Multifactorial Intervention in Type Diabetes mellitus

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Peter Gwde, Oluf Pedersen

Steno Diabetes Centre, Copenhagen, Denmark

Introduction

The prevalence of type 2 diabetes mellitus is rapidly increasing. Patients with type 2 diabetes suffer from micro- as well as macrovascular complications, the latter causing the excess mortality seen in these patients compared to the background population.

Several risk factors for the outcome of type 2 diabetes have been identified in prospective epidemiological studies. However, until recently the treatment of type 2 diabetes has been empirical rather than evidence based from randomized intervention studies. Although the diagnosis of diabetes is based on blood glucose levels, it is important to realize that patients with type 2 diabetes mellitus share many clinical features with the metabolic syndrome such as dyslipidaemia, hypertension, hyperinsulinaemia and an increased risk of cardiovascular disease. In cardiovascular medicine a multifactorial treatment approach of several risk factors for cardiovascular disease is generally accepted. We suggest a similar approach in the treatment of type 2 diabetes mellitus based on the results from several intervention studies in patients with this disease.

Evidence for the Treatment Effect of Hyperglycaemia

The importance of strict glycaemic control for the development and progression 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 followed for a median of 10 years. Mean HbA1c in the intensive group over this period was 7.0% as compared to a mean value of 7.9% in the conventional group. A significant risk reduction of 25% for microvascular events with intensive therapy was found while only a borderline significant effect of 16% (p = 0.05) was seen on myocardial infarctions and no effect was seen on mortality. The number of patients needed to treat over a 5-year period to prevent one complication was 39.2.

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. Traditionally, 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 P-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 VO2max 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

Proteins

Exercise Smoking

Percent of total energy intake 55%

Percent of total energy intake 15%

Percent of total energy intake 30% Fat composition

Saturated fatty acids 1/3

Monounsaturated fatty acids 1/3

Polyunsaturated fatty acids 1/3 Moderate, 30 min/day No smoking

Clinical

Body mass index Systolic blood pressure Diastolic blood pressure

Biochemical

HbA1c (normal range 5.2-6.4%) Fasting total cholesterol Fasting LDL cholesterol Fasting HDL cholesterol Fasting triglycerides Urinary albumin excretion rate in the normal range <5.0 mmol/l <2.6 mmol/l >1.1 mmol/l <1.7 mmol/l < 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 gly-caemic 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 sulphonylu-reas, 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 HbA1c 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 P-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 < 90, < 85 and < 80 mm Hg. A long-acting calcium antagonist, felodopine, was the primary drug with addition of an ACE inhib-

itor, p-blocker or diuretic if blood pressure goals were not obtained. In a subgroup analysis in the hypertensive diabetic patients, significant risk reductions in the group assigned to the lowest blood pressure group compared to the highest was found for cardiovascular mortality (67%) and major cardiovascular events while (51%) only a borderline significant reduction was found for all-cause mortality (44%). The number needed to treat to prevent one complication is in accordance with the numbers found in the UKPDS (table 2).

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 mmHg 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 p-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 p-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 p-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 16.0

Cardiovascular mortality 27.0

Dyslipidaemia

4S study (subgroup analysis) [Pyorala et al., 1997]

Major CHD event 4.8 CARE [Sacks etal., 1986]

Microalbuminuria

Ravid study [Ravid et al., 1993]

Progression to nephropathy 3.4

Aspirin

HOT Study [Hansson et al., 1998]

Major cardiovascular events 125.0

Myocardial infarction 153.8

US Male Physicians' Health Study [Final report, 1989]

Myocardial infarction 108.2

Multifactorial intervention

Any microvascular endpoint 4.7

Progression to nephropathy 5.4

used that is essential in treating hypertension in type 2 diabetic patients. As mentioned above, most patients will need treatment with two or more antihypertensive drugs in order to obtain a desired treatment response.

