Uncontrolled diabetes mellitus (DM) is associated with high cardiovascular morbidity and mortality. The coexistence of hypertension and DM multiplies the diabetic complications manifold. Earlier studies have shown that lowering blood glucose, blood pressure (BP), or both decreases the diabetic complications. On the basis of these results, national and international guidelines have recommended aggressive blood glucose and BP control in patients with DM to glycosylated hemoglobin <7.0% and BP <130/80 mm Hg. However, several recent clinical outcomes trials have demonstrated that lowering glycosylated hemoglobin to <7.0% and BP to <130/80 mm Hg does not add any additional benefit to patients with DM and hypertension and may be detrimental to their health. The consensus of scientific opinion at present is that BP should be reduced to 130 to 139/70 to 80 mm Hg in patients with DM with increased cardiovascular risk. The investigators conducted a Medline search of English-language papers published from 1998 to 2010 regarding aggressive blood glucose and BP control in patients with DM and hypertension, and 15 pertinent reports were selected. In conclusion, a review of recent research findings suggests less aggressive control of glucose and BP, and “the lower the better” may not be defensible at present, until new data become available.
Diabetes mellitus (DM) is a major cause of cardiovascular disease (CVD), renal disease, peripheral arterial disease, and strokes. Also, it is estimated that up to 80% of patients with DM will eventually develop CVD or die from it. Because of this, DM has been considered a “cardiovascular risk equivalent,” conferring the same risk for future CVD complications, like those who have had previous myocardial infarctions (MIs). In addition, there is a direct relation between blood glucose levels and CVD complications. In contrast, decreases in glucose and glycosylated hemoglobin (HbA 1c ) levels are associated with a reduction of CVD complications. However, besides hyperglycemia, patients with DM have other co-morbid conditions, such as hypertension and dyslipidemia, which play a significant role in the incidence of CVD complications, whereas decreases of blood pressure (BP) and cholesterol are associated with a reduction in CVD complications. On the basis of the proved benefits of tight glucose and BP control, several national and international guidelines recommend aggressive glucose (HbA 1c <7%) and BP control (BP <130/80 mm Hg), and “the lower the better.” However, recent clinical outcomes trials have shown that this might not be the case. For this review, we conducted a Medline search of English-language papers published from 1998 to 2010, and 15 pertinent reports were selected. These reports, with collateral published research, are discussed in this review.
The Cardiovascular Protective Effects of Intensive Blood Glucose Control
The pertinent findings from an overview of several clinical trials examining intensive compared to conventional glucose control on cardiovascular complications are listed in Table 1 .
| Study | n | Age (years) | Treatment | Follow-Up (years) | Results | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Intensive | Conventional | Intensive | Conventional | RR or HR | p Value | |||||
| UKPDS33 8 | 3,867 | 54 | Sulfa, insulin | Diet | 10.0 | HbA 1c | 7.0% | 7.9% | RR | |
| Any DM end point | 35.3% | 38.5% | 12% | 0.029 | ||||||
| Microvascular | 8.2% | 10.6% | 25% | 0.0099 | ||||||
| All-cause death | 17.9% | 18.7% | 6% | 0.44 | ||||||
| UKPDS34 9 | 1,704 | 53 | Metformin | Diet | 10.7 | HbA 1c | 7.4% | 8.0% | RR | |
| Any DM end point | 10.3% | 38.9% | 32% | 0.0023 | ||||||
| Microvascular | 2.5% | 9.2% | 29% | 0.19 | ||||||
| All-cause death | 5.3% | 21.7% | 36% | 0.011 | ||||||
| ACCORD | 10,251 | 62 | Any antidiabetic drug | Any antidiabetic drug | 3.4 | HbA 1c | 6.4% | 7.5% | HR | |
| Composite end point | 6.9% | 0.90 | 0.16 | |||||||
| Nonfatal MI | 3.6% | 4.6% | 0.76 | 0.04 | ||||||
| Nonfatal stroke | 1.3% | 1.2% | 1.06 | 0.74 | ||||||
| All-cause death | 5.0% | 4.0% | 1.22 | 0.041 | ||||||
| ADVANCE | 11,140 | 66 | Maximum doses of metformin, rosiglitazone, glimepiride | Standard doses of same drugs | 4.9 | HbA 1c | 6.5% | 7.9% | HR | |
| Microvascular | 9.4% | 10.9% | 0.86 | 0.01 | ||||||
| Macrovascular | 10.3% | 10.6% | 0.94 | 0.32 | ||||||
| All-cause death | 8.89% | 9.6% | 0.93 | 0.28 | ||||||
| VADT | 1,791 | 60 | Maximum doses of metformin + rosiglitazone or glimepiride + rosiglitazone | Half of maximum dose of same drugs | 5.6 | HbA 1c | 6.9% | 8.4% | HR | |
| Major CV event | 29.5% | 33.5% | 0.88 | 0.41 | ||||||
| All-cause death | 11.4% | 10.6 | 1.07 | 0.08 | ||||||
In the first United Kingdom Prospective Diabetes Study (UKPDS33), 3,867 newly diagnosed subjects with type 2 DM were randomized into an intensive glucose treatment group with sulfonylurea or insulin, compared to a conventionally treated group with diet modification. The subjects were followed for 10 years, and the following end points were prespecified: microvascular complications (nephropathy, retinopathy), DM-related end points (sudden death, hypoglycemia, hyperglycemia, fatal or nonfatal MI, angina, heart failure, stroke), and all-cause mortality. At the end of the study, there were no significant differences between the 2 groups with respect to cardiovascular death and all-cause mortality. The most significant finding was a 25% decrease in microvascular complications in the intensively treated group ( Table 1 ).
