Diabetes Control and Cardiovascular Risk: ACCORD, ADVANCE, AVOID, and SANDS

There is increasing interest in the impact of diabetes on cardiovascular (CV) risk. Herein are presented 4 recent studies with impact on the evaluation of interventions related to atherosclerosis and renal disease, the latter itself a risk factor for CV events. Interventions were directed at glucose control, lipid management, and/or blood pressure control in the various studies. More than the usual number of studies are being presented because of the fortuitous clustering of these results in a short period. The characteristic of most of these investigations is the comparison of multiple agents by standardized to aggressive treatment goals involving several targets (levels of glycated hemoglobin [HbA1c], lipids, and blood pressure) in regard to effects on CV events and renal function. Summary. ACCORD is a randomized study of 10,251 type 2 diabetics with a median HbA1c level of 8.1% who were assigned to intensive therapy or standard therapy to reduce HbA1c levels to <6.0% or 7.0% to 7.9%. After 3.5 years of intensive therapy, there was no difference in the primary outcome of CV events, although mortality was significantly increased by 22% in the intensive therapy group and hypoglycemia and weight gain were more frequent in that group. Not reported yet are ongoing studies of subgroups involving random assignments to intensive or standard blood pressure control or lipid management. Rationale. Adjusted for other risk factors, increases in HbA1c in diabetics increases risk of CV events,2 death, retinopathy, and renal failure. Differences of only 1% in HbA1c levels can increase mortality by >10% and retinopathy or renal failure by almost 40%.3 It is conceivable that lowering HbA1c values in diabetics to below the 7.0% target level suggested by guidelines may decrease outcome events. Study Design. The study was conducted in 77 centers in the United States and Canada, with patient selection based on presence of type 2 diabetes with HbA1c levels of ≥7.5%, CV disease, and/or significant risk factors for CV disease. Although albuminuria was used as an inclusion criterion, a creatinine level >1.5 mg/dL was an exclusion criterion. The main trial targeted an HbA1c level of <6.0% or 7.0% to 7.9%. In addition, these patients were randomized to either the blood pressure or lipid control studies that are still under way. Patients received behavioral counseling on diabetic care. Both groups had serial group visits, with more frequent visits and contacts in the intensive treatment group. The prespecified primary outcome was first nonfatal myocardial infarction (MI), nonfatal stroke, or CV death. Secondary outcomes included all-cause mortality. Other secondary outcomes were not reported in this paper. Results. The study was stopped by the safety monitoring committee because of excess all-cause mortality in the aggressive treatment group. Baseline characteristics in the 10,251 patients included a mean age of 62 years; 38% were female and 19% were black. Previous CV events occurred in 35%, and mean baseline blood pressure was 136/75 mm Hg. Mean HbA1c was 8.3%. After a mean 3.5-year follow-up, the median HbA1c level in the aggressively treated group was 6.4%, and in the standard treatment group it was 7.5%. The primary outcome of composite CV events in the intensive therapy group vs the standard therapy group did not differ (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.78–1.04) (Figure 1). However, total mortality was significantly higher in the intensive therapy group (HR, 1.22; 95% CI, 1.01–1.14; P=.04], which was the reason for discontinuing the study. Hypoglycemia requiring assistance developed in 16% of those in the intensive therapy group vs 5% in the standard therapy group (P<.001). Weight gain >10 kg from baseline occurred in 28% of the intensive treatment group vs 14% of the standard group (P<.001). The results indicated harmful effects of intensive HbA1c lowering in type 2 diabetics at high CV risk. ACCORD study. Kaplan-Meier curves comparing intensive therapy vs standard therapy for (A) primary outcome of combined nonfatal myocardial infarction, stroke, and total mortality and (B) total mortality. The primary outcome was not significantly different, but total mortality was significantly increased in the intensive treatment group. Reprinted with permission from The Action to Control Cardiovascular Risk in Diabetes Study Group, 2008.1 Summary. ADVANCE is a randomized study in 11,140 type 2 diabetics using standard or intensive glucose control followed for 5 years to evaluate differences in major macrovascular and microvascular events. Intensive glucose control significantly decreased combined events by 10% and major microvascular events by 14%, although no significant difference was seen in major macrovascular events alone, total mortality, or CV mortality. Hypoglycemia was more common with intensive treatment (2.7% vs 1.5%). Rationale. The rationale was similar to that of ACCORD. Study Design. Using a factorial design somewhat similar to that in ACCORD; type 2 diabetics were initially treated with the angiotensin-converting enzyme inhibitor (ACEI) perindopril and the diuretic indapamide or placebo and either intensive blood glucose control to targeted HbA1c levels ≤6.5% or standard targeted levels based upon local guidelines. Those with intensive glucose control received the sulfonylurea modified-release