Skip Navigation
Skip to contents

CPP : Cardiovascular Prevention and Pharmacotherapy

Sumissioin : submit your manuscript
SEARCH
Search

Articles

Page Path
HOME > Cardiovasc Prev Pharmacother > Volume 6(4); 2024 > Article
Review Article
Paradigm shift from glucocentric to organ protection for the management of hyperglycemia in patients with type 2 diabetes
Jie-Eun Lee1orcid, Jong Chul Won2orcid
Cardiovascular Prevention and Pharmacotherapy 2024;6(4):116-122.
DOI: https://doi.org/10.36011/cpp.2024.6.e15
Published online: October 31, 2024

1Division of Endocrinology and Metabolism, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea

2Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea

Correspondence to Jong Chul Won, MD Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University Sanggye Paik Hospital, Inje University College of Medicine, 1342 Dongil-ro, Nowon-gu, Seoul 01757, Korea Email: drwonjc@gmail.com
• Received: October 3, 2024   • Revised: October 13, 2024   • Accepted: October 14, 2024

© 2024 Korean Society of Cardiovascular Disease Prevention; Korean Society of Cardiovascular Pharmacotherapy.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

prev next
  • The UK Prospective Diabetes Study was the first study to investigate the effectiveness of glycemic control in patients with type 2 diabetes. Since then, many studies have evaluated the impact of intensive glycemic control on diabetes-related morbidities and mortality. The results of these studies were intended to change the paradigm for controlling glycated hemoglobin and preventing diabetes-related complications, but the beneficial outcomes were limited to microvascular diseases rather than diabetes-related cardiorenal diseases and deaths. This has emphasized the need for comprehensive management of other risk factors (hypertension, dyslipidemia, renal failure, etc.) in addition to hyperglycemia to prevent atherosclerotic cardiovascular diseases and end-stage renal disease in type 2 diabetes. Since 2008, clinical trials to demonstrate cardiovascular safety have shown a beneficial effect of sodium-glucose transporter 2 inhibitors or glucagon-like peptide-1 receptor agonists on macrovascular or renal complications in patients with type 2 diabetes. Recently, major societies around the world including the Korean Diabetes Association, have shifted the goals of diabetes management from the typical glucocentric view to cardiorenal outcome-oriented (organ protection) care, which has been widely accepted and is gradually applied to primary care.
The primary goal of diabetes treatment is to alleviate wasting symptoms by regulating blood glucose levels and to prevent diabetes-specific chronic complications, such as microvascular complications, thereby maintaining a normal life expectancy [1]. Blood glucose levels should be kept below 180 mg/dL to prevent wasting symptoms, and medications should be administered promptly with diet and exercise therapy, to stave off chronic complications. Despite these efforts, most diabetes patients do not achieve a normal lifespan due to associated conditions such as cardiovascular diseases (CVDs) and diabetic kidney disease (DKD) [2]. Therefore, an ideal antidiabetic drug should not only provide hypoglycemic effects but also fundamentally reduce mortality associated with diabetes. This article explores the "paradigm shift in diabetes management," moving from the traditional "glucocentric" approach in managing type 2 diabetes to the recently emphasized concept of "organ protection," and examines how this shift has evolved over time.
The UK Prospective Diabetes Study (UKPDS) [3], a landmark study that established the importance of blood glucose regulation in managing type 2 diabetes, was designed based on a clear link between hyperglycemia and microvascular complications identified in earlier observational studies [4,5]. The UKPDS found that type 2 diabetes patients who maintained strict blood glucose control (fasting blood glucose, <106 mg/dL) using sulfonylureas or insulin from the time of their diagnosis had better composite outcomes, including both vascular and nonvascular indices, than those who did not (fasting blood glucose, <270 mg/dL). However, it did not significantly reduce macrovascular complications or diabetes-related mortality [3]. Two decades ago, the only antidiabetic drugs available in clinical practice were sulfonylureas, insulin, metformin, and thiazolidinediones (TZDs). At that time, glycated hemoglobin A1c (A1c), now a common indicator of blood glucose regulation, was not yet used [6], and major adverse cardiovascular