- Email: [email protected]
TREATMENT
TR E AT MEN T
Diabetic individuals with no history of MI had a similar risk of death from CHD as non-diabetic individuals with a history of MI Haffner SM, Lehto S, RoK nnemaa T, PyoK raK laK K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229d234
OBJECTIVE To compare the 7-year incidence of cardiovascular events among diabetic and non-diabetic subjects with and without a history of MI at baseline. DESIGN Population-based study with maximal follow-up of 7.93 years.
stroke. The primary outcomes were fatal or non-fatal MI, fatal or non-fatal stroke and death from cardiovascular causes. Medical records and autopsy reports were used to assign cause of death. A computerized hospital-discharge database was consulted for hospital admissions for all participants.
ASSESSMENT OF PROGNOSTIC FACTORS Smoking status was ascertained by interview, and BP, fasting plasma glucose, serum lipids and lipoproteins were measured at baseline between 1982 and 1984. The medical records of all participants who reported having been hospitalized for chest pain were reviewed. A history of previous verified definite or possible MI or stroke was assessed using World Health Organization criteria.
MAIN RESULTS Among non-diabetic subjects, the 7-year incidence of MI was 3.5% in those without prior MI and 18.8% in those with prior MI. Among diabetic subjects, the 7-year incidence of MI was 20.2% in those without prior MI and 45.0% in those with prior MI. Kaplan-Meier estimates of the probability of death from CHD demonstrated that non-diabetic subjects without prior MI had the best prognosis while diabetic subjects with prior MI had the worst. Non-diabetic subjects with prior MI and diabetic participants without prior MI had a similar intermediate risk. Among these two intermediate-risk groups, there was no difference between non-diabetic subjects with prior MI (n"69) and diabetic subjects without prior MI (n"890) in the age- and sex-adjusted hazard ratio (HR 1.4; 95% CI 0.7–2.6). Further adjustment for smoking status, hypertension, LDL and HDL cholesterol and triglycerides continued to demonstrate no significant difference (HR 1.2; CI 0.6–2.4).
MAIN OUTCOME MEASURES The medical records of participants were reviewed when responses to questionnaire indicated hospitalization for chest pain or symptoms suggestive of
CONCLUSION Diabetic participants with no history of MI had a similar risk of death from CHD as non-diabetic participants with a history of MI.
SETTING The Finnish Social Insurance Institution database, limited to participants born and living in two university hospital regions in Finland. PARTICIPANTS All type-2 diabetic patients aged 45–64 years who had received reimbursement for drugs (n"1059) and a random control sample of non-diabetic participants aged 45–64 years from the same geographic regions (n"1373).
Intensive therapy with insulin or sulphonylureas failed to prevent macrovascular complications in patients with type 2 diabetes UK Prospective Diabetes Study (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 1998;352:837d853
OBJECTIVE To compare intensive blood glucose control with either sulphonylureas or insulin therapy, against conventional dietary therapy on the risk of microvascular and macrovascular complications among patients with type-2 diabetes. DESIGN Randomized, controlled, multi-center trial with allocation concealment and open-label follow-up of 11 years. SETTING 23 clinical centers in the UK with study subjects referred by family physicians. PATIENTS patients (mean age 53.3 years, 61% men) with newly diagnosed type-2 diabetes and fasting blood glucose (FBG) 6–15 ^ 1999 Harcourt Brace & Co. Ltd
mmol/l following a 3-month dietary run-in period were entered into the study. INTERVENTION Patients were randomized to receive either intensive control with insulin (30%), a sulphonylurea (40%; chlorpropamide or glibenclamide), or conventional control starting with dietary therapy (30%). The aim of intensive therapy was a FBG (6 mmol/L and, in insulin-treated patients, pre-meal glucose 4–7 mmol/L. The aim of conventional therapy was a FBG(15 mmol/L without symptoms of hyperglycemia. Additional hypoglycemic therapies were added only if there were hyperglycemic symptoms or FBG'15 mmol/L. Evidence-based Cardiovascular Medicine (1999) 3, 21d25
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MAIN OUTCOME MEASURES Three aggregate end-points: (1) any diabetes-related end-point (including microvascular and macrovascular events); (2) diabetes-related death; and (3) all-cause mortality. MAIN RESULTS Over 10 years, hemoglobin A1 was significantly lower in the intensive group compared with the conventional group (median 7.0 vs 7.9%; P (0.0001). There were significantly fewer diabetes-related end-points in the intensive therapy groups than in the conventional group (RR 0.88; 95% CI 0.79–0.99; P"0.029). There was also a trend toward fewer diabetes-related deaths (RR 0.90; CI 0.73–1.11; P"0.34) and fewer deaths from all causes (RR 0.94; CI 0.80–1.10; P"0.44). The observed prevention of diabetes-related events was greatly influenced by a highly significant reduction in microvascular end-points (RR 0.75; CI 0.60–0.93; P"0.0099) but only
a borderline significant reduction in the incidence of MI (RR 0.84; CI 0.71–1.00; P"0.052) and a trend toward reduction of amputation and death from peripheral vascular disease. There was no difference in the rate of any aggregate end-point between any of the three intensive agents (chlorpropamide, glibenclamide, or insulin; all P'0.36). There was significantly greater mean weight gain in the intensive groups than in the conventional group (3.1 kg; 99% CI!0.9 to #7.0; P( 0.0001) at 10 years. Mean weight gain was greatest among those assigned to insulin (4.0 kg more than those assigned to conventional therapy). CONCLUSION Intensive therapy with insulin or sulphonylureas reduced diabetes-related end-points and led to a marginally significant reduction in MIs in patients with type-2 diabetes.
