Clinical Trial Abstracts
DCCT (glycaemia in type 1 diabetes)
DPP (diabetes prevention program)
STENO (multiple risk factor control in type 2)
UKPDS (blood pressure)
Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38
Editorials by Orchard and Mogensen Papers pp 713 , 720 This paper was prepared for publication by Robert Turner, Rury Holman, Irene Stratton, Carole Cull, Valeria Frighi, Susan Manley, David Matthews, Andrew Neil, Heather McElroy, Eva Kohner, Charles Fox, David Hadden, and David Wright.
UK Prospective Diabetes Study Group
Correspondence to: Professor R Turner, UK Prospective Diabetes Study Group, Diabetes Research Laboratories, Radcliffe Infirmary, Oxford OX2 6HE
Objective: To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes.
Design: Randomised controlled trial comparing tight control of blood pressure aiming at a blood pressure of <150/85 mm Hg (with the use of an angiotensin converting enzyme inhibitor captopril or a 
blocker atenolol as main treatment) with less tight control aiming at a blood pressure of <180/105 mm Hg.
Setting: 20 hospital based clinics in England, Scotland, and Northern Ireland.
Subjects: 1148 hypertensive patients with type 2 diabetes (mean age 56, mean blood pressure at entry 160/94 mm Hg); 758 patients were allocated to tight control of blood pressure and 390 patients to less tight control with a median follow up of 8.4 years.
Main outcome measures: Predefined clinical end points, fatal and non-fatal, related to diabetes, deaths related to diabetes, and all cause mortality. Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography.
Results: Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control (144/82 mm Hg) compared with the group assigned to less tight control (154/87 mm Hg) (P<0.0001). Reductions in risk in the group assigned to tight control compared with that assigned to less tight control were 24% in diabetes related end points (95% confidence interval 8% to 38%) (P=0.0046), 32% in deaths related to diabetes (6% to 51%) (P=0.019), 44% in strokes (11% to 65%) (P=0.013), and 37% in microvascular end points (11% to 56%) (P=0.0092), predominantly owing to a reduced risk of retinal photocoagulation. There was a non-significant reduction in all cause mortality. After nine years of follow up the group assigned to tight blood pressure control also had a 34% reduction in risk in the proportion of patients with deterioration of retinopathy by two steps (99% confidence interval 11% to 50%) (P=0.0004) and a 47% reduced risk (7% to 70%) (P=0.004) of deterioration in visual acuity by three lines of the early treatment of diabetic retinopathy study (ETDRS) chart. After nine years of follow up 29% of patients in the group assigned to tight control required three or more treatments to lower blood pressure to achieve target blood pressures.
Conclusion: Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinically important reduction in the risk of deaths related to diabetes, complications related to diabetes, progression of diabetic retinopathy, and deterioration in visual acuity.
Key messages
This study showed that tight control of blood pressure based on captopril or atenolol as first agents and aiming for both a systolic blood pressure <150 mm Hg and diastolic pressure <85 mm Hg achieved a mean 144/82 mm Hg compared with 154/87 mm Hg in a control group 29% of patients in the tight control group required three or more hypotensive treatments Tight control of blood pressure reduced the risk of any non-fatal or fatal diabetic complications and of death related to diabetes; deterioration in visual acuity was also reduced Reducing blood pressure needs to have high priority in caring for patients with type 2 diabetes.
UKPDS (glycaemia)
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)
UK Prospective Diabetes Study (UKPDS) Group*
*Study organisation given at end of paper
Correspondence to: Prof Robert Turner, UKPDS Group, Diabetes Research Laboratories, Radcliffe Infirmary, Oxford OX2 6HE, UK
Summary
Background Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial.
Methods 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 4860 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6·115·0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy.
