GLP-1 receptor agonists, often referred to as incretin mimetics, work by augmenting the effects of the incretin hormone GLP-1.
Under physiologic conditions, GLP-1 and other incretins are released from cells of the GI tract after a meal. Incretin mimetics
Drug Interactions. Coadministration of canagliflozin with UDP-glucuronosyltransferase inducers—such as rifampin, phenytoin, or phenobarbital—can decrease canagliflozin efficacy. Accordingly, if used with such an agent, the 300-mg canagliflozin dose should be considered. Because canagliflozin causes a diuretic effect, the risk of dehydration and hypotension may be increased when used in combination with thiazide and loop diuretics.
Preparations, Dosage, and Administration. Canagliflozin [Invokana]
is available as 100- and 300-mg tablets. Canagliflozin is recommended at a starting dose of 100 mg daily taken before the first meal of the day. The dose can be increased to 300 mg once daily, requiring additional glycemic control and an estimated glomerular filtration rate [GFR] of 60 mL/min/1.73 m2 or greater. The once-daily dose of 100 mg is recommended for individuals with a GFR of less than 60 mL/min/1.73 m2. Because SGLT-2 inhibitors don’t work as well in people with significantly compromised kidney function, canagliflozin is not recommended for people with an estimated GFR below 30 mL/min/1.73 m2.
Dapagliflozin
Actions and Therapeutic Use. Dapagliflozin [Farxiga] was the second SGLT-2 inhibitor approved in the United States. By inhibiting SGLT-2, dapagliflozin suppresses glucose reuptake from tubular urine and thereby increases urinary glucose excretion. As a result, blood levels of glucose decline and weight loss can be seen.
Pharmacokinetics. The half-life of dapagliflozin following oral admin-istration is approximately 13 hours; thus it can be taken once daily.
Adverse Effects. The most common side effects noted with dapagliflozin in clinical studies were vulvovaginitis and other genital infections, back pain, polyuria, and an increased hematocrit. Orthostasis (particularly if used with diuretics) is possible.
Drug Interactions. Because dapagliflozin induces a diuretic effect in the kidney, the risk of dehydration and hypotension may be increased when used in combination with thiazide and loop diuretics. When used with other antidiabetic agents, patients should also monitor carefully to avoid the possibility of hypoglycemia.
Preparations, Dosage, and Administration. Dapagliflozin [Farxiga]
is available as 5- and 10-mg tablets. Dapagliflozin is dosed initially as 5 mg once daily in the morning with or without food. The dose can be subsequently increased to 10 mg once daily, if needed, to achieve desired glycemic control.
Because SGLT-2 inhibitors do not work as well in people with diminished kidney function, dapagliflozin is not recommended for use in people with an estimated GFR consistently less than 60 mL/min/1.73 m2.
Empagliflozin
Actions and Therapeutic Use. Empagliflozin [Jardiance] was the third SGLT-2 inhibitor approved by the FDA. Similar to other medications in this class, empagliflozin increases urinary glucose excretion to decrease glucose levels and weight via caloric loss through the urine. A large cardiovascular outcomes trial performed with empagliflozin showed that this medication can help prevent cardiovascular events in patients with diabetes and established cardiovascular disease.
Pharmacokinetics. The apparent terminal half-life of empagliflozin is approximately 12 hours, allowing for once-daily oral administration.
Adverse Effects. The most common adverse reactions associated with the use of empagliflozin in clinical trials were urinary tract infections and female genital mycotic infections. Similar to other agents in the SGLT-2 inhibitor class, patients taking empagliflozin may be at increased risk for hypotension, more severe urinary tract infections (urosepsis and pyelonephritis), and euglycemic DKA. Patients taking empagliflozin and other agents in this class should be monitored and counseled regarding these potential rare adverse effects.
Drug Interactions. Similar to other SGLT-2 inhibitors, there is an added risk for hypotension and dehydration when used in combination with diuretic medications. When used in combination with insulin and insulin secretagogue medications, there is also an increased risk for hypoglycemic events.
Preparations, Dosage, and Administration. Empagliflozin [Jardiance]
is available as 10- and 25-mg tablets. Empagliflozin is dosed initially as 10 mg taken once daily in the morning with or without food. The dose can be increased to 25 mg once daily in patients who require additional glycemic control. Like other medications in this class, empagliflozin is dosed based on renal function.
For patients with an eGFR less than 45 mL/min/1.73 m2, it is recommended that empagliflozin not be initiated. If patients taking empagliflozin experience a drop in their GFR to a level consistently below 45 mL/min/1.73 m2, it is recommended that the medication be discontinued.
