Incretin Odyssey: A Journey to Optimal Diabetes Care | Day 1
02 May 2024
Navigating the therapeutic options to find the
most appropriate treatment for persons with Type 2 Diabetes Mellitus (T2DM) can
be challenging amidst the rapid development in this field. Recognizing the
clinical predicament, a scientific medical symposium was organized by ZPTherapeutics
(ZPT) last February 25 at The Westin Manila in Ortigas, Mandaluyong, entitled
“Incretin Odyssey: A Journey to Optimal Diabetes Care”.
Distinguished diabetes specialists from around the Asia-Pacific region comprised the panel of speakers including Dr. Araceli Panelo, Chairman of the Board, University of the East Ramon Magsaysay Memorial Medical Center (UERMMMC) – Institute for the Studies on Diabetes Foundation, Inc, in Manila, Dr. Chan Siew Pheng, Professor Emeritus and Consultant Endocrinologist at the University of Malaya, Kuala Lumpur, Malaysia and Dr. Aileen Cynthia F. De Lara, Chief of the Section of Cardiology, Jose Reyes Memorial Medical Center, in Manila. The hybrid event was attended live by almost 200 medical doctors in the Philippines with several others from Taiwan, Malaysia, Indonesia, and Thailand joining online.
Dr. Murtaza Qasuri, Vice President for Medical Affairs of ZP Therapeutics, opened the event and reiterated the company’s commitment as an active collaborator in the continuing medical education of healthcare professionals.
The Evolving Story of Incretins in Metabolic Disease
Dr. Panelo revisited the evolution of knowledge on incretins starting from the discovery of “secretin” until the momentous discovery of the incretin effect in the 1960s.1,2 This ushered in an era of intensive research leading to the identification of molecules such as the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). GLP-1 showed multiple antidiabetic properties, drawing much interest from the scientific research community.2,3
In the 1990s, the GLP-1 and the dipeptidyl peptidase 4 (DPP-4) enzyme were already firmly established as targets for further development of drugs against diabetes. By the mid-2000s, the first GLP-1 receptor agonist (GLP-1 RA) and the first dipeptidyl peptidase 4 inhibitors (DPP-4i) were approved for the treatment of T2DM. 2,3 GLP-1 RAs are structurally similar GLP-1 and thus bind and activate GLP-1 receptors. It has improved pharmacokinetic properties. On the other hand, DPP-4is inhibits the activity of DPP4 preventing the degradation and inactivation of GLP-1. It optimizes the therapeutic use of endogenous GLP-1 and the GIP.4 Continued research further improved the drugs’ pharmacokinetics, delivery systems, therapeutic indications to include obesity, and the profiling of its protective cardiovascular effect that bolstered its clinical utility.5,6
Several landmark cardiovascular outcome trials (CVOTs) affirmed the cardiovascular benefit of GLP-1 RAs.7,8 With its well-established efficacy and safety, GLP-1 RAs and DPP-4is are now prominently recommended by multiple international guidelines as first line monotherapy drugs or in combination treatment especially in multiple-risk populations with renal and cardiovascular concerns.9 Continuing clinical and pharmacological studies on these drugs will hopefully maximize its clinical use.6,10
Individualized Approach in T2DM in Asian Patients
In her talk, Professor Chan emphasized that amidst all the robust development in the diabetes landscape, good glucose control remains paramount.11 Citing results from the landmark United Kingdom Prospective Diabetes Study (UKPDS), she stressed that intensive glucose control is worthwhile as it is proven to decrease complications of diabetes.12 Further, the 44-year clinical outcomes from the same study clearly established a legacy effect showing that early glycemic control maximizes benefits of reducing risk of complications and mortality in the long term. Delaying glycemic control on the other hand, was associated with poor outcomes.13-15 The UKPDS also showed that type 2 diabetes mellitus is progressive, and intensification of therapy over time is appropriate.16 She presented 3 case studies that highlighted the use of DPP4-i in various T2DM presentations. The first case of a 42-year-old Asian woman with normal BMI, with T2DM but no other comorbidities, the second was an elderly woman with an active lifestyle and was on a diabetic diet with high risk for hypoglycemia, and the third case was of an elderly man who had multiple comorbidities including coronary artery disease (CAD) with stents and chronic kidney disease (CKD) stage 3a in whom insulin glargine was started. The cases highlighted the efficacy and safety of sitagliptin in combination with metformin for glycemic control. The addition of sodium-glucose co-transporter 2 (SGLT2) inhibitors to the sitagliptin-metformin combination also prove valuable especially in those with CAD and CKD. Combination with insulin was also shown to be effective and safe even as part of a multidrug T2DM regimen.