Evidence for the Treatment Effect of Dyslipidaemia

The term dyslipidaemia covers many patterns of lipid changes from the normal values. The most common pattern in type 2 diabetic patients is elevated serum triglyceride levels and decreased serum HDL cholesterol levels. Evidence for a positive treatment effect of dyslipidaemia in type 2 diabetes mellitus comes from post-hoc analyses of diabetic patients participating in larger secondary intervention studies comprising patients with known cardiovascular disease. Since the risk of a first myocardial infarction in patients with type 2 diabetes is the same as the risk for a re-infarction in a nondiabetic subject, it seems reasonable to extrapolate from the overall results from these studies.

The Scandinavian Simvastatin Survival Study (4S) included 4,444 patients with a recent myocardial infarction or angina pectoris and an increased fasting serum-cholesterol level in the range 5.5-8.0 mmol/l. Of these, 202 had diabetes. Patients were randomized to treatment with placebo or simvastatin. The median follow-up time for the diabetic patients was 5.3 years. A significant risk reduction of 55% with lipid-lowering drug therapy was seen for major cardiovascular events, while no effect was seen on total and cardiovascular mortality. The number needed to treat to prevent one major cardiovascular event during a 5-year period was 4.8.

The Cholesterol and Recurrent Events (CARE) trial was also a secondary intervention study including 4,159 patients with a fasting serum-cholesterol level <6.2 mmol/l, thus examining the effect of cholesterol-lowering therapy in patients with cardiovascular disease and a fasting serum cholesterol level within the normal range. 586 diabetic patients participated in the study. A borderline significant risk reduction of 25% was found for major cardiovascular events (death from cardiovascular disease or nonfatal myocardial infarction, coronary artery bypass grafting, or percutaneous transluminal coronary angi-oplasty). No effect on mortality was found.

The Helsinki Heart Study was a primary intervention trial enrolling both nondiabetic and diabetic patients with high fasting serum non-HDL cholesterol levels. The overall result was a significant 34% reduction in the risk for cardiovascular disease with treatment with a fibrate (gemfibrozil), however the 38% risk reduction found in a subanalysis in the type 2 diabetic population was not significant.

Table 3. Various type of drug therapy of dyslipidaemia

LDL cholesterol Triglyceride lowering lowering

Combined dyslipidaemia

Drug of choice Statins Combination Resins

Nicotinic acid or statins Fibrates

Fibrates

Statins

It is important to repeat that the evidence for a positive treatment effect of dyslipidaemia is based on post-hoc analyses from secondary intervention studies in mixed populations. No primary intervention trials in type 2 diabetic patients have been published.

Treatment Approach for Dyslipidaemia

Patients with dyslipidaemia should be examined in order to exclude secondary dyslipidaemia (e.g. renal disease, hypothyroidism), in which case the underlying cause should be treated.

Behaviour Modification

Diet should be optimized with a reduction in dietary content of saturated fatty acids. Weight loss and increased physical activity will lead to decreased serum triglyceride and increased fasting serum HDL cholesterol levels. Maximal effect of this approach is a reduction in fasting serum LDL cholesterol of 0.4-0.6 mmol/l.

Pharmacological Therapy

Glucose-lowering therapy reduces both serum levels of triglycerides and to a lesser extent serum LDL cholesterol levels, thus optimizing glycaemic control is prior to treatment with specific dyslipidaemic drugs. The serum LDL cholesterol level for initiation of drug therapy is still debated, but the more risk factors the lower level. In high-risk patients the limit is 2.6 mmol/l. Various types of drug therapy for the different forms of dyslipidaemia are shown in table 3.

Evidence for theTreatment Effect of Microalbuminuria

Microalbuminuria (urinary albumin excretion rate in the range 30-300 mg/ 24 h) is an important risk factor for the development of both micro- and macrovascular disease. It is known that both the treatment of hyperglycaemia and hypertension can reduce the albumin excretion rate. However, treatment with ACE inhibitors seems to reduce urinary albumin excretion rate independently of the blood pressure-lowering effect of these drugs. 94 patients with type 2 diabetes mellitus and microalbuminuria and a blood pressure < 140/90 mm Hg were randomized to treatment with 10 mg enalapril daily or placebo. Over the study period of 5 years, 6 patients in the ACE inhibitor group and 19 in the placebo group developed diabetic nephropathy. This difference could not be attributed to differences in glycaemic control, body mass index, or blood pressure values, which were similar in both groups throughout the study period. Reciprocal plasma creatinine levels as a measure for renal function decreased significantly in the placebo group as a sign of deterioration of kidney function but remained stable in the enalapril group.

