Hypertension in Diabetes: Treatment Considerations

Abstract

Treatment of blood pressure in the patient with diabetes remains a challenge. While data extrapolated from many trials seemed to imply that lower blood pressures leads to more favorable cardiovascular outcomes, this paper reviews newer trials designed to treat to blood pressure targets below 130/80 mmHg in patients with long term established diabetes, which showed that this goal may prove more harmful than helpful. In clinical practice this may be less relevant due to the fact that less than half of patients are even at the goal of 130/80. The interaction between glucose control and blood pressure control are also discussed, emphasizing the importance of multifactorial treatment. J Clin Hypertens (Greenwich). 2011;13:314–318. © 2011 Wiley Periodicals, Inc.

Hypertension and diabetes are well‐known to go hand in hand, with a 75% prevalence of hypertension among persons with diabetes. ¹ Conversely, hypertension is associated with a nearly 5‐fold increase in likelihood of diabetes. ² Approximately half of persons with hypertension have insulin resistance, ³ with increased likelihood of developing diabetes. The combination of both hypertension and diabetes in an older population doubles the risk of stroke, death from cardiovascular (CV) causes, and all‐cause mortality when compared with that of nondiabetic hypertensive patients. ⁴ , ⁵ , ⁶ , ⁷ , ⁸ Furthermore, hypertension is a major risk factor for progression of diabetic nephropathy, ⁹ , ¹⁰ retinopathy, ¹¹ left ventricular hypertrophy, ¹² and heart failure. ¹³

BP Treatment for Persons With Diabetes: Evidence for Benefit

There is considerable evidence that blood pressure (BP) lowering reduces the complications of diabetes. One of the first trials to show the effect of lowering BP in patients with diabetes was a subtrial of the United Kingdom Prospective Diabetes Study (UKPDS). A group of 1148 diabetic patients with baseline BP 160/94 mm Hg were randomized to what was at that time described as tight BP control (<150/85 mm Hg) with β‐blockers or angiotensin‐converting enzyme (ACE) inhibitors as baseline therapy, with addition of other medications as needed, achieving mean BP 144/82 mm Hg, or to less tight control (<180/105 mm Hg), with mean BP 154/87 mm Hg. Approximately 9 years later, patients assigned to tight control of BP had a 24% lower risk of all diabetes‐related end points, a 32% reduction in death related to diabetes, a 44% decrease in stroke, and a 37% decrease in microvascular disease. ¹⁴

An observational analysis of the UKPDS data showed that the risk of each of the macrovascular and microvascular complications of type 2 diabetes was strongly associated with mean systolic BP. On average, each 10‐mm Hg reduction in systolic BP was associated with a 12% decrease in the risk of any end point related to diabetes and a 15% reduction in the risk of death related to diabetes. The increase in risk showed no evidence of a threshold, doubling over the range of systolic BP from <120 mm Hg (median 114 mm Hg) to >160 mm Hg (168 mm Hg), with the authors concluding, “There are no natural thresholds under which the risk of microvascular and macrovascular complications in diabetes are fully prevented.” ¹⁵

The Hypertension Optimal Treatment (HOT) trial was a large trial of almost 19,000 patients randomized to a target diastolic BP of 90 mm Hg, 85 mm Hg, or 80 mm Hg. Felodipine was used as baseline therapy, with addition of ACE inhibitors or β‐blockers and diuretics as needed. A subgroup of 1501 with diabetes attained diastolic BPs of 85 mm Hg, 83 mm Hg, and 81 mm Hg, respectively, with a 51% reduction in CV end points in the lower compared with the high BP group. ⁸ Another major study, the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, evaluated antihypertensive therapy with the ACE inhibitor perindopril and the diuretic indapamide vs placebo in patients with type 2 diabetes having a baseline BP 145/81 mm Hg. ¹⁶ Mean BPs attained were 134/74 mm Hg vs 140/76 mm Hg, leading to a lower combined rate of major macrovascular and microvascular events (15.5% vs 16.8%), as well as reduction in CV mortality (3.8% vs 4.6%) and all‐cause mortality (7.3% vs 8.5%).

