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Pathophysiology of type 2 diabetes mellitus: potential role of incretin-based therapies
Glucose-lowering effects of incretin-based therapies
Safety, tolerability, and nonglycemic effects of incretin-based therapies
- Patient education, which is essential for successful patient self-management, can be provided by a multidisciplinary diabetes care team
- The dosing and administration of glucagon-like peptide (GLP)-1 agonists or dipeptidyl peptidase (DPP)-4 inhibitors offer significant flexibility to meet patient needs
- The GLP-1 agonists and DPP-4 inhibitors vary in administration, effect on weight, contraindications, and dosing adjustments for patients with renal impairment
- The relatively high cost ($7 to $14 per day) of therapy with a GLP-1 agonist or DPP-4 inhibitor may be covered by insurance, so cost to the patient may be limited to copays
The authors received editorial assistance from the Primary Care Education Consortium and WriteHealth, LLC in the development of this activity and honoraria from the Primary Care Education Consortium. They have disclosed that Dr Campbell is on the advisory board for Daiichi-Sankyo and the speakers bureau for Eli Lilly and Co; Dr Cobble is on the advisory board for Abbott Laboratories, AstraZeneca, and Eli Lilly and Co and speakers bureau for Abbott Laboratories, AstraZeneca/Bristol Myers Squibb, Eli Lilly and Co, GlaxoSmithKline, and Novo Nordisk Inc; Dr Reid is on the advisory board and speakers bureau for Amylin Pharmaceuticals, Medtronic, Novo Nordisk Inc, and sanofi-aventis; and Dr Shomali is on the advisory board for Novo Nordisk Inc and speakers bureau for Amylin Pharmaceuticals, Eli Lilly and Co, sanofi-aventis, and Takeda Pharmaceuticals.
Introduction
The comprehensive and long-term management of patients with type 2 diabetes mellitus (T2DM) requires that they assume primary responsibility for daily self-management. For this to occur, patient education is critical, yet it is time-consuming. Because our time as primary care physicians is limited, developing a diabetes care team, even informally, can be helpful in providing the comprehensive care that is needed. Beyond easing the amount of time we need to provide the patient education required, the patient is able to benefit from the specialized skills and knowledge of other team members, such as a nurse, pharmacist, dietitian, certified diabetes educator, or an exercise specialist. It is important, however, that as primary care physicians, we coordinate the care provided by the team so that treatment goals are clear, communication is maintained, and patient outcomes are optimal.
With this need for patient self-management supported by ongoing education in mind, let’s turn our attention to some issues of special importance with respect to the GLP-1 agonists and DPP-4 inhibitors.
Dosing and administration
There is considerable variability among the GLP-1 agonists and DPP-4 inhibitors with respect to their dosing and administration (TABLE).1-4 This variability enables you and your patients to select a treatment that best meets their needs.
Case 2
As you begin to talk about the GLP-1 agonists and DPP-4 inhibitors as treatment options for modifying his therapy, this 47-year-old office manager wants to know what side effects are likely and which, if any, might pose a problem at work.
You can begin by telling the patient that transient nausea has been a common occurrence in patients treated with a GLP-1 agonist and that a key factor regarding this side effect is how the medication is titrated (see accompanying article “Safety, tolerability, and nonglycemic effects of incretin-based therapies”). Exenatide and liraglutide should be administered using the dose escalation strategy outlined in the TABLE. You tell him that nausea is typically mild and usually peaks within 8 weeks of commencing treatment with exenatide5 and within 4 to 6 weeks with liraglutide.6,7 Should nausea persist and be troublesome, taking liraglutide with food has been helpful for some patients; otherwise, liraglutide can be taken at the same time each day irrespective of meals.2 You also note that saxagliptin and sitagliptin can be taken with or without food.3,4 While the prescribing information indicates that exenatide can be taken at any time within the 60-minute period before a meal,1 exenatide can be administered during but not after the meal if necessary to reduce nausea, without sacrificing its glucose-lowering effects8; the satiety effect, however, may be blunted in some patients. Reduction in the postprandial glucose level has been shown to be greatest when exenatide is taken between 60 minutes before or by the end of the meal. Exenatide should not be taken after the meal, because transient low blood glucose levels may occur.8
In patients with renal dysfunction, the dose of sitagliptin and saxagliptin but not liraglutide needs to be adjusted (TABLE).1-4 Exenatide should not be used in patients with a CrCl <30 mL/min. Exenatide and sitagliptin are contraindicated in patients with a known hypersensitivity reaction to the drug.1,3 Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia (MEN) syndrome type 2.2 There are no contraindications listed for saxagliptin.4
TABLE
| GLP-1 | DPP-4 | |||
|---|---|---|---|---|
