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

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 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.

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 MDI 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:

• Drug: Insulin
• Drug: Glimepiride
• Drug: Rosiglitazone
• Drug: Metformin

• Active Comparator: 1
  Standard glycemic control to maintain HbA1c between 8.0-9.0%.
  Interventions:

  • Drug: Insulin
  • Drug: Glimepiride
  • Drug: Rosiglitazone
  • Drug: Metformin
• Experimental: 2
  Intensive glycemic control lower HbA1c below 7.0%.
  Interventions:

  • Drug: Insulin
  • Drug: Glimepiride
  • Drug: Rosiglitazone
  • Drug: Metformin

• 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. Epub 2008 Dec 17.
• Moritz T, Duckworth W, Abraira C. Veterans Affairs diabetes trial--corrections. N Engl J Med. 2009 Sep 3;361(10):1024-5. 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. Epub 2009 Aug 31.
• 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. Epub 2009 Aug 5.
• 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. 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. 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. 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. Review.
• 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.
• 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.
• 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.
• 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. Epub 2011 Jul 20.
• 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. Epub 2010 Nov 8.
• 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. 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. Epub 2009 Nov 2. Review.

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,
• AMI 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,
• 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.