Glycemic Control and Complications in Diabetes Mellitus Type 2 (VADT) (VADT)

• ClinicalTrials.gov Identifier: NCT00032487
• Recruitment Status: Completed
• First Posted: March 22, 2002
• Results First Posted: February 12, 2014
• Last Update Posted: March 30, 2017
• Sponsor: VA Office of Research and Development
• Collaborators: National Eye Institute (NEI); SmithKline Beecham
• Information provided by (Responsible Party): VA Office of Research and Development

Study Description

Brief Summary:

This study is a prospective, 2-arm, randomized controlled trial to determine whether glycemic control, achieved through intensification of treatment, is effective in preventing clinical macrovascular complications in patients with type 2 DM who are no longer responsive to oral agents alone. The study consists of a two-year accrual period and five years of follow-up (7 years total) of 1700 patients across 20 centers. We have powered the study to detect a 21% reduction in the primary event rate. Additional study goals are to determine whether the expenditures, discomfort, and adverse effects associated with intensive intervention are justified in terms of their clinical benefits, considering both macrovascular and microvascular complications.

Condition or disease	Intervention/treatment	Phase
Type 2 Diabetes Mellitus	Drug: Insulin; Drug: Glimepiride; Drug: Rosiglitazone; Drug: Metformin	Phase 3

Detailed Description:

Primary Hypothesis: Intensive glycemic control reduces major macrovascular morbidity and mortality compared to standard glycemic control in type 2 diabetics who have failed simple therapy.

Secondary Hypotheses: Intensive glycemic control, compared to standard glycemic control, reduces other macrovascular morbidity and total mortality.

Intervention: The intervention is tight glycemic control, aiming at normalization of HbA1c. This will be achieved through stepped care therapy, using all categories of tools available to most diabetologists. These categories include: patient education of diabetes control (e.g. diet, exercise, etc.), oral diabetes medications, and insulin. All drugs to be used are approved. Specific agents will be used within the different classes to promote consistency across sites.

The comparison is standard control, aiming at HbA1c of 8 - 9%. The same agents will be used, but at reduced doses.

The general approach to the stepped care treatment protocol is to treat both groups with the same agents, but at different intensities (doses) (taking into account intolerance/contraindications). The sequence of steps is shown below.

STEP 1: Either Metformin (obese) or Glimepiride (lean)in combination with Rosiglitazone STEP 2: Insulin STEP 3: Increase doses in STEPS 1,2 in the Standard group. Since the Intensive group is already at maximal doses of oral agents, they will intensify insulin and may add Acarbose/Miglitol.

STEP 4: For standard, proceed as in STEP 3 for Intensive; Intensives will use multiple daily injection (MDI) of insulin STEP 5: "Tool Box": Miscellaneous agents, tailored to the individual patient.

Primary Outcomes: Time to one of the following major macrovascular events: myocardial infarction, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, invasive intervention for coronary artery or peripheral vascular disease, inoperable coronary artery disease, or cardiovascular death.

Secondary Outcomes: Angina, transient ischemic attack, intermittent claudication, critical limb ischemia, and total mortality.

Study Abstract: A quarter of the patients treated by the Department of Veterans Affairs (VA) Health Administration have type 2 diabetes mellitus (DM). The costs of care for the treatment of patients with type 2 DM are extremely high, both in treatment expenditures for the metabolic disorder and for the care of end-organ complications. Although patients initially respond to diet and oral agent treatment, most eventually need insulin to near-normalize their glucose level, as the disease is characterized by progressive loss of insulin secretory capacity.

