FAQ
Diabetes control and macrovascular complications
The complications resulting from uncontrolled diabetes mellitus (DM) can be categorized as either microvascular or macrovascular. As suggested by the term, microvascular complications involve abnormalities in small vessels that lead to various organs, such as the eye, kidney, and nerves, resulting in retinopathy, nephropathy, and neuropathy, respectively. Macrovascular complications are caused by changes in large vessels that lead to the heart and brain and are involved in peripheral circulation, which can result in myocardial infarction, stroke, and peripheral vascular disease.
Studies evaluating the effect of intensive diabetes control on these complications have consistently shown reduction in microvascular disease but have failed to demonstrate an impact on macrovascular complications. The Diabetes Control and Complications Trial demonstrated a 60% reduction in microvascular disease in type 1 DM patients who achieved a mean glycated hemoglobin (A1C) of 7.2%. Similarly, the United Kingdom Prospective Diabetes Study (UKPDS) evaluated the effect of tight glycemic control in type 2 DM patients on microvascular and cardiovascular complications. A 25% reduction in microvascular disease occurred in those patients who achieved a median A1C of 7%. A significant impact on cardiovascular disease was observed with tight blood pressure control, but not with glycemic control. In order to further explore the effect of DM control on macrovascular disease, larger studies have recently been conducted. The results of 2 of these studies are summarized below.
ACCORD and ADVANCE - design
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) randomized 10,251 type 2 DM patients to either intensive DM or standard treatment. Patients were further randomized to achieve a systolic blood pressure goal of either <120 mm Hg or <140 mm Hg or lipid treatment with fenofibrate or placebo. The planned duration of the trial was between 4 to 8 years; however, the trial was terminated early due to concerns of increased mortality in the intensive therapy group. Currently, only the results of the glycemic control portion of the trial are published; the median duration of treatment was 3.5 years.
A second trial, the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE), involved randomization of 11,140 type 2 DM patients to either intensive or standard glucose control. A separate component of the study also evaluated the effect of blood pressure control on macrovascular complications. Patients were randomized to treatment with either perindopril/indapamide combination or placebo; a significant lowering of major cardiovascular events and death was seen with active treatment. Median duration of follow-up in the ADVANCE trial was 5 years.
Table 1 lists selected differences between the ACCORD and ADVANCE trials. Although the composite of macrovascular events were primary endpoints in both trials, the ADVANCE trial also included microvascular events as a primary endpoint. Patients in the ACCORD trial had higher baseline A1C levels and higher baseline and endpoint use of thiazolidinediones (TZD) (over 90% rosiglitazone) and insulin. Baseline weight was higher in ACCORD patients and at 3 years, the mean weight gain was 3.5 kg in the intensive group with 28% of patients experiencing a >10 kg weight gain from baseline. Minimal weight gain was observed in either group in the ADVA NCE trial. Sulfonylurea use was higher in ADVANCE as gliclazide was used as part of the treatment protocol for the intensive therapy group.
Table 1. Selected differences between ACCORD and ADVANCE trials
ACCORD |
ADVANCE |
|||
| Design and methods | ||||
| Study locations |
United States and Canada |
20 countries from Asia, Australia, Europe and North America |
||
| A1C inclusion criteria |
≥ 7.5% |
No A1C requirement |
||
| A1C target in study groups |
Intensive: <6%
Standard: 7% to 7.9% |
Intensive: ≤6.5%
Standard: based on local guidelines |
||
| Treatment |
A suggested protocol was provided but treatment decisions were left to the discretion of the provider |
All patients in the intensive group received gliclazide 30 to 120 mg daily
A suggested protocol was provided but treatment decisions were left to the discretion of the provider |
||
| Primary outcome |
Composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes |
Macrovascular, microvascular events, and the composite of both events |
||
| Baseline characteristics | ||||
Intensive |
Standard |
Intensive |
Standard |
|
| Median A1C (%) |
8.1 |
8.1 |
7.2 |
7.2 |
| TZD use (% of patients) |
19.5 |
19.2 |
3.6 |
3.7 |
| Secretagogue use (% of patients) |
50.8 |
49.4 |
73.6 |
72.6 |
| Insulin use (% of patients) |
34.1 |
35.7 |
1.5 |
1.4 |
| Weight (kg) |
93.5 |
93.6 |
78.2 |
78 |
| Endpoint characteristics | ||||
Intensive |
Standard |
Intensive |
Standard |
|
| Median A1C (%) |
6.7 |
7.5 |
6.3 |
7 |
| TZD use (% of patients) |
91.7 |
58.3 |
16.8 |
10.9 |
| Secretagogue use (% of patients) |
86.6 |
73.8 |
93.6 |
61.5 |
| Insulin use (% of patients) |
77.3 |
55.4 |
40.5 |
24.1 |
| Weight (kg)
|
NR
|
NR
|
78.1
|
77
|
ACCORD and ADVANCE - Study outcomes
Table 2 highlights the main results achieved in both trials. The composite primary endpoint of macrovascular events in the ACCORD trial was not significantly different between the intensive and standard treatment groups. However, in the ADVANCE trial, the composite primary endpoint of macrovascular and microvascular events was significantly lower in the intensive control group compared to the standard control group. When evaluated separately, the main reason for the reduction in the primary endpoint was the decrease in microvascular events, particularly new or worsening nephropathy, in the intensive therapy group.