BP Goals

Although these and other trials showed benefits of lowering BP, none of them were designed to treat to targets below 130/80 mm Hg. Less than half of patients with diabetes achieve a BP at such a currently recommended goal, ¹⁷ with those not at goal often at substantially higher levels. ¹⁸

Hypertension guidelines set out by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, ¹⁹ the World Health Organization, ²⁰ the British Hypertension Society, ²¹ the European Society of Hypertension/European Society of Cardiology, ²² the American Heart Association, ²³ and the American Diabetes Association ²⁴ all advocate treating BP to <130/80 mm Hg for patients with diabetes mellitus, assuming that treating to such targets will achieve the reduction in CV morbidity and mortality predicted from epidemiologic observational studies. The evidence for such treatment may not be as conclusive as has been thought, with meta‐analyses showing nonsignificant trends for reduction in mortality and total CV events comparing 85 mm Hg vs 90 mm Hg diastolic BP in diabetes. ²⁵

The BP arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial prospectively investigated whether lower BP at such levels further reduced CV events in high‐risk patients with type 2 diabetes followed during an 8‐year period. ²⁶ In the hypertension arm of the trial, 4733 patients aged 40 to 79 with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic BP of <120 mm Hg, or standard therapy, targeting a BP of <140 mm Hg. The patients had diabetes for an average of 10 years. During the follow‐up period of 4.7 years, the average systolic BP was 119 mm Hg in the intensively treated group and 133.5 mm Hg in the standard therapy group. No significant differences were found between the intensive group and the standard group in rates of a combined end point of nonfatal myocardial infarction, nonfatal stroke, or death from CV causes (208 CV events in the intensive group, 237 events in the standard group). The two study groups did not differ with respect to most of the secondary outcomes, although there were significant differences in the rate of total stroke, at 0.32% vs 0.53% per year. The intensively treated group was, however, more likely to experience side effects, such as hypotension, hypokalemia, and in particular worsening of renal function, with elevation in creatinine in 561 vs 367 participants, although none of the events were said to have caused serious complications.

An observational subgroup analysis of the International Verapamil SR and Trandolapril Study (INVEST) trial ²⁷ that analyzed data on 6400 patients with diabetes and established coronary artery disease also suggests that lowering BP to <130/80 mm Hg may cause harm. Patients were followed during a 5‐year period, receiving initially either a calcium antagonist or β‐blocker, followed by an ACE inhibitor, a diuretic, or both to achieve a systolic BP of <130 mm Hg and a diastolic BP of <85 mm Hg. Patients were categorized as having tight control if they could maintain their systolic BP at <130 mm Hg; usual control if it ranged from 130 mm Hg to <140 mm Hg; and uncontrolled if it was ≥140 mm Hg. Total mortality was 22.8% in the tight control vs 21.8% in the usual control group.

Another study, Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET), analyzed the impact of BP on CV events in high‐risk patients with atherosclerotic disease or diabetes with organ damage. In this study, 37.5% of the patients had diabetes and treated hypertension. The study analyzed the relationship between baseline BP and its changes with treatment on subsequent CV outcomes. Among study participants who were randomized to ramipril, telmisartan, or both, there was a J‐shaped pattern of CV mortality, with nadir at 130 mm Hg, and of myocardial infarction, with nadir at 126 mm Hg, although, as in ACCORD, the risk of stroke continued to decrease at lower BP levels. ²⁸

A Cochrane library meta‐analysis is currently underway to determine whether there is a reduction in total mortality and morbidity associated with treatment of BP to “lower targets” as compared with “standard targets,” defining lower targets as a BP ≤130/80 mm Hg. ²⁹ At the present time, however, for people with long‐standing diabetes, especially those with established CV disease, we should be concerned as to whether BP <130/80 mm Hg may cause harm. Whether such aggressive management of BP would be beneficial for patients who are younger or have had a shorter duration of diabetes has not been studied. With the low event rate in such populations, dauntingly large trials would be required to address this question.

BP vs Glycemic Treatment: Is One More Important Than the Other?