gliclazide 30 to 120 mg, with sequential use of other agents as needed. The standard control group was given a substituted sulfonylurea and other agents as need to achieve target levels. The primary study outcomes were macrovascular and microvascular events, combined and separate. Macrovascular events included CV death, nonfatal MI, and nonfatal stroke. Microvascular events included new or worsening nephropathy, renal replacement therapy, renal disease death, or retinopathy. Results. Baseline characteristics of the 11,140 patients included an average age of 66 years; 42% were female; 32% had previous MI, stroke, or other macrovascular disease; and 10% had microvascular disease including microalbuminuria and microvascular eye disease. Initial HbA1c was 7.5% and blood pressure was 140/85 mm Hg. At the end of follow-up, HbA1c decreased to 6.5% in the intensive control group vs 7.3% in the standard control group, and blood pressure decrease was similar in both groups (−10/−7 mm Hg vs −8/−6 mm Hg, respectively). No significant weight changes were seen in either group, unlike in ACCORD. In terms of primary outcomes, combined macrovascular and microvascular events over 5 years were reduced in the intensive control group (18.1% vs 20.0% [HR, 0.90; 95% CI, 0.82–0.98]) (Figure 2). This was primarily due to a decrease in microvascular events (9.4% vs 10.9% [HR, 0.86; 95% CI, 0.77–0.97]). No significant differences were found in macrovascular events (HR, 0.94; 95% CI, 0.84–1.06). Total mortality and CV mortality were slightly but not significantly decreased in the intensive control group (HR, 0.93; P=0.28 and HR, 0.88; P=.12, respectively). Severe hypoglycemia was relatively uncommon but significantly higher in the intensive control group (2.7% vs 1.5% [HR, 1.86; 95% CI, 1.42–2.40]). No significant differences were found in other specific secondary end points such as coronary events, cerebrovascular events, all CV events, new-onset microalbuminuria, visual deterioration, neuropathy, or hospitalization. ADVANCE study. Cumulative incidences of events comparing intensive control vs standard control. Intensive control produced a significant reduction in combined events (A), and major microvascular events (C), but not major macrovascular events (B) or death of any cause (D). Reprinted with permission from The ADVANCE Collaborative Group, 2008.4 Comment: ACCORD and ADVANCE. Because of the similarity of the two studies summarized above, the significance of the results will be compared here. The accompanying editorial has provided an excellent comparison5 and will be summarized here, along with some further observations. The studies had a similar number of participants, a little over 10,000, with mean patient age in the early to mid 60s. Both patient groups had a similar mean duration of diabetes (8–10 years) and a history of macrovascular disease (32%–35%). Mean HbA1c was lower in the ADVANCE study (7.2% vs 8.1%), and the median duration of the ADVANCE study was longer (5.0 vs 3.5 years). Comparing medical treatment at study completion, the use of antihypertensive agents was high and similar in both (88%–92%). However, statin use was greater in ACCORD (88% vs 47%), as was aspirin use (76% vs 56%). Could the increased use of these two agents in ACCORD have accounted for the relatively low event rate in the standard control group? Also, is it possible that the increased use of thiazolidinediones in ACCORD (75% vs 14%), and especially in the intensive control groups (92% vs 17%), was at least partly responsible for adverse effects in the intensive control group in ACCORD? There is evidence from a meta-analysis that rosiglitazone may be associated with CV events such as MI and possibly death from CV causes.6 In fact, insulin and metformin were also more heavily used in ACCORD. It is possible that the increased presence of hypoglycemia in the ACCORD intensive control group may have had an adverse role in CV outcomes. In ACCORD, 4.5% of the entire study group died of any cause (5% intensive vs 4% standard control, a significant difference between groups). In ADVANCE, 9.3% of the entire study group died, but the differences between intensive vs standard control were not significant (8.9% vs 9.6%, respectively). Even given that the median duration of ADVANCE was almost 50% longer, the death rate was still higher in ADVANCE. In comparing intensive control groups from both studies, aside from the significantly higher death rate from all causes and from CV causes in the intensive vs standard control group only in ACCORD, major hypoglycemia and weight gain were also significantly increased in the intensive control group only in ACCORD. The major findings in both studies were the lack of benefit with intensive glycemic control in the primary outcomes of CV events in comparison with standard control and, in the case of ACCORD, an evident harm in such an intervention. The results of these studies suggest that the guidelines of about 7% for targeted glycemic control should not be lowered. Moreover, the differences in average mortality rates between studies, with the lower mortality rates in the ACCORD trial vs those in ADVANCE, and the greater percentage of patients being on statins and aspirin in ACCORD underscore the contending influences of ancillary beneficial risk factor interventions in evaluation of putative beneficial interventions. Summary. This was a multinational randomized double-blind study