Impact of Glucose-Lowering Medications on Cardiovascular and Metabolic Risk in Type 2 Diabetes
Abstract
:1. Introduction
2. Search Strategy
3. Traditional Anti-Diabetic Drugs
4. Novel Anti-Diabetic Drugs
4.1. Glucagon Like Peptide-1 Receptor Agonists (GLP-1RAs)
4.2. Sodium Glucose coTransporter-2 Inhibitors (SGLT2-is)
4.3. Dipeptidyl Peptidase-4 Inhibitors (DPP4-is)
5. Discussion and Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Class Drug | Agent | Administration | Mechanism of Action | Reference |
---|---|---|---|---|
Biguanides | Metformin | oral | ↑ Insulin sensitivity by activating Adenosine Mono Phosphate-activated protein kinase (AMP-k) ↓ Hepatic glucose production | [2] |
Thiazolidinediones | Pioglitazone | oral | ↑ Insulin sensitivity by activation of Peroxisome Proliferator Activated Receptor gamma (PPAR-γ) ↓ Peripheral glucose uptake | [4,5,6] |
Sulfonylureas | Glimepiride Gliclazide | oral oral | ↑ Insulin secretion | [1,5] |
Insulin | Glargine Degludec | injective | ↑ Glucose disposal ↓ Hepatic glucose production | [7,8] |
Dipeptidyl Peptidase-4 Inhibitors (DPP4-is) | Sitagliptin Linagliptin Omarigliptin | Oral oral oral | ↓ Half-life and promoting the insulinotropism of Glucagon Like Peptide-1(GLP-1) ↑ Insulin secretion (glucose-dependent) ↓ Glucagon secretion (glucose-dependent) Enzymatic activities against chemotactic molecules and hormones modulating the intricate inflammatory, vascular and immune processes Improving glycemic control ↓ Total cholesterol and triglyceride levels Improve weight neutrality ↓ Risk factors Ameliorating cardiac function and vascular repair Block cleavage of many circulating peptides | [9,10] |
Glucagon Like Peptide-1 Receptor Agonists (GLP-1RAs) | Liraglutide Exenatide Semaglutide Lixisenatide Albiglutide Dulaglutide | Injective Injective oral / injective Injective Injective Injective | ↑ Insulin secretion (glucose-dependent) ↑ ß-cell proliferation ↑ Insulin biosynthesis ↓ ß-cell apoptosis ↓ Glucagon secretion (glucose-dependent) from pancreatic α-cells ↓ Rate of endogenous glucose production ↓ Gastric emptying ↑ Satiety ↓ Food intake ↓ Weight loss Improved blood pressure ↑ Control of cholesterol/dyslipidemia ↑ Low Density Lipoproteins particles oxidised (ox-LDL) ↓ Carotid Intima Media Thickness (CIMT) ↓ Flow-Mediated Dilation (FMD) ↓ Artery endothelial dysfunctions ↓ Atherosclerotic risk factors direct effects on both plaque initiation/formation and progression | [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40] |
Sodium Glucose coTransporter-2 Inhibitors (SGLT2-is) | Empagliflozin Canagliflozin Dapagliflozin | Oral oral oral | ↓ Renal threshold for glucose reabsorption increasing glycosuria Modify insulin sensitivity lower insulin requirements ↓ Body weight ↓ Blood pressure ↓ Extracellular volume little changes in High Density Lipoprotein-Cholesterol (HDL-C), triglyceride, and Low Density Lipoproteins-Cholesterol (LDL-C) ↓ Small dense LDL-C | [41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73] |
Agent | Study | Patients (N. and Type) | CVD-Reduction (Hazard Ratio HR, Confidence Interval CI, and p-Value) | Reference |
---|---|---|---|---|
Metformin | UK Prospective Diabetes Study (UKPDS study) | 4075 overweight patients with newly diagnosed type 2 diabetes recruited in 15 centres | −32% HR (95% CI 13-47) p = 0.002 | [2] |
Pioglitazone | Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) | 5238 patients with type 2 diabetes who had evidence of macrovascular disease | −16% HR 0.84 (95% CI 0.72–0.98) p = 0.027 | [4] |
Pioglitazone | Thiazolidinediones or Sulfonylureas Cardiovascular Accidents Intervention (TOSCA) | 3028 patients with type 2 diabetes inadequately controlled with metformin monotherapy | HR 0.96 (95% CI 0.74–1.26) p = 0.79 | [5] |
Pioglitazone | Insulin Resistance Intervention After Stroke (IRIS) | 3876 participants and 12% with a history of coronary artery disease | −24% HR 0.71 (95% CI 0.54–0.94) p = 0.02 | [6] |
Degludec | Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes (DEVOTE) | 7637 patients with type 2 diabetes; 3818 patients with insulin degludec and 3819 patients with insulin glargine U100 | HR 0.91 (95% CI 0.78–1.06) p = 0.21 | [8] |