| Exenatide1 | Liraglutide2 | Sitagliptin3 | Saxagliptin4 | |
| Route | Subcutaneous | Subcutaneous | Oral | Oral |
| Frequency | Twice daily | Once daily | Once daily | Once daily |
| Relation to meals | Within 60 min prior to eating | With/without food | With/without food | With/without food |
| Timing | Before the 2 main daily meals, ≥6 h apart | Any time of day | Any time of day | Any time of day |
| Dosing, initial | 5 μg BID; increase to 10 μg BID after 1 mo if needed for glucose control | 0.6 mg OD x 1 week, then 1.2 mg OD; increase to 1.8 mg OD if needed for glucose control | 100 mg OD | 2.5 mg or 5 mg OD |
| Dosing, renal disease | Do not use if CrCl <30 mL/min or in ESRD; use with caution in patient with renal transplantation | No adjustment; use with caution | CrCl ≥30 to <50 mL/min, 50 mg OD; CrCl <30 mL/min or ESRD requiring dialysis, 25 mg OD | CrCl ≤50 mL/min or ESRD requiring hemo-dialysis, 2.5 mg OD |
| BID, twice daily; CrCl, creatinine clearance; ESRD, end-stage renal disease; OD, once daily. | ||||
Case 1
During your discussion with this building contractor, you begin to talk about the GLP-1 agonists and DPP-4 inhibitors as treatment options. You begin to discuss the need to self-inject the GLP-1 agonist, when he interrupts you and tells you that he does not want to hear anything about insulin or other medications that would require him to self-inject, because his work environment and schedule would make this impossible.
While his feelings are understandable, open communication with this patient can do much to allay his concerns. Although concerns about injecting outside the home are common with insulin, the need for this with a GLP-1 agonist is unlikely because of the twice-daily exenatide and once-daily liraglutide dosing schedules and the lack of need to intensely monitor blood glucose levels. However, if the patient eats breakfast at work or doesn’t eat breakfast at all, this may become an issue with exenatide because of the need to eat within 60 minutes of taking a dose.
Concerns about self-injecting also can be addressed by showing patients the pen injection device and its small-gauge needle and instructing them in its use. Having a patient self-inject the first dose in the office can relieve much anxiety. Patients often comment about how easy and painless it is to inject themselves. One caution, however, is that if a patient self-injects a dose of exenatide in the office, he or she must be reminded of the need to eat within the next hour.
Talking about risks
Case 3
During your discussion with this 68-year-old woman about modifying her therapy, you include the GLP-1 agonists and DPP-4 inhibitors as treatment options. She replies, “Yes, I’ve seen information about them at my job at the library. They can cause cancer, can’t they?”
This comment highlights the importance of talking openly with patients to help them make good decisions about their health. Discussions often focus on the anticipated benefits of medications, but as we know, there are risks associated with every medication choice. Initially discussing risks with this patient could avoid having her return to the office angry with you for not warning her before she began taking the medication.
In this situation, as part of your discussion about liraglutide, you could refer her to the manufacturer’s Web site for information about the Risk Evaluation and Mitigation Strategy (REMS) program for liraglutide, sitagliptin, and saxagliptin. You also could provide her with the patient medication guide included with the program. REMS programs have been implemented for several glucose-lowering medications, since implementation of the REMS program by the US Food and Drug Administration (FDA) in 2007; these include exenatide, liraglutide, pioglitazone with or without glimepiride, rosiglitazone with or without glimepiride, and sitagliptin with or without metformin. Medication guides and other information are available online from the FDA at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm.
Medication cost
Case 3
You continue your discussion with this 68-year-old part-time librarian about the benefits and risks of insulin, a thiazolidinedione, and a glinide, as well as a GLP-1 agonist and a DPP-4 inhibitor. Suddenly she asks you how much these medications cost.
The cost of health care in general and medications in particular continue to dominate discussions. This is especially true for medications that have arrived on the market more recently, including the GLP-1 agonists and the DPP-4 inhibitors, which range in cost from about $7 to $14 per day.9-12 These agents, however, may be covered by health insurance, so cost to the patient may be limited to copays. The lower risk of hypoglycemia observed with the GLP-1 agonists and DPP-4 inhibitors compared with some other glucose-lowering therapies may make it possible to perform self-monitoring of blood glucose less frequently, but this is an individual patient issue.
Although it may be difficult or uncomfortable to talk about the costs of treatment, it has a great impact on medication adherence and overall treatment satisfaction. In this case, in addition to discussing insurance coverage and what she can afford, you should also talk with the patient about ways the cost of her medications might be reduced.