events (MACEs), a primary outcome of recent CVD research, had not been introduced. Additionally, neither statins nor angiotensin receptor blockers were in use [7]. Nonetheless, it was discovered that early and strict blood glucose control could have a "legacy effect" in preventing myocardial infarction [8]. While the benefits of strict blood glucose control in preventing CVDs in patients with diabetes have not been established, the results of interventional studies focusing on controlling risk factors other than hyperglycemia during the 1990s have been in the spotlight. UKPDS 75 demonstrated that blood pressure management is more effective than blood glucose control in preventing CVDs in diabetic patients [9]. Furthermore, the secondary and primary prevention of CVDs by low-density lipoprotein cholesterol reduction with statins was also demonstrated [10]. Therefore, the importance of comprehensive management of CVD risk factors through blood pressure control, management of dyslipidemia, and antiplatelet medications rather than strict glycemic control alone has been recognized [11]. Reflecting these insights, the emphasis in managing type 2 diabetes has shifted towards "blood glucose lowering" as a component of broader regulatory strategies. The Korean Diabetes Association’s guidelines recommend selecting antidiabetic drugs based on the level of hyperglycemia, categorized by A1c levels: 8.0%, 8.0%–10.0%, and 10% [12].
Subsequent observations revealed that A1c values have a linear relationship with CVD events or death in patients with type 2 diabetes [2]. This led to the planning of studies to prevent CVDs by actively lowering A1c levels. ACCORD (Action to Control Cardiovascular Risk in Diabetes) [13], ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) [14], and VADT (Veterans Affairs Diabetes Trial) [15] assessed whether CVDs could be prevented by strictly controlling blood glucose through combination therapy using TZDs or alpha-glucosidase inhibitors. These drugs, known for their low risk of hypoglycemia, have been in use since the 1990s. However, these studies showed that strict blood glucose control led to increased side effects such as weight gain, hypoglycemia, and arrhythmia, and that the risks outweighed the benefits concerning CVDs. Additionally, rosiglitazone, a TZD drug, was found to increase the risk of CVDs, sparking debates [16]. In response, the US Food and Drug Administration required new antidiabetic drugs to demonstrate CVD safety [17]. In addition, it became essential to establish individualized goals when selecting antidiabetic drugs for patients with type 2 diabetes [18].
Dipeptidyl peptidase-4 (DPP-4) inhibitors were the first subject of CVD safety evaluation guidelines for antidiabetic drugs. Introduced into clinical practice after 2006, DPP-4 inhibitors have a modest hypoglycemic effect, reducing A1c by about 0.8%. However, their low risks of hypoglycemia or weight gain make them the most commonly used drug in combination therapy with metformin in Korea [19]. Compared to placebos and other antidiabetic drugs, DPP-4 inhibitors have shown a slight tendency to reduce MACEs, although this reduction was not statistically significant. Generally, they are considered neutral regarding CVD safety (Table 1) [20]. In the SAVOR-TIMI 53 (Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53) study, the saxagliptin group exhibited a significant increase in hospitalizations due to heart failure compared to the placebo group (3.5% vs. 2.8%, P=0.007) [21]. A mechanism has been suggested in which DPP-4 inhibition leads to heart failure due to a “class effect” of increased substance P and neuropeptide Y, which stimulates the sympathetic nervous system [22]. In contrast, some reports have suggested that certain DPP-4 inhibitors do not increase the risk of heart failure, as they offset the increase in blood pressure by increased natriuresis [23]. Consequently, the association between DPP-4 inhibitors and heart failure has not been clearly established, but these studies have led to a renewed recognition of diabetic cardiomyopathy (DCM) as one of the chronic complications of type 2 diabetes. Although the UKPDS study predicted a 16% increase in heart failure for every 1% increase in A1c [4], intensive glycemic control alone has not been shown to prevent heart failure, suggesting that DCM is caused by pathogenic mechanisms other than hyperglycemia. However, the exact pathogenesis of DCM has not yet been elucidated [1315], although there are several likely mechanisms. The current prevailing hypothesis is that the cascade of events in