Treatment Approach for Microalbuminuria

Since both the treatment of hyperglycaemia and hypertension decreases urinary albumin excretion rate, these treatment modalities should be optimized. In case of increased albumin excretion rate despite sufficient antihyperten-sive treatment without an ACE inhibitor, treatment with this drug should be initiated. Treatment with an ACE inhibitor should be started in a low dose and gradually increased, especially in patients with normotension because of the risk for orthostatic hypotension.

Evidence for the Treatment Effect of Aspirin

The beneficial effect of low-dose acetylsalicylic acid as secondary prevention of cardiovascular disease is well established in both the diabetic and nondiabetic population. The previously described HOT trial also examined the effect of treatment with acetylsalicylic acid in patients with hypertension. Of the 18,790 patients, half were randomized to 75 mg aspirin daily and the other half to placebo. No specific data for the diabetic subgroup have been published. For the whole study population a significant 15% reduction in the risk for major cardiovascular events was seen, primarily due to a 36% reduction in the risk for myocardial infarction. Fatal bleeds were equally common in the two groups, but nonfatal bleeds (primarily gastrointestinal) were significantly more frequent among patients receiving acetylsalicylic acid than in those receiving placebo.

The US Physicians Health Study was a primary prevention trial in which a low-dose aspirin regimen (375 mg every other day) was compared with placebo in 22,071 male physicians. There was an overall significant 44% risk reduction for myocardial infarction in the acetylsalicylic acid-treated group, whereas subgroup analysis in the diabetic physicians revealed a relative risk of 0.39 for the diabetic men taking aspirin.

Who Should be Treated with Aspirin

Primary prevention: Consider aspirin therapy as a primary prevention strategy in type 2 diabetic subjects with at least one of the following criteria: family history of coronary artery disease; cigarette smoking; controlled hypertension; micro- or macroalbuminuria.

Secondary prevention: Aspirin should be used as a secondary prevention strategy in all diabetic patients with evidence of large vessel disease.

People with aspirin allergy, bleeding tendency, anticoagulant therapy, ongoing or recent gastrointestinal bleeding, and clinically active hepatic disease are not to be treated with aspirin. Therapy should be given as enteric-coated aspirin in doses of 75-325 mg/day.

Evidence for the Effect of Smoking Cessation

Smoking may be one of the most important risk factors for cardiovascular disease in type 2 diabetes mellitus. This is based on several epidemiological studies, where smoking is found to be a risk factor for both all-cause mortality, cardiovascular disease and stroke in both the diabetic and nondiabetic population.

The Multiple Risk Factor Intervention Trial (MRFIT) randomized 12,866 subjects to a control group or an intervention group with intervention against several risk factors such as diet, smoking and blood pressure. Smoking cessation programmes were used with individual advice by a doctor. A 13% reduction in the number of smokers in the intervention group was seen after 6 years. However, no significant effects on total mortality or mortality from cardiovascular disease was seen in the overall analyses. Despite these negative results from one of the most successful smoking cessation intervention programmes, it is because of the epidemiological evidence recommended that all diabetic patients quit smoking.

Smoking Cessation Programmes

Trying to convince patients to stop smoking is one of the hardest and most disillusioning tasks for the health worker. Even though several smoking cessation programmes and nicotine replacement therapy exist, the percentage of smokers who quit smoking in these programmes is low. The average rate of success is around 8% after 1 year in unselected smokers. This number can be increased by selecting motivated patients (e.g. patients with myocardial infarctions) but a 1-year stop rate of more than 25% is rarely seen.

Since most patients who actually quit smoking normally have had two or three unsuccessful smoking cessation periods, it is important to keep on motivating patients to try another programme even though they have already failed once or more.