Liraglutide | Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results-A Long Term Evaluation (LEADER) | 9340 patients with type 2 diabetes with a previous cardiovascular problem or chronic heart failure or at least one cardiovascular risk factor | −13.9% HR 0.87 (95% CI 0.78–0.97) p < 0.001 | [15] |
Exenatide LAR | Exenatide Study of Cardiovascular Event Lowering (EXSCEL) | 14,752 patients; 10,782 had previous cardiovascular disease | −12% HR 0.91 (95% CI 0.83–1.00) p = 0.061 | [19] |
Semaglutide | Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes CardioVascular Outcome Trial-CVOT (SUSTAIN-6) | 3297 patients with type 2 diabetes | −6.6% HR 0.74 (95% CI 0.58–0.95) p < 0.001 | [30] |
Lixisenatide | Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) | 6068 patients with type 2 diabetes who had had a myocardial infarction or who had been hospitalized for unstable angina within the previous 180 days | HR 1.02 (95% CI 0.89–1.17) p = 0.81 | [32] |
Albiglutide | Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (HARMONY 1-8 trials) | 21,135 patients. Most patients had, or were at high risk for, cardiovascular disease. | −25% HR 0.78 (95% CI 0.68–0.90) p < 0.0001 | [35,36] |
Dulaglutide | Dulaglutide on Major Cardiovascular Events in Patients with Type 2 Diabetes: Researching Cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) | 9901 participants occurred in 370 sites located in 24 countries with type 2 diabetes; 31% had prior cardiovascular disease | HR 0.88 (95% CI 0.79–0.99) p = 0.026 | [37] |
Empagliflozin | Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG CT) | 22,830 diabetic patients | −38%; HR 0.62 (95% CI, 0.49–0.77) p < 0.001 | [47] |
Canagliflozin | Canagliflozin Cardiovascular Assessment Study (CANVAS) | 10,142 participants with type 2 diabetes and high cardiovascular risk | HR 0.86 (95% CI, 0.75–0.97) p < 0.001 | [48] |
Dapagliflozin | Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL Nordic trial) | 40,908 patients with type 2 diabetes; 23% had cardiovascular disease | HR 0.59 (95% CI, 0.49–0.72) p < 0.001 | [49,50] |
Dapagliflozin | Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes (DECLARE) | 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease | HR 0.83 (95% CI, 0.73–0.95) p = 0.005 | [54] |
Sitagliptin | Sitagliptin Cardiovascular Outcomes (TECOS) | 14,671 patients with type 2 diabetes and cardiovascular disease | HR 0.98 (95% CI, 0.88–1.09) p < 0.001 | [65] |
Linagliptin | Cardiovascular and Renal Microvascular Outcome Study with Linagliptin (CARMELINA) | 6991 diabetic patients with high cardiovascular risk | HR 1.02 (95% CI, 0.89–1.17) p < 0.001 | [66] |
Omarigliptin | A Study to Assess Cardiovascular Outcomes Following Treatment with Omarigliptin (OMNeON study) | 4202 patients with type 2 diabetes mellitus and established cardiovascular disease | HR 1.00 (95% CI 0.77–1.29) p = 0.77 | [67,68] |
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Patti, A.M.; Rizvi, A.A.; Giglio, R.V.; Stoian, A.P.; Ligi, D.; Mannello, F. Impact of Glucose-Lowering Medications on Cardiovascular and Metabolic Risk in Type 2 Diabetes. J. Clin. Med. 2020, 9, 912. https://doi.org/10.3390/jcm9040912
Patti AM, Rizvi AA, Giglio RV, Stoian AP, Ligi D, Mannello F. Impact of Glucose-Lowering Medications on Cardiovascular and Metabolic Risk in Type 2 Diabetes. Journal of Clinical Medicine. 2020; 9(4):912. https://doi.org/10.3390/jcm9040912
Chicago/Turabian StylePatti, Angelo Maria, Ali A Rizvi, Rosaria Vincenza Giglio, Anca Pantea Stoian, Daniela Ligi, and Ferdinando Mannello. 2020. "Impact of Glucose-Lowering Medications on Cardiovascular and Metabolic Risk in Type 2 Diabetes" Journal of Clinical Medicine 9, no. 4: 912. https://doi.org/10.3390/jcm9040912
APA StylePatti, A. M., Rizvi, A. A., Giglio, R. V., Stoian, A. P., Ligi, D., & Mannello, F. (2020). Impact of Glucose-Lowering Medications on Cardiovascular and Metabolic Risk in Type 2 Diabetes. Journal of Clinical Medicine, 9(4), 912. https://doi.org/10.3390/jcm9040912