DCM, such as cardiomyocyte hypertrophy, inflammation, fibrosis, and death, starts with an increase in metabolites such as advanced glycation end products from hyperglycemia and a shift in energy source of cardiomyocytes, lipotoxicity from an increase in fatty acids due to insulin resistance, followed by mitochondrial dysfunction and a decrease in the efficiency of adenosine triphosphate production [24,25]. The mechanisms underlying the beneficial action of antidiabetic drugs in heart failure are also not fully understood, but research is ongoing to verify the potential role of these drugs based on the mechanisms described above [15]. Therefore, the focus has shifted from solely emphasizing the hypoglycemic effects of antidiabetic drugs to selecting a drug that does not increase the risk of CVDs and side effects such as weight gain or hypoglycemia. In other words, a “balanced and safe antidiabetic drug” has become a necessary and sufficient condition for blood glucose regulation in patients with type 2 diabetes (Fig. 1) [26,27].
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors (first introduced in 2005 and 2012, respectively) both offer significant benefits including a low risk of hypoglycemia and substantial weight loss effects. The EMPA-REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose) trial [28] and the LEADER (Liraglutide Effect and Action in Diabetes) trial [29], published after 2015, marked significant progress in the management of type 2 diabetes. These studies demonstrated that SGLT2 inhibitors and GLP-1RAs not only regulate blood glucose but also control dyslipidemia and hypertension and provide benefits in managing CVDs even when antiplatelet agents are used (Table 1) [20]. SGLT2 inhibitors and GLP-1RAs have been shown to reduce MACEs in high-risk type 2 diabetes patients and have also exhibited primary prevention effects for CVDs. Furthermore, SGLT2 inhibitors have significantly reduced outcomes such as death from kidney-related diseases and hospitalizations due to kidney failure [30]. Beyond their impact on CVDs and DKD, additional mechanisms related to these benefits, aside from blood glucose regulation, have been identified [31]. Recent studies have also revealed that these two drug classes positively affect heart failure and CVDs in patients with heart failure who do not have a history of diabetes or in those who are overweight or obese, respectively [32,33]. These findings have prompted a shift in the guidelines for selecting antidiabetic medications in patients with type 2 diabetes, from a primarily glucocentric approach to one focused on organ protection to prevent the progression of comorbidities. This approach is reflected in the latest treatment guidelines from the Korean Diabetes Association. Metformin is recommended as the initial treatment, accompanied by diet and exercise, for patients with type 2 diabetes [12]. Additionally, it is important to identify risk factors such as atherosclerosis, heart failure, or DKD, and choose either GLP-1RAs or SGLT2 inhibitors based on these risks. It is recommended that individual agents from these two classes should be selected for their confirmed CVD benefits and that other classes should be considered as combination therapy for glycemic control based on the clinical characteristics of the individual patient. Moreover, it is advised to avoid TZDs in patients with heart failure or those at high risk (Fig. 1) [27,34].
"Medicine is an ever-changing science" [35]. This statement underscores the reality that medical standards can evolve based on new research and clinical experiences. Since the discovery of insulin in 1921 [36], the management of type 2 diabetes has undergone significant transformations. Initially, the focus was on a "glucocentric” concept, prioritizing "efficacy" through intensive blood glucose control. This approach later shifted to a "safety” concept, aimed at mitigating risks associated with weight gain, hypoglycemia, and CVDs. More recently, the focus has moved towards "organ protection," addressing serious complications such as CVDs and DKD, which are associated with mortality among diabetes patients. Furthermore, it is also anticipated that the results of cardiovascular outcome trials for new agents such as GLP1/glucose-dependent insulinotropic polypeptide (GIP) dual agonists and GLP1/GIP/glucagon triple agonists soon to be available in Korea will change the paradigm. Current management strategies for type 2 diabetes require a holistic approach that not only addresses hyperglycemia but also considers the risks associated with CVDs and DKD.