Evidence for the Treatment Effect of Multifactorial Intervention

Several treatment modalities in type 2 diabetes mellitus have been described, some apparently more effective than treatment of hyperglycaemia, thus providing a rationale for multifactorial intervention. The Steno 2 Study compared the effect of intensive multifactorial intervention with standard multifactorial intervention. The study population was 160 type 2 diabetic patients with microalbuminuria. 80 of these patients were randomized to intensive multifactorial intervention comprising behaviour modification (diet, exercise, smoking cessation) and polypharmacological therapy targeting several risk factors (hyperglycaemia, hypertension, dyslipidaemia, albumin excretion rate). Patients were followed for a mean of 3.8 years yielding significant risk reductions for both nephropathy (56%), retinopathy (40%), and neuropathy (62%). Extrapolating these risk reductions, the number of patients needed to treat for a 5-year period to prevent one microvascular complication in this high-risk diabetic population was only 4.7. No differences between groups were seen for major cardiovascular events, however follow-up time may have been too short to detect such a difference because of the small size of the two treatment groups.

Treatment Approach for Multifactorial Intervention

Multifactorial intervention is a mixture of the treatment modalities already described. It is based on the simultaneous treatment of several risk factors. Frequent and thorough examinations are mandatory, since risk factors may interact and change thus requiring a shift in treatment strategy. This is also the case if there is lack of patient compliance, that may be caused by side effects of the different drugs used.

Side Effects

Since intensive multifactorial intervention requires the use of polyphar-macological therapy, it is crucial to inform patients about the risk of side effects. The physician should consider patients' age, kidney and liver function and contraindications against the different drugs before starting pharmacological treatment. Drug interactions may present as a major problem. A classic example is the masking of hypoglycaemic symptoms with P-blocker treatment, but many drugs also cause increased or decreased response to oral hypoglycaemic agents. Patients treated with anticoagulants should be monitored closely when treatment with statins or fibrates, or P-blockers is initiated. Patient compliance decreases with the number of side effects experienced, however informing patients and starting with low doses may diminish this problem.

Suggested Reading

Final report on aspirin component of the ongoing Physicians' Health Study. N Engl J Med 1989;321: 1825-1828.

Frick MH, Elo O, Haapa K, et al: Helsinki Heart Study: Primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med 1987;317:1237-1245.

Gsde P, Vedel P, Parving HH, Pedersen O: Intensified multifactorial intervention in patients with type 2 diabetes and microalbuminuria: The Steno Type 2 randomised study. Lancet 1999;353:617-622.

Hansson L, Lindholm LH, Niskanen L, et al: Effect of angiotensin-converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: The Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999;353:611-616.

Hansson L, Zanchetti A, Carruthers SG, et al: Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351:1755-1762.

Multiple Risk Factor Intervention Trial Research Group: Multiple Risk Factor Intervention Trial: Risk factor changes and mortality results. JAMA 1982;248:1465-1477.

Pyorala K, Pedersen TR, Kjekshus J, Fsrgeman O, Olsson AG, Thorgeirsson G: Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. Diabetes Care 1997;20:614-620.

Ravid M, Savin H, Jutrin I, Bental T, Katz B, Lishner M: Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type 2 diabetic patients. Ann Intern Med 1993;118:577-581.

Sacks FM, Pfeffer MA, Moye LA, et al: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-1009.

Tuomilehto J, Rastenyte D, Birkenhager WH, et al: Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med 1999;340:677-684.

UKPDS Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998a;352:837-853.

UKPDS Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998b;317:703-713.

Yki-Jarvinen H, Nikkila K, Ryysy L, Tulokas T, Vanamo R, Heikkila M: Comparison of bedtime insulin regimens in NIDDM: Metformin prevents insulin-induced weight gain. Diabetologia 1996; 39(suppl 1):A33.

Dr Oluf Pedersen, Steno Diabetes Centre, Niels Steensens Vej 2,

DK-2820 Copenhagen (Denmark)

Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment. Basel, Karger, 2000, pp 241-252

Chapter XVIII

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