After several clinical trials in both type 1 and type 2 DM, there is a reasonable certainty that about half of the incidence and rate of progression of indicators of microvascular complications (retinopathy, nephropathy, and neuropathy) can be prevented or delayed by achieving and maintaining near-normalization of glycemic levels. Consequently, there has been a uniform trend in recent guidelines to advise a near-normalization of glycemic levels in both type 1 and type 2 DM. Note, however, that the clinical consequences of microvascular deterioration are dependent not only on glycemic levels but also on the duration of the disease. With the early onset of diabetes typical in type 1 patients, there is sufficient time for development of clinical microvascular complications, and prevention of these complications is a goal of treatment in type 1 diabetics. In contrast, the prevalence of hard clinical endpoints indicative of microangiopathy, such as renal failure or blindness, is very low in patients in whom the disease is diagnosed after the 5th decade, the greatest age of prevalence of patients with type 2 DM in this country. Furthermore, microvascular complications can be minimized by the well-established benefits of blood pressure and lipid control, as well as by therapeutic intervention (photocoagulation, cataract extraction). Since the costs and efforts necessary to reach near-normal levels of glycemia are very high, there is a need to determine the cost/benefit ratios of such expenditures in the population subject to type 2 diabetes, namely patients in their 6th to 8th decades of life.

In contrast with the late and relatively infrequent appearance of clinical endpoints of microangiopathy, macrovascular complications (i.e., coronary heart disease and peripheral vascular disease) are responsible for the overwhelming majority of the mortality, morbidity and treatment costs in the American population of type 2 diabetics, even more so in the older VA diabetic population. In the recently concluded United Kingdom Prospective Diabetes Study (UKPDS) on type 2 DM, macrovascular mortality was 70 times higher than that of microvascular mortality. Intervention studies to determine the effect of rigorous glycemic control on these macrovascular events are inconclusive and contradictory. Intensive treatment in patients who are newly diagnosed has failed to demonstrate a beneficial effect of tight control on cardiovascular complications. The few studies conducted in later stages of the disease (i.e., in patients requiring insulin treatment, alone or in combination with oral agents) have been conflicting and indeterminate.

The decision on intensity of treatment is further compromised by current recommendations to attenuate glycemic control goals, especially when usage of insulin is required, both in patients with the common comorbidities of overweight or preexisting cardiovascular disease, and in those in the later decades of life. These concerns are based on fears that intensive insulin treatment might be associated with weight gain, increased cardiovascular risk factors (hypertriglyceridemia, dyslipidemia, hyperinsulinemia, and insulin resistance), and adverse effects of recurrent hypoglycemic events. The prevalent level of glycemic control in insulin-treated type 2 diabetics is relatively poor, likely due to a combination of practical difficulties and the uncertainties of what are the safe and effective glycemic goals. There is no long-term study currently being done in the high-risk population typical of the patient population in the VA. Before the Department of Veterans Affairs devotes considerable resources to a widespread intervention (a quarter of patients) that may be of little value, and might even be counterproductive, a trial to determine the value of the intervention is mandated. It is expected that CSP #465 will provide the scientific data on which the VA can base clinical treatment of Type II diabetes.

CSP #465 is a prospective, 2-arm, randomized controlled trial to determine whether glycemic control, achieved through intensification of treatment, is effective in preventing clinical macrovascular complications in patients with type 2 DM who are no longer responsive to oral agents alone. The study consists of a two-year accrual period and five years of follow-up (7 years total) of 1700 patients across 20 centers. We have powered the study to detect a 25% reduction in the primary event rate. Additional study goals are to determine whether the expenditures, discomfort, and adverse effects associated with intensive intervention are justified in terms of their clinical benefits, considering both macrovascular and microvascular complications.

