Let’s REWIND: Looking back to the roots of GLP1-RAs
04 Jul 2023
byJoanne G. Blanco, MD
Over the years, the goals of diabetes management have
evolved to encompass not only glycemic control but also the prevention and
management of associated complications. Managing diabetes requires a
comprehensive, holistic, and person-centered approach that goes beyond simply
controlling blood glucose levels. There are four fundamental pillars of
diabetes care that can guide the approach to achieving optimal outcomes: blood
glucose control, risk factor management, organ protection, and weight
management.1
Revisiting the goals of care in diabetes
Preventing complications is one of the primary goals of diabetes care.1 Diabetes can lead to a wide range of complications, including ischemic heart disease, stroke, retinopathy, nephropathy, and neuropathy. However, the importance of optimizing quality of life for individuals with diabetes should not be overlooked. Diabetes can significantly impact daily life affecting physical, emotional, and social well-being. Patient education plays an instrumental role in empowering patients to take an active role in their care. In the same way, encouraging a well-balanced diet, weight management, regular exercise, and adequate sleep can help control blood sugar levels and improve overall well-being.1,2
More than just weight loss
Originally known for their weight loss properties, GLP-1 RAs have demonstrated far-reaching effects beyond weight management alone.3 The development of GLP-1 RAs can be traced back to the discovery of glucagon-like peptide-1 (GLP-1) in the early 1980s.4 GLP-1 is an incretin hormone secreted by the intestine in response to food intake, stimulating insulin secretion and suppressing glucagon release.5 Researchers recognized the potential of harnessing the therapeutic effects GLP-1 but the short half-life of native GLP-1 limited its clinical utility. This led to the development of GLP-1 RAs, which have a longer duration of action and enhanced stability.6
Cardioprotective Effects
Because individuals with diabetes are prone to cardiovascular comorbidities, cardioprotective treatment approaches are crucial for these cases. Recent findings from randomized trials indicate that various novel types of glucose-lowering medications, such as DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors, have positive effects on the cardiovascular outcomes of diabetics, and enhance metabolic restructuring in individuals with type 2 diabetes mellitus (T2DM). One such drug is dulaglutide, one of the newer long-acting GLP-1 RA that significantly improves cardiovascular outcomes.7
Several studies have explored the cardioprotective effects of dulaglutide. Significant trials include the REWIND trial, a multicenter, randomized, double-blind, placebo-controlled trial that recruited individuals with T2DM who had either a previous cardiovascular event or multiple cardiovascular risk factors. The trial compared cardiovascular outcomes between groups receiving either weekly subcutaneous injection of dulaglutide (1.5 mg) or placebo.
REWIND lasted for 5.4 years and showed that a weekly injection of 1.5 mg dulaglutide reduced the risk of cardiovascular outcomes compared with placebo.8 A subgroup analysis of the trial also showed that dulaglutide is cardioprotective with or without background metformin in patients with diabetes and established or high risk for coronary vascular disease.9
Figure 1. Middle-aged and older adults with type 2 diabetes and additional cardiovascular risk factors assigned the GLP-1 receptor agonist dulaglutide were 24% less likely to experience stroke during 5 years of follow-up compared with those assigned placebo.
