Hypertension in Diabetics
Part 1

Diabetes Guidelines recommend treating patients with hypertension to a target blood pressure of 130/80 and place an emphasis on using ACEI or ARB as first line drugs. Where do these recommendations come from? What evidence is there to support this? In these articles I will explore the results from several large landmark trials that have provided the basis for these guidelines. In the first article we will look at the BP 130/80 and in the second article we will explore the role of ACEI and ARB as first line drugs in the treatment of hypertension.

The Pressure

THE HOT TRIAL

This is the largest randomized trial done to date on hypertension. 18,719 patients from 26 countries were recruited. They were aged between 50-80 years. They had to be hypertensive with diastolic pressure between 100 and 115 at baseline. They were randomly assigned to a target diastolic blood pressure of less than or equal to 90, less than or equal to 85, and less than or equal to 80.

Felodipine was used as a baseline agent with a five step titration regime. In addition, half the patients were assigned to 75 mg of enteric-coated aspirin. The three groups did attain different diastolic blood pressures with the lowest group averaging 81.1, the middle group 83.2, and the highest 85.2. The results themselves were quite interesting. In the whole trial, there was no difference in major cardiovascular events, cardiovascular mortality or total mortality. Myocardial infractions were slightly less likely in the group assigned to a diastolic of less than 80. This was of borderline statistical significance with a P value= .05. The numbers needed to treat (NNT) was 273 over the 3.8 years of average follow up. Essentially there was no difference amongst the three randomized groups in most major end points.

The results amongst the diabetic subgroup were very different. There were 1501 diabetics at baseline. They were equally divided amongst the three target blood pressure groups. There was over a 50% relative risk reduction (RRR) in cardiovascular events between the target groups of 80 versus 90. The P value was also highly significant at .005, and the NNT was only 22. Cardiovascular mortality was also reduced with a RRR of 66% p=.016 and NNT 35. There was also a strong trend towards improvement in all myocardial infractions, all strokes, all cardiovascular mortality and total mortality but the results were not statistically significant.

Now remember, this was not primarily a diabetic trial. It had a little less than 10% of its participants being diabetics at baseline. These impressive results were also gained with a very modest 5mm difference in the highest versus lowest diastolic blood pressure group. Interestingly, there was hardly any difference in the non-diabetic population.

Half the patients were assigned to be on ECASA 75 in a double blind placebo controlled way. The ASA treated group had a statistically significantly reduction in major cardiovascular events with a RRR 15% and NNT 179. Myocardial infractions were 36%, less frequent in the aspirin group, with a highly significant P value of .002, and NNT 208.

The relative benefit of aspirin for major cardiovascular events and myocardial infractions was about the same in the groups of patients with diabetes, as it was in the whole HOT population. Presumably the NNT would be a lot lower in the diabetic population as the event rate was much higher in this group, but the numbers are not presented in the trial publication.

THE UKPDS TRIAL

The UKPDS is the largest trial ever done on Type 2 diabetics. It is a very complicated trial lasting over 20 years, with multiple sub-studies, only 3 of which will be discussed here:

UKPDS 38

In this randomized trial tight controlled blood pressure was compared to less tight control. Tight control was defined as the blood pressure of less than 150/85, and the less tight control as less than 180/105. The tight control group was further randomly assigned to either captopril or atenolol based treatment (The difference between these two groups will be discussed under UKPDS 39.) The mean blood pressure over nine years of follow up was 144/82 in the tight control group and 154/87 in the less tightly controlled group. The diastolic difference of 5ml was much the same as in the HOT trial, while systolic blood pressure difference of 10 ml was more than the 4ml difference in the HOT trial.

The results are quite dramatic. The tight control group had 24% RRR for any diabetes related endpoint with NNT 60.6 per year. Death related to diabetes was also reduced significantly, with a RRR of 32%, and the NNT of 151 per year. Stroke was reduced by 44%, with the NNT of 196 per year. And interestingly, microvascular disease was also decreased very significantly RRR 37%, with NNT of 138 per year. The magnitude of the benefit with tighter controlled blood pressure far outweighs the magnitude of the benefits seen with tight glucose control, as reported in UKPDS 33.