Main Manuscript:Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N et al., VADT investigators: Glucose Control and Complications in the VA Diabetes Trial (VADT). N Eng J of Med 360:129-139, 2009.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1791 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: CSP #465 - Glycemic Control and Complications in Diabetes Mellitus Type 2 (VADT)
• Actual Study Start Date: December 1, 2000
• Actual Primary Completion Date: May 30, 2008
• Actual Study Completion Date: May 30, 2008

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Standard glycemic control; Standard glycemic control to maintain HbA1c between 8.0-9.0%. Metformin 500 mg Rosiglitazone 4 mg Glimepiride 2 mg Insulin 1 unit 9 lbs	Drug: Insulin; Insulin (intermediate or long-lasting) in a.m. 1 unit 9 lbs Arm 1 Insulin (intermediate or long-lasting) in a.m. 1 unit 9 lbs, add one injection of insulin Arm 2; Other Name: Lente; Drug: Glimepiride; Glimepiride 2 mg Arm 1 Glimepiride 8 mg Arm 2; Other Name: Amaryl; Drug: Rosiglitazone; Rosiglitazone 4 mg Arm 1 Rosiglitazone 4 mg bid Arm 2; Other Name: Avandia; Drug: Metformin; Metformin 500 mg (go up to 1000 mg) Arm 1 Metformin 500 mg (go up to 2000 mg) Arm; Other Name: Glumetza
Experimental: Intensive glycemic control; Intensive glycemic control lower HbA1c below 6.0%. Metformin 500 mg (go up to 2000 mg) Rosiglitazone 4 mg bid Glimepiride 8 mg Insulin 1 unit 9 lbs add one injection to Arm 1	Drug: Insulin; Insulin (intermediate or long-lasting) in a.m. 1 unit 9 lbs Arm 1 Insulin (intermediate or long-lasting) in a.m. 1 unit 9 lbs, add one injection of insulin Arm 2; Other Name: Lente; Drug: Glimepiride; Glimepiride 2 mg Arm 1 Glimepiride 8 mg Arm 2; Other Name: Amaryl; Drug: Rosiglitazone; Rosiglitazone 4 mg Arm 1 Rosiglitazone 4 mg bid Arm 2; Other Name: Avandia; Drug: Metformin; Metformin 500 mg (go up to 1000 mg) Arm 1 Metformin 500 mg (go up to 2000 mg) Arm; Other Name: Glumetza

Outcome Measures

Primary Outcome Measures :

1. Primary Major Macrovascular Events [ Time Frame: Post baseline time to the first major macrovascular event up to 82 months ]
   Myocardial infarction (MI), intervention for coronary artery or Peripheral Vascular Disease (PVD), severe inoperable Coronary Artery Disease (CAD), new or worsening Congestive Heart Failure (CHF), stroke, Cardiovascular (CV) death, or amputation for ischemic gangrene.

Secondary Outcome Measures :

1. Secondary Endpoint [ Time Frame: Post baseline time to first event up to 82 months ]
   New or worsening angina, new transient ischemic attack (TIA), new intermittent claudication or critical limb ischemia with Doppler evidence or total mortality.

Eligibility Criteria

• Ages Eligible for Study: 40 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patients with type 2 DM who are no longer responsive to maximum dose of one or more oral agents.

Exclusion Criteria:

• Angina pectoris, Canadian Class I-II,
• congestive heart failure, Class III-IV,
• stroke, incapacitating or in last 6 months,
• Myocardial infarction (MI) or invasive cardiovascular procedure within the past six months,
• ongoing diabetic gangrene,
• BMI > 40,
• hemoglobinopathy that interferes with A1c monitoring,
• serum creatinine > 1.6 mg/dL,
• fasting C-peptide < 0.21 pmol/ml,
• Alanine Amino Transaminase (ALT) > 3 times normal or serum bilirubin > 1.9 mg/dL,
• malignancy or noncardiac life-threatening diseases making life expectancy < 5 years,
• autonomic neuropathy,
• symptomatic pancreatic insufficiency (endocrine or exocrine),
• recurrent seizures within the past year,
• hypopituitarism,
• pregnancy, lactation, or planning a pregnancy,
• active psychosis or substance abuse,
• lack of access to a person who can assist or be called in an emergency,
• underlying conditions that in the site PI's judgment may prevent adherence to protocol,
• current participation in another clinical trial