Intensive glucose control with metformin was associated with fewer diabetes-related events in overweight patients UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) Lancet 1998;352:854d865
OBJECTIVE To compare intensive blood glucose control with metformin, against conventional therapy starting with diet on the clinical complications of diabetes in overweight patients with type2 diabetes, and to compare outcomes among patients receiving intensive control starting with insulin or sulphonylureas to those patients starting with metformin. DESIGN Randomized, controlled, multi-center trial with median follow-up of 10.7 years. SETTING 15 centers in the UK. PATIENTS 1704 overweight ('120% ideal bodyweight) participants (54% women; mean age 53 years) with newly diagnosed type-2 diabetes and a mean fasting blood glucose (FBG) 6–15 mmol/L following a 3-month dietary run-in period. INTERVENTION In the primary study, patients were allocated to receive either metformin (n"342) or conventional dietary therapy (n"411). In a secondary analysis of the data, patients receiving insulin or sulphonylurea (n"951) were compared to those receiving metformin. Patients receiving conventional dietary therapy who experienced symptoms of hyperglycemia or FBG'15 mmol/L were additionally randomized to receive non-intensive pharmacologic therapy. Patients allocated to sulphonylurea with symptoms of hyperglycemia were additionally given metformin, or insulin if needed.
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Evidence-based Cardiovascular Medicine (1999) 3, 21d25
MAIN OUTCOME MEASURES Three aggregate end-points: (1) any diabetes-related end-point; (2) diabetes-related death; and (3) all-cause mortality. MAIN RESULTS Patients allocated to metformin had a 32% decrease in the risk of any diabetes-related end-point (95% CI 13–47%; P"0.0023), a 42% reduction in diabetes-related death (CI 9–63%; P"0.017), a 36% reduction in all-cause mortality (CI 9–55%; P"0.011) and a 39% reduction in MI (CI 11–59%; P"0.01) compared to patients allocated to conventional dietary therapy. Compared to participants allocated to other intensive therapies, those allocated to metformin had significantly reduced risks of any diabetes-related end-point, all-cause mortality and stroke. The addition of metformin to sulphonylurea in both overweight and non-overweight patients was paradoxically associated with a 96% increase in diabetes-related deaths (CI 2–275%; P"0.039) compared to sulphonylurea alone. To explore this discrepancy, the datasets were merged. The combined data showed a 19% reduction (CI 2–33%; P"0.033) in any diabetes-related end-point and a number of additional analyses suggested that the apparent increase in diabetes-related deaths when metformin was added to sulphonylurea was likely to be due to the play of chance. Patients receiving metformin and conventional therapy had similar changes in bodyweight over 10 years, lower than that observed in participants receiving insulin or sulphonylurea. CONCLUSION Intensive glucose control with metformin in overweight type-2 diabetic patients led to fewer diabetes-related events and MIs than control with conventional therapy.
^ 1999 Harcourt Brace & Co. Ltd
Tight control of BP reduced risk of diabetes-related morbidity and mortality UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703d713
OBJECTIVE To determine whether tight control of blood pressure reduces clinical complications of diabetes in patients with type-2 diabetes. DESIGN Randomized, controlled, multi-center trial with median follow-up of 8.4 years. SETTING 20 clinical centers in the UK. PATIENTS 1148 hypertensive patients (55% men; mean age 56 years) with newly diagnosed type-2 diabetes and a mean fasting blood glucose (FBG) between 6 and 15 mmol/L following a 3-month dietary run-in period. Hypertension was defined as systolic BP (SBP) *160 mmHg and/or diastolic BP (DBP)*90 mmHg in persons not receiving antihypertensive treatment and SBP*150 mmHg and/or DBP*85 mmHg in persons receiving antihypertensive treatment. INTERVENTION Patients were randomly allocated to receive either tight BP control with ACE inhibitors (n"400) and b-blockers (n"358) used as first-line agents (aiming for a BP (150/85 mmHg); or less tight BP control (n"390) avoiding ACE inhibitors and b-blockers (aiming for a BP(180/105 mm Hg).
MAIN OUTCOME MEASURES Three aggregate end-points: (1) any diabetes-related end-point; (2) diabetes-related death; and (3) all-cause mortality. MAIN RESULTS Mean BP over the follow-up period was 144/82 mm Hg among those assigned tight BP control and 154/87 mm Hg among those assigned to less tight control (P(0.0001). At the end of follow-up 56% and 37% of patients in the tight control and less tight control groups achieved a BP(150/85 mm Hg. At 9 years of follow-up, 29% of those assigned to tight control required 3 or more agents compared to 11% of those assigned to less tight control. There was a significant 24% reduction in the risk of any diabetes-related end-point (95% CI 8-38%; P"0.0046) and a 32% reduction in the risk of diabetes-related death (CI 6–51%; P"0.019) but no significant reduction in the risk of all-cause mortality among patients assigned to tight control of BP. When all macrovascular diseases (MI, stroke, peripheral vascular disease) were considered together, there was a significant 34% reduction in the risk in the group assigned to tight control (P"0.019). Tight control also resulted in a highly significant 37% reduction in the risk of microvascular disease (CI 11–56%; P"0.0092). CONCLUSION Tight control of BP with an ACE inhibitor or a b-blocker reduced the risk of diabetes-related morbidity and mortality among patients with newly diagnosed type-2 diabetes.