While no generic formulations are available for exenatide, liraglutide, saxagliptin, or sitagliptin, each manufacturer offers a prescription assistance program. Patients should also be encouraged to check manufacturers’ Web sites for available coupons or discount programs.
With this patient, you also might talk about how different medications can affect total cost of her diabetes treatment differently. Limited retrospective analyses suggest that compared with glimepiride, liraglutide reduces the total cost of care, including care for ocular events and neuropathy leading to amputation.13 Other studies indicate that the overall cost of care with exenatide is lower than with insulin glargine,14 including care for hypoglycemia-related events.15
Summary
Working closely with patients and providing ongoing education, ideally in conjunction with a diabetes care team, can help ensure that the best treatment options are selected for an individual patient and that the patient is capable of effective self-management.
1. Byetta [package insert]. San Diego, CA: Amylin Pharmaceuticals, Inc; 2009.
2. Victoza [package insert]. Princeton, NJ: Novo Nordisk Inc; 2010.
3. Januvia [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; February 2, 2010.
4. Onglyza [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2009.
5. DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1092-1100.
6. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373:473-481.
7. Nauck M, Frid A, Hermansen K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009;32:84-90.
8. Linnebjerg H, Kothare PA, Skrivanek Z, et al. Exenatide: effect of injection time on postprandial glucose in patients with type 2 diabetes. Diabet Med. 2006;23:240-245.
9. Byetta (exenatide) pen. Drugstore.com. http://www.drugstore.com/pharmacy/prices/drugprice.asp?ndc=66780021201&trx=1Z5005. Accessed August 18, 2010.
10. Januvia (sitagliptin) tablets. Drugstore.com. http://www.drugstore.com/pharmacy/drugindex/rxsearch.asp?drug=Januvia&trx=1Z5005. Accessed August 18, 2010.
11. Onglyza (saxagliptin) tablets. Drugstore.com. http://www.drugstore.com/pharmacy/prices/drugprice.asp?ndc=00003421521&trx=1Z5006. Accessed August 18, 2010.
12. Victoza (liraglutide) injection. Drugstore.com. http://www.drugstore.com/pharmacy/prices/drugprice.asp?ndc=00169406012&trx=1Z5006. Accessed August 18, 2010.
13. Sullivan SD, Alfonso-Cristancho R, Conner C, et al. A simulation of the comparative long-term effectiveness of liraglutide and glimepiride monotherapies in patients with type 2 diabetes mellitus. Pharmacotherapy. 2009;29:1280-1288.
14. Misurski D, Lage MJ, Fabunmi R, et al. A comparison of costs among patients with type 2 diabetes mellitus who initiated therapy with exenatide or insulin glargine. Appl Health Econ Health Policy. 2009;7:245-254.
15. Fabunmi R, Nielsen LL, Quimbo R, et al. Patient characteristics, drug adherence patterns, and hypoglycemia costs for patients with type 2 diabetes mellitus newly initiated on exenatide or insulin glargine. Curr Med Res Opin. 2009;25:777-786.
Pathophysiology of type 2 diabetes mellitus: potential role of incretin-based therapies
Glucose-lowering effects of incretin-based therapies
Safety, tolerability, and nonglycemic effects of incretin-based therapies
- Patient education, which is essential for successful patient self-management, can be provided by a multidisciplinary diabetes care team
- The dosing and administration of glucagon-like peptide (GLP)-1 agonists or dipeptidyl peptidase (DPP)-4 inhibitors offer significant flexibility to meet patient needs
- The GLP-1 agonists and DPP-4 inhibitors vary in administration, effect on weight, contraindications, and dosing adjustments for patients with renal impairment
- The relatively high cost ($7 to $14 per day) of therapy with a GLP-1 agonist or DPP-4 inhibitor may be covered by insurance, so cost to the patient may be limited to copays
The authors received editorial assistance from the Primary Care Education Consortium and WriteHealth, LLC in the development of this activity and honoraria from the Primary Care Education Consortium. They have disclosed that Dr Campbell is on the advisory board for Daiichi-Sankyo and the speakers bureau for Eli Lilly and Co; Dr Cobble is on the advisory board for Abbott Laboratories, AstraZeneca, and Eli Lilly and Co and speakers bureau for Abbott Laboratories, AstraZeneca/Bristol Myers Squibb, Eli Lilly and Co, GlaxoSmithKline, and Novo Nordisk Inc; Dr Reid is on the advisory board and speakers bureau for Amylin Pharmaceuticals, Medtronic, Novo Nordisk Inc, and sanofi-aventis; and Dr Shomali is on the advisory board for Novo Nordisk Inc and speakers bureau for Amylin Pharmaceuticals, Eli Lilly and Co, sanofi-aventis, and Takeda Pharmaceuticals.