Renoprotective Effects
While prevention of cardiovascular disease is an important therapeutic target in diabetes, diabetic kidney disease is a significant concern as well. Evidence has found that dulaglutide can still provide glycemic control across stages 1-4 of chronic kidney disease, and that it can help reduce estimated glomerular filtration rate (eGFR) decline in CKD patients.10
The results of the REWIND trial also showed that dulaglutide reduced negative renal effects, represented by the composite renal outcome of the development of macroalbuminuria, a sustained 30% or greater decline in eGFR calculated using serum creatinine, and the need for renal replacement therapy.8
The AWARD-7 study found that dulaglutide helped slow the progression of kidney disease and prevent the progression of albuminuria in patients with both T2DM and moderate-to-severe CKD (stages 3-4), with an HbA1c of 7∙5–10∙5%, and who were being treated with insulin or insulin plus an oral antihyperglycemic drug and were taking a maximum tolerated dose of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. This study is significant as it used cystatin C instead of creatinine to estimate GFR.11
Anti-inflammatory Effects
Dulaglutide has also shown anti-inflammatory effects, including reductions in markers such as C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and advanced glycation end products (AGEs) in patients with T2DM. These findings could be significant, as chronic low-grade inflammation is associated with diabetes, as well as its progression and complications.12
Understanding the indications of GLP-1 RAs
GLP-1 RAs are primarily used as an adjunct to diet and exercise to improve glycemic control in patients with T2DM. They are indicated for individuals who have not achieved adequate glycemic control with oral antidiabetic agents or those who require additional glucose-lowering medications. GLP-1 RAs are commonly prescribed when metformin alone is insufficient or not tolerated.13
GLP-1 RAs have shown efficacy in T2DM patients with various comorbidities, including overweight or obese individuals, those with cardiovascular disease or CKD, and patients seeking weight loss benefits alongside glucose control. They can be used as monotherapy or in combination with other antidiabetic agents such as metformin, sulfonylureas, or insulin.14
What sets dulaglutide apart
Based on the results of the REWIND trial, Dulaglutide is the first and only GLP-1 RA to demonstrate primary and secondary prevention of major adverse CV events8 in patients with T2DM at CV risk. The results of the REWIND trial suggest that dulaglutide could be added to the management of patients with diabetes and additional cardiovascular risk factors to reduce glucose concentrations, minimize hypoglycemia, reduce weight and blood pressure, and reduce cardiovascular events.8
Dulaglutide has been shown to reduce major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, in patients with T2DM with or without established CVD.8,9 It has also shown a reduction in albuminuria, which is an important marker of kidney disease progression, and it may benefit patients with both T2DM and CKD.10
Another feature of dulaglutide is its extended half-life of roughly 5 days, allowing for once-weekly dosing, which is advantageous compared to some GLP1-RAs, which require once- or twice-daily dosing.15,16 The less frequent dosing schedule of dulaglutide enhances convenience and treatment adherence for patients, reducing the burden of daily injections. Additionally, in a study comparing the time and accuracy of use and participants' satisfaction and preferences with pen devices for the once-weekly GLP-1 RAs dulaglutide, exenatide, and semaglutide, most of the participants (75%) preferred the dulaglutide device overall.17
Evidence also shows that dulaglutide compares favorably to other GLP-1 RAs, with studies showing dulaglutide having greater HbA1c reductions than liraglutide, and higher adherence rates compared to exenatide and liraglutide.16
Overall, dulaglutide has a favorable safety profile. Common side effects include gastrointestinal symptoms such as nausea, vomiting, and diarrhea, which are usually mild and transient. Hypoglycemia is less likely to occur with dulaglutide monotherapy but can occur when combined with sulfonylureas or insulin.15
Conclusion
Dulaglutide, a member of the GLP1-RA class, offers several distinguishing features that set it apart from other medications in its category. Its benefits on glycemic control, cardiovascular and renal outcomes, and even on weight make dulaglutide a reliable choice for healthcare professionals managing T2DM.
References:
