Incretin-Based Therapy in Focus: Addressing the Core Defects of Type 2 Diabetes Mellitus
02 Aug 2023
byJoanne G. Blanco, MD
Diabetes mellitus is a growing health problem traditionally characterized by peripheral insulin resistance (IR), increased hepatic gluconeogenesis, and impaired pancreatic beta-cell function.1 However, the pathophysiology of T2DM is complex, and disease progression is linked to factors beyond insulin dysregulation and reduced first-phase insulin response.2 Unfortunately, many existing anti-hyperglycemic medications cause side effects such as hypoglycemia and weight gain, which may reduce adherence to treatment. In contrast, ideal diabetes medications would control glycemia without a risk of hypoglycemia, while providing additional beneficial effects on beta-cell function, body weight, lipid profiles, hypertension and cardiovascular risk.3
Understanding the Core Defects in T2DM
In T2DM, multiple pathophysiologic defects contribute to disease progression. The complex pathophysiology in patients with the disease has been referred to as the “Ominous Octet" which refers to the three aforementioned physiological issues, as well as the following five core defects: accelerated lipolysis, hyperglucagonemia, increased renal glucose resorption, central nervous system IR, and reduced incretin activity. In the previous years, studies have described four more hormones which complete the “Dirty Dozen” (dopamine, testosterone, renin-angiotensin system, Vitamin D).4 And more recently, some studies have incriminated iron and gut-derived serotonin in the etiopathogenesis of diabetes, which make the core defects into a “Faithless Fourteen.”5
In light of these multiple abnormalities, an optimal treatment approach may involve the early initiation of more than one antidiabetes agent to target the underlying defects of the disease. Advances in our understanding of the pathophysiology have spurred improvements in the way we approach and manage the disease.
Diabetes has evolved significantly from being considered a disease of insulin deficiency, to one of insulin resistance (mediated by the liver, muscle and fat cell) and deficiency combined, to the multifaceted syndrome we now know it to be.1 As a result, optimal diabetes management has shifted away from “one size fits all” care to an individualized approach for each patient.
Emergence of Incretin-Based Therapies: GLP-1 RAs and DPP-4is
In T2DM, there is a decline in the secretion and action of incretins, leading to impaired insulin secretion, delayed gastric emptying, increased glucagon release, and reduced satiety. Incretin-based therapies aim to restore the defective incretin system and overcome the core defects in T2DM. Among these defects, abnormalities of the enteroendocrine system play a crucial role.
The release of hormones in the gut follows food intake.6 Oral glucose provides a sustained increase in insulin secretion called “the incretin effect,” which is primarily a function of the actions of two intestinal insulin-stimulating hormones: Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).1 GIP promotes insulin secretion and regulates fat metabolism without affecting glucagon secretion or gastric emptying. GLP-1 enhances glucose-dependent insulin secretion and becomes inactive when glucose levels reach or fall below the normal range. GLP-1 is considered the more physiologically relevant incretin for glucose homeostasis. It also suppresses post-prandial glucagon secretion and slows gastric emptying and reduces food intake and body weight, and may promote beta-cell growth.2
Two main classes of incretin-based therapies have gained prominence: DPP-4is and GLP-1 RAs. These two address parts of the complex pathophysiology of T2DM by providing GLP-1 in pharmacologic amounts or significantly increasing endogenous levels of the hormone by inhibiting its degradation.1
DPP-4is work by inhibiting the catalytic activity of dipeptidyl peptidase-4 which rapidly degrades endogenous GLP-1 and GIP, thereby prolonging the action of these incretins. Moreover, as the actions of GLP-1 are strictly glucose-dependent, DPP-4is are typically not associated with any increased risk of hypoglycemia.7
GLP-1 RAs mimic the actions of endogenous GLP-1 by binding to and activating the GLP-1 receptor. This leads to enhanced glucose-dependent insulin secretion, suppression of glucagon release, delayed gastric emptying, and increased satiety. Up to 80% of circulating GLP-1 is degraded within 2 minutes by the enzyme DPP-4 in patients with or without T2DM. Therefore, administration with GLP-1 receptor agonists that are resistant to degradation by DPP-4 results in supraphysiologic concentrations of GLP-1, significantly enhancing the biologic effects of GLP-1.1,8