Introduction
The comprehensive and long-term management of patients with type 2 diabetes mellitus (T2DM) requires that they assume primary responsibility for daily self-management. For this to occur, patient education is critical, yet it is time-consuming. Because our time as primary care physicians is limited, developing a diabetes care team, even informally, can be helpful in providing the comprehensive care that is needed. Beyond easing the amount of time we need to provide the patient education required, the patient is able to benefit from the specialized skills and knowledge of other team members, such as a nurse, pharmacist, dietitian, certified diabetes educator, or an exercise specialist. It is important, however, that as primary care physicians, we coordinate the care provided by the team so that treatment goals are clear, communication is maintained, and patient outcomes are optimal.
With this need for patient self-management supported by ongoing education in mind, let’s turn our attention to some issues of special importance with respect to the GLP-1 agonists and DPP-4 inhibitors.
Dosing and administration
There is considerable variability among the GLP-1 agonists and DPP-4 inhibitors with respect to their dosing and administration (TABLE).1-4 This variability enables you and your patients to select a treatment that best meets their needs.
Case 2
As you begin to talk about the GLP-1 agonists and DPP-4 inhibitors as treatment options for modifying his therapy, this 47-year-old office manager wants to know what side effects are likely and which, if any, might pose a problem at work.
You can begin by telling the patient that transient nausea has been a common occurrence in patients treated with a GLP-1 agonist and that a key factor regarding this side effect is how the medication is titrated (see accompanying article “Safety, tolerability, and nonglycemic effects of incretin-based therapies”). Exenatide and liraglutide should be administered using the dose escalation strategy outlined in the TABLE. You tell him that nausea is typically mild and usually peaks within 8 weeks of commencing treatment with exenatide5 and within 4 to 6 weeks with liraglutide.6,7 Should nausea persist and be troublesome, taking liraglutide with food has been helpful for some patients; otherwise, liraglutide can be taken at the same time each day irrespective of meals.2 You also note that saxagliptin and sitagliptin can be taken with or without food.3,4 While the prescribing information indicates that exenatide can be taken at any time within the 60-minute period before a meal,1 exenatide can be administered during but not after the meal if necessary to reduce nausea, without sacrificing its glucose-lowering effects8; the satiety effect, however, may be blunted in some patients. Reduction in the postprandial glucose level has been shown to be greatest when exenatide is taken between 60 minutes before or by the end of the meal. Exenatide should not be taken after the meal, because transient low blood glucose levels may occur.8
In patients with renal dysfunction, the dose of sitagliptin and saxagliptin but not liraglutide needs to be adjusted (TABLE).1-4 Exenatide should not be used in patients with a CrCl <30 mL/min. Exenatide and sitagliptin are contraindicated in patients with a known hypersensitivity reaction to the drug.1,3 Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia (MEN) syndrome type 2.2 There are no contraindications listed for saxagliptin.4
TABLE
| GLP-1 | DPP-4 | |||
|---|---|---|---|---|
| Exenatide1 | Liraglutide2 | Sitagliptin3 | Saxagliptin4 | |
| Route | Subcutaneous | Subcutaneous | Oral | Oral |
| Frequency | Twice daily | Once daily | Once daily | Once daily |
| Relation to meals | Within 60 min prior to eating | With/without food | With/without food | With/without food |
| Timing | Before the 2 main daily meals, ≥6 h apart | Any time of day | Any time of day | Any time of day |
| Dosing, initial | 5 μg BID; increase to 10 μg BID after 1 mo if needed for glucose control | 0.6 mg OD x 1 week, then 1.2 mg OD; increase to 1.8 mg OD if needed for glucose control | 100 mg OD | 2.5 mg or 5 mg OD |
| Dosing, renal disease | Do not use if CrCl <30 mL/min or in ESRD; use with caution in patient with renal transplantation | No adjustment; use with caution | CrCl ≥30 to <50 mL/min, 50 mg OD; CrCl <30 mL/min or ESRD requiring dialysis, 25 mg OD | CrCl ≤50 mL/min or ESRD requiring hemo-dialysis, 2.5 mg OD |
| BID, twice daily; CrCl, creatinine clearance; ESRD, end-stage renal disease; OD, once daily. | ||||
Case 1
During your discussion with this building contractor, you begin to talk about the GLP-1 agonists and DPP-4 inhibitors as treatment options. You begin to discuss the need to self-inject the GLP-1 agonist, when he interrupts you and tells you that he does not want to hear anything about insulin or other medications that would require him to self-inject, because his work environment and schedule would make this impossible.