Findings Over 10 years, haemoglobin A 1c (HbA 1c ) was 7·0% (6·28·2) in the intensive group compared with 7·9% (6·98·8) in the conventional group--an 11% reduction. There was no difference in HbA 1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 121, p=0·029) for any diabetes-related endpoint; 10% lower (11 to 27, p=0·34) for any diabetes-related death; and 6% lower (10 to 20, p=0·44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (740, p=0·0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin).
Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0·0001). The rates of major hypoglycaemic episodes per year were 0·7% with conventional treatment, 1·0% with chlorpropamide, 1·4% with glibenclamide, and 1·8% with insulin. Weight gain was significantly higher in the intensive group (mean 2·9 kg) than in the conventional group (p<0·001), and patients assigned insulin had a greater gain in weight (4·0 kg) than those assigned chlorpropamide (2·6 kg) or glibenclamide (1·7 kg).
Interpretation Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes. None of the individual drugs had an adverse effect on cardiovascular outcomes. All intensive treatment increased the risk of hypoglycaemia.
Lancet 1998; 352: 83753
DCCT (glycaemia and type 1 diabetes)
The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus
The Diabetes Control and Complications Trial Research Group
ABSTRACT
Background Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications.
Methods A total of 1441 patients with IDDM -- 726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.
Results In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of 
40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of 
300 mg per 24 hours) by 54 percent (95 percent confidence interval, 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia.
Conclusions Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.
HPS (statins)
MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial
Heart Protection Study Collaborative Group*
*Collaborators and participating hospitals are listed at the end of the report
Correspondence to: Heart Protection Study, Clinical Trial Service Unit and Epidemiological Studies Unit, Radcliffe Infirmary, Oxford OX2 6HE , UK (e-mail: hps@ctsu.ox.ac.uk )
Summary
Background Throughout the usual LDL cholesterol range in Western populations, lower blood concentrations are associated with lower cardiovascular disease risk. In such populations, therefore, reducing LDL cholesterol may reduce the development of vascular disease, largely irrespective of initial cholesterol concentrations.
Methods 20 536 UK adults (aged 40-80 years) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive 40 mg simvastatin daily (average compliance: 85%) or matching placebo (average non-study statin use: 17%). Analyses are of the first occurrence of particular events, and compare all simvastatin-allocated versus all placebo-allocated participants. These "intention-to-treat" comparisons assess the effects of about two-thirds (85% minus 17%) taking a statin during the scheduled 5-year treatment period, which yielded an average difference in LDL cholesterol of 1·0 mmol/L (about two-thirds of the effect of actual use of 40 mg simvastatin daily). Primary outcomes were mortality (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity.
Findings All-cause mortality was significantly reduced (1328 [12·9%] deaths among 10 269 allocated simvastatin versus 1507 [14·7%] among 10 267 allocated placebo; p=0·0003), due to a highly significant 18% (SE 5) proportional reduction in the coronary death rate (587 [5·7%] vs 707 [6·9%]; p=0·0005), a marginally significant reduction in other vascular deaths (194 [1·9%] vs 230 [2·2%]; p=0·07), and a non-significant reduction in non-vascular deaths (547 [5·3%] vs 570 [5·6%]; p=0·4). There were highly significant reductions of about one-quarter in the first event rate for non-fatal myocardial infarction or coronary death (898 [8·7%] vs 1212 [11·8%]; p<0·0001), for non-fatal or fatal stroke (444 [4·3%] vs 585 [5·7%]; p<0·0001), and for coronary or non-coronary revascularisation (939 [9·1%] vs 1205 [11·7%]; p<0·0001). For the first occurrence of any of these major vascular events, there was a definite 24% (SE 3; 95% CI 19-28) reduction in the event rate (2033 [19·8%] vs 2585 [25·2%] affected individuals; p<0·0001). During the first year the reduction in major vascular events was not significant, but subsequently it was highly significant during each separate year. The proportional reduction in the event rate was similar (and significant) in each subcategory of participant studied, including: those without diagnosed coronary disease who had cerebrovascular disease, or had peripheral artery disease, or had diabetes; men and, separately, women; those aged either under or over 70 years at entry; and--most notably--even those who presented with LDL cholesterol below 3·0 mmol/L (116 mg/dL), or total cholesterol below 5·0 mmol/L (193 mg/dL). The benefits of simvastatin were additional to those of other cardioprotective treatments. The annual excess risk of myopathy with this regimen was about 0·01%. There were no significant adverse effects on cancer incidence or on hospitalisation for any other non-vascular cause.