No difference in the effects of captopril and atenolol on microvascular and macrovascular complications of diabetes UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998;317:713d720
OBJECTIVE To determine whether tight control of blood pressure with either an ACE inhibitor or b-blocker reduces microvascular and macrovascular complications of diabetes in patients with type-2 diabetes. DESIGN Randomized, controlled, multi-center trial with median follow-up of 8.4 years. SETTING 20 clinical centers in the UK PATIENTS 758 hypertensive patients (54% men; mean age 56 years) with newly diagnosed type-2 diabetes and a mean fasting blood glucose (FBG) between 6 and 15 mmol/L following a 3-month dietary run-in period. Hypertension was defined as systolic BP (SBP) *160 mm Hg and/or diastolic BP (DBP) *90 mm Hg in persons not receiving antihypertensive treatment and ^ 1999 Harcourt Brace & Co. Ltd
SBP*150 mm Hg and/or DBP*85 mm Hg in persons receiving antihypertensive treatment. INTERVENTION Patients were randomly allocated to receive either ACE inhibitors (captopril; n"400) or b-blockers (atenolol; n"358), aiming at a BP (150/85 mmHg. If BP goal was not met despite maximal allocated treatment, other agents were sequentially added (furosemide, slow release nifedipine, methyldopa and prazosin). MAIN OUTCOME MEASURES Three aggregate end-points: (1) any diabetes-related end-point; (2) diabetes-related death; and (3) all-cause mortality. MAIN RESULTS Baseline BP was 159/93 mmHg in both groups. Blood pressure was reduced over 9 years to 144/83 and Evidence-based Cardiovascular Medicine (1999) 3, 21d25
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143/81 mmHg in the captopril and atenolol groups, respectively. There was no significant difference in the relative risks of any diabetes-related end-point (RR for captopril 1.10; 95% CI 0.86–1.41), diabetes-related death (RR 1.27; CI 0.82–1.97), and all-cause mortality (RR 1.14; CI 0.81–1.61). Similarly, there was no significant difference in the risk of any macrovascular disease (MI, stroke, peripheral vascular disease) or microvascular disease. There was also no significant difference in the risk of heart failure or renal
failure, two pre-determined clinical end-points. Similar proportions of patients in the captopril (27%) and atenolol (31%) groups required three or more agents. Weight gain over the 9 years was lower in the captopril group (1.6 vs 3.4 kg; P"0.02). CONCLUSION There was no difference in the effects of captopril or atenolol on clinical complications of diabetes in hypertensive, type-2 diabetic patients.
Commentary Diabetes is a common metabolic disorder characterized by hyperglycemia, that affects 1 in 12 adults in North America.1 The fasting plasma glucose threshold above which a patient is classified as having diabetes is 7.0 mmol/L.2 This glucose value is that which clearly identifies people at high subsequent risk of eye and kidney disease (the so-called microvascular complications of diabetes). For many years, it was also clearly recognized that individuals with diabetes have a high risk of cardiovascular disease. For example, the Framingham study clearly showed that the risk of cardiovascular disease was 2d3 fold higher in diabetic men and 3d4 fold higher in diabetic women than in non-diabetic individuals.3 The epidemiologic study by Haffner et al. provides further evidence of the high cardiovascular risk of middle-aged patients with diabetes. This analytic cohort study reported the 8-year incidence of CHD mortality, MI, and stroke in Finnish patients with type 2 diabetes and a control population of non-diabetic Finnish individuals. Both cohorts were carefully assessed at baseline to identify those individuals with a previous MI. The authors could not detect a difference between the incidence of CHD death for diabetic participants with no history of MI and for non-diabetic participants with a previous MI (approximately 2.5% per year). Of note is the fact that the diabetic and non-diabetic populations were not matched for most demographic and risk variables at baseline. Moreover, the small number of non-diabetic individuals with no prior MI (n"69) provides low power to detect even moderate differences. Nevertheless, the inability to detect a difference even after adjustment for baseline variables, and the observation that the risk of these two groups was intermediate between the risk of the non-diabetic participants with no prior MI and the diabetic participants with a prior MI both support the conclusion that the risk of CHD death in these two cohorts is similar. Of particular interest is the finding that 42% of diabetic patients with a previous MI, and 15% of diabetic patients with no previous MI died from cardiovascular causes within 8 years of followup. This is a somber reminder of the high event rate in diabetic individuals. Most importantly, these high event rates highlight the importance of aggressive risk factor reduction in diabetic patients. Indeed, interventions may lead to higher absolute risk reductions when applied to diabetic patients than when applied to non-diabetic patients. This was clearly noted in the SHEP study,4 in which the identical 34% relative risk reduction for cardiovascular events in both the diabetic and non-diabetic subgroups meant that approximately 10 diabetics needed to be treated for 5 years to prevent one event compared to 20 non-diabetic patients (i.e. the absolute risk reductions were 10.1% and 4.9% respectively). Despite data such as these that show that diabetic patients may clearly benefit from cardiovascular interventions, most trials of primary and secondary cardiovascular prevention have either excluded patients with diabetes or have recruited very small numbers. The final results of the United Kingdom Prospective Diabetes Study (UKPDS) therefore provide long-awaited information on the effectiveness of various interventions to prevent clinical outcomes in patients with the most common type of diabetes d type 2 diabetes. This study enrolled newly-diagnosed patients with type 2 diabetes. Individuals were allocated to a policy of tight glycemic control vs conventional glycemic control. Despite the best efforts of the investigators, they were not able to maintain a stable level of glycemic control in the intervention group. Indeed, following an initial drop in hemoglobin A1c (HbA1c) in the intervention group, the steady rise in HbA1c in both groups at a similar
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Evidence-based Cardiovascular Medicine (1999) 3, 21d25
