How Low to Go With Glucose, Cholesterol, and Blood Pressure in Primary Prevention of CVD

Kimberly N. Hong, MD, MHSA; Valentin Fuster, MD; Robert S. Rosenson, MD; Clive Rosendorff, MD, PHD; Deepak L. Bhatt, MD, MPH


J Am Coll Cardiol. 2017;70(17):2171-21-85. 

In This Article


Pre-DM is a recognized risk factor for the development of both DM and CVD.[27,28] However, there are limited data to support pharmacological antihyperglycemic treatment in pre-diabetic patients. The Diabetes Prevention Program study randomized pre-diabetic individuals between 1996 and 1999 to intensive lifestyle modifications, metformin, or placebo.[29] The lifestyle modification group had the highest reduction in incident DM compared with both metformin and placebo. Although metformin was also superior to placebo in this primary outcome, the effect size was smaller in the subset of patients with lower body mass index, and the gastrointestinal side effects were significantly greater.[29] Interestingly, when the trial was extended to include 10-year follow-up data, with intensive lifestyle support offered to all trial participants, there was no difference in DM incidence rates during the follow-up period.[30] This suggests that in patients exposed to intensive lifestyle modification, metformin may not have a sustained benefit in reducing progression to DM. The ORIGIN (Outcome Reduction with an Initial Glargine Intervention) study randomized high-risk CVD individuals (of whom 59% had prior CVD) with impaired glucose tolerance, impaired fasting glucose, or newly diagnosed type 2 DM to glargine versus a standard-of-care antihyperglycemic regimen. Of interest is that although this study did not test a more-versus less-intense glucose control regimen, pre-DM patients randomized to glargine had lower incident rates of DM at 3 months (p < 0.05), but at a cost of increased rates of severe hypoglycemia. However, even with delayed progression to DM, there was no difference in cardiovascular events between the 2 treatment groups after a median follow-up of 6.2 years.[31] Similarly, 2 meta-analyses assessing the effect of insulin secretagogues (sulfonylureas), metformin, dipeptidyl-peptidase (DPP)-4 inhibitors, and glucagon-like peptide–1 analogues on the incidence of DM concluded that there were insufficient data to support initiation of these pharmacologic agents in pre-diabetic individuals.[32,33] Pre-DM is associated with hyperlipidemia and obesity, and current evidence supports counseling these individuals based on their overall risk and on modification of concomitant risk factors.[28]

Does Early Versus Late Disease Course Affect the HgA1c Target in Diabetic Patients?

The SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis In Myocardial Infarction 53) trial was a prospective, double-blinded, placebo-controlled trial that randomized individuals with type 2 DM to saxagliptin versus placebo in addition to usual care.[34] This trial included individuals with known CVD (79%) and those at risk of developing CVD (21%), defined as at least age 55 years with HTN, hyperlipidemia, or active smoking. The primary endpoint was a composite of CVD death, MI, or ischemic stroke at 2 years. In a risk-adjusted analysis that was stratified by baseline HgA1c, individuals with HgA1c <7% had the lowest risk of developing the primary endpoint at 2 years. These results suggest an association between HgA1c levels and macrovascular events.

Two trials that included newly diagnosed diabetic patients and assessed glycemic control on CVD were the UKPDS (United Kingdom Prospective Diabetes Study) and the DCC/EDIC (Diabetes Control and Complications/Epidemiology of Diabetes Interventions and Complications Trial).[35,36] Because patients were newly diagnosed, there was a higher likelihood that these individuals did not have end-organ complications at randomization. The outcomes of these trials suggest a benefit to earlier glucose control and that CVD risk accrues over time.

As a result of earlier interventions, the duration of health without CVD may be prolonged, and longer clinical follow-up may be required to assess the effect of these interventions. UKPDS was a prospective trial that randomized newly diagnosed individuals with type 2 DM to either intensive (fasting plasma glucose 106 mg/dl) or conventional glycemic control (fasting plasma glucose 270 mg/dl).[35] The primary endpoint in the trial was a composite that included death and evidence of end-organ disease.[35] The mean age of the study population was 53 years, with a mean HgA1c of 7%. At baseline, 36% of patients had retinopathy and 2% had proteinuria. Both of these characteristics have been used to identify patients with microvascular involvement in a trial with a median 10-year follow-up. The mean HgA1c achieved was 7% in the intensive group and 7.9% in the nonintensive group. The statistically significant risk reduction of 12% in the DM-related complication endpoint was driven by a 25% reduction in renal and retinal microvascular complications. There was a trend toward reduced MIs (p = 0.052),[35] which became significant (p = 0.02) 10 years after the close of the original trial. Of note, by this time point, differences in glycemic control were no longer present (HgA1c was 8% in both groups).[15]