While his feelings are understandable, open communication with this patient can do much to allay his concerns. Although concerns about injecting outside the home are common with insulin, the need for this with a GLP-1 agonist is unlikely because of the twice-daily exenatide and once-daily liraglutide dosing schedules and the lack of need to intensely monitor blood glucose levels. However, if the patient eats breakfast at work or doesn’t eat breakfast at all, this may become an issue with exenatide because of the need to eat within 60 minutes of taking a dose.
Concerns about self-injecting also can be addressed by showing patients the pen injection device and its small-gauge needle and instructing them in its use. Having a patient self-inject the first dose in the office can relieve much anxiety. Patients often comment about how easy and painless it is to inject themselves. One caution, however, is that if a patient self-injects a dose of exenatide in the office, he or she must be reminded of the need to eat within the next hour.
Talking about risks
Case 3
During your discussion with this 68-year-old woman about modifying her therapy, you include the GLP-1 agonists and DPP-4 inhibitors as treatment options. She replies, “Yes, I’ve seen information about them at my job at the library. They can cause cancer, can’t they?”
This comment highlights the importance of talking openly with patients to help them make good decisions about their health. Discussions often focus on the anticipated benefits of medications, but as we know, there are risks associated with every medication choice. Initially discussing risks with this patient could avoid having her return to the office angry with you for not warning her before she began taking the medication.
In this situation, as part of your discussion about liraglutide, you could refer her to the manufacturer’s Web site for information about the Risk Evaluation and Mitigation Strategy (REMS) program for liraglutide, sitagliptin, and saxagliptin. You also could provide her with the patient medication guide included with the program. REMS programs have been implemented for several glucose-lowering medications, since implementation of the REMS program by the US Food and Drug Administration (FDA) in 2007; these include exenatide, liraglutide, pioglitazone with or without glimepiride, rosiglitazone with or without glimepiride, and sitagliptin with or without metformin. Medication guides and other information are available online from the FDA at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm.
Medication cost
Case 3
You continue your discussion with this 68-year-old part-time librarian about the benefits and risks of insulin, a thiazolidinedione, and a glinide, as well as a GLP-1 agonist and a DPP-4 inhibitor. Suddenly she asks you how much these medications cost.
The cost of health care in general and medications in particular continue to dominate discussions. This is especially true for medications that have arrived on the market more recently, including the GLP-1 agonists and the DPP-4 inhibitors, which range in cost from about $7 to $14 per day.9-12 These agents, however, may be covered by health insurance, so cost to the patient may be limited to copays. The lower risk of hypoglycemia observed with the GLP-1 agonists and DPP-4 inhibitors compared with some other glucose-lowering therapies may make it possible to perform self-monitoring of blood glucose less frequently, but this is an individual patient issue.
Although it may be difficult or uncomfortable to talk about the costs of treatment, it has a great impact on medication adherence and overall treatment satisfaction. In this case, in addition to discussing insurance coverage and what she can afford, you should also talk with the patient about ways the cost of her medications might be reduced.
While no generic formulations are available for exenatide, liraglutide, saxagliptin, or sitagliptin, each manufacturer offers a prescription assistance program. Patients should also be encouraged to check manufacturers’ Web sites for available coupons or discount programs.
With this patient, you also might talk about how different medications can affect total cost of her diabetes treatment differently. Limited retrospective analyses suggest that compared with glimepiride, liraglutide reduces the total cost of care, including care for ocular events and neuropathy leading to amputation.13 Other studies indicate that the overall cost of care with exenatide is lower than with insulin glargine,14 including care for hypoglycemia-related events.15
Summary
Working closely with patients and providing ongoing education, ideally in conjunction with a diabetes care team, can help ensure that the best treatment options are selected for an individual patient and that the patient is capable of effective self-management.