CHAPTER 57 Drugs for Diabetes Mellitus
decrease in fasting blood glucose and a large decrease in postprandial blood glucose. Patients did not gain any weight, and many lost weight. In contrast, injecting exenatide extended-release for injectable suspension [Bydureon] 2 mg subQ once weekly has a greater effect on fasting glucose as opposed to postprandial blood glucose. These differences are related to the varying pharmacokinetic profiles of these two products.
Pharmacokinetics. For exenatide [Byetta], plasma levels peak 2.1 hours after subQ injection and decline with a half-life of 2.4 hours. Exenatide ER suspension [Bydureon], in contrast, is released slowly from microspheres over approximately 10 weeks, with a peak level of drug reached at around 2 weeks after administration. Exenatide is excreted unchanged in the urine. In patients with mild to moderate renal impairment, clearance is reduced only slightly, and hence no dosage reduction is needed. By contrast, in patients with end-stage renal disease, clearance is reduced significantly, and hence the drug should not be used.
Adverse Effects. Dose-related hypoglycemia is common when exenatide is combined with a sulfonylurea (but not when combined with metformin). To minimize hypoglycemia, sul-fonylurea dosage may need a reduction. Gastrointestinal effects—nausea, vomiting, and diarrhea—are common with exenatide [Byetta]. Exenatide ER suspension [Bydureon] is better tolerated in terms of nausea and vomiting, but can result in injection-site irritation and pruritus. In some patients, anti-exenatide antibodies develop. These antibodies do not cause adverse effects, but they can reduce exenatide’s effects.
Exenatide poses a risk of pancreatitis. Severe cases have led to pancreatic necrosis, pancreatic hemorrhage, and even death. Patients should be informed about signs and symptoms of pancreatitis—typically severe and persistent abdominal pain, with or without vomiting—and instructed to stop exenatide immediately if symptoms arise. If pancreatitis is confirmed, exenatide should not be resumed. Patients with a history of pancreatitis should probably not use this drug.
Exenatide can cause renal impairment, sometimes requiring hemodialysis or a kidney transplant. Fortunately, the incidence is low—about 1 case for every 13,000 patients. Risk of renal impairment may be increased by nausea, vomiting, or diarrhea, or any other event that can cause dehydration. Exenatide should be avoided in patients with severe renal impairment and should be used with caution in kidney transplant recipients.
In pregnant animals, doses of exenatide only 3 times the human dose caused fetal harm, manifesting as reduced growth and skeletal abnormalities. At this time, the drug is classified in FDA Pregnancy Risk Category C,b and hence should be used only if the benefits are believed to outweigh the fetal risk. Furthermore, given the established safety and efficacy of insulin in pregnancy, there seems to be little reason to even try exenatide.
There have been postmarketing reports of serious hyper-sensitivity reactions, including anaphylaxis and angioedema.
If severe reaction occurs, patients should stop taking exenatide and seek immediate medical attention.
Drug Interactions. Exenatide delays gastric emptying and hence can slow the absorption of oral drugs, thereby decreasing peak plasma levels and prolonging the time to peak serum activate receptors for GLP-1 and thereby cause the same effects
as endogenous incretins. That is, they slow gastric emptying, stimulate glucose-dependent release of insulin, inhibit post-prandial release of glucagon, and suppress appetite. Due to augmentation of these effects, incretin mimetics are effective in improving glucose control and can induce weight loss. You will recall that DPP-4 inhibitors “boost” the effects of incretin hormones by slowing their degradation by the enzyme DPP-4.
GLP-1 receptor agonists, in contrast, are structurally related to the native GLP-1 hormone but are resistant to metabolism by DPP-4. There are currently four GLP-1 receptor agonist products approved in the United States, with multiple other agents currently in development.
Exenatide
Exenatide [Byetta] was the first incretin mimetic. The drug is used to improve glucose control in patients with type 2 diabetes.
A longer-acting formulation of exenatide known as Exenatide Once Weekly [Bydureon] is also currently available and is dosed once weekly (compared to twice daily with Byetta).
Nausea is common, and hypoglycemia can occur, particularly if used in combination with a sulfonylurea.
Description and Actions. Exenatide is a synthetic analog of GLP-1, a peptide hormone in the incretin family. Exenatide activates receptors for GLP-1 and thereby causes the same effects as endogenous incretins. That is, it slows gastric empty-ing, stimulates glucose-dependent release of insulin, inhibits postprandial release of glucagon, and suppresses appetite.