Professor Chan shared data that demonstrated that DPP-4 inhibitors, specifically sitagliptin, increased plasma levels of GIP and GLP-1 and this translated to improved β-cell function by 37 ±12%.17 Studies also show that DPP-4i were efficacious in lowering HbA1c as an add-on to metformin and it reduced glycemic variability delaying insulin use, especially when given early.18
Japanese studies have shown a potentially more favorable response by Asians to sitagliptin compared to other ethnicities.19 Data from clinical trials also show sitagliptin has consistent efficacy regardless of the degree of renal impairment.20-22 The Compo-SIT trial also show that DPP-4 inhibitor use with insulin helps achieve better levels of HbA1c with similar incidence of hypoglycemia compared to insulin alone and lessens insulin requirements.23
Potential Benefit of Treatment Intensification on Cardiovascular Disease Prevention
Dr. De Lara reiterated that CVD continues to be a major cause of morbidity and mortality in patients with diabetes and in coexistence with hypertension and dyslipidemia, diabetes can markedly decrease life expectancy especially when diagnosed early in life.24,25 She further emphasized that more risk factors mean poorer outcomes especially if intervention is delayed. The immediate 8-10 years after diagnosis are critical as this is when CVD complications come into play.26 Evidence from clinical studies have demonstrated the importance of early intensive glycemic control. The Steno-2 study showed that intensive control of risk factors reduces risk of cardiovascular events in the long term.27 The UKPDS demonstrated the legacy effect that early blood sugar control is beneficial in decreasing long term risks even when sugar levels later equalize with those who had late glycemic control, and delaying intervention to control blood sugar levels results in increased risk of cardiovascular events.28-30 The DISCOVER study also emphasized that early diagnosis and early intensification of therapy is important to achieve long term glycemic goals and improve clinical outcomes.31
American Diabetes Association (ADA) guidelines have recommended GLP-1 inhibitors especially in high-risk categories like in atherosclerotic cardiovascular disease (ASCVD) or high risk for ASCVD. The consensus recommendation is for GLP-1 RAs with proven cardioprotective effects to be used in the management of T2DM or in combination with SGLT2 inhibitors if HbA1c is persistently above target levels.32 The cardiovascular protection conferred by GLP-1 RA s go beyond lowering blood pressure and inducing weight loss as it also possesses beneficial pleiotropic effects that exert anti-inflammatory and anti-atherosclerotic effects, improve endothelial function, and has beneficial action on the myocardium by reducing infarct or injury size.33
Data from the landmark REWIND trial was reviewed by Dr. De Lara as it employed superiority testing as the sole primary objective and most closely matched with reference population in terms of HbA1c, sex and proportion with a prior MI.34,35 Data showed that cardiovascular outcomes and all-cause mortality were significantly reduced by the GLP-1 RA dulaglutide, across all subgroups.34 Heart failure events were also marginally reduced. Microvascular outcomes were also significantly better than placebo.36
In the 2019 update to its consensus statement, the ADA/ EASD stated that the level of evidence supporting GLP-1 RAs for the primary prevention of major adverse cardiovascular events is strongest for dulaglutide but lacking for other drugs in the same class.37
Q&A Session
An engaging discussion between the speakers and the participants followed the presentations. Dr. Cecille Cruz, a Consultant Endocrinologist, and Clinical Associate Professor at the UP College of Medicine was the moderator of the open forum. The availability of the new classes of medications like GLP1-RAs in public clinics for the lower income population were identified as limiting factors but there was optimism that these will be made available soon. Dr. De Lara emphasized that the REWIND study best represents real-world population and Professor Chan highlighted the primary protection from CV risk conferred by GLP1-RA as shown in the study. Professor Chan also made it clear that ethnicity doesn’t affect treatment outcomes in diabetes, including effect on weight. Combining GLP-1 RA and DPP-4i was also raised from the audience, which the speakers clarified that there were no studies yet on potential interaction and preclinical data show there is no clear advantage for a combination of the 2 drugs in terms of glycemic control.