rate was such that median value in the intensive policy group during the second and third 5-year periods was essentially equal to that in the conventional group during the first and second 5-year periods. Furthermore, the median absolute separation in HbA1c achieved during the first 10 years of the study was only 0.9% (a difference considerably less than the 2% separation achieved in the Diabetes Control and Complications Trial that established the value of intensified insulin therapy in patients with type 1 diabetes5). These difficulties mirror the experience of all clinicians who try to achieve excellent glycemic control with currently available agents in patients with type 2 diabetes. It is in this context that the results need to be viewed. Despite the very modest difference in glucose levels, there was a clinically important difference in diabetes-related deaths and all-cause mortality. There was also a borderline significant 16% reduction in MI. There was no difference in the risk reduction achieved by either sulfonylureas or insulin, despite the fact that insulin levels were clearly higher in the group receiving insulin than in the conventional control group and in the group receiving sulfonylureas. These latter observations should clearly allay any anxieties regarding giving insulin to patients with type 2 diabetes. They provide no support whatsoever for concerns that attempts to achieve tight glucose control with exogenous insulin might increases the risk for cardiovascular events. Conversely, they provide a lot of support for the conclusion that glucose lowering, regardless of how it is achieved, decreases all-cause mortality and is likely to reduce cardiovascular events. The supplementary analysis done in an obese subset of patients in the UKPDS is less clear. This analysis did confirm that a very modest reduction of HbA1c using metformin (a median decrease of 0.6% over 10 years of follow-up) resulted in a lower risk of all-cause mortality and any diabetes-related end-point than conventional therapy. The effect of metformin on these endpoints was clearly greater than the effect of sulfonylureas or insulin. Although this analysis suggests that metformin may have a particular advantage in patients with type 2 diabetes, the subsequent analysis, showing that the addition of metformin to sulfonylurea may increase adverse outcomes, leaves this area open to question and further study. No firm conclusions regarding the role of metformin can therefore be made from this data other than the fact that, like other methods of glucose lowering, it appears to benefit patients with type 2 diabetes and is associated with less weight gain than either sulfonylureas or insulin in obese patients. The UKPDS also provided a unique opportunity to assess various strategies of blood pressure lowering in patients with type 2 diabetes. The investigators used a factorial design to do a blood pressure control study in a subset of individuals. Participants were randomized to a policy of tight blood pressure vs less tight blood pressure control and followed for a median duration of 8.4 years. Despite the fact that only a modest difference in blood pressure was achieved between the two groups, a clinically significant difference in diabetes-related outcomes and death was noted. Similar to observations made in other studies of blood pressure control in patients with diabetes, there was a significant decrease in the risk of macrovascular disease. Unique to the study was the observation that blood pressure control will reduce the risk of microvascular complications of diabetes. Taken together with other large blood pressure lowering studies that enrolled large numbers of diabetic patients and analyzed their outcomes,4,6 the evidence that blood pressure control is very important in patients with type 2 diabetes is clear. In the UKPDS study, the number of patients needed to treated for 10 years to prevent one diabetes-related complication was 6.1.
^ 1999 Harcourt Brace & Co. Ltd
Finally, the UKPDS assessed whether blood pressure control achieved with either captopril or atenolol has a particular advantage. No difference in the incidence of any diabetes-related end-point was noted between the groups. The 758 patients studied provided approximately 80% power to detect a 30% relative difference and a 10% absolute difference between the two groups. This suggests that if there is an undetected advantage of either an ACE-inhibitor or }-blocker for preventing diabetes-related end-points, the benefit is modest. Until further evidence demonstrating a difference is reported, either agent may therefore be an acceptable choice. Indeed, this report should allay any concerns regarding the use of selective }-blockers in patients with diabetes. The observation that more patients were non-compliant with atenolol because of more adverse effects provides some support for choosing an ACE-inhibitor (especially in patients with peripheral vascular disease, claudication, or lung disease) if there is no other reason to choose a }-blocker. The main message from the study is that blood pressure control, regardless of how it is achieved, is a key intervention for patients with diabetes. What then are the key messages from these five studies? First, diabetes is an important risk factor for cardiovascular disease. It is also a modifiable risk factor; aggressive intervention in patients with diabetes will improve the prognosis. Second, the degree of hyperglycemia is a modifiable risk factor for diabetes-related outcomes in patients with type 2 diabetes. Even modest reductions in blood sugar levels with
^ 1999 Harcourt Brace & Co. Ltd
sulfonylureas, insulin, or metformin can delay or prevent these outcomes. Third, even a modest reduction in blood pressure with either an ACE-inhibitor or }-blocker yields clinically important benefits in patients with diabetes. There is, therefore, no longer any room for therapeutic nihilism in the management of diabetes. Patients and physicians can make an important difference. Such a difference requires significant investment in time and effort on both parts but will pay off in improved health and reduced morbidity and mortality. Hertzel C. Gerstein, MD, MSc McMaster University, Hamilton, Ontario, Canada
Literature cited 1. Harris MI, Flegal KM, Cowie CC, et al. Diabetes Care 1998; 21: 518d524 2. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20: 1183d1197 3. Kannel WB, McGee DL. JAMMA 1979; 241: 2035d2038 4. Curb, JD, Pressel SL, Cutler JA, et al. JAMA 1996; 276; 1886d1892 5. Diabetes Control and Complications Trial Research Group. N Engl J Med 1993; 329: 977d986 6. Hansson L, Zanchetti A, Carruthers SG, et al. Lancet 1998; 351: 1755d1762
Evidence-based Cardiovascular Medicine (1999) 3, 21d25
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Diabetic individuals with no history of MI had a similar risk of death from CHD as non-diabetic individuals with a history of MI Haffner SM, Lehto S, RoK nnemaa T, PyoK raK laK K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229d234
OBJECTIVE To compare the 7-year incidence of cardiovascular events among diabetic and non-diabetic subjects with and without a history of MI at baseline. DESIGN Population-based study with maximal follow-up of 7.93 years.
stroke. The primary outcomes were fatal or non-fatal MI, fatal or non-fatal stroke and death from cardiovascular causes. Medical records and autopsy reports were used to assign cause of death. A computerized hospital-discharge database was consulted for hospital admissions for all participants.