Time to event is another important factor to consider. As in the UKPDS trial, the DCC/EDIC trial did not find any differences in CVD outcomes until after trial completion. Analysis at the end of the original study, which included 6.5 years of treatment, showed a nonsignificant decrease in CVD outcomes including MI, stroke, or death.[36] This trial randomized type 1 DM patients between 1983 and 1993. After the study closed, the surviving patient cohort (97% of the original) were enrolled in an epidemiological study to assess the long-term effects of glycemic control. The mean HgA1c was 7% in the intensive group and 9% in the standard control group during the active treatment study. During the subsequent follow-up study, which had a mean follow-up time of 17 years, the HgA1c for both groups was 8%. There was a 57% reduction in the composite CVD endpoint compared with the standard arm (p = 0.02).[15,36] Because this trial enrolled individuals with type 1 DM only, the mean baseline age was 27 years, with only 5% having microalbuminuria and no enrollees having HTN or hyperlipidemia. The younger age of this patient population and likely decreased time of exposure to hyperglycemia suggests that their vascular health was probably better at baseline than those in UKPDS.

The UKPDS and DCC/EDIC trials suggest that the maladaptive response to hyperglycemia is dose-dependent and that the benefit of intensive glycemic control may persist after treatment. This has been termed the legacy effect.[37] Similarly, just as treatment benefits accrue with time, time is also required for the maladaptive vascular response to hyperglycemia to become irreversible and have CVD significance.

Unlike the 2 aforementioned trials, which included newly diagnosed diabetic patients, the enrollees in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), VADT (Veterans Affairs Diabetes Trial), and ACCORD (Action to Control Cardiovascular Risk in Diabetes) trials had a higher risk profile. The enrollment criteria for these trials, outcomes, and baseline characteristics are shown in Table 1.

In ADVANCE, although there was a statistically significant difference in the primary composite outcome that combined both macrovascular and microvascular events (hazard ratio [HR]: 0.9; p = 0.013), this was driven by fewer microvascular events and particularly by a reduction in diabetic nephropathy.[38] Although there were no differences in the secondary outcomes, there was an expected increase in severe hypoglycemia (HR: 1.86; p < 0.001).[38]

In VADT, there was no significant difference in the primary outcome between treatment groups. Secondary analyses, which stratified enrollees by duration of DM, found in the intensive arm that there was a mortality benefit in individuals with DM duration <12 years and an increased risk of mortality in those with DM duration >18 years.[16,38,39] Similarly, analysis stratified by coronary artery calcium score showed that patients with scores <100 had reduced CVD events.[39] Of note, severe hypoglycemia, which was seen in 20% of the intensive group compared with only 8% in the conventional group, was associated with a 4-fold increase in CVD death. A subsequent study followed enrollees who survived the active part of the VADT trial for a median time of 9.7 years. In this follow-up study, a statistically significant risk reduction in the primary outcome (0.83; p = 0.04) was eventually achieved. Of note, there was no change in CVD or all-cause mortality. Similar to the other studies, the HgA1c in the 2 groups narrowed to 7.8% and 8.3%.[40]

ACCORD showed a 22% relative increase in mortality (1% absolute increase) over the 3.5-year treatment period in diabetic individuals who were treated to a target HgA1c <6%. Interestingly, 3 years after randomization, there was a decrease in the primary outcome that was driven by a significant reduction in nonfatal MIs. In the subgroup analysis, patients without prior CVD had a significantly lower primary outcome (a composite of MI, stroke, and CVD death) if their blood glucose target was <6.0 mg/dl versus 7 to 7.9 mg/dl.[41] This again suggests that in a subgroup of patients who may not have overt CHD, there may be a benefit to more aggressive glucose control.[41] One consideration when interpreting these data is that the target HgA1c occurred within 4 months of randomization. This is in contrast to VADT, where target HgA1c was achieved over 2 years.[39]

Risks of Intensive Glycemic Control

ACCORD was the only trial to show an increased risk of mortality. Otherwise, hypoglycemia is a consistent adverse effect of intensive glucose control. The VADT trial showed an increase in CVD events with severe hypoglycemia. The postulated mechanism for this is increased adrenergic activation and an associated increase in heart rate, systolic blood pressure (SBP), and cardiac output, which can exacerbate ischemia in at-risk vessels.[15] This is further evidenced by the lack of association between CVD events and hypoglycemia in the lower-risk population included in the UKPDS study.[15]

Microvascular disease is likely a precursor to macrovascular disease, and although it may be overly simplistic to suggest this, early prevention of hyperglycemia or even risk stratification of patients by retinal imaging and proteinuria may be necessary to determine the appropriate glycemic target. Furthermore, because vascular complications likely occur in a time-dependent spectrum that begins in the microvasculature and ends with macrovascular complications, the benefit of glycemic control may not be evident for several years. This should be considered in individuals who may have had DM for longer and in older individuals, in whom the risk of hypoglycemia as well as macrovascular complications may outweigh the incremental benefit that accrues over time with tighter glycemic control.