How GLP-1 RAs Outshine DPP-4 Inhibitors and Other Injectables in Diabetes Control
Superior Glycemic Control: GLP-1 RAs exert a more potent glucose-lowering effect compared to DPP-4is. Their ability to promote glucose-dependent insulin secretion, suppress glucagon release, and delay gastric emptying contributes to better glycemic control, with lower risks of hypoglycemia.9-11
Weight Loss Benefits: GLP-1 RAs are associated with significant weight loss due to their central effect on appetite regulation and delayed gastric emptying, as well as the resulting reduction in food intake.12,13 In contrast, DPP-4is have a neutral effect on body weight.9
Cardiovascular Benefits: Several GLP-1 RAs including dulaglutide have demonstrated cardiovascular benefits in patients with T2DM. These agents have shown a reduction in major adverse cardiovascular events including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke making them an attractive option for patients at high cardiovascular risk.14,15 Moreover, GLP-1 RAs have been found to be associated with atherosclerotic prevention, blood pressure reduction, neuroprotection in Alzheimer’s disease, and improvement in nonalcoholic fatty liver disease.6,8
Renal Benefits: GLP-1 RAs have also shown renoprotective effects including a reduction in albuminuria, enhancement of urine albumin-to-creatinine ratio, and reductions in renal impairment as well as the need for renal replacement therapies.16 GLP-1 RAs have also been associated with reduced composite kidney events compared to DPP-4is in patients with advanced diabetic kidney disease.17
Dulaglutide vs. Other GLP-1 RAs: Understanding the Unique Advantages and Clinical Benefits
The Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial – which investigated the effect of dulaglutide versus placebo on CV events in patients with T2DM – stands out among GLP-1 RA trials because of its long follow-up period and its unique patient population, 69% of which had no history of CV events.
These factors make it suitable for testing the hypothesis that dulaglutide reduces a clinical outcome reflecting atherosclerosis progression in T2DM.
REWIND was a multicenter, double-blind trial that randomized 9,901 patients with type 2 diabetes and high CV risk or previous CV events to either dulaglutide (1.5 mg/week subcutaneously; n = 4,949) or placebo (n = 4,952). With a median follow-up of 5.4 years, the trial found that dulaglutide significantly reduced the study’s primary composite outcome of nonfatal myocardial infarction, nonfatal stroke, and death from CV or unknown causes (hazard ratio [HR] 0.88; 95% CI 0.79–0.99; p = 0.026).18
Emerging evidence also suggests that dulaglutide may slow the progression of renal impairment by reducing estimated glomerular filtration rate decline in patients with CKD stages 1-4.19 Dulaglutide is also associated with significant weight loss compared to both placebo and DPP-4is, offering an additional benefit to patients struggling with both obesity and T2DM.9
Conclusion
Incretin-based therapies, such as DPP-4is and GLP-1 RAs, provide a targeted approach to address the core defects of T2DM related to abnormalities of the enteroendocrine system. GLP-1 RAs – particularly dulaglutide – offer advantages over DPP-4is and other injectable therapies including superior glycemic control, weight loss benefits, and additional cardiovascular and renal benefits. With their multifaceted effects, incretin-based therapies continue to revolutionize the management of T2DM, providing patients with more comprehensive and individualized treatment options.
References:
1. Jellinger PS. Postgrad Med 2011;123(1):53–65.
2. Martin CL. Diabetes Educ 2008;34 Suppl 3:66S–72S.
3. Nauck, M. Diabetes, Obesity and Metabolism 2016;18(3):203–216.
4. Kalra S, Chawla R, Madhu SV. Indian J Endocrinol Metab 2013;17(3):367–369.
5. Maladkar M, et al. International Journal of Diabetes and Endocrinology 2022;4(2):22–28.
6. Ricardo-Silgado ML, McRae A, Acosta A. Obes Med 2021;23:100332.
7. Deacon CF. Nat Rev Endocrinol 2020;16(11):642–653.
8. Ordóñez-Vázquez AL, et al. Med Sci Monit 2022;28:e938365.
9. Brunton S. Int J Clin Pract 2014;68(5):557–567.
10. Cornell S. J Clin Pharm Ther 2020; 45(Suppl 1):17–27.
11. Li JX, Cummins CL. Nat Rev Endocrinol 2022;18:540–557.
12. Dailey MJ, Moran TH. Trends Endocrinol Metab 2013;24(2):85–91.
13. van Bloemendaal L, et al. Diabetes 2014;63(12):4186–4196.
