Disease Prevention in Clinical Practice Base on Patient Specific Physiology

Official title

Physiology of Disease Prevention Observational Study in Clinical Practice

Overview

It is well known that the Type 2 diabetes and vascular disease are preceded by over ten years by metabolic dysfunction and anatomic changes that can be quantified. In order to develop effective preventive strategies and reduce the cost burden to the health care system, recognition of the earliest pathophysiology of Type 2 diabetes and vascular disease is clinically relevant. The interval retrospective evaluation of data from patient records, reflect the effectiveness of the various treatments implemented in clinical practice. Prevalence of "prediabetes" among American adults is estimated to be \~84 million, or one out of three Americans. Over a 5-7 year period approximately one third of these prediabetic individuals will progress to type 2 diabetes. Prediabetes is a heterogenous group comprised of individuals with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and increased A1c (5.7-6.4%). Although different pathophysiologies are present in individuals with IFG and IGT, their conversion rate to overt type 2 diabetes mellitus (T2DM) is similar. Insulin resistance is a common causal feature of many of the pathophysiologic mechanisms linking macrovascular disease and type 2 diabetes. Because hyperglycemia is the major factor responsible for the development of microvascular complications, it logically follows that prevention of progression of prediabetes to overt diabetes should retard/prevent the development of the microvascular complications. From the measurement of plasma glucose, insulin, and c-peptide levels during the oral glucose tolerance test, one can derive measures of the two core defects responsible for the development of T2DM, i.e. insulin resistance and beta cell dysfunction as well as the degree of dysglycemia. By combining a standard medical evaluation with the evaluation of cardiovascular biomarkers, patients at intermediate risk of vascular disease can be identified. In these patients, carotid intima media thickness (IMT) and carotid plaque evaluation is offered to attempt to clarify risk. The hypothesis of this observational study is that the characterization of the physiology and anatomy of patients at risk of developing type 2 diabetes and/or cardiovascular disease can stratify risk of developing disease and direct treatment strategies tailored to the identified physiologic defect, leading to improvements in the delay or prevention of disease.

Detailed description

It is well known that the Type 2 diabetes and vascular disease are preceded by over ten years by metabolic dysfunction and anatomic changes that can be quantified. In order to develop effective preventive strategies and reduce the cost burden to the health care system, recognition of the earliest pathophysiology of Type 2 diabetes and vascular disease is clinically relevant. In patients with risk factors for type 2 diabetes and/or vascular disease, we have quantified this dysmetabolic state using glucose tolerance testing to quantify insulin resistance and beta cell function while measuring vascular biomarkers as well as Intima-media thickness and carotid plaque to characterize cardiovascular risk. The interval retrospective evaluation of data from patient records, reflect the effectiveness of the various treatments implemented in clinical practice.

Prevalence of "prediabetes" among American adults is estimated to be \~84 million, or one out of three Americans. Over a 5-7 year period approximately one third of these prediabetic individuals will progress to type 2 diabetes. Prediabetes is a heterogenous group comprised of individuals with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and increased A1c (5.7-6.4%). Although different pathophysiologies are present in individuals with IFG and IGT, their conversion rate to overt type 2 diabetes mellitus (T2DM) is similar.

Prospective epidemiologic studies have demonstrated that \~40% of subjects who progress to T2DM over 5 years had Normal glucose tolerance (NGT) at baseline, suggesting that a large group of NGT subjects also are at increased T2DM risk. It has previously been demonstrated that a 1-hour plasma glucose concentration \>155 mg/dl identifies a subgroup of NGT subjects with high future T2DM risk.

Further, multiple studies have demonstrated that background retinopathy, microalbuminuria, and peripheral neuropathy are present in 10-20% of prediabetic individuals. Compared with normoglycemic patients, those with prediabetes were associated with a 13-30% higher risk for composite cardiovascular disease.

Insulin resistance is a common causal feature of many of the pathophysiologic mechanisms linking macrovascular disease and type 2 diabetes. Because hyperglycemia is the major factor responsible for the development of microvascular complications, it logically follows that prevention of progression of prediabetes to overt diabetes should retard/prevent the development of the microvascular complications. From the measurement of plasma glucose, insulin, and c-peptide levels during the oral glucose tolerance test, one can derive measures of the two core defects responsible for the development of T2DM, i.e. insulin resistance and beta cell dysfunction as well as the degree of dysglycemia.