ASSESSMENT OF PROGNOSTIC FACTORS Smoking status was ascertained by interview, and BP, fasting plasma glucose, serum lipids and lipoproteins were measured at baseline between 1982 and 1984. The medical records of all participants who reported having been hospitalized for chest pain were reviewed. A history of previous verified definite or possible MI or stroke was assessed using World Health Organization criteria.
MAIN RESULTS Among non-diabetic subjects, the 7-year incidence of MI was 3.5% in those without prior MI and 18.8% in those with prior MI. Among diabetic subjects, the 7-year incidence of MI was 20.2% in those without prior MI and 45.0% in those with prior MI. Kaplan-Meier estimates of the probability of death from CHD demonstrated that non-diabetic subjects without prior MI had the best prognosis while diabetic subjects with prior MI had the worst. Non-diabetic subjects with prior MI and diabetic participants without prior MI had a similar intermediate risk. Among these two intermediate-risk groups, there was no difference between non-diabetic subjects with prior MI (n"69) and diabetic subjects without prior MI (n"890) in the age- and sex-adjusted hazard ratio (HR 1.4; 95% CI 0.7–2.6). Further adjustment for smoking status, hypertension, LDL and HDL cholesterol and triglycerides continued to demonstrate no significant difference (HR 1.2; CI 0.6–2.4).
MAIN OUTCOME MEASURES The medical records of participants were reviewed when responses to questionnaire indicated hospitalization for chest pain or symptoms suggestive of
CONCLUSION Diabetic participants with no history of MI had a similar risk of death from CHD as non-diabetic participants with a history of MI.
SETTING The Finnish Social Insurance Institution database, limited to participants born and living in two university hospital regions in Finland. PARTICIPANTS All type-2 diabetic patients aged 45–64 years who had received reimbursement for drugs (n"1059) and a random control sample of non-diabetic participants aged 45–64 years from the same geographic regions (n"1373).
Intensive therapy with insulin or sulphonylureas failed to prevent macrovascular complications in patients with type 2 diabetes UK Prospective Diabetes Study (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 1998;352:837d853
OBJECTIVE To compare intensive blood glucose control with either sulphonylureas or insulin therapy, against conventional dietary therapy on the risk of microvascular and macrovascular complications among patients with type-2 diabetes. DESIGN Randomized, controlled, multi-center trial with allocation concealment and open-label follow-up of 11 years. SETTING 23 clinical centers in the UK with study subjects referred by family physicians. PATIENTS patients (mean age 53.3 years, 61% men) with newly diagnosed type-2 diabetes and fasting blood glucose (FBG) 6–15 ^ 1999 Harcourt Brace & Co. Ltd
mmol/l following a 3-month dietary run-in period were entered into the study. INTERVENTION Patients were randomized to receive either intensive control with insulin (30%), a sulphonylurea (40%; chlorpropamide or glibenclamide), or conventional control starting with dietary therapy (30%). The aim of intensive therapy was a FBG (6 mmol/L and, in insulin-treated patients, pre-meal glucose 4–7 mmol/L. The aim of conventional therapy was a FBG(15 mmol/L without symptoms of hyperglycemia. Additional hypoglycemic therapies were added only if there were hyperglycemic symptoms or FBG'15 mmol/L. Evidence-based Cardiovascular Medicine (1999) 3, 21d25
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MAIN OUTCOME MEASURES Three aggregate end-points: (1) any diabetes-related end-point (including microvascular and macrovascular events); (2) diabetes-related death; and (3) all-cause mortality. MAIN RESULTS Over 10 years, hemoglobin A1 was significantly lower in the intensive group compared with the conventional group (median 7.0 vs 7.9%; P (0.0001). There were significantly fewer diabetes-related end-points in the intensive therapy groups than in the conventional group (RR 0.88; 95% CI 0.79–0.99; P"0.029). There was also a trend toward fewer diabetes-related deaths (RR 0.90; CI 0.73–1.11; P"0.34) and fewer deaths from all causes (RR 0.94; CI 0.80–1.10; P"0.44). The observed prevention of diabetes-related events was greatly influenced by a highly significant reduction in microvascular end-points (RR 0.75; CI 0.60–0.93; P"0.0099) but only
a borderline significant reduction in the incidence of MI (RR 0.84; CI 0.71–1.00; P"0.052) and a trend toward reduction of amputation and death from peripheral vascular disease. There was no difference in the rate of any aggregate end-point between any of the three intensive agents (chlorpropamide, glibenclamide, or insulin; all P'0.36). There was significantly greater mean weight gain in the intensive groups than in the conventional group (3.1 kg; 99% CI!0.9 to #7.0; P( 0.0001) at 10 years. Mean weight gain was greatest among those assigned to insulin (4.0 kg more than those assigned to conventional therapy). CONCLUSION Intensive therapy with insulin or sulphonylureas reduced diabetes-related end-points and led to a marginally significant reduction in MIs in patients with type-2 diabetes.