Therapeutic Use. Exenatide is indicated to improve glycemic control in patients with type 2 diabetes. In clinical trials, injecting exenatide [Byetta] 5 or 10 mcg subQ twice daily before the two largest meals of the day produced a modest
Brand Name Generic Name
Metaglip Glipizide-metformin
Glucovance Glyburide-metformin
Jentadueto Linagliptin-metformin
Kombiglyze XR Saxagliptin-metformin
Janumet, Janumet XR Sitagliptin-metformin
Kazano Alogliptin-metformin
Oseni Alogliptin-pioglitazone
Duetact Pioglitazone-glimepiride
ActoPlus Met, ActoPlus Met XR Pioglitazone-metformin
Avandamet Rosiglitazone-metformin
Avandaryl Rosiglitazone-glimepiride
PrandiMet Repaglinide-metformin
Synjardy, Synjardy XR Empagliflozin-metformin
Glyxambi Empagliflozin-linagliptin
Invokamet, Invokamet XR Canagliflozin-metformin
Xigduo XR Dapagliflozin-metformin
Qtern Dapagliflozin-saxagliptin
TABLE 57.12 ■ Combination Oral Agents for the Treatment of Type 2 Diabetes
bAs of 2020, the FDA will no longer use Pregnancy Risk Categories. Please refer to Chapter 9 for more information.
Because liraglutide delays gastric emptying, it might delay the absorption of some oral drugs, thereby reducing their peak serum levels and prolonging the time to peak serum levels.
Preparations, Dosage, and Administration. Liraglutide [Victoza]
is supplied in pre-filled multidose injector pens that deliver 0.6, 1.2, or 1.8 mg/
dose. Administration is by subQ injection into the abdomen, thigh, or upper arm. Dosing is done once a day, at any time and independent of meals. The initial dosage is low—0.6 mg once a day—to minimize GI side effects. After 1 week, dosage is increased to 1.2 mg once a day. If that dosage proves inadequate, it can be increased to 1.8 mg once a day.
Lixisenatide
Actions and Therapeutic Use. Lixisenatide [Adlyxin] is another short-acting incretin mimetic indicated for the treatment of type 2 diabetes mellitus in combination with diet and exercise. Being a shorter-acting agent, lixisenatide is recommended to be administered once daily via subcutaneous injection. The safety and tolerability profile of lixisenatide is very similar to other agents in this therapeutic class.
Preparations, Dosage, and Administration. Lixisenatide [Adlyxin]
is commercially available in a pre-filled pen device. The starting dose of lixisenatide is 10 mcg injected once daily within 1 hour before the morning meal. The 10-mcg dose is administered for 14 days. On day 15 of treatment, the dose is recommended to be increased to 20 mcg daily.
Albiglutide
Actions and Therapeutic Use. Albiglutide [Tanzeum] is an incretin mimetic indicated as an adjunct to diet and exercise to enhance glycemic control in adults with type 2 diabetes. Like exenatide ER suspension, albiglutide is administered once weekly via subcutaneous injection. The safety and toler-ability profile of albiglutide is likewise similar to that of exenatide ER suspension.
Preparations, Dosage, and Administration. Albiglutide [Tanzeum]
is supplied as single-dose pens for administration of 30- and 50-mg doses.
Albiglutide is recommended to be initiated at 30 mg once weekly. The dose can be increased to 50 mg once weekly in patients requiring additional glycemic control.
Dulaglutide
Actions and Therapeutic Use. Dulaglutide [Trulicity] is a long-acting incretin mimetic indicated for the treatment of type 2 diabetes in combination with diet and exercise. It is administered once weekly. As a member of the incretin mimetic class of medications, dulaglutide has an efficacy and safety profile similar to that of other once-weekly products in this drug class.
Preparations, Dosage, and Administration. Dulaglutide [Trulicity] is available in 0.75- and 1.5-mg pre-filled pens for injection. Dulaglutide differs from other once-weekly products, such as exenatide ER and albiglutide, in that it is formulated in solution. This is a potential advantage because the other currently available once-weekly products require reconstitution and preparation before administration. The recommended starting dose of dulaglutide is 0.75 mg subcutaneously once weekly. The dose can be administered at any time of day without regard to meals. Depending on clinical response and if needed for additional glycemic control, the dose may be increased to 1.5 mg weekly.
Amylin Mimetic: Pramlintide
Pramlintide [Symlin] is an amylin mimetic. The drug is used to complement the effects of mealtime insulin in patients with type 1 or type 2 diabetes.
Severe hypoglycemia is a concern, and nausea is common.
Description and Actions
Pramlintide is a synthetic analog of amylin, a peptide hormone made in the pancreas and co-released with insulin. Both amylin and pramlintide, which mimics the effects of amylin, reduce postprandial levels of glucose, mainly by delaying gastric emptying and suppressing glucagon secretion. In addition, both agents act in the brain to increase the sense of satiety, helping to lower caloric intake.
