to SGLT-2 inhibitors.14-18 In patients with renal impairment, there is also an increased risk of hypotension because of intravascular depletion.14-18 Patients should be advised to drink plenty of water while taking SGLT2 inhibitors to prevent dehydration. They should also be instructed to report any symptoms of urinary tract infections or genital yeast infections to their healthcare provider.14-18

Older adults and those on antihypertensive agents are also at a greater risk of hypotension.14-18 SGLT-2 inhibitors may increase the risk of lower limb amputations, and other risk factors, such as a prior amputation, peripheral vascular disease, and neuropathy, should be weighed against the benefits of therapy prior to starting one of these agents. 14-18

Other Oral Agents

Other OAD medications are not often used but may benefit specific patient subsets. These include meglitinides, alpha-glucosidase inhibitors, bile acid sequestrants, amylin analogs, and bromocriptine. These agents will not be discussed in detail.

Alpha-glucosidase inhibitors (acarbose and miglitol) work by competitively inhibiting maltase, isomaltase, sucrase, and glucoamylase in the small intestine, which delays the breakdown of complex carbohydrates.1 This

results in reduced postprandial glucose levels.1 These agents only moderately lower A1C levels and are associated with many GI side effects.1

Meglitinides include nateglinide and repaglinide.1 These agents work by stimulating the release of insulin from pancreatic beta cells, thereby increasing insulin levels in the blood; they have both a faster onset and shorter duration compared to sulfonylureas.1 They may reduce A1C levels by 0.8-1%, and major side effects include weight gain and hypoglycemia.1

Colesevelam is a bile acid sequestrant approved for treating T2DM. Its mechanism of action as it relates to DM is unclear.1 Patients needing small decreases in A1C and LDL-C lowering may benefit from its use.1

Bromocriptine is a dopamine receptor agonist that stimulates dopamine receptors in the brain.1 It lowers blood glucose levels modestly, and the mechanism by which it does so is unknown.1

Pramlintide is an injectable analog of amylin.1 Amylin is a neurohormone secreted from beta-cells along with insulin and plays key roles in glucose regulation.1 It may lower A1C levels from 0.4-0.5% and is typically used in patients with T1DM as adjunctive therapy.1

Choice of Glucose-Lowering Therapy

According to ADA guidelines, the management of T2DM typically begins with lifestyle modifications, such as exercise and diet changes.3 However, pharmacologic therapy is often needed to achieve glycemic control.3 When considering pharmacologic therapy, the ADA recommends a patient-centered approach that considers a patient's need for cardiorenal protection, glycemic control, and weight loss and balances this with personal preferences and medical profiles.3 Pharmacologic agents that assist in these treatment goals, including combination therapies, should be started at the time of diagnosis.3

Combination Therapy

The ADA guidelines recommend initial combination therapy for patients with an A1C level that is 1.5-2% above their target goal.3 Various trials have demonstrated the efficacy of initial combination therapy to achieve glycemic targets more quickly and the use of later combination therapy to ensure a longer durability of glycemic control.3 For example, in the VERIFY trial, initial combination therapy with metformin and vildagliptin was found to be superior to the sequential addition of medications.19

Glycemic Control

Reductions in A1C levels associated with the major OAD medications are presented in Table 10.1 Metformin, sulfonylureas, TZDs and SGLT-2 inhibitors have high glucose-lowering efficacy.3 DPP-4 inhibitors have intermediate glucose-lowering efficacy.3

Table 10. OAD Medication A1C Level Reductions

a: More efficacious in patients with higher baseline A1C levels

Weight Effects

The OAD medications can also be compared in terms of their effects on weight. SGLT-2 inhibitors have the potential to cause intermediate weight loss.3 Metformin may lead to modest weight loss but is generally weight neutral.3 Table 11 presents the OAD medications effects on weight.

Table 11. OAD Medication Effects on Weight

Hypoglycemia

The risk of hypoglycemia should be considered when selecting an OAD medication. Table 12 compares the agents in this regard. Sulfonylureas are the only agents with a risk of hypoglycemia when used as monotherapy.3

Table 12. OAD Risk of Hypoglycemia

Cardiovascular and Renal Protection

Current ADA guidelines place an emphasis on selecting therapies that reduce cardiorenal risk in patients with T2DM and an established or high risk of atherosclerotic cardiovascular disease, heart failure, and/or chronic kidney disease (CKD).3 Table 13 compares available OAD medications in this regard.3 Metformin may reduce the risk of cardiovascular events.3 Many trials have supported the use of specific SGLT2-inhibitors for the reduction of cardiovascular events in patients with T2DM.3 Guidelines now recommend use of SGLT2-inhibitors in patients in need of cardiovascular benefits.3

Table 13. Cardiorenal Effects

Cost

Finally, given the rising cost of diabetes medications, the price of OAD medications and a patient’s ability to afford and access these medications should be considered prior to initiating a regimen. Table 14 provides a cost comparison of these medications.3

Table 14. Cost Comparison of OAD

Summary

The management of Type 2 diabetes mellitus (T2DM) involves a holistic, patient-centered approach that encompasses lifestyle modifications and the use of pharmacologic therapies.3 Within the current American Diabetes Association (ADA) Standards of Care 2023 guidelines, oral antidiabetic (OAD)

medications have important roles in many patients' care plans. Numerous classes of OADs are available, each with its unique mechanism of action, efficacy, and safety profile. Healthcare providers should be knowledgeable regarding these various medications and considerations for adding them to a T2DM therapeutic regimen.