Intensive glucose control with metformin was associated with fewer diabetes-related events in overweight patients UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) Lancet 1998;352:854d865
OBJECTIVE To compare intensive blood glucose control with metformin, against conventional therapy starting with diet on the clinical complications of diabetes in overweight patients with type2 diabetes, and to compare outcomes among patients receiving intensive control starting with insulin or sulphonylureas to those patients starting with metformin. DESIGN Randomized, controlled, multi-center trial with median follow-up of 10.7 years. SETTING 15 centers in the UK. PATIENTS 1704 overweight ('120% ideal bodyweight) participants (54% women; mean age 53 years) with newly diagnosed type-2 diabetes and a mean fasting blood glucose (FBG) 6–15 mmol/L following a 3-month dietary run-in period. INTERVENTION In the primary study, patients were allocated to receive either metformin (n"342) or conventional dietary therapy (n"411). In a secondary analysis of the data, patients receiving insulin or sulphonylurea (n"951) were compared to those receiving metformin. Patients receiving conventional dietary therapy who experienced symptoms of hyperglycemia or FBG'15 mmol/L were additionally randomized to receive non-intensive pharmacologic therapy. Patients allocated to sulphonylurea with symptoms of hyperglycemia were additionally given metformin, or insulin if needed.
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Evidence-based Cardiovascular Medicine (1999) 3, 21d25
MAIN OUTCOME MEASURES Three aggregate end-points: (1) any diabetes-related end-point; (2) diabetes-related death; and (3) all-cause mortality. MAIN RESULTS Patients allocated to metformin had a 32% decrease in the risk of any diabetes-related end-point (95% CI 13–47%; P"0.0023), a 42% reduction in diabetes-related death (CI 9–63%; P"0.017), a 36% reduction in all-cause mortality (CI 9–55%; P"0.011) and a 39% reduction in MI (CI 11–59%; P"0.01) compared to patients allocated to conventional dietary therapy. Compared to participants allocated to other intensive therapies, those allocated to metformin had significantly reduced risks of any diabetes-related end-point, all-cause mortality and stroke. The addition of metformin to sulphonylurea in both overweight and non-overweight patients was paradoxically associated with a 96% increase in diabetes-related deaths (CI 2–275%; P"0.039) compared to sulphonylurea alone. To explore this discrepancy, the datasets were merged. The combined data showed a 19% reduction (CI 2–33%; P"0.033) in any diabetes-related end-point and a number of additional analyses suggested that the apparent increase in diabetes-related deaths when metformin was added to sulphonylurea was likely to be due to the play of chance. Patients receiving metformin and conventional therapy had similar changes in bodyweight over 10 years, lower than that observed in participants receiving insulin or sulphonylurea. CONCLUSION Intensive glucose control with metformin in overweight type-2 diabetic patients led to fewer diabetes-related events and MIs than control with conventional therapy.
^ 1999 Harcourt Brace & Co. Ltd
Tight control of BP reduced risk of diabetes-related morbidity and mortality UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703d713
OBJECTIVE To determine whether tight control of blood pressure reduces clinical complications of diabetes in patients with type-2 diabetes. DESIGN Randomized, controlled, multi-center trial with median follow-up of 8.4 years. SETTING 20 clinical centers in the UK. PATIENTS 1148 hypertensive patients (55% men; mean age 56 years) with newly diagnosed type-2 diabetes and a mean fasting blood glucose (FBG) between 6 and 15 mmol/L following a 3-month dietary run-in period. Hypertension was defined as systolic BP (SBP) *160 mmHg and/or diastolic BP (DBP)*90 mmHg in persons not receiving antihypertensive treatment and SBP*150 mmHg and/or DBP*85 mmHg in persons receiving antihypertensive treatment. INTERVENTION Patients were randomly allocated to receive either tight BP control with ACE inhibitors (n"400) and b-blockers (n"358) used as first-line agents (aiming for a BP (150/85 mmHg); or less tight BP control (n"390) avoiding ACE inhibitors and b-blockers (aiming for a BP(180/105 mm Hg).
MAIN OUTCOME MEASURES Three aggregate end-points: (1) any diabetes-related end-point; (2) diabetes-related death; and (3) all-cause mortality. MAIN RESULTS Mean BP over the follow-up period was 144/82 mm Hg among those assigned tight BP control and 154/87 mm Hg among those assigned to less tight control (P(0.0001). At the end of follow-up 56% and 37% of patients in the tight control and less tight control groups achieved a BP(150/85 mm Hg. At 9 years of follow-up, 29% of those assigned to tight control required 3 or more agents compared to 11% of those assigned to less tight control. There was a significant 24% reduction in the risk of any diabetes-related end-point (95% CI 8-38%; P"0.0046) and a 32% reduction in the risk of diabetes-related death (CI 6–51%; P"0.019) but no significant reduction in the risk of all-cause mortality among patients assigned to tight control of BP. When all macrovascular diseases (MI, stroke, peripheral vascular disease) were considered together, there was a significant 34% reduction in the risk in the group assigned to tight control (P"0.019). Tight control also resulted in a highly significant 37% reduction in the risk of microvascular disease (CI 11–56%; P"0.0092). CONCLUSION Tight control of BP with an ACE inhibitor or a b-blocker reduced the risk of diabetes-related morbidity and mortality among patients with newly diagnosed type-2 diabetes.
