Blood pressure control in type 2 diabetes—what does the United Kingdom prospective diabetes study (UKPDS) tell us?

Rudy Bilous

University of Newcastle upon Tyne and South Tees Acute Trust, Middlesbrough, UK

Correspondence and offprint requests to: Rudy Bilous MD, South Tees Acute Trust, Middlesbrough, TS4 3BW, UK.

Hypertension is a commonly associated condition with type 2 diabetes; depending on its definition, it is present in at least 25% of patients [1]. Using the current definition of 130/85 mmHg proposed by the Joint National Commission VI Report from the USA [2] then 85% of 1565 type 2 patients in our diabetic clinic in Middlesbrough would be classified as hypertensive. The publication of the Hypertension Optimum Treatment (HOT) [3] and Systolic Hypertension in Europe (Syst-Eur) [4] studies have demonstrated that lowering blood pressure reduces stroke rate in both non-diabetic and diabetic patients, with a significantly greater benefit in diabetes. There is continuing debate about which drug should be used, however.

The UK Prospective Diabetes Study (UKPDS) was initially set up in 1977 with the aim of determining whether intensive glycaemic control with oral medication and/or insulin could prevent diabetic complications in newly diagnosed type 2 diabetic patients [5]. Ten years later, the Hypertension in Diabetes Study was introduced to the UKPDS in a factorial design in 20 out of the 23 participating centres [6]. Hypertension was defined as an untreated resting blood pressure of >160/90 or >150/85 mmHg on antihypertensive therapy at diagnosis of diabetes. 1148 (30%) out of the total cohort of 3867 patients were randomized to either tight (target BP <150/85 mmHg, n=758) or less tight (BP<180/105 mmHg, n=390) control. The tight group were further randomized to either captopril 25–50 mg twice daily (n=400) or atenolol 50–100 mg daily (n=358) as first line therapy [7]. The less tight group could use any therapy except ACE inhibitors or beta-blockers. If BP targets were not met then the suggested sequence of frusemide (<40 mg twice daily), slow release nifedipine (<40 mg twice daily), methyldopa (<500 mg twice daily) and prazosin (<5 mg thrice daily) was applied. There was a mean follow-up of 8.4 years; 56% of patients in the tight group achieved the target blood pressure of 150/85 mmHg and 27% of them needed three or more antihypertensive agents in order to do so. Average blood pressure was significantly lower in the tight versus less tight groups (144/82 vs 154/87 mmHg; P<0.0001), with a slight difference in diastolic pressure in those allocated to atenolol (143/81 mmHg) compared to captopril (144/83 mmHg; P=0.02).

In the overall study, there was an 18% mortality over 15 years with over one half of the deaths due to myocardial infarction (MI) and stroke [5]. Moreover, for each 10 mmHg increase in systolic blood pressure there was a 15% increase in macrovascular (MI, stroke, and peripheral amputation) events [6].

Tight blood pressure control significantly reduced the incidence of fatal and non-fatal stroke by 44% (P=0.013); and heart failure by 56% (P=0.0043), but the reduction in fatal and non-fatal MI of 21% was not significant (P=0.13). Interestingly there was also a significant 34% reduction in the progression of retinopathy (P=0.0038), the first time this has been demonstrated.

Around 17% of patients had microalbuminuria (urinary albumin concentration (UAC) >50 mg/l) and 3.5% clinical nephropathy (UAC>300 mg/l) at baseline. At 6 years, there was a significant reduction in microalbuminuria in the tight compared to the less tight groups (20.3 vs 28.5%; P<0.009) but this was lost by 9 years (28.8 vs 33.1%; P=0.33) perhaps because of a smaller sample size. There was no difference in the effects of captopril versus atenolol in the tight control group for any of the primary or secondary end points [7].

What do these results tell us? Firstly, that type 2 diabetes is a serious disease with an appreciable mortality (mainly from cardiovascular disease) after 15 years known duration, and many patients have established microvascular complications at diagnosis. Second, that most type 2 diabetic patients will be hypertensive by current criteria and that blood pressure relates closely to cardiovascular outcome. Third, lowering blood pressure reduces stroke and heart failure (despite the use of beta-blockers) with no obvious threshold of benefit. Myocardial infarction rates were reduced but not significantly, which is a similar finding to the Syst-Eur Study [4]. This finding implies a multifactorial cause of coronary artery disease, underlined by the borderline significant reduction of MI in the intensive glycaemic control group of the main UKPDS (16%; P=0.052) [5]. The multiple risk factor approach of the Steno 2 study which showed a definite benefit of the combination of ACE inhibitors, cholesterol lowering, intensive glycaemic control, low dose aspirin, antioxidant therapy, and anti-smoking strategies on micro and macrovascular end points supports this view [8]. Notwithstanding, antihypertensive therapy to the targets of the UKPDS would prevent one death per 15 patients treated for 10 years.

Fourth, lowering blood pressure is associated with a lower incidence of microalbuminuria but not clinical nephropathy. These results may reflect the relatively modest blood pressure levels achieved in the tight control group with an average mean arterial pressure (MAP; diastolic+one third pulse pressure) of 103 mmHg for the whole group, but 44% had an average MAP of >107 mmHg. This may be too high as a recent review has suggested that reno-protection may be best served by a MAP<95 mmHg (equivalent to <125/80 mmHg) [9]. The UKPDS experience suggests that most patients will need at least four or more different drugs to achieve such a target. Finally, there appear to be no benefits of ACE inhibitors versus beta-blockers, at least at these blood pressure levels. Whether ACE inhibitors would be more effective in patients with heavier proteinuria such as in the REIN study [10], or in those with a degree of renal impairment as in the Collaborative Study Group Trial [11] is not certain.

Other studies in hypertensive type 2 patients have shown a reduction in albuminuria with ACE inhibitors but often after shorter periods of treatment. Part of the problem with UKPDS may be a reliance on a single annual spot urine sample for UAC, the reported values are medians of three successive results. However, the sample size should compensate for this lack of sensitivity. Interestingly, few patients in either group developed clinical nephropathy or renal impairment during the course of the study. The Captopril Prevention Project (CAPPP) trial also failed to find a benefit of ACE inhibitors versus beta-blockers in 10985 patients, although the 572 with diabetes at baseline had fewer fatal and non-fatal MI on captopril (relative risk 0.34; P=0.002) [13]. Moreover, fewer patients developed diabetes during the course of the trial in the captopril group, and in both the CAPPP and UKPDS, tablet compliance was better in the ACE inhibitor groups. For these reasons ACE inhibitors should remain an early choice for the management of hypertension in type 2 diabetes.

Antihypertensive therapy is an important part of the management of the type 2 diabetic patient and is of proven benefit. A UK survey has provided sobering information on the standard of blood pressure control in our patients, with less than 50% of patients with a blood pressure >160/95 mmHg on treatment and only 57% achieving a target of less than this. A major challenge from the UKPDS is to transfer their results into better clinical management of our patients, acknowledging that this will require intensive supervision and multiple therapies with all of their resource implications.

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