Therapeutic Use
Pramlintide is indicated as a supplement to mealtime insulin in patients with type 1 or type 2 diabetes who have failed to achieve glucose control despite optimal insulin therapy. In clinical trials, adding subQ pramlintide to mealtime insulin decreased postprandial glucose levels, smoothed out glucose fluctuations, and reduced the needed mealtime dose of insulin. Mean reductions in A1C were about 0.39% for those with type 1 diabetes and 0.55% for those with type 2 diabetes.
levels. Reduced absorption is of particular concern with oral contraceptives and antibiotics, which require high peak con-centrations to be maximally effective. To minimize this interaction, give oral drugs at least 1 hour before exenatide.
Preparations, Dosage, and Administration. Exenatide [Byetta] is supplied in pre-filled, 60-dose injector pens that deliver 5 or 10 mcg per dose. Injections are made subQ into the thigh, abdomen, or upper arm. The initial dosage is 5 mcg twice daily, administered 0 to 60 minutes before the morning and evening meals—never after the meal. After 1 month, the dosage may be increased to 10 mcg twice daily. If the patient is taking a sulfonylurea, its dosage may need a reduction (to avoid hypoglycemia). If the patient is taking metformin, no dosage reduction is needed. Because of greatly reduced clear-ance, exenatide should not be used by patients with severe renal impairment. Exenatide ER suspension [Bydureon] is supplied as 2-mg ER powder in single-dose vials or pens for suspension in diluent for injection. Injections are made subQ in the thigh, abdomen, or upper arm.
Liraglutide
Actions and Uses. Liraglutide [Victoza] is an incretin mimetic similar to exenatide. The drug is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Like exenatide, liraglutide is an analog of human GLP-1 that causes direct activation of GLP-1 receptors and thereby slows gastric emptying, stimulates glucose-dependent insulin release, and inhibits postprandial release of glucagon. Liraglutide is more convenient that exenatide (dosing is done just once a day without regard to meals, rather than twice a day before meals).
Liraglutide can be used alone or combined with other antidiabetic drugs.
Most often, the drug is combined with metformin, a sulfonylurea, or another agent. Because sulfonylureas actively drive down blood glucose levels, adding liraglutide to a sulfonylurea regimen increases the risk of hypoglycemia.
Reducing the sulfonylurea dosage at the start of liraglutide treatment seems to lower the risk.
Liraglutide has been shown to be effective as an add-on to rosiglitazone, a drug that is all but gone from use. Although liraglutide has not been studied as an add-on to pioglitazone (the only other glitazone still on the market), it seems likely that liraglutide would be effective with pioglitazone too.
Pharmacokinetics. Pharmacokinetics of liraglutide are unremarkable.
Plasma levels peak 8 to 13 hours after subQ dosing. The drug undergoes metabolic breakdown followed by excretion in the urine and feces. The plasma half-life is 13 hours—long enough to permit once-daily dosing.
Adverse Effects. Dose-related GI effects are common, developing in 41% of patients. Specific effects include nausea, diarrhea, and constipation.
Hypoglycemia can also occur, especially when liraglutide is combined with a sulfonylurea (but not with metformin).
In clinical trials, 8.6% of patients developed anti-liraglutide antibodies.
This is surprising, given that liraglutide is nearly identical to human GLP-1, and hence should not be antigenic. In theory, these antibodies could neutralize liraglutide. However, to date, there is no evidence this has happened.
Like exenatide, liraglutide has been associated with rare cases of pancre-atitis. If pancreatitis is suspected, liraglutide should be discontinued immediately.
If pancreatitis is confirmed, the drug should never be used again. However, if pancreatitis is ruled out, use of liraglutide can resume.
Like exenatide, liraglutide has been associated with rare cases of renal impairment, including new acute renal failure and worsening of chronic renal failure. Most cases occurred in patients who had experienced nausea, vomiting, diarrhea, or any other event that can cause dehydration. Renal impairment may reverse with supportive treatment and discontinuation of liraglutide and any other potentially causative agents.
There is concern that liraglutide may cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC). In tests on rodents, clinically relevant doses have caused C-cell tumors. However, there is no proof that liraglutide has caused these tumors in humans. Nonetheless, the package label bears a black box warning about possible thyroid cancer, including a contraindication against using the drug in patients with a family history of MTC or in those with multiple endocrine neoplasia syndrome type 2.
Drug Interactions. As noted, combined use with a sulfonylurea can increase the risk of hypoglycemia. Dosage of the sulfonylurea may need a reduction.
CHAPTER 57 Drugs for Diabetes Mellitus