The UKPDS34 study included 1,704 obese patients with DM randomized to an intensive glucose control with metformin, or other agents, and a conventionally treated group with diet modification. After 10.7 years of observation, intensive treatment resulted in significant decreases in any DM-related end points and all-cause mortality compared to the conventionally treated group ( Table 1 ). However, hypoglycemia was more common in the intensively treated groups.
In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, 10,251 high-risk patients with DM (mean age 62.2 years) were randomized to an intensive-treatment group (HbA 1c <6.0%) or to a standard-therapy group (HbA 1c 7.0% to 7.9%) and followed for 3.5 years. At the end of the study, HbA 1c values were 6.4% and 7.5% in the intensively and conventionally treated groups, respectively ( Table 1 ). There was no difference in the composite end point of nonfatal MI, nonfatal stroke, or death from cardiovascular causes between the 2 groups. However, the secondary end points of nonfatal MI, nonfatal stroke, death from cardiovascular causes, and all-cause mortality were significantly increased in the intensively treated group ( Table 1 ). A greater number of subjects in the intensive treatment group developed severe hypoglycemia compared to the conventionally treated group.
The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study randomized 11,140 subjects with type 2 DM into standard and intensively treated groups. At baseline, 32.3% of subjects had histories of macrovascular events, and 10.4% had histories of major microvascular events. The primary outcomes of the study were a composite of macrovascular events (death from CVD, nonfatal MI, or nonfatal stroke) and a composite of microvascular events (nephropathy, retinopathy). All-cause mortality was a secondary end point. After a mean follow-up period of 5 years, the mean HbA 1c in the intensively treated group was 6.5%, compared to 7.3% in the standard-treatment group. There was no significant difference between the 2 treatment groups in the incidence of macrovascular events. However, there were significantly fewer microvascular events in the intensively treated group ( Table 1 ).
The Veterans Affairs Diabetes Trial (VADT) was an open-label trial comparing the effects of intensive and conventional treatment on glucose control and cardiovascular outcomes in 1,791 veterans with type 2 DM. In this study, 40% of subjects had previous cardiovascular events at the time of enrollment. The primary outcome included a composite of MI, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary artery disease, and amputation for ischemic gangrene. The aim was to reduce HbA 1c by 1.5% from baseline with intensive treatment. After 5.6 years of observation, HbA 1c was 6.9% in the intensively treated group compared to 8.4% in the conventionally treated group. There was no significant difference between the 2 groups in any component of the primary outcome or in death from any cause ( Table 1 ).
Cardioprotective Effects of Aggressive Blood Pressure Control
Hypertension is a well-recognized major risk factor for CVD, stroke, and renal failure, and a major meta-analysis of 1 million hypertensive subjects demonstrated a direct and sustained effect of BP on CVD and strokes from 115/75 to 160/100 mm Hg or higher, regardless of age or gender. A complementary meta-analysis also showed a direct effect of BP reduction, with decreases in CVD and strokes, although BP did not decrease to <130/80 mm Hg.
The first studies to demonstrate a beneficial effect of BP reduction in patients with DM and hypertension were the Hypertension Optimal Treatment (HOT) study and UKPDS38, respectively. Subsequently, several studies were conducted testing the significance of very tight BP control on CVD complications in subjects with type 2 DM. All these studies are listed in Table 2 .
| Study | n | Age (years) | Follow-Up (years) | BP (mm Hg) | CV End Points | RR (%) | p Value | |
|---|---|---|---|---|---|---|---|---|
| Aggressive | Less Aggressive | |||||||
| HOT | 1,501 | 61.5 | 3.8 | 81.1 (diastolic) | 85.2 (diastolic) | CVD | ND | NS |
| Stroke | 51 | 0.005 | ||||||
| UKPDS38 11 | 1,148 | 56.0 | 8.4 | 144/82 | 154/87 | Composite end point | 24 | 0.005 |
| DM death | 32 | 0.019 | ||||||
| Stroke | 44 | 0.013 | ||||||
| Microvascular | 37 | 0.009 | ||||||
| ABCD | 470 | 58.0 | 5.3 | 132/78 | 138/86 | CVD | ND | NS |
| All-cause death | 48.6 | 0.037 | ||||||
| ADVANCE | 11,140 | 66.0 | 4.3 | 139/79 | 145/81 | CVD | ND | NS |
| Macrovascular + microvascular | 9 | 0.04 | ||||||
| All-cause death | 14 | 0.03 | ||||||
| INVEST | 6,400 | 66.0 | 2.7 | <130 (systolic) | <140 (systolic) | CVD | ND | NS |
| All-cause death | ND | NS | ||||||
| ACCORD | 4,733 | 62.0 | 4.7 | 119.3 (systolic) | 133.5 (systolic) | Composite end point | ND | NS |
| All-cause death | ND | NS | ||||||
| Stroke | 47 | 0.01 | ||||||
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