Evidence for the Treatment Effect of Hyperglycaemia

The importance of strict glycaemic control for the development and pro- gression of microvascular complications was definitely confirmed in the United Kingdom Prospective Diabetes Study (UKPDS). 3,867 patients with newly diagnosed type 2 diabetes were randomized to intensive therapy with oral hypoglycaemic agents or insulin, or to conventional therapy. Patients were The importance of strict glycaemic control for the development and pro- gression of microvascular complications was definitely confirmed in the United Kingdom Prospective Diabetes Study (UKPDS). 3,867 patients with newly diagnosed type 2 diabetes were randomized to intensive therapy with oral hypoglycaemic agents or insulin, or to conventional therapy. Patients were

Even though no overall effect on cardiovascular disease was seen in the UKPDS, it is still important to remember that hyperglycaemia is one of

the most important predictors for cardiovascular disease in epidemiological studies. There is therefore every reason to believe that intervention against hyperglycaemia also has beneficial effects on this complication in type 2 diabetes mellitus, however the final proof from a randomized intervention study has still to come.

Treatment Approach for Hyperglycaemia Treatment goals for different risk factors are shown in table 1. Tradition-

ally, lifestyle modification is the first and basic treatment approach, since this is cheap and without major side effects. Even though pharmacological treatment may be needed, it is important to emphasize the necessity of this basic treatment to patients. Since deterioration of b-cell function is inevitable, regular controls are necessary in order to change treatment whenever needed.

Diet An immediate effect on dieting on blood glucose levels is seen in most

studies. However, the UKPDS demonstrated that less than half of patients with a normalization of fasting blood glucose after 3 months of dieting alone were able to maintain this effect after 1 year. Therefore, in order to reach the recommended treatment goals, supplemental pharmacological treatment is needed in most cases.

Exercise Even 30 min of moderate exercise with an intensity of 50–80% of V O 2 max 3–4 times a week has beneficial effects both on carbohydrate metabolism and on insulin sensitivity. However, many patients suffer from complications, e.g. cardiovascular complications, arthroses or peripheral neuropathy, which should be taken into account when recommending type of exercise.

Oral Hypoglycaemic Agents Different classes of oral hypoglycaemic agents with different mechanism

of action exist. Thus, drugs can be combined. It is important to realize that

Table 1. Treatment goals for behaviour modification, and clinical as well as biochemical variables in type 2 diabetes mellitus

Behaviour modification Diet

Carbohydrates Percent of total energy intake 55% Proteins

Percent of total energy intake 15% Fat

Percent of total energy intake 30%

Fat composition

Saturated fatty acids

1/3 Monounsaturated fatty acids

1/3 Polyunsaturated fatty acids

1/3 Exercise

Moderate, 30 min/day

Smoking

No smoking

Clinical Body mass index

25 kg/m 2

Systolic blood pressure

= 130 mm Hg

Diastolic blood pressure

85 mm Hg

Biochemical HbA 1c (normal range 5.2–6.4%)

in the normal range

Fasting total cholesterol

5.0 mmol/l

Fasting LDL cholesterol

2.6 mmol/l

Fasting HDL cholesterol

1.1 mmol/l

Fasting triglycerides

1.7 mmol/l

Urinary albumin excretion rate

30 mg/24 h

5–10% of patients experience oral hypoglycaemic drug failure per year, in which case insulin treatment must be initiated to maintain satisfactory glycaemic control. In a substudy in the UKPDS, the effect of metformin versus conventional treatment and sulphonylureas or insulin in obese patients was examined. Patients randomized to metformin had lower risks for all-cause mortality, strokes and any diabetes-related endpoint than patients on conventional treatment, sulphonylureas or insulin and metformin was found to cause less weight gain and fewer hypoglycaemic attacks than sulphonylureas or insulin. In another substudy in patients with secondary failure to sulphonylureas, addition of metformin doubled the risk of mortality compared to patients continuing sulphonylureas alone. These results are difficult to interpret because of the study design. However, until results from a randomized study specifically designed to answer the question about the effect of metformin on mortality in secondary failure to sulphonylureas, according to the American Diabetes Association no restrictions in the use of metformin in combination with sulphonylureas is justified.

Insulin Insulin treatment can be given as monotherapy or as combination therapy

with insulin and oral hypoglycaemic agents. From studies comparing several insulin regimens, bedtime NPH insulin in combination with metformin twice daily and self-adjustment of insulin dose based on patients’ own fasting blood glucose measurements seems to be an easy and safe way of obtaining optimal glycaemic control. This combined insulin and metformin treatment regimen is associated with less weight gain than monotherapy with insulin. Whereas hypoglycaemia is frequent in type 1 diabetes mellitus, this is not the case in insulin resistant type 2 diabetes mellitus, even with large insulin doses and

HbA 1c values near the normal range. It has been discussed whether insulin per se is atherogenous, since hyperinsulinaemia is a risk factor for cardiovascular disease in epidemiological studies, however this effect has not been demonstrated in clinical studies.