Pathophysiology of type 2 diabetes mellitus: potential role of incretin-based therapies
Glucose-lowering effects of incretin-based therapies
Safety, tolerability, and nonglycemic effects of incretin-based therapies
- Patient education, which is essential for successful patient self-management, can be provided by a multidisciplinary diabetes care team
- The dosing and administration of glucagon-like peptide (GLP)-1 agonists or dipeptidyl peptidase (DPP)-4 inhibitors offer significant flexibility to meet patient needs
- The GLP-1 agonists and DPP-4 inhibitors vary in administration, effect on weight, contraindications, and dosing adjustments for patients with renal impairment
- The relatively high cost ($7 to $14 per day) of therapy with a GLP-1 agonist or DPP-4 inhibitor may be covered by insurance, so cost to the patient may be limited to copays
The authors received editorial assistance from the Primary Care Education Consortium and WriteHealth, LLC in the development of this activity and honoraria from the Primary Care Education Consortium. They have disclosed that Dr Campbell is on the advisory board for Daiichi-Sankyo and the speakers bureau for Eli Lilly and Co; Dr Cobble is on the advisory board for Abbott Laboratories, AstraZeneca, and Eli Lilly and Co and speakers bureau for Abbott Laboratories, AstraZeneca/Bristol Myers Squibb, Eli Lilly and Co, GlaxoSmithKline, and Novo Nordisk Inc; Dr Reid is on the advisory board and speakers bureau for Amylin Pharmaceuticals, Medtronic, Novo Nordisk Inc, and sanofi-aventis; and Dr Shomali is on the advisory board for Novo Nordisk Inc and speakers bureau for Amylin Pharmaceuticals, Eli Lilly and Co, sanofi-aventis, and Takeda Pharmaceuticals.
Introduction
The comprehensive and long-term management of patients with type 2 diabetes mellitus (T2DM) requires that they assume primary responsibility for daily self-management. For this to occur, patient education is critical, yet it is time-consuming. Because our time as primary care physicians is limited, developing a diabetes care team, even informally, can be helpful in providing the comprehensive care that is needed. Beyond easing the amount of time we need to provide the patient education required, the patient is able to benefit from the specialized skills and knowledge of other team members, such as a nurse, pharmacist, dietitian, certified diabetes educator, or an exercise specialist. It is important, however, that as primary care physicians, we coordinate the care provided by the team so that treatment goals are clear, communication is maintained, and patient outcomes are optimal.
With this need for patient self-management supported by ongoing education in mind, let’s turn our attention to some issues of special importance with respect to the GLP-1 agonists and DPP-4 inhibitors.
Dosing and administration
There is considerable variability among the GLP-1 agonists and DPP-4 inhibitors with respect to their dosing and administration (TABLE).1-4 This variability enables you and your patients to select a treatment that best meets their needs.
Case 2
As you begin to talk about the GLP-1 agonists and DPP-4 inhibitors as treatment options for modifying his therapy, this 47-year-old office manager wants to know what side effects are likely and which, if any, might pose a problem at work.
You can begin by telling the patient that transient nausea has been a common occurrence in patients treated with a GLP-1 agonist and that a key factor regarding this side effect is how the medication is titrated (see accompanying article “Safety, tolerability, and nonglycemic effects of incretin-based therapies”). Exenatide and liraglutide should be administered using the dose escalation strategy outlined in the TABLE. You tell him that nausea is typically mild and usually peaks within 8 weeks of commencing treatment with exenatide5 and within 4 to 6 weeks with liraglutide.6,7 Should nausea persist and be troublesome, taking liraglutide with food has been helpful for some patients; otherwise, liraglutide can be taken at the same time each day irrespective of meals.2 You also note that saxagliptin and sitagliptin can be taken with or without food.3,4 While the prescribing information indicates that exenatide can be taken at any time within the 60-minute period before a meal,1 exenatide can be administered during but not after the meal if necessary to reduce nausea, without sacrificing its glucose-lowering effects8; the satiety effect, however, may be blunted in some patients. Reduction in the postprandial glucose level has been shown to be greatest when exenatide is taken between 60 minutes before or by the end of the meal. Exenatide should not be taken after the meal, because transient low blood glucose levels may occur.8
In patients with renal dysfunction, the dose of sitagliptin and saxagliptin but not liraglutide needs to be adjusted (TABLE).1-4 Exenatide should not be used in patients with a CrCl <30 mL/min. Exenatide and sitagliptin are contraindicated in patients with a known hypersensitivity reaction to the drug.1,3 Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia (MEN) syndrome type 2.2 There are no contraindications listed for saxagliptin.4
TABLE
| GLP-1 | DPP-4 | |||
|---|---|---|---|---|
| Exenatide1 | Liraglutide2 | Sitagliptin3 | Saxagliptin4 | |
| Route | Subcutaneous | Subcutaneous | Oral | Oral |
| Frequency | Twice daily | Once daily | Once daily | Once daily |
| Relation to meals | Within 60 min prior to eating | With/without food | With/without food | With/without food |
| Timing | Before the 2 main daily meals, ≥6 h apart | Any time of day | Any time of day | Any time of day |
| Dosing, initial | 5 μg BID; increase to 10 μg BID after 1 mo if needed for glucose control | 0.6 mg OD x 1 week, then 1.2 mg OD; increase to 1.8 mg OD if needed for glucose control | 100 mg OD | 2.5 mg or 5 mg OD |
| Dosing, renal disease | Do not use if CrCl <30 mL/min or in ESRD; use with caution in patient with renal transplantation | No adjustment; use with caution | CrCl ≥30 to <50 mL/min, 50 mg OD; CrCl <30 mL/min or ESRD requiring dialysis, 25 mg OD | CrCl ≤50 mL/min or ESRD requiring hemo-dialysis, 2.5 mg OD |
| BID, twice daily; CrCl, creatinine clearance; ESRD, end-stage renal disease; OD, once daily. | ||||
Case 1
During your discussion with this building contractor, you begin to talk about the GLP-1 agonists and DPP-4 inhibitors as treatment options. You begin to discuss the need to self-inject the GLP-1 agonist, when he interrupts you and tells you that he does not want to hear anything about insulin or other medications that would require him to self-inject, because his work environment and schedule would make this impossible.