Contacts and Locations

Locations

United States, Arizona

Carl T. Hayden VA Medical Center

Phoenix, Arizona, United States, 85012

Southern Arizona VA Health Care System, Tucson

Tucson, Arizona, United States, 85723

United States, California

VA Central California Health Care System, Fresno

Fresno, California, United States, 93703

VA Medical Center, Long Beach

Long Beach, California, United States, 90822

VA San Diego Healthcare System, San Diego

San Diego, California, United States, 92161

United States, Florida

Miami VA Healthcare System, Miami, FL

Miami, Florida, United States, 33125

United States, Illinois

Edward Hines, Jr. VA Hospital

Hines, Illinois, United States, 60141-5000

United States, Indiana

Richard Roudebush VA Medical Center, Indianapolis

Indianapolis, Indiana, United States, 46202-2884

United States, Kentucky

VA Medical Center, Lexington

Lexington, Kentucky, United States, 40502

United States, Minnesota

VA Medical Center, Minneapolis

Minneapolis, Minnesota, United States, 55417

United States, Nebraska

VA Medical Center, Omaha

Omaha, Nebraska, United States, 68105-1873

United States, New Jersey

VA New Jersey Health Care System, East Orange

East Orange, New Jersey, United States, 07018

United States, Pennsylvania

VA Pittsburgh Health Care System

Pittsburgh, Pennsylvania, United States, 15240

United States, South Carolina

Ralph H Johnson VA Medical Center, Charleston

Charleston, South Carolina, United States, 29401-5799

United States, Tennessee

VA Medical Center

Nashville, Tennessee, United States, 37212-2637

United States, Texas

Michael E. DeBakey VA Medical Center (152)

Houston, Texas, United States, 77030

VA South Texas Health Care System, San Antonio

San Antonio, Texas, United States, 78229

United States, Virginia

Hunter Holmes McGuire VA Medical Center

Richmond, Virginia, United States, 23249

VA Medical Center, Salem VA

Salem, Virginia, United States, 24153

United States, Washington

VA Puget Sound Health Care System, Seattle

Seattle, Washington, United States, 98108

Puerto Rico

VA Medical Center, San Juan

San Juan, Puerto Rico, 00921

Sponsors and Collaborators

VA Office of Research and Development

National Eye Institute (NEI)

SmithKline Beecham

Investigators

• Study Chair: Carlos Abraira, MD; Miami VA Healthcare System, Miami, FL
• Study Chair: William Duckworth, MD; Phoenix VA Health Care System, Phoenix, AZ

More Information

Publications of Results:

Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009 Jan 8;360(2):129-39. doi: 10.1056/NEJMoa0808431. Epub 2008 Dec 17. Erratum In: N Engl J Med. 2009 Sep 3;361(10):1028. N Engl J Med. 2009 Sep 3;361(10):1024-5.

Moritz T, Duckworth W, Abraira C. Veterans Affairs diabetes trial--corrections. N Engl J Med. 2009 Sep 3;361(10):1024-5. doi: 10.1056/NEJMc096250. No abstract available.

Emanuele N, Moritz T, Klein R, Davis MD, Glander K, Khanna A, Thottapurathu L, Bahn G, Duckworth W, Abraira C; Veterans Affairs Diabetes Trial Study Group. Ethnicity, race, and clinically significant macular edema in the Veterans Affairs Diabetes Trial (VADT). Diabetes Res Clin Pract. 2009 Nov;86(2):104-10. doi: 10.1016/j.diabres.2009.08.001. Epub 2009 Aug 31.

Control Group; Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, Duckworth WC, Evans GW, Gerstein HC, Holman RR, Moritz TE, Neal BC, Ninomiya T, Patel AA, Paul SK, Travert F, Woodward M. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009 Nov;52(11):2288-98. doi: 10.1007/s00125-009-1470-0. Epub 2009 Aug 5. Erratum In: Diabetologia. 2009 Nov;52(1):2470. Control Group [added].