No difference in the effects of captopril and atenolol on microvascular and macrovascular complications of diabetes UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998;317:713d720
OBJECTIVE To determine whether tight control of blood pressure with either an ACE inhibitor or b-blocker reduces microvascular and macrovascular complications of diabetes in patients with type-2 diabetes. DESIGN Randomized, controlled, multi-center trial with median follow-up of 8.4 years. SETTING 20 clinical centers in the UK PATIENTS 758 hypertensive patients (54% men; mean age 56 years) with newly diagnosed type-2 diabetes and a mean fasting blood glucose (FBG) between 6 and 15 mmol/L following a 3-month dietary run-in period. Hypertension was defined as systolic BP (SBP) *160 mm Hg and/or diastolic BP (DBP) *90 mm Hg in persons not receiving antihypertensive treatment and ^ 1999 Harcourt Brace & Co. Ltd
SBP*150 mm Hg and/or DBP*85 mm Hg in persons receiving antihypertensive treatment. INTERVENTION Patients were randomly allocated to receive either ACE inhibitors (captopril; n"400) or b-blockers (atenolol; n"358), aiming at a BP (150/85 mmHg. If BP goal was not met despite maximal allocated treatment, other agents were sequentially added (furosemide, slow release nifedipine, methyldopa and prazosin). MAIN OUTCOME MEASURES Three aggregate end-points: (1) any diabetes-related end-point; (2) diabetes-related death; and (3) all-cause mortality. MAIN RESULTS Baseline BP was 159/93 mmHg in both groups. Blood pressure was reduced over 9 years to 144/83 and Evidence-based Cardiovascular Medicine (1999) 3, 21d25
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143/81 mmHg in the captopril and atenolol groups, respectively. There was no significant difference in the relative risks of any diabetes-related end-point (RR for captopril 1.10; 95% CI 0.86–1.41), diabetes-related death (RR 1.27; CI 0.82–1.97), and all-cause mortality (RR 1.14; CI 0.81–1.61). Similarly, there was no significant difference in the risk of any macrovascular disease (MI, stroke, peripheral vascular disease) or microvascular disease. There was also no significant difference in the risk of heart failure or renal
failure, two pre-determined clinical end-points. Similar proportions of patients in the captopril (27%) and atenolol (31%) groups required three or more agents. Weight gain over the 9 years was lower in the captopril group (1.6 vs 3.4 kg; P"0.02). CONCLUSION There was no difference in the effects of captopril or atenolol on clinical complications of diabetes in hypertensive, type-2 diabetic patients.
Commentary Diabetes is a common metabolic disorder characterized by hyperglycemia, that affects 1 in 12 adults in North America.1 The fasting plasma glucose threshold above which a patient is classified as having diabetes is 7.0 mmol/L.2 This glucose value is that which clearly identifies people at high subsequent risk of eye and kidney disease (the so-called microvascular complications of diabetes). For many years, it was also clearly recognized that individuals with diabetes have a high risk of cardiovascular disease. For example, the Framingham study clearly showed that the risk of cardiovascular disease was 2d3 fold higher in diabetic men and 3d4 fold higher in diabetic women than in non-diabetic individuals.3 The epidemiologic study by Haffner et al. provides further evidence of the high cardiovascular risk of middle-aged patients with diabetes. This analytic cohort study reported the 8-year incidence of CHD mortality, MI, and stroke in Finnish patients with type 2 diabetes and a control population of non-diabetic Finnish individuals. Both cohorts were carefully assessed at baseline to identify those individuals with a previous MI. The authors could not detect a difference between the incidence of CHD death for diabetic participants with no history of MI and for non-diabetic participants with a previous MI (approximately 2.5% per year). Of note is the fact that the diabetic and non-diabetic populations were not matched for most demographic and risk variables at baseline. Moreover, the small number of non-diabetic individuals with no prior MI (n"69) provides low power to detect even moderate differences. Nevertheless, the inability to detect a difference even after adjustment for baseline variables, and the observation that the risk of these two groups was intermediate between the risk of the non-diabetic participants with no prior MI and the diabetic participants with a prior MI both support the conclusion that the risk of CHD death in these two cohorts is similar. Of particular interest is the finding that 42% of diabetic patients with a previous MI, and 15% of diabetic patients with no previous MI died from cardiovascular causes within 8 years of followup. This is a somber reminder of the high event rate in diabetic individuals. Most importantly, these high event rates highlight the importance of aggressive risk factor reduction in diabetic patients. Indeed, interventions may lead to higher absolute risk reductions when applied to diabetic patients than when applied to non-diabetic patients. This was clearly noted in the SHEP study,4 in which the identical 34% relative risk reduction for cardiovascular events in both the diabetic and non-diabetic subgroups meant that approximately 10 diabetics needed to be treated for 5 years to prevent one event compared to 20 non-diabetic patients (i.e. the absolute risk reductions were 10.1% and 4.9% respectively). Despite data such as these that show that diabetic patients may clearly benefit from cardiovascular interventions, most trials of primary and secondary cardiovascular prevention have either excluded patients with diabetes or have recruited very small numbers. The final results of the United Kingdom Prospective Diabetes Study (UKPDS) therefore provide long-awaited information on the effectiveness of various interventions to prevent clinical outcomes in patients with the most common type of diabetes d type 2 diabetes. This study enrolled newly-diagnosed patients with type 2 diabetes. Individuals were allocated to a policy of tight glycemic control vs conventional glycemic control. Despite the best efforts of the investigators, they were not able to maintain a stable level of glycemic control in the intervention group. Indeed, following an initial drop in hemoglobin A1c (HbA1c) in the intervention group, the steady rise in HbA1c in both groups at a similar
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Evidence-based Cardiovascular Medicine (1999) 3, 21d25