14. Del Olmo-Garcia MI, Merino-Torres JF. J Diabetes Res 2018;2018:4020492.
15. Marx N, Husain M, Lehrke M, Verma S, Sattar N. Circulation 2022;146:1882–1894.
16. Rojano Toimil A, Ciudin A. J Clin Med 2021;10(17):3955.
17. Lin Y, Wang TH, Tsai ML, et al. Cardiovasc Diabetol 2023;22:60.
18. Ferrannini G, et al. European Heart Journal 2020;41:3353.
19. Kim S, et al. PLoS One. 2022;17:e0273004.
PH-NP-LILLY-TRULIC-NR-HCP-000018 JULY 2023
Understanding the Core Defects in T2DM
In T2DM, multiple pathophysiologic defects contribute to disease progression. The complex pathophysiology in patients with the disease has been referred to as the “Ominous Octet" which refers to the three aforementioned physiological issues, as well as the following five core defects: accelerated lipolysis, hyperglucagonemia, increased renal glucose resorption, central nervous system IR, and reduced incretin activity. In the previous years, studies have described four more hormones which complete the “Dirty Dozen” (dopamine, testosterone, renin-angiotensin system, Vitamin D).4 And more recently, some studies have incriminated iron and gut-derived serotonin in the etiopathogenesis of diabetes, which make the core defects into a “Faithless Fourteen.”5
In light of these multiple abnormalities, an optimal treatment approach may involve the early initiation of more than one antidiabetes agent to target the underlying defects of the disease. Advances in our understanding of the pathophysiology have spurred improvements in the way we approach and manage the disease.
Diabetes has evolved significantly from being considered a disease of insulin deficiency, to one of insulin resistance (mediated by the liver, muscle and fat cell) and deficiency combined, to the multifaceted syndrome we now know it to be.1 As a result, optimal diabetes management has shifted away from “one size fits all” care to an individualized approach for each patient.
Emergence of Incretin-Based Therapies: GLP-1 RAs and DPP-4is
In T2DM, there is a decline in the secretion and action of incretins, leading to impaired insulin secretion, delayed gastric emptying, increased glucagon release, and reduced satiety. Incretin-based therapies aim to restore the defective incretin system and overcome the core defects in T2DM. Among these defects, abnormalities of the enteroendocrine system play a crucial role.
The release of hormones in the gut follows food intake.6 Oral glucose provides a sustained increase in insulin secretion called “the incretin effect,” which is primarily a function of the actions of two intestinal insulin-stimulating hormones: Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).1 GIP promotes insulin secretion and regulates fat metabolism without affecting glucagon secretion or gastric emptying. GLP-1 enhances glucose-dependent insulin secretion and becomes inactive when glucose levels reach or fall below the normal range. GLP-1 is considered the more physiologically relevant incretin for glucose homeostasis. It also suppresses post-prandial glucagon secretion and slows gastric emptying and reduces food intake and body weight, and may promote beta-cell growth.2
Two main classes of incretin-based therapies have gained prominence: DPP-4is and GLP-1 RAs. These two address parts of the complex pathophysiology of T2DM by providing GLP-1 in pharmacologic amounts or significantly increasing endogenous levels of the hormone by inhibiting its degradation.1
DPP-4is work by inhibiting the catalytic activity of dipeptidyl peptidase-4 which rapidly degrades endogenous GLP-1 and GIP, thereby prolonging the action of these incretins. Moreover, as the actions of GLP-1 are strictly glucose-dependent, DPP-4is are typically not associated with any increased risk of hypoglycemia.7
GLP-1 RAs mimic the actions of endogenous GLP-1 by binding to and activating the GLP-1 receptor. This leads to enhanced glucose-dependent insulin secretion, suppression of glucagon release, delayed gastric emptying, and increased satiety. Up to 80% of circulating GLP-1 is degraded within 2 minutes by the enzyme DPP-4 in patients with or without T2DM. Therefore, administration with GLP-1 receptor agonists that are resistant to degradation by DPP-4 results in supraphysiologic concentrations of GLP-1, significantly enhancing the biologic effects of GLP-1.1,8
How GLP-1 RAs Outshine DPP-4 Inhibitors and Other Injectables in Diabetes Control
Superior Glycemic Control: GLP-1 RAs exert a more potent glucose-lowering effect compared to DPP-4is. Their ability to promote glucose-dependent insulin secretion, suppress glucagon release, and delay gastric emptying contributes to better glycemic control, with lower risks of hypoglycemia.9-11
Weight Loss Benefits: GLP-1 RAs are associated with significant weight loss due to their central effect on appetite regulation and delayed gastric emptying, as well as the resulting reduction in food intake.12,13 In contrast, DPP-4is have a neutral effect on body weight.9
Cardiovascular Benefits: Several GLP-1 RAs including dulaglutide have demonstrated cardiovascular benefits in patients with T2DM. These agents have shown a reduction in major adverse cardiovascular events including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke making them an attractive option for patients at high cardiovascular risk.14,15 Moreover, GLP-1 RAs have been found to be associated with atherosclerotic prevention, blood pressure reduction, neuroprotection in Alzheimer’s disease, and improvement in nonalcoholic fatty liver disease.6,8
Renal Benefits: GLP-1 RAs have also shown renoprotective effects including a reduction in albuminuria, enhancement of urine albumin-to-creatinine ratio, and reductions in renal impairment as well as the need for renal replacement therapies.16 GLP-1 RAs have also been associated with reduced composite kidney events compared to DPP-4is in patients with advanced diabetic kidney disease.17
Dulaglutide vs. Other GLP-1 RAs: Understanding the Unique Advantages and Clinical Benefits
The Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial – which investigated the effect of dulaglutide versus placebo on CV events in patients with T2DM – stands out among GLP-1 RA trials because of its long follow-up period and its unique patient population, 69% of which had no history of CV events.
