Glycemic Control and CVD: Making Sense of the Studies

Dr. Ford is a clinical pharmacy specialistat the University of North CarolinaHospitals and an assistant professorat the University of North CarolinaDepartment of Family Medicine.

Patients with diabetes have a 2-to 4-fold higher risk of strokeand death from heart diseasecompared with people without diabetes.Hyperglycemia also causes damageto the microvasculature, leadingto blindness, kidney disease requiringdialysis, neuropathy, and amputations.These risks can be reduced witha combination of exercise, healthyeating habits, and medications.

Another important factor in improvingdiabetes care is education toempower patients with information tobetter manage the disease themselves.Pharmacists are in a unique position toeducate patients on medicines for glucosecontrol and those used to manageor prevent complications of diabetes.

Improving glycemic control is knownto reduce the risk of microvascularcomplications of diabetes, but previousstudies have failed to demonstratea reduction in cardiovascular disease(CVD) with improved glycemic control.The United Kingdom ProspectiveDiabetes Study (UKPDS),¹ publishedin 1998, showed a 25% reduction inmicrovascular complications&#8212;but nodifference in macrovascular disease&#8212;in patients with type 2 diabetes randomizedto intensive glycemic controlwith insulin and sulfonylureas, comparedwith standard control. Patientsin the intensive control group achieveda mean A1C of 7%, compared with 7.9%in the standard control group. CurrentAmerican Diabetes Association (ADA)guidelines2 recommend targeting a goalA1C of <7% in the general population ofpatients with type 2 diabetes, althoughmost other organizations recommendlower A1C targets.

Two recently reported trials&#8212;ACCORD³and ADVANCE⁴&#8212;weredesigned to test the effects of moreintensive glycemic control on vascularoutcomes in type 2 diabetes patients.The ACCORD trial received extensivemedia attention when a press conferencewas held in March announcing anincrease in mortality in the intensivecontrol group. The ADVANCE study,which did not demonstrate an increasein mortality in the intensive controlgroup, was published simultaneouslywith ACCORD in June 2008.

The ACCORD Trial

The ACCORD trial³ is a prospectiverandomized study of 10,251 patients todetermine whether intensive glycemiccontrol (goal A1C of <6%) would reducethe rates of cardiovascular events comparedwith standard therapy (goal A1Cof 7%-7.9%) in patients with type 2 diabetesand CVD or at high risk for vascularevents. After a mean of 3.5 years offollow-up, the rates of all-cause mortalitywere 5% in the intensive glycemiccontrol group and 4% in the standardtherapy group (hazard ratio, 1.22; P =.04), indicating an increase in 1 deathper 100 patients treated with intensivetherapy over 3.5 years. An increase incardiovascular mortality was noted withintensive therapy compared with standardtherapy (0.79% annually vs 0.56%;hazard ratio, 1.35; P = .02). Of note,annual rates of nonfatal myocardialinfarction were decreased with intensivetherapy compared with standardtherapy (1.11% vs 1.45%; hazard ratio,0.76; P = .004).

Median A1C levels at follow-upwere 6.4% and 7.5% in the intensiveand standard therapy groups, respectively,from a baseline of 8.1%. Ratesof hypoglycemia requiring assistancewere significantly higher in the intensivecontrol group compared with thestandard control group (16.2% vs 5.1%;P <.001). Similarly, weight gain >10kg was more common with intensivetherapy&#8212;28% over 3.5 years, versus 14%in the standard group. Despite manyanalyses, the investigators were unableto determine an explanation for the findingof increased mortality with intensivetherapy, including an analysis of thepotential contribution of specific drugssuch as rosiglitazone. Data on microvasculardisease were collected during thisstudy, but have not yet been published.

The ADVANCE Trial

The ADVANCE trial⁴ also aimed todetermine the effects of intensive glucosecontrol on major vascular eventsin patients with type 2 diabetes. Similarto the ACCORD study, patients wereincluded only if they had documentedmacrovasular or microvasular disease orrisk factors for vascular disease; >11,000patients were enrolled. ADVANCE participantshad lower A1C levels at baselineand a shorter duration of diabetes andcould not be treated with insulin prior toentry. Patients randomized to intensiveglucose control were treated with a specificsulfonylurea.gliclazide.plus othermedications determined at the discretionof the treating physician to a goal A1C of.6.5%. Patients randomized to standardglucose control were treated to a goalA1C determined by local guidelines.