The need for improvement in the identification of asymptomatic atherosclerosis is exemplified by the observation that nearly 50% of patients suffering a first myocardial infarction have either, none or only one of the standard risk factors; smoking, diabetes, hypercholesterolemia, hypertension and family history of heart disease. By combining a standard medical evaluation with the evaluation of cardiovascular biomarkers, patients at intermediate risk of vascular disease can be identified. In these patients, carotid intima media thickness and carotid plaque evaluation is offered to attempt to clarify risk.

Further associations exist between insulin resistance and other medical conditions including; fatty liver, epicardial fat, diastolic dysfunction, arrhythmia, dementia and cancer. Quantifying insulin resistance may allow advances in preventive strategies.

Following these evaluations, a discussion of the scientific literature as well as the risk, benefits and alternatives available, a personalized treatment plan is generated. Interval reassessment is carried out as part of the routine medical care of the patients in the practice.

The hypothesis of this observational study is that the characterization of the physiology and anatomy of patients at risk of developing type 2 diabetes and/or cardiovascular disease can stratify risk of developing disease and direct treatment strategies tailored to the identified physiologic defect, leading to improvements in the delay or prevention of disease.

Interventions

• Other Lifestyle modification in routine care of patients
  Diabetes Prevention Program Lifestyle recommendations and non-investigational pharmacotherapy in routine care of patients

Primary outcome measures

• Number of participants who develop type 2 diabetes based on response to oral glucose tolerance test [Time frame: 6 months and an average of every 2 years through the study completion, approximately 20 years]
• Time to development of type 2 diabetes [Time frame: 6 months and an average of every 2 years through the study completion, approximately 20 years]

Eligibility criteria

Inclusion criteria

• American Diabetic Association (ADA)/American Association of Clinical Endocrinologists (AACE) criteria for patients at risk for developing type 2 diabetes

Exclusion criteria

• Patients with prior treatment with medications for type 2 diabetes

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and Trends in Diabetes Among Adults in the United States, 1988-2012. JAMA. 2015 Sep 8;314(10):1021-9. doi: 10.1001/jama.2015.10029. PMID 26348752
• Abdul-Ghani MA, Tripathy D, DeFronzo RA. Contributions of beta-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care. 2006 May;29(5):1130-9. doi: 10.2337/diacare.2951130. PMID 16644654
• Abdul-Ghani MA, Jenkinson CP, Richardson DK, Tripathy D, DeFronzo RA. Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study. Diabetes. 2006 May;55(5):1430-5. doi: 10.2337/db05-1200. PMID 16644701
• Diabetes Prevention Program Research Group. The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program. Diabet Med. 2007 Feb;24(2):137-44. doi: 10.1111/j.1464-5491.2007.02043.x. PMID 17257275
• DREAM Trial Investigators; Dagenais GR, Gerstein HC, Holman R, Budaj A, Escalante A, Hedner T, Keltai M, Lonn E, McFarlane S, McQueen M, Teo K, Sheridan P, Bosch J, Pogue J, Yusuf S. Effects of ramipril and rosiglitazone on cardiovascular and renal outcomes in people with impaired glucose tolerance or impaired fasting glucose: results of the Diabetes REduction Assessment with ramipril and rosiglit PMID 18268075
• Asghar O, Petropoulos IN, Alam U, Jones W, Jeziorska M, Marshall A, Ponirakis G, Fadavi H, Boulton AJ, Tavakoli M, Malik RA. Corneal confocal microscopy detects neuropathy in subjects with impaired glucose tolerance. Diabetes Care. 2014 Sep;37(9):2643-6. doi: 10.2337/dc14-0279. Epub 2014 Jun 26. PMID 24969581
• Gibbons CH, Goebel-Fabbri A. Microvascular Complications Associated With Rapid Improvements in Glycemic Control in Diabetes. Curr Diab Rep. 2017 Jul;17(7):48. doi: 10.1007/s11892-017-0880-5. PMID 28526993
• Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009 Apr;58(4):773-95. doi: 10.2337/db09-9028. No abstract available. PMID 19336687

Identifiers

NCT: NCT03308773 · 2017000308

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