Evidence for the Treatment Effect of Hypertension

The effect of antihypertensive treatment in type 2 diabetes was examined in a substudy in the UKPDS. 1,148 hypertensive patients were randomized

either to tight blood pressure control aiming for a blood pressure =150/85 mm Hg with the use of angiotensin-converting enzyme (ACE) inhibitors or

b -blockers or to less tight blood pressure control aiming at a blood pressure = 180/105 mm Hg and if possible avoiding the previous mentioned drugs. The mean blood pressure during follow-up was 144/82 mm Hg in the group assigned tight blood pressure control compared to 154/87 mm Hg in the group assigned to less tight control. Significant risk reductions were found for deaths related to diabetes (32%), strokes (44%) and microvascular disease (37%). The effect of blood pressure control was independent of blood glucose control. The number of patients needed to treat over a 5-year period to prevent one diabetes- related death was 30.0 while it was 12.2 for microvascular disease. Thus based upon the results from intervention trials it seems that blood pressure control is more effective than blood glucose control in type 2 diabetes mellitus. Another important message from this study is that in order to obtain the specified blood pressure goal it is in most cases necessary with two or more different antihypertensive drugs.

The results from the Hypertensive Optimal Treatment (HOT) randomized trial also underline the importance of tight blood pressure control. 18,790 patients with hypertension were randomly assigned to three groups with target diastolic blood pressure of p90, p85 and p80 mm Hg. A long-acting calcium antagonist, felodopine, was the primary drug with addition of an ACE inhib- The results from the Hypertensive Optimal Treatment (HOT) randomized trial also underline the importance of tight blood pressure control. 18,790 patients with hypertension were randomly assigned to three groups with target diastolic blood pressure of p90, p85 and p80 mm Hg. A long-acting calcium antagonist, felodopine, was the primary drug with addition of an ACE inhib-

A positive treatment effect for the elderly hypertensive type 2 diabetic patients was recently demonstrated in a post-hoc analysis from The Systolic

Hypertension in Europe Trial. Of the originally enrolled 4,695 patients with systolic hypertension (systolic blood pressure ?160 mm Hg and diastolic blood pressure =95 mm Hg), all patients ?60 years of age, 492 had diabetes. Patients were randomized to treatment with a calcium antagonist, nitrendipine, or placebo. In the group receiving active treatment significant risk reductions were obtained for total mortality (55%), mortality from cardiovascular disease (76%), all cardiovascular events combined (69%), fatal and nonfatal strokes (73%), and all cardiac events combined (63%) compared to the group receiving placebo. The suspicion that calcium channel blockers may be harmful in patients with hypertension and diabetes mellitus could clearly not be confirmed in this study.

The question of which kind of antihypertensive drug treatment should

be used was also investigated in the Captopril Prevention Project (CAPPP). 10,985 patients with hypertension were randomly assigned the ACE inhibitor captopril or conventional antihypertensive therapy with diuretics or b-blockers. The risk of a major cardiovascular event during an average follow-up of 6.1 years did not differ between treatment groups. An overall reduction in the rate of fatal cardiovascular events was reported in the diabetic subpopulation (n>572), however no data on blood pressure control and actual drug regimens in this subgroup was reported making the results difficult to interpret. Similar, the previously described UKPDS did not find any difference between the treatment effect of ACE inhibitors or b-blockers in the type 2 diabetic patients randomized to tight blood pressure control.

Treatment Approach for Hypertension Basic dietary advice recommending weight reduction in obese, a low

sodium intake and regular exercise are important in the treatment of hypertension and should be given for 2–3 months before initiating pharmacological therapy.

Positive treatment effects have been demonstrated with the use of ACE inhibitors, diuretics, calcium antagonists and b-blockers. This clearly suggests

that it is the obtained blood pressure level rather than the type of drug

Table 2. Number of patients needed to treat for 5 years to prevent one complication in different trials (unless indicated with p value, only significant

results from the different studies are shown; numbers are based on extrapolation of results from the original follow-up period to a 5-year period)

Trials Number needed to treat

Hyperglycaemia UKPDS [UKPDS Group, 1998a] Any diabetes-related endpoint

39.2 Myocardial infarction (p>0.05)

92.4 Any microvascular endpoint

71.4 Hypertension

UKPDS [UKPDS Group, 1998b] Any diabetes-related endpoint

12.2 Diabetes-related death

30.0 HOT Study (subgroup analysis) [Hansson et al., 1998] Major cardiovascular event

Evidence for the Treatment Effect of Hyperglycaemia