of 599 patients with hypertension, diabetes, and nephropathy assigned to the oral renin inhibitor aliskiren and the angiotensin receptor blocker (ARB) losartan or losartan with placebo. Study participants followed for 9 months demonstrated efficacy of aliskiren/losartan in reducing the urinary albumin/creatinine ratio with a borderline lower blood pressure, compared with the placebo/losartan group. The study suggested an enhancement of the renoprotective effect of the ARB by the renin inhibitor possibly independent of blood pressure changes. Rationale. In renal disease, proteinuria is associated with renal and CV events. Reducing proteinuria slows progression of renal disease and is associated with decreased CV events in hypertension and diabetes.8,9 Blocking the renin-angiotensin-aldosterone system (RAAS) has been shown to be beneficial in this regard, specifically with ACEIs and ARBs.10,11 It is possible that further blockade of the RAAS using a newly available direct renin inhibitor may enhance the effect of an ARB. Study Design. Patients with hypertension and type 2 diabetes with evidence of nephropathy on the basis of abnormal albumin/creatinine morning urinalysis results were recruited. The study was conducted in 15 countries and 150 centers after a 3-month open-label period for discontinuation of previous RAAS blockers and initiation of losartan (100 mg/d), with additional antihypertensive agents if necessary. Patients were then randomized to (1) aliskiren 150 mg/d for 3 months, then 300 mg/d for an additional 3 months or (2) matching placebo for 6 months. Target blood pressure for all patients was <130/80 mm Hg. The primary outcome was a reduction in early morning urinary albumin/creatinine ratio. Results. A total of 599 patients were enrolled. Sixty percent of the aliskiren group received ≥3 concomitant antihypertensive medications in addition to losartan, and 82% received at least ≥2 agents. In the placebo group, 67% received ≥3 additional agents, and 82% received ≥2 additional agents. The primary outcome was a reduction in the urinary albumin/creatinine ratio by 20% (95% CI, 9%–30%) in the aliskiren group vs placebo (Figure 3A). Albuminuria was reduced by at least 50% in 25% of the aliskiren group vs 12.5% in the placebo group (Figure 3B). These differences in outcomes ensued despite small differences in blood pressure changes (2/1-mm Hg lower in the aliskiren group; P=.07 and .08 for systolic vs diastolic pressure differences, respectively). Glomerular filtration rate was slightly but not significantly less in the aliskiren group than in the placebo group (−2.4 vs −3.8 mL/min/1.73 m2; P=.07). Total and serious adverse events were similar in both groups. A higher presence of at least 1 potassium level ≥6 mmol/L of borderline significance was found in the aliskiren group (4.7% vs 1.7%; P=.06). AVOID study. Changes from baseline in aliskiren and placebo groups (both receiving losartan) in (A) urinary albumin/creatinine ratio (%) and (B) albumin excretion rate (%). The beneficial effects of aliskiren were significant and dose-dependent (dose was 150 mg for first 12 weeks, 300 mg last 12 weeks). Reprinted with permission from Parving et al, 2008.7 Comment. The postulated value of adding a renin inhibitor to an ARB or ACEI in the quest for reducing blood pressure and preserving renal function against the ravages of the RAAS is that renin activity itself is the rate-limiting step of the system in producing angiotensin I from angiotensinogen and has actions independent of its production of angiotensin I through renin receptors. The effect of aliskiren, which became commercially available in the United States in 2007, is a modest decrease in blood pressure, which may also be incremental to that of other antihypertensive agents such as ARBs and ACEIs,12,13 although no large-scale study of renin activity inhibition on renal function in diabetics with nephropathy has been undertaken. The AVOID trial demonstrated a beneficial effect of a renin activity antagonist plus an ARB in reducing proteinuria in type 2 diabetes vs an ARB alone. Whether this effect is independent of blood pressure control is questionable since there was a borderline significant decrease in blood pressure in the combined group vs the ARB group. The major question would be the effect on protection of glomerular filtration rate and CV events. The study was too short and involved too few patients to answer these questions, but the borderline significant decrease in rate of decline in the combination group compared with the ARB group in only 24 weeks does suggest this possibility. The major concern in combinations of a renin activity inhibitor with an ARB or ACEI is the increase in potassium concentration. Although hyperkalemia was reported in similar percentages of patients in both groups, a borderline significant increase in at least one value at ≥6 mm/L was found in the combination group. Nonetheless, it is possible that the blockade of renin activity on renin receptors in the kidney may be beneficial in decreasing fibrosis and apoptosis in the kidney, based on animal model studies.14,15 Summary. This trial randomized 499 American Indian men and women with type 2 diabetes and no prior CV events to aggressive vs standard treatment and evaluated them at baseline and 12 months after intervention by common carotid artery intima-media thickness (CCA-IMT). Mean low-density lipoprotein cholesterol levels during