Distinguished diabetes specialists from around the Asia-Pacific region comprised the panel of speakers including Dr. Araceli Panelo, Chairman of the Board, University of the East Ramon Magsaysay Memorial Medical Center (UERMMMC) – Institute for the Studies on Diabetes Foundation, Inc, in Manila, Dr. Chan Siew Pheng, Professor Emeritus and Consultant Endocrinologist at the University of Malaya, Kuala Lumpur, Malaysia and Dr. Aileen Cynthia F. De Lara, Chief of the Section of Cardiology, Jose Reyes Memorial Medical Center, in Manila. The hybrid event was attended live by almost 200 medical doctors in the Philippines with several others from Taiwan, Malaysia, Indonesia, and Thailand joining online.
Dr. Murtaza Qasuri, Vice President for Medical Affairs of ZP Therapeutics, opened the event and reiterated the company’s commitment as an active collaborator in the continuing medical education of healthcare professionals.
The Evolving Story of Incretins in Metabolic Disease
Dr. Panelo revisited the evolution of knowledge on incretins starting from the discovery of “secretin” until the momentous discovery of the incretin effect in the 1960s.1,2 This ushered in an era of intensive research leading to the identification of molecules such as the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). GLP-1 showed multiple antidiabetic properties, drawing much interest from the scientific research community.2,3
In the 1990s, the GLP-1 and the dipeptidyl peptidase 4 (DPP-4) enzyme were already firmly established as targets for further development of drugs against diabetes. By the mid-2000s, the first GLP-1 receptor agonist (GLP-1 RA) and the first dipeptidyl peptidase 4 inhibitors (DPP-4i) were approved for the treatment of T2DM. 2,3 GLP-1 RAs are structurally similar GLP-1 and thus bind and activate GLP-1 receptors. It has improved pharmacokinetic properties. On the other hand, DPP-4is inhibits the activity of DPP4 preventing the degradation and inactivation of GLP-1. It optimizes the therapeutic use of endogenous GLP-1 and the GIP.4 Continued research further improved the drugs’ pharmacokinetics, delivery systems, therapeutic indications to include obesity, and the profiling of its protective cardiovascular effect that bolstered its clinical utility.5,6
Several landmark cardiovascular outcome trials (CVOTs) affirmed the cardiovascular benefit of GLP-1 RAs.7,8 With its well-established efficacy and safety, GLP-1 RAs and DPP-4is are now prominently recommended by multiple international guidelines as first line monotherapy drugs or in combination treatment especially in multiple-risk populations with renal and cardiovascular concerns.9 Continuing clinical and pharmacological studies on these drugs will hopefully maximize its clinical use.6,10
Individualized Approach in T2DM in Asian Patients
In her talk, Professor Chan emphasized that amidst all the robust development in the diabetes landscape, good glucose control remains paramount.11 Citing results from the landmark United Kingdom Prospective Diabetes Study (UKPDS), she stressed that intensive glucose control is worthwhile as it is proven to decrease complications of diabetes.12 Further, the 44-year clinical outcomes from the same study clearly established a legacy effect showing that early glycemic control maximizes benefits of reducing risk of complications and mortality in the long term. Delaying glycemic control on the other hand, was associated with poor outcomes.13-15 The UKPDS also showed that type 2 diabetes mellitus is progressive, and intensification of therapy over time is appropriate.16 She presented 3 case studies that highlighted the use of DPP4-i in various T2DM presentations. The first case of a 42-year-old Asian woman with normal BMI, with T2DM but no other comorbidities, the second was an elderly woman with an active lifestyle and was on a diabetic diet with high risk for hypoglycemia, and the third case was of an elderly man who had multiple comorbidities including coronary artery disease (CAD) with stents and chronic kidney disease (CKD) stage 3a in whom insulin glargine was started. The cases highlighted the efficacy and safety of sitagliptin in combination with metformin for glycemic control. The addition of sodium-glucose co-transporter 2 (SGLT2) inhibitors to the sitagliptin-metformin combination also prove valuable especially in those with CAD and CKD. Combination with insulin was also shown to be effective and safe even as part of a multidrug T2DM regimen.