1. Davies MJ, Aroda VR, Collins BS, et al. Diabetes Care 2022;45:2753–2786.
2. Fenton JJ, Von Korff M, Lin EH, Ciechanowski P, Young BA. Ann Fam Med 2006;4:32–39.
3. Sheahan KH, Wahlberg EA, Gilbert MP. Postgrad Med J 2020;96:156–161.
4. Manandhar B, Ahn JM. J Med Chem 2015;58:1020–1037.
5. Cornell S. J Clin Pharm Ther 2020;45:17–27.
6. McBrayer DN, Tal-Gan Y. Drug Dev Res 2017;78:292–299.
7. Xie S, et al. J Am Heart Assoc 2022;11:e026728.
8. Gerstein HC, et al. The Lancet 2019;394:121–130.
9. Ferrannini G, et al. European Heart Journal 2020;41:3353.
10. Kim S, et al. PLoS One. 2022;17:e0273004.
11. Tuttle KR, et al. Lancet Diabetes Endocrinol 2018;6:605–17.
12. Xie D, et al. Cardiovasc Diabetol 2022;21:200.
13. Hinnen D. Diabetes Spectr 2017;30:202–210.
14. Blonde L, et al. Endocrine Practice 2022;28:923–1049.
15. Smith LL, et al. Pharmacy & Therapeutics 2016;41:357–360.
16. Latif W, et al. 2023 Mar 27. In: StatPearls [Internet]
17. Wettergreen SA, et al. Diabetes Spectr 2023;36:5–13.
PH-NP-LILLY-TRULIC-NR-HCP-000014 JUNE 2023
Revisiting the goals of care in diabetes
Preventing complications is one of the primary goals of diabetes care.1 Diabetes can lead to a wide range of complications, including ischemic heart disease, stroke, retinopathy, nephropathy, and neuropathy. However, the importance of optimizing quality of life for individuals with diabetes should not be overlooked. Diabetes can significantly impact daily life affecting physical, emotional, and social well-being. Patient education plays an instrumental role in empowering patients to take an active role in their care. In the same way, encouraging a well-balanced diet, weight management, regular exercise, and adequate sleep can help control blood sugar levels and improve overall well-being.1,2
More than just weight loss
Originally known for their weight loss properties, GLP-1 RAs have demonstrated far-reaching effects beyond weight management alone.3 The development of GLP-1 RAs can be traced back to the discovery of glucagon-like peptide-1 (GLP-1) in the early 1980s.4 GLP-1 is an incretin hormone secreted by the intestine in response to food intake, stimulating insulin secretion and suppressing glucagon release.5 Researchers recognized the potential of harnessing the therapeutic effects GLP-1 but the short half-life of native GLP-1 limited its clinical utility. This led to the development of GLP-1 RAs, which have a longer duration of action and enhanced stability.6
Cardioprotective Effects
Because individuals with diabetes are prone to cardiovascular comorbidities, cardioprotective treatment approaches are crucial for these cases. Recent findings from randomized trials indicate that various novel types of glucose-lowering medications, such as DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors, have positive effects on the cardiovascular outcomes of diabetics, and enhance metabolic restructuring in individuals with type 2 diabetes mellitus (T2DM). One such drug is dulaglutide, one of the newer long-acting GLP-1 RA that significantly improves cardiovascular outcomes.7
Several studies have explored the cardioprotective effects of dulaglutide. Significant trials include the REWIND trial, a multicenter, randomized, double-blind, placebo-controlled trial that recruited individuals with T2DM who had either a previous cardiovascular event or multiple cardiovascular risk factors. The trial compared cardiovascular outcomes between groups receiving either weekly subcutaneous injection of dulaglutide (1.5 mg) or placebo.
REWIND lasted for 5.4 years and showed that a weekly injection of 1.5 mg dulaglutide reduced the risk of cardiovascular outcomes compared with placebo.8 A subgroup analysis of the trial also showed that dulaglutide is cardioprotective with or without background metformin in patients with diabetes and established or high risk for coronary vascular disease.9
Figure 1. Middle-aged and older adults with type 2 diabetes and additional cardiovascular risk factors assigned the GLP-1 receptor agonist dulaglutide were 24% less likely to experience stroke during 5 years of follow-up compared with those assigned placebo.Renoprotective Effects
While prevention of cardiovascular disease is an important therapeutic target in diabetes, diabetic kidney disease is a significant concern as well. Evidence has found that dulaglutide can still provide glycemic control across stages 1-4 of chronic kidney disease, and that it can help reduce estimated glomerular filtration rate (eGFR) decline in CKD patients.10
The results of the REWIND trial also showed that dulaglutide reduced negative renal effects, represented by the composite renal outcome of the development of macroalbuminuria, a sustained 30% or greater decline in eGFR calculated using serum creatinine, and the need for renal replacement therapy.8