These factors make it suitable for testing the hypothesis that dulaglutide reduces a clinical outcome reflecting atherosclerosis progression in T2DM.
REWIND was a multicenter, double-blind trial that randomized 9,901 patients with type 2 diabetes and high CV risk or previous CV events to either dulaglutide (1.5 mg/week subcutaneously; n = 4,949) or placebo (n = 4,952). With a median follow-up of 5.4 years, the trial found that dulaglutide significantly reduced the study’s primary composite outcome of nonfatal myocardial infarction, nonfatal stroke, and death from CV or unknown causes (hazard ratio [HR] 0.88; 95% CI 0.79–0.99; p = 0.026).18
Emerging evidence also suggests that dulaglutide may slow the progression of renal impairment by reducing estimated glomerular filtration rate decline in patients with CKD stages 1-4.19 Dulaglutide is also associated with significant weight loss compared to both placebo and DPP-4is, offering an additional benefit to patients struggling with both obesity and T2DM.9
Conclusion
Incretin-based therapies, such as DPP-4is and GLP-1 RAs, provide a targeted approach to address the core defects of T2DM related to abnormalities of the enteroendocrine system. GLP-1 RAs – particularly dulaglutide – offer advantages over DPP-4is and other injectable therapies including superior glycemic control, weight loss benefits, and additional cardiovascular and renal benefits. With their multifaceted effects, incretin-based therapies continue to revolutionize the management of T2DM, providing patients with more comprehensive and individualized treatment options.
References:
1. Jellinger PS. Postgrad Med 2011;123(1):53–65.
2. Martin CL. Diabetes Educ 2008;34 Suppl 3:66S–72S.
3. Nauck, M. Diabetes, Obesity and Metabolism 2016;18(3):203–216.
4. Kalra S, Chawla R, Madhu SV. Indian J Endocrinol Metab 2013;17(3):367–369.
5. Maladkar M, et al. International Journal of Diabetes and Endocrinology 2022;4(2):22–28.
6. Ricardo-Silgado ML, McRae A, Acosta A. Obes Med 2021;23:100332.
7. Deacon CF. Nat Rev Endocrinol 2020;16(11):642–653.
8. Ordóñez-Vázquez AL, et al. Med Sci Monit 2022;28:e938365.
9. Brunton S. Int J Clin Pract 2014;68(5):557–567.
10. Cornell S. J Clin Pharm Ther 2020; 45(Suppl 1):17–27.
11. Li JX, Cummins CL. Nat Rev Endocrinol 2022;18:540–557.
12. Dailey MJ, Moran TH. Trends Endocrinol Metab 2013;24(2):85–91.
13. van Bloemendaal L, et al. Diabetes 2014;63(12):4186–4196.
14. Del Olmo-Garcia MI, Merino-Torres JF. J Diabetes Res 2018;2018:4020492.
15. Marx N, Husain M, Lehrke M, Verma S, Sattar N. Circulation 2022;146:1882–1894.
16. Rojano Toimil A, Ciudin A. J Clin Med 2021;10(17):3955.
17. Lin Y, Wang TH, Tsai ML, et al. Cardiovasc Diabetol 2023;22:60.
18. Ferrannini G, et al. European Heart Journal 2020;41:3353.
19. Kim S, et al. PLoS One. 2022;17:e0273004.
PH-NP-LILLY-TRULIC-NR-HCP-000018 JULY 2023