According to the UKPDS data, if you have a choice of treating either blood pressure or sugar, you are better off treating blood pressure. Twenty-nine percent of patients in the tight controlled group required three or more anti-hypertensive medications, and remember the tight controlled group wasn't particularly tightly controlled.

UKPDS 39

This was a randomized controlled trial comparing the ace inhibitor captopril with the betablocker atenolol in patients with Type 2 diabetes aiming for a blood pressure of less than 150 / 85. Unfortunately, there were only 400 patients in the captopril group and 358 in the atenolol group, whilst 390 patients allocated to less tightly controlled blood pressure acted as the control group. There was no difference noted between the captopril and atenolol groups. The final conclusion was the blood pressure lowering with either agent was similarly effective in reducing incidence of diabetic complications.

UKPDS 36

This is a prospective observational study, which correlated systolic blood pressure with clinical outcomes in the UKPDS, whether they were assigned to treatment or not. This study demonstrated that the incidence of clinical complications was significantly associated with systolic blood pressure. For every 10mm decrease in systolic blood pressure, there was an associated 12% reduction in any complication of diabetes, 15% reduction in death-related to diabetes, 11% reduction for myocardial infractions, and 13% for micro vascular complications. There was no threshold of risk observed for any endpoint, and the curve was linear right down to a blood pressure of 110 systolic. Remember, this is an observational study, which demonstrates the lower the systolic blood pressure in a diabetic, the better the clinical outcome. This is quite different from concluding lowering your blood pressure by pharmacological means will demonstrate the same effect.

ABCD TRIAL

The appropriate blood pressure control in diabetes trial was a prospective randomized clinical trial that compared the effect of intensive versus moderate blood pressure control, on the incidence and the progression of Type 2 diabetes complications. 470 hypertensive diabetics defined as having baseline diastolic pressure >90 were randomized for intensive blood pressure control, with a diastolic goal of 75, versus moderate control with a diastolic goal between 80 and 89. Mean blood pressure achieved in the intensive group was 132/78, and in the moderately intensive group was 138/86. Over five years of follow-up, no difference was observed between the groups with respect to kidney function, progression to micoalbuminuria or overt albuminuria. There was no difference in the progression of diabetic retinopathy or neuropathy. However, all cause mortality was markedly reduced in the intensively treated group (5.5% versus 10.7% p=.037). This is a rather stunning NNT of 19.2 over five years to prevent one death.

As you can see many large randomized trials have consistently demonstrated that lower BP is better in diabetics. Various target BP have been studied and various BP have been actually achieved in these trails. The final consensus by the writers of the guidelines is that we should be aiming for a target of <130/80. To achieve the more modest goals in the UKPDS, 30% of patients required at least 3 or more drugs. To get to 130/80 large numbers of our patients will require 4 or more drugs. Along with 2 or 3 drugs needed to get to the HgA1C targets of <7%, a statin to get the LDL down and the use of low dose ASA, clearly polypharmacy is the order of the day.

- Farokh Buhariwalla

Thanks to Dr. Hector Baillie for reviewing the draft copy of this article. Dr. Baillie is a graduate of University of Glasgow, Scotland. He has spent 16 years in community based IM practice in British Columbia and is currently Secretary of the Canadian Society of Internal Medicine and examiner for the RCPSC.

1. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group Lancet 1998 Jun 13;351(9118):1755-62
    
2. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998 Sep 12;317(7160):703-13
    
3. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ. 1998 Sep 12;317(7160):713-20.
    
4. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000 Aug 12;321(7258):412-9.
    
5. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. (ABCD) Diabetes Care. 2000 Apr;23 Suppl 2:B54-64.
    
6. Effect of diuretic-based antihypertensive treatment on cardiovascular disease in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Cooperative Research Group. (SHEP) JAMA 1996 Dec 18; 276(23):1886-92
    
7. Effects of calcium channel blockade in older patients with diabetes and systolic hypertension. Systolic hypertension Europe trial investigators. (Syst-Eur) NEJM, 1999, Mar 4;340 (9):677-84
    
8. Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events Randomized Trial. (FACET) in patients with hypertension and NIDDM. Diabetes care 1998 April;21 (4):597-603
    
9. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin Ðdependant diabetes and hypertension. (ABCD) NEJM 1998 Mar 5; 338(10):645-52
    
10. Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ace inhibitor

You can search for abstracts of the above references by following this link: PubMed