Professor Chan shared data that demonstrated that DPP-4 inhibitors, specifically sitagliptin, increased plasma levels of GIP and GLP-1 and this translated to improved β-cell function by 37 ±12%.17 Studies also show that DPP-4i were efficacious in lowering HbA1c as an add-on to metformin and it reduced glycemic variability delaying insulin use, especially when given early.18
Japanese studies have shown a potentially more favorable response by Asians to sitagliptin compared to other ethnicities.19 Data from clinical trials also show sitagliptin has consistent efficacy regardless of the degree of renal impairment.20-22 The Compo-SIT trial also show that DPP-4 inhibitor use with insulin helps achieve better levels of HbA1c with similar incidence of hypoglycemia compared to insulin alone and lessens insulin requirements.23
Potential Benefit of Treatment Intensification on Cardiovascular Disease Prevention
Dr. De Lara reiterated that CVD continues to be a major cause of morbidity and mortality in patients with diabetes and in coexistence with hypertension and dyslipidemia, diabetes can markedly decrease life expectancy especially when diagnosed early in life.24,25 She further emphasized that more risk factors mean poorer outcomes especially if intervention is delayed. The immediate 8-10 years after diagnosis are critical as this is when CVD complications come into play.26 Evidence from clinical studies have demonstrated the importance of early intensive glycemic control. The Steno-2 study showed that intensive control of risk factors reduces risk of cardiovascular events in the long term.27 The UKPDS demonstrated the legacy effect that early blood sugar control is beneficial in decreasing long term risks even when sugar levels later equalize with those who had late glycemic control, and delaying intervention to control blood sugar levels results in increased risk of cardiovascular events.28-30 The DISCOVER study also emphasized that early diagnosis and early intensification of therapy is important to achieve long term glycemic goals and improve clinical outcomes.31
American Diabetes Association (ADA) guidelines have recommended GLP-1 inhibitors especially in high-risk categories like in atherosclerotic cardiovascular disease (ASCVD) or high risk for ASCVD. The consensus recommendation is for GLP-1 RAs with proven cardioprotective effects to be used in the management of T2DM or in combination with SGLT2 inhibitors if HbA1c is persistently above target levels.32 The cardiovascular protection conferred by GLP-1 RA s go beyond lowering blood pressure and inducing weight loss as it also possesses beneficial pleiotropic effects that exert anti-inflammatory and anti-atherosclerotic effects, improve endothelial function, and has beneficial action on the myocardium by reducing infarct or injury size.33
Data from the landmark REWIND trial was reviewed by Dr. De Lara as it employed superiority testing as the sole primary objective and most closely matched with reference population in terms of HbA1c, sex and proportion with a prior MI.34,35 Data showed that cardiovascular outcomes and all-cause mortality were significantly reduced by the GLP-1 RA dulaglutide, across all subgroups.34 Heart failure events were also marginally reduced. Microvascular outcomes were also significantly better than placebo.36
In the 2019 update to its consensus statement, the ADA/ EASD stated that the level of evidence supporting GLP-1 RAs for the primary prevention of major adverse cardiovascular events is strongest for dulaglutide but lacking for other drugs in the same class.37
Q&A Session
An engaging discussion between the speakers and the participants followed the presentations. Dr. Cecille Cruz, a Consultant Endocrinologist, and Clinical Associate Professor at the UP College of Medicine was the moderator of the open forum. The availability of the new classes of medications like GLP1-RAs in public clinics for the lower income population were identified as limiting factors but there was optimism that these will be made available soon. Dr. De Lara emphasized that the REWIND study best represents real-world population and Professor Chan highlighted the primary protection from CV risk conferred by GLP1-RA as shown in the study. Professor Chan also made it clear that ethnicity doesn’t affect treatment outcomes in diabetes, including effect on weight. Combining GLP-1 RA and DPP-4i was also raised from the audience, which the speakers clarified that there were no studies yet on potential interaction and preclinical data show there is no clear advantage for a combination of the 2 drugs in terms of glycemic control.