Course Test

Which of the following classes of oral antidiabetic (OAD) medications exerts its effect via binding the peroxisome proliferator-activated receptor-gamma?

SGLT-2 inhibitors

Thiazolidinediones (TZDs)

DPP-4 inhibitors

Sulfonylureas

Which of the following medications activates adenosine monophosphate-activated protein kinase (AMPK), leading to increased glucose uptake in skeletal muscle and suppressed hepatic glucose production?

Metformin

Glipizide

Empagliflozin

Sitagliptin

Which of the following medications is contraindicated for a patient with an eGFR less than 30 mL/min/1.73 m2?

Linagliptin

Metformin

Pioglitazone

Sitagliptin

Possible side effects of SGLT-2 inhibitors include which of the following?

Lactic acidosis, vitamin B12 deficiency, nausea

Upper respiratory tract infections, fractures, headache

Hypoglycemia, weight gain, dizziness

Nocturia, urinary tract infections, vaginal mycosis

Which of the following classes of medications is associated with a high risk of hypoglycemia?

TZDs

Biguanides

SGLT-2 inhibitors

Sulfonylureas

A patient recently diagnosed with T2DM also has heart failure. Per the ADA guidelines, which of the following medications should be initiated, given that there are no contraindications?

Pioglitazone

Canagliflozin

Metformin

Linagliptin

A patient with T2DM wants to avoid injectable medications and has a goal of weight loss. Which of the following medications should he consider starting?

Glipizide

Empagliflozin

Sitagliptin

Pioglitazone

Which of the following is an appropriate counseling point for a patient taking metformin?

Patients should be informed that taking metformin with food can help minimize GI side effects

Patients should be told metformin is associated with a risk of bladder cancer

Patients should be counseled on the increased risk of hypoglycemia and how to manage hypoglycemia

Patients should be counseled on the signs and symptoms of pancreatitis

Which of the following would be recommended for a patient wanting an OAD medication that will not worsen the progression of his chronic kidney disease and is low cost?

Sitagliptin

Empagliflozin

Canagliflozin

Pioglitazone

Which of the following classes of OAD medications work by stimulating the release of insulin from pancreatic beta cells, thereby increasing insulin levels in the blood?

Alpha glucosidase inhibitors

Meglitinides

Bile acid sequestrants

Amylin analogs

References

Trujillo J, Haines S. Diabetes Mellitus. In: DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey L. eds. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. McGraw Hill; 2023. Accessed May 30, 2023.

Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2020. Estimates of Diabetes and Its Burden in the United States. Atlanta, GA. Available

at: https://www.cdc.gov/diabetes/pdfs/data/statistics/national- diabetes-statistics-report.pdf. Accessed June 1, 2021.

Standards of Care in Diabetes 2023. American Diabetes Association. Diabetes Care. 2023; 46(1).

Lexicomp Online, Metformin. Waltham, MA: UpToDate, Inc.; June 6, 2023. https://online.lexi.com. Accessed May 30, 2023.

Lexicomp Online, Glipizide. Waltham, MA: UpToDate, Inc.; May 19, 2023. https://online.lexi.com. Accessed May 30, 2023.

Lexicomp Online, Glimepiride. Waltham, MA: UpToDate, Inc.; June 6, 2023. https://online.lexi.com. Accessed May 30, 2023.

Lexicomp Online, Glyburide. Waltham, MA: UpToDate, Inc.; June 6, 2023. https://online.lexi.com. Accessed May 30, 2023.

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Lexicomp Online, Rosiglitazone. Waltham, MA: UpToDate, Inc.; June 6, 2023. https://online.lexi.com. Accessed May 30, 2023.

Lexicomp Online, Sitagliptin. Waltham, MA: UpToDate, Inc.; May 6, 2023. https://online.lexi.com. Accessed May 30, 2023.

Lexicomp Online, Alogliptin. Waltham, MA: UpToDate, Inc.; May 6, 2023. https://online.lexi.com. Accessed May 30, 2023.

Lexicomp Online, Saxagliptin. Waltham, MA: UpToDate, Inc.; June 6, 2023. https://online.lexi.com. Accessed May 30, 2023.

Lexicomp Online, Linagliptin. Waltham, MA: UpToDate, Inc.; June 6, 2023. https://online.lexi.com. Accessed May 30, 2023.

Lexicomp Online, Bexagliflozin. Waltham, MA: UpToDate, Inc.; June 5, 2023. https://online.lexi.com. Accessed May 30, 2023.

Lexicomp Online, Canagliflozin. Waltham, MA: UpToDate, Inc.; May 6, 2023. https://online.lexi.com. Accessed May 30, 2023.

Lexicomp Online, Dapagliflozin. Waltham, MA: UpToDate, Inc.; June 6, 2023. https://online.lexi.com. Accessed May 30, 2023.

Lexicomp Online, Empagliflozin. Waltham, MA: UpToDate, Inc.; June 6, 2023. https://online.lexi.com. Accessed May 30, 2023.

Lexicomp Online, Ertugliflozin. Waltham, MA: UpToDate, Inc.; June 6, 2023. https://online.lexi.com. Accessed May 30, 2023.

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