the 12 months were 72 vs 104 mg/dL for aggressive vs standard treatment, and systolic blood pressure levels were 117 vs 129 mm Hg. Compared with baseline, CCA-IMT regressed in the aggressive treatment group and progressed in the standard treatment group (P<.001). A greater decrease in left ventricular mass was also found in the aggressive treatment group. In the short period of intervention, CV events did not differ between groups. Rationale. The strong risk of CV events in diabetics has produced guidelines equating the risk of a first CV event in a diabetic to that in nondiabetics with a previous CV event. Accordingly, these same guidelines recommend aggressive intervention to decrease risk factors such as low-density lipoprotein cholesterol and blood pressure levels. Some studies have demonstrated further reduction in CV events in patients treated to reduce low-density lipoprotein cholesterol to below current target levels, and similarly, aggressive systolic blood pressure reduction to levels <130 mm Hg appears to decrease progression of renal failure such as reduced albuminuria and decreased progression to end-stage renal disease.17–19 In American Indians, especially, diabetes carries a strong risk of CV events. This study focused on the aggressive reduction of two components of risk rather than lipid levels and blood pressure alone, using the surrogate determinant of atherosclerosis progression, CCA-IMT. Study Design. A total of 548 American Indian men and women were recruited for the study from 4 clinical centers in the western United States and randomized to aggressive or standard treatment of low-density lipoprotein cholesterol and systolic blood pressure. Entry criteria included type 2 diabetes, low-density lipoprotein cholesterol ≥100 mg/dL, and systolic blood pressure >130 mm Hg during the previous 12 months without previous CV events. Exclusion criteria included, among other factors, systolic blood pressure >180 mm Hg, severe congestive heart failure, and secondary hypercholesterolemia. Goals for the aggressive treatment group were systolic blood pressure ≤115 and ≤130 mm Hg in the aggressive and standard groups and low-density lipoprotein cholesterol ≤70 and ≤100 mg/dL, respectively. Antihypertensive interventions in stepwise progression were ACEIs or ARBs, followed by hydrochlorothiazide and then calcium channel blockers, α-blockers, and other vasodilators as necessary to achieve target goals. For low-density lipoprotein cholesterol interventions, statins were to be used first, followed by ezetimibe and, if non–high-density lipoprotein cholesterol goals were not reached (levels of non–high-density lipoprotein cholesterol >30 mg/dL above low-density lipoprotein cholesterol target goals indicated above), fish oil, fenofibrate, or niacin was added. The end point was effect on CCA-IMT and left ventricular mass. Results. A total of 499 patients were evaluated, since patients with previous CV disease were excluded after recruitment. Initial low-density lipoprotein cholesterol levels were 104 mg/dL. Baseline systolic blood pressure was significantly lower in the aggressive treatment group (128 mm Hg) than in the standard treatment group (133 mm Hg). After 36 months, mean low-density lipoprotein cholesterol decreased in the aggressive treatment group and remained unchanged in the standard treatment group. Systolic blood pressure decreased in the aggressive treatment group and decreased slightly in the standard treatment group. In terms of the primary outcome event, CCA-IMT regressed in the aggressive treatment group and progressed in the standard treatment group (Table). Left ventricular mass index decreased slightly but significantly more in the aggressive treatment group (Table). Clinical CV events, not a major outcome measure in this study, were no different between groups: 1.5 to 1.6 per 100 person-years, a result that was lower than expected. Adverse events were higher in the aggressive treatment group (38.5% vs 26.7%), primarily due to antihypertensive medications. Comment. This study stands out as one of the first to evaluate aggressive combinations of lipid-lowering and antihypertensive therapy in primary prevention. That it involves a special population at increased risk for CV events is also important—some of the authors have been involved with CV epidemiologic and clinical trial investigations in American Indians for over a decade, and such studies promise to increase the profile of risk assessment and effects of interventions that would complement earlier investigations primarily in white populations. It is interesting that the effects on lowering of left ventricular mass and regression of CCA-IMT were independently affected by antihypertensive agents and low-density lipoprotein cholesterol reduction, respectively. One may argue that regression of CCA-IMT still requires demonstration of decreased CV events or even that aggressive low-density lipoprotein cholesterol lowering may not be associated with regression of CCA-IMT.20 Of concern were the greater adverse effects of hypotension and hyperkalemia with aggressive blood pressure treatment. The concerns about aggressive blood pressure reduction may be allayed or bolstered depending upon the results of the blood pressure arm of the ACCORD study and the National Heart, Lung, and Blood Institute Systolic Blood Pressure Intervention Trial (SPRINT).20,21

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