Abraira C, Duckworth WC, Moritz T; VADT Group. Glycaemic separation and risk factor control in the Veterans Affairs Diabetes Trial: an interim report. Diabetes Obes Metab. 2009 Feb;11(2):150-6. doi: 10.1111/j.1463-1326.2008.00933.x. Epub 2008 Jul 29.

Emanuele N, Klein R, Moritz T, Davis MD, Glander K, Anderson R, Reda D, Duckworth W, Abraira C; VADT Study Group. Comparison of dilated fundus examinations with seven-field stereo fundus photographs in the Veterans Affairs Diabetes Trial. J Diabetes Complications. 2009 Sep-Oct;23(5):323-9. doi: 10.1016/j.jdiacomp.2008.02.010. Epub 2008 Apr 11.

Meyers CD, McCarren M, Wong ND, Abraira C, Duckworth WC, Kashyap ML; VADT Investigators. Baseline achievement of lipid goals and usage of lipid medications in patients with diabetes mellitus (from the Veterans Affairs Diabetes Trial). Am J Cardiol. 2006 Jul 1;98(1):63-5. doi: 10.1016/j.amjcard.2006.01.061. Epub 2006 May 4.

Duckworth WC, McCarren M, Abraira C; VADT Investigators. Control of cardiovascular risk factors in the Veterans Affairs Diabetes Trial in advanced type 2 diabetes. Endocr Pract. 2006 Jan-Feb;12 Suppl 1:85-8. doi: 10.4158/EP.12.S1.85.

Kirkman MS, McCarren M, Shah J, Duckworth W, Abraira C; VADT Study Group. The association between metabolic control and prevalent macrovascular disease in Type 2 diabetes: the VA Cooperative Study in diabetes. J Diabetes Complications. 2006 Mar-Apr;20(2):75-80. doi: 10.1016/j.jdiacomp.2005.06.013.

Emanuele N, Sacks J, Klein R, Reda D, Anderson R, Duckworth W, Abraira C; Veterans Affairs Diabetes Trial Group. Ethnicity, race, and baseline retinopathy correlates in the veterans affairs diabetes trial. Diabetes Care. 2005 Aug;28(8):1954-8. doi: 10.2337/diacare.28.8.1954.

Abraira C, Duckworth W, McCarren M, Emanuele N, Arca D, Reda D, Henderson W; VA Cooperative Study of Glycemic Control and Complications in Diabetes Mellitus Type 2. Design of the cooperative study on glycemic control and complications in diabetes mellitus type 2: Veterans Affairs Diabetes Trial. J Diabetes Complications. 2003 Nov-Dec;17(6):314-22. doi: 10.1016/s1056-8727(02)00277-5.

Duckworth WC, McCarren M, Abraira C; VA Diabetes Trial. Glucose control and cardiovascular complications: the VA Diabetes Trial. Diabetes Care. 2001 May;24(5):942-5. doi: 10.2337/diacare.24.5.942. No abstract available.

Anderson RJ, Bahn GD, Moritz TE, Kaufman D, Abraira C, Duckworth W; VADT Study Group. Blood pressure and cardiovascular disease risk in the Veterans Affairs Diabetes Trial. Diabetes Care. 2011 Jan;34(1):34-8. doi: 10.2337/dc10-1420. Epub 2010 Nov 8.

Agrawal L, Azad N, Emanuele NV, Bahn GD, Kaufman DG, Moritz TE, Duckworth WC, Abraira C; Veterans Affairs Diabetes Trial (VADT) Study Group. Observation on renal outcomes in the Veterans Affairs Diabetes Trial. Diabetes Care. 2011 Sep;34(9):2090-4. doi: 10.2337/dc11-0175. Epub 2011 Jul 20.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Zhou JJ, Koska J, Bahn G, Reaven P. Fasting Glucose Variation Predicts Microvascular Risk in ACCORD and VADT. J Clin Endocrinol Metab. 2021 Mar 25;106(4):1150-1162. doi: 10.1210/clinem/dgaa941.