While his feelings are understandable, open communication with this patient can do much to allay his concerns. Although concerns about injecting outside the home are common with insulin, the need for this with a GLP-1 agonist is unlikely because of the twice-daily exenatide and once-daily liraglutide dosing schedules and the lack of need to intensely monitor blood glucose levels. However, if the patient eats breakfast at work or doesn’t eat breakfast at all, this may become an issue with exenatide because of the need to eat within 60 minutes of taking a dose.
Concerns about self-injecting also can be addressed by showing patients the pen injection device and its small-gauge needle and instructing them in its use. Having a patient self-inject the first dose in the office can relieve much anxiety. Patients often comment about how easy and painless it is to inject themselves. One caution, however, is that if a patient self-injects a dose of exenatide in the office, he or she must be reminded of the need to eat within the next hour.
Talking about risks
Case 3
During your discussion with this 68-year-old woman about modifying her therapy, you include the GLP-1 agonists and DPP-4 inhibitors as treatment options. She replies, “Yes, I’ve seen information about them at my job at the library. They can cause cancer, can’t they?”
This comment highlights the importance of talking openly with patients to help them make good decisions about their health. Discussions often focus on the anticipated benefits of medications, but as we know, there are risks associated with every medication choice. Initially discussing risks with this patient could avoid having her return to the office angry with you for not warning her before she began taking the medication.
In this situation, as part of your discussion about liraglutide, you could refer her to the manufacturer’s Web site for information about the Risk Evaluation and Mitigation Strategy (REMS) program for liraglutide, sitagliptin, and saxagliptin. You also could provide her with the patient medication guide included with the program. REMS programs have been implemented for several glucose-lowering medications, since implementation of the REMS program by the US Food and Drug Administration (FDA) in 2007; these include exenatide, liraglutide, pioglitazone with or without glimepiride, rosiglitazone with or without glimepiride, and sitagliptin with or without metformin. Medication guides and other information are available online from the FDA at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm.
Medication cost
Case 3
You continue your discussion with this 68-year-old part-time librarian about the benefits and risks of insulin, a thiazolidinedione, and a glinide, as well as a GLP-1 agonist and a DPP-4 inhibitor. Suddenly she asks you how much these medications cost.
The cost of health care in general and medications in particular continue to dominate discussions. This is especially true for medications that have arrived on the market more recently, including the GLP-1 agonists and the DPP-4 inhibitors, which range in cost from about $7 to $14 per day.9-12 These agents, however, may be covered by health insurance, so cost to the patient may be limited to copays. The lower risk of hypoglycemia observed with the GLP-1 agonists and DPP-4 inhibitors compared with some other glucose-lowering therapies may make it possible to perform self-monitoring of blood glucose less frequently, but this is an individual patient issue.
Although it may be difficult or uncomfortable to talk about the costs of treatment, it has a great impact on medication adherence and overall treatment satisfaction. In this case, in addition to discussing insurance coverage and what she can afford, you should also talk with the patient about ways the cost of her medications might be reduced.
While no generic formulations are available for exenatide, liraglutide, saxagliptin, or sitagliptin, each manufacturer offers a prescription assistance program. Patients should also be encouraged to check manufacturers’ Web sites for available coupons or discount programs.
With this patient, you also might talk about how different medications can affect total cost of her diabetes treatment differently. Limited retrospective analyses suggest that compared with glimepiride, liraglutide reduces the total cost of care, including care for ocular events and neuropathy leading to amputation.13 Other studies indicate that the overall cost of care with exenatide is lower than with insulin glargine,14 including care for hypoglycemia-related events.15
Summary
Working closely with patients and providing ongoing education, ideally in conjunction with a diabetes care team, can help ensure that the best treatment options are selected for an individual patient and that the patient is capable of effective self-management.
