Clinical trial NCT00756613: The VA Diabetes Trial Follow-up Study (VADT-FS)
Official title: CSP #465FS - VA Diabetes Trial Long Term Follow-up Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Diabetes
Glycemic Control
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2008-09-22
Enrollment: 1044
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: To be eligible for the VADT, subjects had to be over 40 years old, have type 2 diabetes and be non-responsive (A1c \> 7.5%) to a maximum daily dose of one or more oral agents or on insulin. And to participate in the VADT-FS the participant had to be active in the VADT study.

Brief summary: CSP #465, "Glycemic Control and Complications in Diabetes Mellitus Type 2," was a randomized unblinded clinical trial comparing tight glycemic control to standard glycemic control. Tight glycemic control consisted of giving patients appropriate diabetic medications to lower the patient's HbA1c to around 7%, whereas standard control attempted to lower the patient's HbA1c to between 8% and 9%. The study was conducted at 20 VA medical centers. 1791 patients were randomized over the 2 year accrual period and then followed for an additional 5 years. Follow-up averaged between 5 and 7 years depending upon when the patient was enrolled in the study. Patients were seen on average every three months in the VA Outpatient Clinics. High blood pressure and elevated cholesterol were aggressively treated in patients in both treatment arms. Education regarding diet, exercise, smoking cessation and management of very high and very low glucose was also provided. Data were collected throughout the study on the patients' physical status, adverse and serious adverse events, concomitant medications, and study end points including mortality, heart attack, stroke and surgery to fix the arteries in the heart, legs or neck. The study consisted of broad use of all anti-diabetic treatments commercially available between 2000 and 2008 including oral medications and insulin. Study required medications and all study clinic visits were provided free of the usual VA co-pay. Active clinical follow-up of the sample ended on May 31, 2008. With the end of the clinical trial the patients were transitioned back to usual patient care services, treatment regimens were adjusted where appropriate and future treatment will be dictated by the patient's health and his/her health care provider.

It is important to clarify that with the completion of the active clinical trial and transitioning of patients to this observational trial, all responsibility for the care, treatment and oversight of the study patients will become the responsibility of the patients' Primary Care Physician. The Long Term Follow-up will not collect adverse or serious adverse events, or actively treat or have any "hands-on" care responsibility for the study participants.

The proposed Long Term Follow-up Study will consist of centralized computer database searches and annual survey questionnaires related to quality of life and self-reported events pertinent to the CSP #465 study.

Detailed description: Diabetes mellitus is a major health problem in the U.S., especially in the VA population. The majority of diabetics are Type 2, and they are at risk for microvascular (e.g. eye, kidney) and macrovascular (e.g. cardiovascular) complications. It is probable that many of the macrovascular and microvascular complications potentially prevented by the 5-7 years of good Glycemic control achieved in the VADT (median follow-up 6.25 years) will occur years after completion of the VADT experimental protocol. This follow-up study will provide the opportunity to see if this holds true up to 9 years following the end of 465.

The results will help the VA in evaluating most appropriate treatments and costs of such treatment.

This is a longitudinal observational follow-up study of CSP #465, "Glycemic Control and Complications in Diabetes Mellitus Type 2",the VA Diabetes Trial (VADT) NCT #00032487. The objectives are: 1) to determine the long term effects of intensive glycemic control in type 2 diabetes on major cardiovascular complications (primary outcome), and 2) to determine the long term effects of intensive glycemic control in type 2 diabetes on four secondary outcomes: a) cardiovascular mortality, b) major microvascular complications, c) health-related quality of life, and d) total mortality.

All patients active at the end of VADT will be approached for participation in VADT-FS. The only exclusion reason will be failure to receive consent for participation. Consented VADT-FS patients will be followed until the end of the study unless they withdraw their consent. Patients will be sent a short, standardized self-administered survey annually. Information collected will include: 1) self-reported health status; 2) occurrence of study endpoints; and 3) VA or non-VA outpatient visits, hospitalizations and procedures. A variety of data sources will be searched to verify endpoints. These sources include: 1) VA and non-VA medical records; 2) data from the Centers for Medicare and Medicaid Services (CMS); and 3) VA and US death records. Patients who do not respond to 3 mailed surveys will be contacted by phone.

If still unsuccessful, their designated surrogate will be contacted. Certain endpoints will be adjudicated by the same committee that was utilized by VADT. Endpoints that will be adjudicated will include: 1) cause of death; 2) reason for amputation; and 3) cardiac-related non-VA hospitalizations. Endpoints of interest in this study include: 1) mortality; 2) acute myocardial infarction requiring hospitalization; 3) stroke; 4) new onset congestive heart failure; 5) coronary revascularization; 6) amputation; 7) peripheral revascularization; 8) renal insufficiency; 9) severe visual impairment; and 10) self-reported health status (diabetes-related quality of life).

Eligibility criteria: Inclusion Criteria:

* All patients active at the end of VADT will be approached for participation.