Author contributions

Conceptualization: all authors; Supervision: JCW; Writing–original draft: all authors; Writing–review & editing: JEL. All authors read and approved the final manuscript.

Conflicts of interest

The authors have no conflicts of interest to declare.

Funding

The authors received no financial support for this study.

Fig. 1.
Paradigm shift of diabetes care from glucocentric to organ protection. UKPDS, UK Prospective Diabetes Study; ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; VADT, Veterans Affairs Diabetes Trial; EMPA-REG, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Diabetes Mellitus Patients-Removing Excess Glucose; LEADER, Liraglutide Effect and Action in Diabetes; A1c, glycated hemoglobin; HF, heart failure; eASCVD, established atherosclerotic cardiovascular disease; CKD, chronic kidney disease. a)Major recommendations for choosing a glucose-lowering agent after diabetes education for lifestyle modification and initial treatment with metformin otherwise severe hyperglycemia in 2007, 2011, and 2021 (from left to right, Ko et al. [12], Ko et al. [26], and Hur et al. [34], respectively). Adapted from Won et al. [27], available under the the Creative Commons Attribution Non-Commercial License.
cpp-2024-6-e15f1.jpg
Table 1.
Major cardiovascular outcomes trials of antidiabetic drugs
Study Drug HR 95% CI Result
SGLT2 inhibitor
 EMPA-REG Empagliflozin 0.86 0.74–0.99 Positive
 CANVAS Program Canagliflozin 0.86 0.75–0.97 Positive
 DECLARE-TIMI 53 Dapagliflozin 0.93 0.84–1.03 Neutral
 VERTIS CV Ertugliflozin 0.97 0.85–1.11 Neutral
 SOLOIST-WHF Sotagliflozin 0.67 0.52–0.85 Positive
GLP-1RA
 ELIXA Lixisenatide 1.02 0.89–1.17 Neutral
 LEADER Liraglutide 0.87 0.78–0.97 Positive
 SUSTAIN-6 Semaglutide 0.74 0.58–0.95 Positive
 EXSCEL Exenatide 0.91 0.83–1.00 Neutral
 HARMONY Albiglutide 0.78 0.68–0.90 Positive
 AMPLITUTE-O Efpeglenide 0.73 0.58–0.92 Positive
DPP-4 inhibitor
 SAVOR-TIMI 53 Saxagliptin 1.00 0.89–1.12 Neutral
 EXAMINE Alogliptin 0.96 ≤1.16 Neutral
 TECOS Sitagliptin 0.98 0.88–1.09 Neutral
 CAMELINA Linagliptin 1.02 0.89–1.17 Neutral
 CAROLINA Linagliptin 0.98 0.84–1.14 Neutral

HR, hazard ratio; CI, confidence interval; SGLT2, sodium-glucose cotransporter 2; EMPA-REG, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose; CANVAS, Canagliflozin Cardiovascular Assessment Study; DECLARE-TIMI 53, Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 53; VERTIS CV, Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes; SOLOIST-WHF, Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure; GLP-1RA, glucagon-like peptide 1 receptor agonist; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; SUSTAIN-6, Semaglutide in Subjects with Type 2 Diabetes; EXSCEL, Exenatide Study of Cardiovascular Event Lowering; HARMONY, Albiglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease; AMPLITUTE-O, Effect of Efpeglenatide on Cardiovascular Outcomes; DPP-4, dipeptidyl peptidase-4; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin Versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; CAMELINA, Cardiovascular Safety and Renal Microvascular Outcome Study with Linagliptin; CAROLINA, Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients with Type 2 Diabetes. Modified from Kim et al. [20], available under the Creative Commons Attribution Non-Commercial License.