rate was such that median value in the intensive policy group during the second and third 5-year periods was essentially equal to that in the conventional group during the first and second 5-year periods. Furthermore, the median absolute separation in HbA1c achieved during the first 10 years of the study was only 0.9% (a difference considerably less than the 2% separation achieved in the Diabetes Control and Complications Trial that established the value of intensified insulin therapy in patients with type 1 diabetes5). These difficulties mirror the experience of all clinicians who try to achieve excellent glycemic control with currently available agents in patients with type 2 diabetes. It is in this context that the results need to be viewed. Despite the very modest difference in glucose levels, there was a clinically important difference in diabetes-related deaths and all-cause mortality. There was also a borderline significant 16% reduction in MI. There was no difference in the risk reduction achieved by either sulfonylureas or insulin, despite the fact that insulin levels were clearly higher in the group receiving insulin than in the conventional control group and in the group receiving sulfonylureas. These latter observations should clearly allay any anxieties regarding giving insulin to patients with type 2 diabetes. They provide no support whatsoever for concerns that attempts to achieve tight glucose control with exogenous insulin might increases the risk for cardiovascular events. Conversely, they provide a lot of support for the conclusion that glucose lowering, regardless of how it is achieved, decreases all-cause mortality and is likely to reduce cardiovascular events. The supplementary analysis done in an obese subset of patients in the UKPDS is less clear. This analysis did confirm that a very modest reduction of HbA1c using metformin (a median decrease of 0.6% over 10 years of follow-up) resulted in a lower risk of all-cause mortality and any diabetes-related end-point than conventional therapy. The effect of metformin on these endpoints was clearly greater than the effect of sulfonylureas or insulin. Although this analysis suggests that metformin may have a particular advantage in patients with type 2 diabetes, the subsequent analysis, showing that the addition of metformin to sulfonylurea may increase adverse outcomes, leaves this area open to question and further study. No firm conclusions regarding the role of metformin can therefore be made from this data other than the fact that, like other methods of glucose lowering, it appears to benefit patients with type 2 diabetes and is associated with less weight gain than either sulfonylureas or insulin in obese patients. The UKPDS also provided a unique opportunity to assess various strategies of blood pressure lowering in patients with type 2 diabetes. The investigators used a factorial design to do a blood pressure control study in a subset of individuals. Participants were randomized to a policy of tight blood pressure vs less tight blood pressure control and followed for a median duration of 8.4 years. Despite the fact that only a modest difference in blood pressure was achieved between the two groups, a clinically significant difference in diabetes-related outcomes and death was noted. Similar to observations made in other studies of blood pressure control in patients with diabetes, there was a significant decrease in the risk of macrovascular disease. Unique to the study was the observation that blood pressure control will reduce the risk of microvascular complications of diabetes. Taken together with other large blood pressure lowering studies that enrolled large numbers of diabetic patients and analyzed their outcomes,4,6 the evidence that blood pressure control is very important in patients with type 2 diabetes is clear. In the UKPDS study, the number of patients needed to treated for 10 years to prevent one diabetes-related complication was 6.1.
^ 1999 Harcourt Brace & Co. Ltd
Finally, the UKPDS assessed whether blood pressure control achieved with either captopril or atenolol has a particular advantage. No difference in the incidence of any diabetes-related end-point was noted between the groups. The 758 patients studied provided approximately 80% power to detect a 30% relative difference and a 10% absolute difference between the two groups. This suggests that if there is an undetected advantage of either an ACE-inhibitor or }-blocker for preventing diabetes-related end-points, the benefit is modest. Until further evidence demonstrating a difference is reported, either agent may therefore be an acceptable choice. Indeed, this report should allay any concerns regarding the use of selective }-blockers in patients with diabetes. The observation that more patients were non-compliant with atenolol because of more adverse effects provides some support for choosing an ACE-inhibitor (especially in patients with peripheral vascular disease, claudication, or lung disease) if there is no other reason to choose a }-blocker. The main message from the study is that blood pressure control, regardless of how it is achieved, is a key intervention for patients with diabetes. What then are the key messages from these five studies? First, diabetes is an important risk factor for cardiovascular disease. It is also a modifiable risk factor; aggressive intervention in patients with diabetes will improve the prognosis. Second, the degree of hyperglycemia is a modifiable risk factor for diabetes-related outcomes in patients with type 2 diabetes. Even modest reductions in blood sugar levels with
^ 1999 Harcourt Brace & Co. Ltd
sulfonylureas, insulin, or metformin can delay or prevent these outcomes. Third, even a modest reduction in blood pressure with either an ACE-inhibitor or }-blocker yields clinically important benefits in patients with diabetes. There is, therefore, no longer any room for therapeutic nihilism in the management of diabetes. Patients and physicians can make an important difference. Such a difference requires significant investment in time and effort on both parts but will pay off in improved health and reduced morbidity and mortality. Hertzel C. Gerstein, MD, MSc McMaster University, Hamilton, Ontario, Canada
Literature cited 1. Harris MI, Flegal KM, Cowie CC, et al. Diabetes Care 1998; 21: 518d524 2. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20: 1183d1197 3. Kannel WB, McGee DL. JAMMA 1979; 241: 2035d2038 4. Curb, JD, Pressel SL, Cutler JA, et al. JAMA 1996; 276; 1886d1892 5. Diabetes Control and Complications Trial Research Group. N Engl J Med 1993; 329: 977d986 6. Hansson L, Zanchetti A, Carruthers SG, et al. Lancet 1998; 351: 1755d1762
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