Exclusion Criteria:

* The only exclusion criterion will be failure to achieve consent for continued participation.

Primary outcomes:
measure: The Long Term Effect of Intensive Glycemic Control in Type 2 Diabetes on Major Cardiovascular Complication.
timeFrame: 15 years
Secondary outcomes:
measure: The Long Term Effects of Intensive Glycemic Control in Type 2 Diabetes on the Secondary Outcome Total Mortality.
timeFrame: 15 years
measure: The Long Term Effects of Intensive Glycemic Control in Type 2 Diabetes on the Secondary Outcome Cardiovascular Mortality.
timeFrame: 15 years
measure: Number of Events on Major Microvascular or Macrovascular Outcome
timeFrame: 15 years
measure: Patients Reported Health Related Quality of Life
timeFrame: 9 years
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix VA Health Care System, Phoenix, AZ
state: Arizona
city: Hines
country: United States
facility: Hines VAMC, Hines IL
state: Illinois
Study officials:
affiliation: Phoenix VA Health Care System, Phoenix, AZ
name: Peter D Reaven, MD
role: STUDY_CHAIR
affiliation: Hines VAMC, Hines IL
name: Nicholas Emanuele, MD
role: STUDY_CHAIR
References:
citation: Azad N, Agrawal L, Emanuele NV, Klein R, Bahn GD, McCarren M, Reaven P, Hayward R, Duckworth W; VADT Study Group. Association of PAI-1 and fibrinogen with diabetic retinopathy in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care. 2014 Feb;37(2):501-6. doi: 10.2337/dc13-1193. Epub 2013 Oct 7.
citation: Azad N, Agrawal L, Emanuele NV, Klein R, Bahn GD, Reaven P; VADT Study Group. Association of blood glucose control and pancreatic reserve with diabetic retinopathy in the Veterans Affairs Diabetes Trial (VADT). Diabetologia. 2014 Jun;57(6):1124-31. doi: 10.1007/s00125-014-3199-7. Epub 2014 Mar 6.
citation: 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.
citation: 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.
citation: 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.
citation: Hayward RA, Reaven PD, Emanuele NV; VADT Investigators. Follow-up of Glycemic Control and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015 Sep 3;373(10):978. doi: 10.1056/NEJMc1508386. No abstract available.
citation: Follow-Up of Glycemic Control and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015 Jul 9;373(2):198. doi: 10.1056/NEJMx150025. No abstract available.
citation: 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.
citation: Zimering MB, Knight J, Ge L, Bahn G; VADT Investigators. Predictors of Cognitive Decline in Older Adult Type 2 Diabetes from the Veterans Affairs Diabetes Trial. Front Endocrinol (Lausanne). 2016 Sep 8;7:123. doi: 10.3389/fendo.2016.00123. eCollection 2016.
citation: Herrington WG, Preiss D. Tightening our understanding of intensive glycaemic control. Lancet Diabetes Endocrinol. 2017 Jun;5(6):405-407. doi: 10.1016/S2213-8587(17)30095-5. Epub 2017 Mar 30. No abstract available.
citation: Zoungas S, Arima H, Gerstein HC, Holman RR, Woodward M, Reaven P, Hayward RA, Craven T, Coleman RL, Chalmers J; Collaborators on Trials of Lowering Glucose (CONTROL) group. Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. Lancet Diabetes Endocrinol. 2017 Jun;5(6):431-437. doi: 10.1016/S2213-8587(17)30104-3. Epub 2017 Mar 30.
citation: Saremi A, Howell S, Schwenke DC, Bahn G, Beisswenger PJ, Reaven PD; VADT Investigators. Advanced Glycation End Products, Oxidation Products, and the Extent of Atherosclerosis During the VA Diabetes Trial and Follow-up Study. Diabetes Care. 2017 Apr;40(4):591-598. doi: 10.2337/dc16-1875. Epub 2017 Feb 1.
citation: Zhou JJ, Schwenke DC, Bahn G, Reaven P; VADT Investigators. Glycemic Variation and Cardiovascular Risk in the Veterans Affairs Diabetes Trial. Diabetes Care. 2018 Oct;41(10):2187-2194. doi: 10.2337/dc18-0548. Epub 2018 Aug 6.
citation: Zhou JJ, Koska J, Bahn G, Reaven P. Glycaemic variation is a predictor of all-cause mortality in the Veteran Affairs Diabetes Trial. Diab Vasc Dis Res. 2019 Mar;16(2):178-185. doi: 10.1177/1479164119827598.
citation: 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.
citation: Agrawal L, Azad N, Bahn GD, Ge L, Reaven PD, Hayward RA, Reda DJ, Emanuele NV; VADT Study Group. Long-term follow-up of intensive glycaemic control on renal outcomes in the Veterans Affairs Diabetes Trial (VADT). Diabetologia. 2018 Feb;61(2):295-299. doi: 10.1007/s00125-017-4473-2. Epub 2017 Nov 3.
citation: 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.