  • 1. Powers AC, Fowler MJ, Rickels MR. Chapter 404. Diabetes mellitus: management and therapies. In: Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson JL, editors. Harrison's principles of internal medicine. 21st ed. McGraw-Hill Education; 2022. p. 2152–80.PDF
  • 2. Emerging Risk Factors Collaboration, Di Angelantonio E, Gao P, Khan H, Butterworth AS, Wormser D, et al. Glycated hemoglobin measurement and prediction of cardiovascular disease. JAMA 2014;311:1225–33.ArticlePubMedPMC
  • 3. UK Prospec­tive Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complica­tions in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53.PubMed
  • 4. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405–12.ArticlePubMedPMC
  • 5. Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973. Diabetes Care 1978;1:252–63.ArticlePDF
  • 6. World Health Organization (WHO). Use of glycated haemoglobin (HbA1c) in diagnosis of diabetes mellitus: abbreviated report of a WHO consultation. WHO; 2011.PDF
  • 7. Marx N, McGuire DK, Perkovic V, Woerle HJ, Broedl UC, von Eynatten M, et al. Composite primary end points in cardiovascular outcomes trials involving type 2 diabetes patients: should unstable angina be included in the primary end point? Diabetes Care 2017;40:1144–51.ArticlePubMedPDF
  • 8. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577–89.ArticlePubMed
  • 9. Stratton IM, Cull CA, Adler AI, Matthews DR, Neil HA, Holman RR. Additive effects of glycaemia and blood pressure exposure on risk of complications in type 2 diabetes: a prospective observational study (UKPDS 75). Diabetologia 2006;49:1761–9.ArticlePubMedPDF
  • 10. Haffner SM. The Scandinavian Simvastatin Survival Study (4S) subgroup analysis of diabetic subjects: implications for the prevention of coronary heart disease. Diabetes Care 1997;20:469–71.ArticlePubMedPDF
  • 11. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580–91.ArticlePubMed
  • 12. Ko SH, Kim SR, Kim DJ, Oh SJ, Lee HJ, Shim KH, et al. 2011 Clinical practice guidelines for type 2 diabetes in Korea. Diabetes Metab J 2011;35:431–6.ArticlePubMedPMC
  • 13. Gerstein HC, Miller ME, Ismail-Beigi F, Largay J, McDonald C, Lochnan HA, et al. Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trial. Lancet 2014;384:1936–41.ArticlePubMedPMC
  • 14. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560–72.ArticlePubMed
  • 15. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129–39.ArticlePubMed
  • 16. Currie CJ, Peters JR, Tynan A, Evans M, Heine RJ, Bracco OL, et al. Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet 2010;375:481–9.ArticlePubMed
  • 17. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140–9.ArticlePubMed
  • 18. Center for Drug Evaluation and Research (CDER). Guidance for industry: diabetes mellitus: evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Food and Drug Administration, US Department of Health and Human Services; 2008.
  • 19. Bae JH, Han KD, Ko SH, Yang YS, Choi JH, Choi KM, et al. Diabetes fact sheet in Korea 2021. Diabetes Metab J 2022;46:417–26.ArticlePubMedPMCPDF
  • 20. Kim GS, Park JH, Won JC. The role of glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors in reducing cardiovascular events in patients with type 2 diabetes. Endocrinol Metab (Seoul) 2019;34:106–16.ArticlePubMedPMCPDF
  • 21. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317–26.ArticlePubMed
  • 22. Scheen AJ. Cardiovascular effects of new oral glucose-lowering agents: DPP-4 and SGLT-2 inhibitors. Circ Res 2018;122:1439–59.ArticlePubMedPMC
  • 23. Sano M. Mechanism by which dipeptidyl peptidase-4 inhibitors increase the risk of heart failure and possible differences in heart failure risk. J Cardiol 2019;73:28–32.ArticlePubMed
  • 24. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 2005;85:1093–129.ArticlePubMed
  • 25. Cadenas S. Mitochondrial uncoupling, ROS generation and cardioprotection. Biochim Biophys Acta Bioenerg 2018;1859:940–50.ArticlePubMed
  • 26. Ko SH, Hur KY, Rhee SY, Kim NH, Moon MK, Park SO, et al. Antihyperglycemic agent therapy for adult patients with type 2 diabetes mellitus 2017: a position statement of the Korean Diabetes Association. Diabetes Metab J 2017;41:337–48.ArticlePubMedPMCPDF
  • 27. Won JC. Paradigm shift in management of hyperglycemia in patients with type 2 diabetes: glucocentric versus organ protection. J Korean Diabetes 2023;24:59–65.ArticlePDF
  • 28. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28.ArticlePubMed
  • 29. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–22.ArticlePubMedPMC
  • 30. Vaduganathan M, Januzzi JL Jr. Preventing and treating heart failure with sodium-glucose co-transporter 2 inhibitors. Am J Med 2019;132:S21–9.Article
  • 31. Home P. Controversies for glucose control targets in type 2 diabetes: exposing the common ground. Diabetes Care 2019;42:1615–23.ArticlePubMedPDF
  • 32. Heerspink HJ, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436–46.ArticlePubMed
  • 33. Ryan DH, Lingvay I, Colhoun HM, Deanfield J, Emerson SS, Kahn SE, et al. Semaglutide effects on cardiovascular outcomes in people with overweight or obesity (SELECT) rationale and design. Am Heart J 2020;229:61–9.ArticlePubMed
  • 34. Hur KY, Moon MK, Park JS, Kim SK, Lee SH, Yun JS, et al. 2021 Clinical practice guidelines for diabetes mellitus of the Korean Diabetes Association. Diabetes Metab J 2021;45:461–81.ArticlePubMedPMC
  • 35. Kibble JD, Halsey CR. The big picture: medical physiology. McGraw-Hill; 2009.PDF
  • 36. Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J 1922;12:141–6.ArticlePubMedPMCPDF