1. Byetta [package insert]. San Diego, CA: Amylin Pharmaceuticals, Inc; 2009.
2. Victoza [package insert]. Princeton, NJ: Novo Nordisk Inc; 2010.
3. Januvia [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; February 2, 2010.
4. Onglyza [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2009.
5. DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1092-1100.
6. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373:473-481.
7. Nauck M, Frid A, Hermansen K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009;32:84-90.
8. Linnebjerg H, Kothare PA, Skrivanek Z, et al. Exenatide: effect of injection time on postprandial glucose in patients with type 2 diabetes. Diabet Med. 2006;23:240-245.
9. Byetta (exenatide) pen. Drugstore.com. http://www.drugstore.com/pharmacy/prices/drugprice.asp?ndc=66780021201&trx=1Z5005. Accessed August 18, 2010.
10. Januvia (sitagliptin) tablets. Drugstore.com. http://www.drugstore.com/pharmacy/drugindex/rxsearch.asp?drug=Januvia&trx=1Z5005. Accessed August 18, 2010.
11. Onglyza (saxagliptin) tablets. Drugstore.com. http://www.drugstore.com/pharmacy/prices/drugprice.asp?ndc=00003421521&trx=1Z5006. Accessed August 18, 2010.
12. Victoza (liraglutide) injection. Drugstore.com. http://www.drugstore.com/pharmacy/prices/drugprice.asp?ndc=00169406012&trx=1Z5006. Accessed August 18, 2010.
13. Sullivan SD, Alfonso-Cristancho R, Conner C, et al. A simulation of the comparative long-term effectiveness of liraglutide and glimepiride monotherapies in patients with type 2 diabetes mellitus. Pharmacotherapy. 2009;29:1280-1288.
14. Misurski D, Lage MJ, Fabunmi R, et al. A comparison of costs among patients with type 2 diabetes mellitus who initiated therapy with exenatide or insulin glargine. Appl Health Econ Health Policy. 2009;7:245-254.
15. Fabunmi R, Nielsen LL, Quimbo R, et al. Patient characteristics, drug adherence patterns, and hypoglycemia costs for patients with type 2 diabetes mellitus newly initiated on exenatide or insulin glargine. Curr Med Res Opin. 2009;25:777-786.
1. Byetta [package insert]. San Diego, CA: Amylin Pharmaceuticals, Inc; 2009.
2. Victoza [package insert]. Princeton, NJ: Novo Nordisk Inc; 2010.
3. Januvia [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; February 2, 2010.
4. Onglyza [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2009.
5. DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1092-1100.
6. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373:473-481.
7. Nauck M, Frid A, Hermansen K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009;32:84-90.
8. Linnebjerg H, Kothare PA, Skrivanek Z, et al. Exenatide: effect of injection time on postprandial glucose in patients with type 2 diabetes. Diabet Med. 2006;23:240-245.
9. Byetta (exenatide) pen. Drugstore.com. http://www.drugstore.com/pharmacy/prices/drugprice.asp?ndc=66780021201&trx=1Z5005. Accessed August 18, 2010.
10. Januvia (sitagliptin) tablets. Drugstore.com. http://www.drugstore.com/pharmacy/drugindex/rxsearch.asp?drug=Januvia&trx=1Z5005. Accessed August 18, 2010.
11. Onglyza (saxagliptin) tablets. Drugstore.com. http://www.drugstore.com/pharmacy/prices/drugprice.asp?ndc=00003421521&trx=1Z5006. Accessed August 18, 2010.
12. Victoza (liraglutide) injection. Drugstore.com. http://www.drugstore.com/pharmacy/prices/drugprice.asp?ndc=00169406012&trx=1Z5006. Accessed August 18, 2010.
13. Sullivan SD, Alfonso-Cristancho R, Conner C, et al. A simulation of the comparative long-term effectiveness of liraglutide and glimepiride monotherapies in patients with type 2 diabetes mellitus. Pharmacotherapy. 2009;29:1280-1288.
14. Misurski D, Lage MJ, Fabunmi R, et al. A comparison of costs among patients with type 2 diabetes mellitus who initiated therapy with exenatide or insulin glargine. Appl Health Econ Health Policy. 2009;7:245-254.
15. Fabunmi R, Nielsen LL, Quimbo R, et al. Patient characteristics, drug adherence patterns, and hypoglycemia costs for patients with type 2 diabetes mellitus newly initiated on exenatide or insulin glargine. Curr Med Res Opin. 2009;25:777-786.