Nonfatal myocardial infarction (MI), nonfatal stroke, and death from cardiovascular causes were not significantly different in either group in the ADVANCE trial. In contrast, the ACCORD trial demonstrated a lower occurrence of nonfatal MI in the intensive control group and a higher occurrence of death from any cause or from cardiovascular causes compared to the standard control group. The higher occurrence of these events led to the early termination of the ACCORD trial. Subgroup analysis demonstrated a significantly lower risk of death from fatal and nonfatal cardiovascular events with intensive control in patients without previous cardiovascular disease (p=0.04) and in patients with a baseline A1C less than 8% (p=0.03).
In both trials, the rate of hypoglycemia was higher with intensive control compared to standard control. In the ACCORD trial, 10.5% of patients receiving intensive therapy required medical assistance for hypoglycemia compared to 3.5% of standard control patients (p<0.001). Any assistance for hypoglycemia was needed for 16.2% of intensive control patients versus 5.1% of standard therapy patients (p<0.001). In the ADVANCE trial, severe hypoglycemia (defined as inability to treat oneself and requiring assistance) was reported in 2.7% of intensive control patients compared to 1.5% in the standard control group (HR 1.86; 95% CI 1.42 to 2.40, p<0.001). Minor hypoglycemia (defined as glucose level of <50 mg/dL or symptoms of hypoglycemia) also occurred more in intensive control patients compared to standard control (120 vs. 90 events per 100 patients per year, p value not given).
Table 2. Selected results of the ACCORD and ADVANCE trials
Results |
ACCORD |
ADVANCE |
||||||
Intensive |
Standard |
HR (95% CI) |
P value |
Intensive |
Standard |
HR (95% CI) |
P value |
|
| Composite primary endpoint | 6.9 |
7.2 |
0.90 (0.78 to 1.04) |
0.16 |
18.1 |
20 |
0.90 (0.82 to 0.98) |
0.01 |
| Macro vascular events | NA |
NA |
NA |
NA |
10 |
10.6 |
0.94 (0.84 to 1.06) |
0.32 |
| Micro vascular events | NA |
NA |
NA |
NA |
9.4 |
10.9 |
0.86 (0.77 to 0.97) |
0.01 |
| Nonfatal MI | 3.6 |
4.6 |
0.76 (0.62 to 0.92) |
0.004 |
2.7 |
2.8 |
NR |
NS |
| Nonfatal stroke | 1.3 |
1.2 |
1.06 (0.75 to 1.50) |
0.74 |
3.8 |
2.8 |
NR |
NS |
| Death from CV causes | 2.6
|
1.8
|
1.35 (1.04 to 1.76)
|
0.02
|
4.5
|
5.2
|
NR
|
NS
|
| Death from any cause | 5
|
4
|
1.22 (1.01 to 1.46)
|
0.04
|
8.9
|
9.6
|
NR
|
NS
|
Summary
Both the ADVANCE and ACCORD trials failed to show a decrease in macrovascular events in patients receiving intensive glycemic therapy. However, what raises more questions is the reason for increase in events with intensive control in the ACCORD study. Higher rosiglitazone use has been suggested as a possible cause; however, statistical analysis failed to identify drug therapy as a cause of increased mortality. Other potential causes may be greater weight gain or the rapidity of achieving target A1C. A 1.4% A1C reduction was achieved within 4 months in the ACCORD trial versus a 0.5% reduction in 6 months in the ADVANCE trial.
As expected, both trials demonstrated a higher occurrence of hypoglycemia with intensive control compared to standard control. The higher overall incidence of hypoglycemia in the ACCORD trial may be due to use of an alternate definition of hypoglycemia compared to the ADVANCE trial and/or greater use of insulin and TZDs. In fact, both intensive and standard control patients in the ACCORD study had higher insulin and TZD use compared to either group in the ADVANCE trial.
The results of these studies do not change current recommendations for managing patients with diabetes. Clinicians should continue to target an A1C of <7% and possibly <6.5% without causing significant hypoglycemia as the ADVANCE study did achieve a mean A1C of 6.3%, which resulted in a significant reduction in nephropathy. Clinicians should also continue to control other cardiovascular risk factors, such as hypertension and hyperlipidemia along with other interventions including the use of antiplatelet therapy, smoking cessation, and lifestyle modification.
References
American Diabetes Association. Implications of the diabetes control and complications trial. Diabetes. 1993;42(11)1555-1558.
American Diabetes Association. Implication of the United Kingdom prospective diabetes study. Diabetes Care. 2003;26(suppl 1):S28-S32.
ADVANCE Management Committee. Study rationale and design of ADVANCE: action in diabetes and vascular disease-preterax and diamicron MR controlled evaluation. Diabetologia. 2001;44:1118-1120.
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.
ACCORD Study Group. Action to control cardiovascular risk in diabetes (ACCORD) trial: design and methods. Am J Cardiol. 2007;99(suppl):21i-33i.
Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): 2545-2559.
Dluhy RG, McMahon GT. Intensive glycemic control in the ACCORD and ADVANCE trials. N Engl J Med. 2008;358(24);2630-2633.
Cefalu WT. Glycemic targets and cardiovascular disease. N Engl J Med. 2008:358(24):2633-2635.