Figure & Data

References

    Citations

    Citations to this article as recorded by  

      Figure
      • 0
      Paradigm shift from glucocentric to organ protection for the management of hyperglycemia in patients with type 2 diabetes
      Image
      Fig. 1. Paradigm shift of diabetes care from glucocentric to organ protection. UKPDS, UK Prospective Diabetes Study; ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; VADT, Veterans Affairs Diabetes Trial; EMPA-REG, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Diabetes Mellitus Patients-Removing Excess Glucose; LEADER, Liraglutide Effect and Action in Diabetes; A1c, glycated hemoglobin; HF, heart failure; eASCVD, established atherosclerotic cardiovascular disease; CKD, chronic kidney disease. a)Major recommendations for choosing a glucose-lowering agent after diabetes education for lifestyle modification and initial treatment with metformin otherwise severe hyperglycemia in 2007, 2011, and 2021 (from left to right, Ko et al. [12], Ko et al. [26], and Hur et al. [34], respectively). Adapted from Won et al. [27], available under the the Creative Commons Attribution Non-Commercial License.
      Paradigm shift from glucocentric to organ protection for the management of hyperglycemia in patients with type 2 diabetes
      Study Drug HR 95% CI Result
      SGLT2 inhibitor
       EMPA-REG Empagliflozin 0.86 0.74–0.99 Positive
       CANVAS Program Canagliflozin 0.86 0.75–0.97 Positive
       DECLARE-TIMI 53 Dapagliflozin 0.93 0.84–1.03 Neutral
       VERTIS CV Ertugliflozin 0.97 0.85–1.11 Neutral
       SOLOIST-WHF Sotagliflozin 0.67 0.52–0.85 Positive
      GLP-1RA
       ELIXA Lixisenatide 1.02 0.89–1.17 Neutral
       LEADER Liraglutide 0.87 0.78–0.97 Positive
       SUSTAIN-6 Semaglutide 0.74 0.58–0.95 Positive
       EXSCEL Exenatide 0.91 0.83–1.00 Neutral
       HARMONY Albiglutide 0.78 0.68–0.90 Positive
       AMPLITUTE-O Efpeglenide 0.73 0.58–0.92 Positive
      DPP-4 inhibitor
       SAVOR-TIMI 53 Saxagliptin 1.00 0.89–1.12 Neutral
       EXAMINE Alogliptin 0.96 ≤1.16 Neutral
       TECOS Sitagliptin 0.98 0.88–1.09 Neutral
       CAMELINA Linagliptin 1.02 0.89–1.17 Neutral
       CAROLINA Linagliptin 0.98 0.84–1.14 Neutral
      Table 1. Major cardiovascular outcomes trials of antidiabetic drugs

      HR, hazard ratio; CI, confidence interval; SGLT2, sodium-glucose cotransporter 2; EMPA-REG, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose; CANVAS, Canagliflozin Cardiovascular Assessment Study; DECLARE-TIMI 53, Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 53; VERTIS CV, Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes; SOLOIST-WHF, Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure; GLP-1RA, glucagon-like peptide 1 receptor agonist; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; SUSTAIN-6, Semaglutide in Subjects with Type 2 Diabetes; EXSCEL, Exenatide Study of Cardiovascular Event Lowering; HARMONY, Albiglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease; AMPLITUTE-O, Effect of Efpeglenatide on Cardiovascular Outcomes; DPP-4, dipeptidyl peptidase-4; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin Versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; CAMELINA, Cardiovascular Safety and Renal Microvascular Outcome Study with Linagliptin; CAROLINA, Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients with Type 2 Diabetes. Modified from Kim et al. [20], available under the Creative Commons Attribution Non-Commercial License.


      CPP : Cardiovascular Prevention and Pharmacotherapy
      TOP