After a median duration of follow-up of5 years, the median A1C in the intensiveglucose control group was 6.3%, comparedwith 7.0% in the standard glucosecontrol group, from a baseline of 7.2%.Patients in the intensive control groupexperienced significantly fewer majormicrovascular events (mostly a reductionin new or worsening nephropathy) thanthose in the standard control group (9.4%vs 10.9%; hazard ratio, 0.86; P = .01), butno difference was reported in the incidenceof major macrovascular events.

In contrast to findings in the ACCORDtrial, investigators found no difference inall-cause mortality between the 2 groups(8.9% in the intensive control group vs9.6% in the standard control group; hazardratio, 0.93; P = .28). Severe hypoglycemia(defined as hypoglycemia requiringhelp from another person) occurredat least once in 2.7% of patients in theintensive control group and in 1.5% ofpatients in the standard control group(hazard ratio, 1.86; P <.001). No increasein weight in the intensive participantsversus standard was reported.

Other Studies

Additionally, results of a 10-year postinterventionfollow-up of intensive glucosecontrol in the UKPDS were recentlypublished.⁵ By the end of the first yearafter study completion, the difference inA1C from the original study (7% vs 7.9%in the intensive control group vs conventionalcontrol) had disappeared, andsimilar A1Cs were maintained throughthe 10-year postinterventional followup.At 10 years, patients in the intensivecontrol group maintained a lower risk ofmicrovascular disease, and reductions inthe risks of diabetes-related death, deathfrom any cause, and myocardial infarctionemerged in the group of patientsoriginally allocated to intensive control.These data indicate that the knownmicrovascular benefits of intensive glycemiccontrol persist despite loss of glycemiccontrol, and although improvedglycemic control may not have an immediateeffect on macrovascular disease,there may be long-term benefits.

Finally, data from another trialdesigned to test the effects of intensiveglycemic control on macrovascular disease,the Veterans Affairs Diabetes Trial(VADT), were presented recently at theADA Scientific Meeting in June.6 The aimof this trial was to lower A1C levels in theintensive treatment group to as close tonormal as possible. Patients in the intensivecontrol arm achieved a mean A1C of6.9%, compared with 8.4% in the controlarm. No statistically significant reductionin cardiovascular events was seen, whichis consistent with the results of ACCORDand ADVANCE. Further data will be availablewhen VADT is published.

Counseling Patients

The data from these recent studies createmore questions than answers. Mountingevidence has been reported that improvingglycemic control does not substantiallydecrease the risk of macrovasculardisease, except perhaps in individualswith earlier disease and longer follow-upand even then at modest effect.

The ACCORD trial and the VADTsuggest that inherent risks may existwith more intensive glycemic control,although these risks were not apparentin the gentler ADVANCE trial. This disparitymay be due to differences in themedications and intensity of applicationto lower A1C, differences in preventivemedications, or differences in the populationsbetween the 2 studies.

In light of the increased mortality withlower A1C levels in the ACCORD study,it is likely prudent to follow the ADArecommendations to target an A1C of<7% instead of more intensive glycemiccontrol, until more information is availableon the risks and benefits of loweringA1C levels further. When counselingpatients, it is important to emphasize theknown benefits of glycemic control inreducing microvascular complicationsof diabetes. Patients should be advisednot to stop their diabetes medicationswithout first talking to their doctor orother diabetes provider.

Additionally, as more information isavailable on the risks and benefits ofintensive glycemic control, it is importantto remember those interventionsthat are known to reduce the risk of CVDin patients with diabetes.smoking cessation,aspirin, and treatment of hypertensionand dyslipidemia.

Acknowledgment: John Buse, MD,PhD, professor and chief, Division ofEndocrinology and Metabolism, Departmentof Medicine, University ofNorth Carolina, and president, Medicineand Science, American DiabetesAssociation, for his review, commentary,and expertise in the preparationof this manuscript.

References

• UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet.1998;352(9131):837-853.
• American Diabetes Association. Standards of medical care in diabetes-2008. Diabetes Care. 2008;31(suppl 1):S12-S54.
• Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-2559.
• The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
• Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577-1589.
• Intense blood glucose control yields no significant effect on CVD in VA diabetes trial [press release]. Washington, DC: American Diabetes Association; June 8, 2008.