Reaven PD, Emanuele NV, Wiitala WL, Bahn GD, Reda DJ, McCarren M, Duckworth WC, Hayward RA; VADT Investigators. Intensive Glucose Control in Patients with Type 2 Diabetes - 15-Year Follow-up. N Engl J Med. 2019 Jun 6;380(23):2215-2224. doi: 10.1056/NEJMoa1806802.

Davis SN, Duckworth W, Emanuele N, Hayward RA, Wiitala WL, Thottapurathu L, Reda DJ, Reaven PD; Investigators of the Veterans Affairs Diabetes Trial. Effects of Severe Hypoglycemia on Cardiovascular Outcomes and Death in the Veterans Affairs Diabetes Trial. Diabetes Care. 2019 Jan;42(1):157-163. doi: 10.2337/dc18-1144. Epub 2018 Nov 19.

Azad N, Bahn GD, Emanuele NV, Agrawal L, Ge L, Reda D, Klein R, Reaven PD, Hayward R; VADT Study Group. Association of Blood Glucose Control and Lipids With Diabetic Retinopathy in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care. 2016 May;39(5):816-22. doi: 10.2337/dc15-1897. Epub 2016 Mar 22.

Saremi A, Bahn GD, Reaven PD; Veterans Affairs Diabetes Trial (VADT). A Link Between Hypoglycemia and Progression of Atherosclerosis in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care. 2016 Mar;39(3):448-54. doi: 10.2337/dc15-2107. Epub 2016 Jan 19.

Hayward RA, Reaven PD, Wiitala WL, Bahn GD, Reda DJ, Ge L, McCarren M, Duckworth WC, Emanuele NV; VADT Investigators. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015 Jun 4;372(23):2197-206. doi: 10.1056/NEJMoa1414266. Erratum In: N Engl J Med. 2015 Jul 9;373(2):198.

Saremi A, Schwenke DC, Bahn G, Ge L, Emanuele N, Reaven PD; VADT Investigators. The effect of intensive glucose lowering therapy among major racial/ethnic groups in the Veterans Affairs Diabetes Trial. Metabolism. 2015 Feb;64(2):218-25. doi: 10.1016/j.metabol.2014.10.010. Epub 2014 Oct 17.

Anderson RJ, Bahn GD, Emanuele NV, Marks JB, Duckworth WC; VADT Study Group. Blood pressure and pulse pressure effects on renal outcomes in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care. 2014 Oct;37(10):2782-8. doi: 10.2337/dc14-0284. Epub 2014 Jul 21.

Koska J, Saremi A, Bahn G, Yamashita S, Reaven PD; Veterans Affairs Diabetes Trial Investigators. The effect of intensive glucose lowering on lipoprotein particle profiles and inflammatory markers in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care. 2013 Aug;36(8):2408-14. doi: 10.2337/dc12-2082. Epub 2013 Mar 27.

Saremi A, Moritz TE, Anderson RJ, Abraira C, Duckworth WC, Reaven PD; Veterans Affairs Diabetes Trial (VADT). Rates and determinants of coronary and abdominal aortic artery calcium progression in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care. 2010 Dec;33(12):2642-7. doi: 10.2337/dc10-1388. Epub 2010 Aug 31.

Meier M, Hummel M. Cardiovascular disease and intensive glucose control in type 2 diabetes mellitus: moving practice toward evidence-based strategies. Vasc Health Risk Manag. 2009;5:859-71. doi: 10.2147/vhrm.s4808. Epub 2009 Nov 2.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT00032487
• Other Study ID Numbers: 465
• First Posted: March 22, 2002
• Results First Posted: February 12, 2014
• Last Update Posted: March 30, 2017
• Last Verified: February 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by VA Office of Research and Development:

DM; glycemic control; insulin; type 2 diabetes mellitus

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Metformin; Glimepiride; Rosiglitazone; Hypoglycemic Agents; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Immunosuppressive Agents; Immunologic Factors