In diabetic patients with hypertension, it has been argued that intensive BP control is more beneficial than tight glucose control. ¹⁴ , ³⁰ For stroke, any diabetic end point, death from diabetes, and microvascular complications, treating hypertension led to much greater relative risk reductions than treating hyperglycemia. If, however, one looks in the UKPDS at the relationship between end points at increasing levels of hemoglobin A_1c and of BP, the patterns are remarkably similar. ¹⁵ , ³¹

Current guidelines recommend a multifactorial approach with simultaneous targeting of elevated BP and glucose levels in individuals with type 2 diabetes. However, it is not known whether combining BP lowering and glucose control can reduce the risk of vascular complications to a greater extent than either treatment alone. Since therapy of each of the risk factors is known to reduce the risk of complications and the presence of both risk factors markedly increases the risk over the presence of just one, there is potential for achieving a major reduction in the incidence of the complications of diabetes by treating both blood glucose and BP. Analysis of outcome among the 887 hypertensive patients in UKPDS randomized to both the glycemia and hypertension intervention arms of the study provides insight pertaining to this question. ³² Of the 887 patients, 87 were allocated to conventional glucose/less tight BP, 155 to conventional glucose/tight BP, 231 to intensive glucose/less tight BP, and 414 to both the intensive glucose and tight BP intervention groups. For the “any diabetes–related end point,” diabetes‐related mortality, and all‐cause mortality, patients allocated to both intensive glucose and to tight BP control had significantly fewer events than those allocated to either group alone or neither. Similar trends were seen for other end points, serving as important evidence for multifactorial treatment for the prevention of complications of type 2 diabetes. An explanation for the apparently lesser effect of the glycemic intervention may be the progressive worsening over time of glycemic control in the UKPDS, regardless of the glycemic treatment to which a given person had been assigned. ³³ The treatment of hypertension may not require the same degree of progressively greater intervention in reducing complications.

Interestingly, the UKPDS 10‐year follow‐up study shows ongoing benefit of the original glycemic intervention, although the glycemic differences between the intensive and conventional group disappeared after the first year of follow‐up, with persistence in the decreased risk of microvascular complications noted at the end of the original study and significant 15% and 13% risk reductions for myocardial infarction and total mortality, respectively. ³⁴ This legacy effect of earlier glucose control is reminiscent of what was observed in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications (DCCT/EDIC) study in patients with type 1 diabetes. ³⁵ Although post‐trial changes in BP were also similar in the intervention and control groups, there did not seem to be a “memory effect” of tight BP control. ³⁶ After a median 8.0 years of post‐trial follow‐up, nearly all the significant relative risk reductions found during the trial in the group receiving tight BP control were lost.

The ADVANCE study was a 2×2 factorial intervention with both BP and glycemia treatment, providing another opportunity to look at the combined effect of both interventions. ³⁷ During the duration of 4.3 years, BP was reduced by an average ± standard error of the mean of 7.1±0.3 mm Hg systolic and 2.9±0.2 mm Hg diastolic in patients assigned to joint treatment compared with those assigned to neither treatment (P<.001). Similarly, hemoglobin A_1c was reduced by 0.61%±0.02% after 4.3 years of follow‐up in patients assigned to joint treatment compared with those assigned to neither treatment (P<.001). Comparing the 4 resultant groups, glucose‐intensive and glucose‐standard with and without perindopril/indapamide, patients assigned to both intensive glucose and BP‐lowering, compared with the standard glucose and placebo BP intervention, had significant 18% and 24% reductions in total and CV mortality, and a 28% reduction in renal events, in particular with 54% reduction in likelihood of new‐onset macroalbuminuria.

The concept of multifactorial intervention among persons with diabetes was most dramatically shown in the Steno‐2 trial of diabetic patients with microalbuminuria. Therapy targeting hyperglycemia, hypertension, dyslipidemia, microalbuminuria, cigarette use, and the need for antithrombotic medication, while achieving systolic BP goal in less than half and glycemic goal in less than one fifth of patients, led to >50% reductions in CV disease, nephropathy, and retinopathy end points during an 8‐year period ³⁸ and to a nearly 50% reduction in total mortality at 13 years. ³⁹

Conclusions

With the high correlation of diabetes and hypertension and the strong association of the latter with a variety of diabetic complications, it is instructive to review the evidence of benefit of BP‐lowering in this group. A variety of interventions have been shown to be beneficial across the spectrum of complications. Some proposals regarding goals of BP‐lowering may not be fully evidence‐based, and it seems possible that excessively aggressive measures may lead to adverse outcome, but it is striking to observe the evidence of beneficial interaction of BP and glycemic treatment, with further benefit of combined lipid, BP, and glycemic treatment. A reasonable strategy then may be to pursue BP‐lowering in persons with diabetes with attention to potential renal and CV adverse effects that might necessitate less aggressive treatment, while continuing at the same time to appropriately treat to glycemic and lipid goals based on careful clinical evaluation of the patient’s needs.