The AWARD-7 study found that dulaglutide helped slow the progression of kidney disease and prevent the progression of albuminuria in patients with both T2DM and moderate-to-severe CKD (stages 3-4), with an HbA1c of 7∙5–10∙5%, and who were being treated with insulin or insulin plus an oral antihyperglycemic drug and were taking a maximum tolerated dose of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. This study is significant as it used cystatin C instead of creatinine to estimate GFR.11
Anti-inflammatory Effects
Dulaglutide has also shown anti-inflammatory effects, including reductions in markers such as C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and advanced glycation end products (AGEs) in patients with T2DM. These findings could be significant, as chronic low-grade inflammation is associated with diabetes, as well as its progression and complications.12
Understanding the indications of GLP-1 RAs
GLP-1 RAs are primarily used as an adjunct to diet and exercise to improve glycemic control in patients with T2DM. They are indicated for individuals who have not achieved adequate glycemic control with oral antidiabetic agents or those who require additional glucose-lowering medications. GLP-1 RAs are commonly prescribed when metformin alone is insufficient or not tolerated.13
GLP-1 RAs have shown efficacy in T2DM patients with various comorbidities, including overweight or obese individuals, those with cardiovascular disease or CKD, and patients seeking weight loss benefits alongside glucose control. They can be used as monotherapy or in combination with other antidiabetic agents such as metformin, sulfonylureas, or insulin.14
What sets dulaglutide apart
Based on the results of the REWIND trial, Dulaglutide is the first and only GLP-1 RA to demonstrate primary and secondary prevention of major adverse CV events8 in patients with T2DM at CV risk. The results of the REWIND trial suggest that dulaglutide could be added to the management of patients with diabetes and additional cardiovascular risk factors to reduce glucose concentrations, minimize hypoglycemia, reduce weight and blood pressure, and reduce cardiovascular events.8
Dulaglutide has been shown to reduce major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, in patients with T2DM with or without established CVD.8,9 It has also shown a reduction in albuminuria, which is an important marker of kidney disease progression, and it may benefit patients with both T2DM and CKD.10
Another feature of dulaglutide is its extended half-life of roughly 5 days, allowing for once-weekly dosing, which is advantageous compared to some GLP1-RAs, which require once- or twice-daily dosing.15,16 The less frequent dosing schedule of dulaglutide enhances convenience and treatment adherence for patients, reducing the burden of daily injections. Additionally, in a study comparing the time and accuracy of use and participants' satisfaction and preferences with pen devices for the once-weekly GLP-1 RAs dulaglutide, exenatide, and semaglutide, most of the participants (75%) preferred the dulaglutide device overall.17
Evidence also shows that dulaglutide compares favorably to other GLP-1 RAs, with studies showing dulaglutide having greater HbA1c reductions than liraglutide, and higher adherence rates compared to exenatide and liraglutide.16
Overall, dulaglutide has a favorable safety profile. Common side effects include gastrointestinal symptoms such as nausea, vomiting, and diarrhea, which are usually mild and transient. Hypoglycemia is less likely to occur with dulaglutide monotherapy but can occur when combined with sulfonylureas or insulin.15
Conclusion
Dulaglutide, a member of the GLP1-RA class, offers several distinguishing features that set it apart from other medications in its category. Its benefits on glycemic control, cardiovascular and renal outcomes, and even on weight make dulaglutide a reliable choice for healthcare professionals managing T2DM.
References:
1. Davies MJ, Aroda VR, Collins BS, et al. Diabetes Care 2022;45:2753–2786.
2. Fenton JJ, Von Korff M, Lin EH, Ciechanowski P, Young BA. Ann Fam Med 2006;4:32–39.
3. Sheahan KH, Wahlberg EA, Gilbert MP. Postgrad Med J 2020;96:156–161.
4. Manandhar B, Ahn JM. J Med Chem 2015;58:1020–1037.
5. Cornell S. J Clin Pharm Ther 2020;45:17–27.
6. McBrayer DN, Tal-Gan Y. Drug Dev Res 2017;78:292–299.
7. Xie S, et al. J Am Heart Assoc 2022;11:e026728.
8. Gerstein HC, et al. The Lancet 2019;394:121–130.
9. Ferrannini G, et al. European Heart Journal 2020;41:3353.
10. Kim S, et al. PLoS One. 2022;17:e0273004.
11. Tuttle KR, et al. Lancet Diabetes Endocrinol 2018;6:605–17.
12. Xie D, et al. Cardiovasc Diabetol 2022;21:200.
13. Hinnen D. Diabetes Spectr 2017;30:202–210.
14. Blonde L, et al. Endocrine Practice 2022;28:923–1049.
15. Smith LL, et al. Pharmacy & Therapeutics 2016;41:357–360.
16. Latif W, et al. 2023 Mar 27. In: StatPearls [Internet]
17. Wettergreen SA, et al. Diabetes Spectr 2023;36:5–13.
PH-NP-LILLY-TRULIC-NR-HCP-000014 JUNE 2023