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Back: Thinking Beyond Glycemic Control For Patients With Type 2 Diabetes

Jeff Unger Picture

 

   Jeff Unger, MD
   PCMG Steering Committee Member
   Charlotte, North Carolina 
   Associate Director for Metabolic Studies
   Catalina Research Institute
   Chino, California


The belief that intensifying glycemic control in patients with type 2 diabetes will minimize risk of microvascular and macrovascular complications has long been surmised based upon the results of the UKPDS and Kumamoto Study. However, other randomized trials such as ACCORD1 have shown adverse cardiovascular effects associated with glycemic intensification. The results of The Veterans Affairs Diabetes Trial (VADT)2 were just published in the New England Journal of Medicine. This study confirmed that intensification of glycemia treatment does little to minimize microvascular or macrovascular events in patients with type 2 diabetes.


In the VADT study, 1791 veterans with poorly controlled type 2 diabetes (A1C >7.5 %, mean age 60.4 years) were randomly assigned to receive either intensive or standard glucose control therapy. Other cardiovascular risk factors were treated uniformly. The goal in the intensive therapy group was an absolute reduction in A1C of 1.5 % as compared with the standard therapy group. The primary outcome was the time from randomization to the first occurrence of a major cardiovascular event, a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene. Microvascular disorders were also evaluated including progression to sensory neuropathy, albuminuria and retinopathy.


In both study groups patients with a BMI of 27 or more were started on metformin plus rosiglitazone; those with a BMI of less than 27 were initiated on glimepiride plus rosiglitazone. Patients in the intensive therapy group were started on maximal doses and those in the standard therapy group were started on half the maximal doses. Before any change in oral medications, insulin was added for patients in the intensive therapy group who did not achieve an A1C of less than 6% and for those in the standard therapy group with a level of less than 9%. Any approved drug could be used at the discretion of the investigator.


Other modifiable cardiovascular risk factors (blood pressure and lipid modification) were treated identically in the two study groups. Treatment guidelines were based on expert opinion from the American Diabetes Association. All patients received statins and aspirin therapy unless contraindicated.


Despite the use of intensification of diabetes control in this study, there were no differences between the two groups in the rates of major cardiovascular events, death or microvascular complications. Thus, clinicians may consider intensifying blood pressure and lipid management in patients with poorly controlled type 2 diabetes as a means reducing long term cardiovascular complications.


So, how does one direct the management of their patients with type 2 diabetes in light of the findings of VADT and ACCORD?  As you may recall, the ACCORD study enrolled patients with T2DM, ages 40-82 (average age 62) who were at especially high risk for cardiovascular disease (CVD). ACCORD subjects had already been diagnosed with CVD or had at least 2 CVD risk factors in addition to diabetes (high LDL-cholesterol, hypertension, smoking or obesity). The ACCORD Trial was powered to determine the best ways to decrease the high rate of major CVD events (e.g., heart attacks, stroke or death from CVD- among people with T2DM). The treatment approaches included lowering blood glucose intensively to an A1C of < 6 % in one arm vs. maintaining an A1C target of 7-7.9 % in the conventionally treated cohort. All routinely used medications for the treatment of T2DM could be administered to patients in ACCORD. These drugs included: rosiglitazone, pioglitazone, metformin, insulins, sulfonylureas, acarbose and exenatide. Patients were also subjected to intensive blood pressure control compared with standard blood pressure management. Lipids were treated using either fibrate plus a statin or a statin alone.


In February 2008, the intensive blood glucose treatment arm of ACCORD was terminated prematurely. Data analyses showed that over an average of almost four years of treatment 257 participants in the intensive-treatment group died, compared with 203 within the standard-treatment group - a difference of 54 deaths, or an excess of about 3 deaths per 1,000 participants treated for a year. This translates to a 20% higher rate of death in the intensive than the standard group. 


The reason for the higher death rate in the intensive arm of ACCORD is still under investigation. I recently spoke with Dr. Bruce Bode from the Atlanta Diabetes Group who provided some valuable insight on statistical analysis related to ACCORD which has yet to be published. Dr. Bode believes that most of the deaths in ACCORD were due to hypoglycemia induced by patients using sulfonylureas. There were no deaths in patients using basal insulins alone or in patients using exenatide. Patients who used more mealtime (prandial insulin) also had a higher risk of mortality. The data on TZDs was unclear. Dr. Bode has expressed an interest in repeating the ACCORD trial but using continuous glucose monitoring on all patients in order to determine the true relationship between hypoglycemia and adverse cardiovascular events in patients with type 2 diabetes.


After reviewing ACCORD and VADT with each of my patients, I believe that every individual has their own "A1C set point." Some patients with multiple cardiovascular risk factors perhaps would benefit from more intensive control of their lipids and blood pressure than risking a severe hypoglycemic event with prandial insulin use. Smoking cessation and lifestyle intervention might play a more critical role in these patients than reaching the American Diabetes Association Targeted A1C of < 7 %.


On the other hand, a patient with newly diagnosed type 2 diabetes, with well controlled hypertension and hyperlipidemia, might be more intensively managed towards the American Association of Clinical Endocrinologist (AACE) A1C target of 6.5-7 %. In attempting to achieve this A1C goal, I believe patients should be placed on the medications which appear to be safe, well tolerated and have durable (long lasting) effects on weight and A1C. At this time, my choices would include metformin, incretin mimetics, TZDs, and basal insulin. Sulfonylureas should probably be avoided because they induce hypoglycemia, cause weight gain, and have low rates of durability
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 QUESTION:  How have the results of VADT and ACCORD changed the way you manage your patients with type 2 diabetes?

Please respond via this blog to share your thoughts and discuss this issue.

Jeff Unger, MD

 

1 Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559.

 

2 Duckworth W, Abraira C, Moritz T, et al. Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. N Engl J Med. 2009;360(2):129-39.