Combined high blood pressure and glucose in type 2 diabetes: double jeopardy

More than three decades ago Harry Keen pinpointed two “bad companions” to diabetes: high blood glucose concentrations and high blood pressure, both associated with microalbuminuria. The long running UK prospective diabetes study has recently extended the number of bad companions to include dyslipidaemia and smoking.¹ Owing to the complexity of the disease, however, and the slow but progressive development of complications over many years, well founded intervention strategies against diabetic complications have been largely lacking in type 2 diabetes. Papers from the UK study published this week in the BMJ and the Lancet now offer clinicians some effective treatment options.

The UK prospective diabetes study started by studying the value of various strategies to achieve tight blood glucose control compared with looser control, but the researchers soon became aware that high blood pressure may be an even stronger risk factor—as we originally observed in diabetic renal disease²—and blood pressure treatment was therefore included in the study. The UK study has thus provided answers to a range of important questions that have haunted diabetes researchers and clinicians for years.

Does a policy of tightly controlling blood glucose concentration reduce the risk of complications in type 2 diabetes? Yes, it does, and, as far as reducing the risk of microvascular complications is concerned, sulphonylureas and insulin produce equally good results.³ The blood glucose study showed only inconclusive evidence of a reduced risk of myocardial infarction, but a key finding is that neither regimen produced specific adverse cardiovascular outcomes. The beneficial effect was also seen with metformin, which was effective in reducing important endpoints in obese patients but worked less well in combination with other drugs, for reasons that remain unclear.⁴

Thus, the hypothesis that it is glucose itself that is toxic in type 2 diabetes is confirmed, in line with the findings of the diabetes control and complications trial for type 1 diabetes,⁵ and controversy should now end.⁶ Diet and exercise presumably still work, since they were used in all patients. But we still know little about the effect of other types of new oral antidiabetic agents on diabetic complications.

Does a policy of tight blood pressure control reduce the risk of complications in diabetes? Yes, and even more convincingly so than the effect of tight blood glucose control. The difference between the treatment regimens in their effect on haemoglobin A_1c concentrations (7.0% v 7.9%) was probably not large enough to result in great differences in cardiovascular outcome. The first paper published in this week’s BMJ, however, shows that long term tight blood pressure control in hypertensive patients with type 2 diabetes results in a significant reduction in all diabetes related endpoints, including diabetes related deaths (p 703).⁷ Differences in all cause mortality failed to reach statistical significance, but important effects were seen in typical diabetic microvascular complications, including diabetic eye disease. As in essential hypertension,⁸ the incidence of cardiovascular complications such as heart failure and stroke was greatly reduced.

The blood pressure study also confirms the importance of early treatment. A new concept in treatment for diabetes is to start treatment early in all microalbuminuric patients, even those who are normotensive.⁹ Combining strict metabolic and blood pressure control should give even better outcomes. It is not surprising that not only is antihypertensive treatment more effective than tight blood glucose control; the beneficial results also come sooner. Late treatment in proteinuric type 2 diabetes is difficult, but new treatment strategies are being tested.

Do angiotensin converting enzyme inhibitors or β blockers have any specific advantages or disadvantages? According to the second paper in this week’s BMJ (p 713),¹⁰ the answer is probably no, although larger and longer term trials may be needed to assess the effects on distant endpoints, such as progressive nephropathy and end stage renal disease. The literature provides arguments for the use of both classes of drugs in diabetes. But the UK prospective diabetes study suggests that blood pressure reduction itself may be more important than the treatment used to achieve it, at least as far as these two types of drugs are concerned. The well known side effects of both classes of agents were seen, but angiotensin converting enzyme inhibitors were better tolerated by most patients. Health economic analyses showed that tight blood pressure control is cost effective when compared with other widely used preventive strategies and is more feasible for most clinicians and patients than tight blood glucose control (p 720).¹¹

Combination drug strategies are often needed, so the evaluation of single drugs is increasingly difficult. The important controversy about calcium channel blockers, recently discussed in the BMJ,¹² remains unsettled, but further information should become available later from the UK study.

The patients with type 2 diabetes included in the UK study are typical of those seen in every day practice, but interestingly the investigators’ definition of diabetes at the onset of the study appears to have been slightly futuristic in that it accords with the standards of today¹³ rather than those of the time of recruitment. Patients with a fasting plasma glucose concentration higher than 6.0 mmol/l were included: a fasting plasma glucose concentration of 6.1-6.9 mmol/l is now designated as “impaired fasting glucose.” According to the new criteria a repeated fasting plasma glucose concentration of above 7.0 mmol/l is diagnostic of diabetes.

Did we know it all before? Certainly not, although small trials showing positive effects of blood glucose control on microvascular disease have been or are about to be published.¹⁴ Interestingly, a series of recent trials of antihypertensive treatment (which included many type 2 diabetic patients) has been published with similar results, such as the SHEP study (low dose diuretics plus β blockers and reserpine),¹⁵ the HOT study (various drugs or combinations added to calcium channel blockers),¹⁶ and the SYST-EUR study (calcium channel blockers with angiotension converting enzyme inhibitors and diuretics as reserves).¹⁷ The ABCD study showed a larger reduction in non-fatal myocardial infarction with angiotensin converting enzyme inhibitors than with calcium channel blockers in hypertensive diabetes and resulted in controversy.¹² No J shaped curves were noted in any of the studies. The blood pressure in the intensive treatment group in the UK prospective diabetes study was reduced to a mean of 144/82 mm Hg —a reduction of 10 mm Hg in systolic and 5 mm Hg in diastolic blood pressure. This level of reduction is comparable to that in other studies, except for the HOT study, where blood pressure was reduced even further, the reduction in diastolic pressure ranging from 20 to 24 mm Hg. The actual goal in clinical management is probably a level of around 140/85 mm Hg, or even lower—as in essential hypertension trials⁸—since the correlation between blood pressure and cardiovascular disease is likely to be curvilinear, with no threshold. The goal for glycosylated haemoglobin is 7% or lower, taking into account the con- dition of the patient. Any reduction of glycosylated hameoglobin from a high value is important, as shown in the in the diabetes control and complications trial.⁵

The “bad companions” of diabetes also include dyslipidaemia, and the 4S study showed that secondary prevention in diabetic patients was effective.¹⁸ An important subject for further research is primary prevention, and a trial of this is now in progress in the UK prospective diabetes study. Research into effective antismoking campaigns in diabetes is similarly important. Increasingly, the evidence suggests that an intensified multifactorial intervention strategy is warranted in type 2 diabetes, possibly including aspirin treatment.¹⁶ The UK prospective diabetes study combines both clinical and basic research, and progress in patient care must be soundly founded on research in both fields. The lesson of this week’s papers, however, is that focusing only on isolated vascular biology without also paying close attention to overall clinical management, in particular blood pressure control, may not be enough.

Editorial p 691, Papers pp 703, 713, 720