Interpretation Adding simvastatin to existing treatments safely produces substantial additional benefits for a wide range of high-risk patients, irrespective of their initial cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rates of myocardial infarction, of stroke, and of revascularisation by about one-quarter. After making allowance for non-compliance, actual use of this regimen would probably reduce these rates by about one-third. Hence, among the many types of high-risk individual studied, 5 years of simvastatin would prevent about 70-100 people per 1000 from suffering at least one of these major vascular events (and longer treatment should produce further benefit). The size of the 5-year benefit depends chiefly on such individuals' overall risk of major vascular events, rather than on their blood lipid concentrations alone.
Lancet 2002; 360: 7-22
HOPE (ACE inhibitors)
Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy |
Heart Outcomes Prevention Evaluation (HOPE) Study Investigators*
*Study organisation and investigators listed at end of paper
Correspondence to: Dr Hertzel C Gerstein, Canadian Cardiovascular Collaboration Project Office, HGH-McMaster Clinic, 237 Barton Street East , Hamilton , Ontario L8L 2X2 , Canada (e-mail: HOPE@ccc.mcmaster.ca )
Summary
Background Diabetes mellitus is a strong risk factor for cardiovascular and renal disease. We investigated whether the angiotensin-converting-enzyme (ACE) inhibitor ramipril can lower these risks in patients with diabetes.
Methods 3577 people with diabetes included in the Heart Outcomes Prevention Evaluation study, aged 55 years or older, who had a previous cardiovascular event or at least one other cardiovascular risk factor, no clinical proteinuria, heart failure, or low ejection fraction, and who were not taking ACE inhibitors, were randomly assigned ramipril (10 mg/day) or placebo, and vitamin E or placebo, according to a two-by-two factorial design. The combined primary outcome was myocardial infarction, stroke, or cardiovascular death. Overt nephropathy was a main outcome in a substudy.
Findings The study was stopped 6 months early (after 4·5 years) by the independent data safety and monitoring board because of a consistent benefit of ramipril compared with placebo. Ramipril lowered the risk of the combined primary outcome by 25% (95% CI 1236, p=0·0004), myocardial infarction by 22% (636), stroke by 33% (1050), cardiovascular death by 37% (2151), total mortality by 24% (837), revascularisation by 17% (230), and overt nephropathy by 24% (340, p=0·027). After adjustment for the changes in systolic (2·4 mm Hg) and diastolic (1·0 mm Hg) blood pressures, ramipril still lowered the risk of the combined primary outcome by 25% (1236, p=0·0004).
Interpretation Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes. The cardiovascular benefit was greater than that attributable to the decrease in blood pressure. This treatment represents a vasculoprotective and renoprotective effect for people with diabetes.
Lancet 2000; 355: 25359
DPP (diabetes prevention program)
|
Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin
Diabetes Prevention Program Research Group
ABSTRACT
Background Type 2 diabetes affects approximately 8 percent of adults in the United States. Some risk factors - elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle - are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes.
Methods We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week. The mean age of the participants was 51 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 34.0; 68 percent were women, and 45 percent were members of minority groups. 68 percent were women, and 45 percent were members of minority groups.
Results The average follow-up was 2.8 years. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence by 58 percent (95 percent confidence interval, 48 to 66 percent) and metformin by 31 percent (95 percent confidence interval, 17 to 43 percent), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin.
Conclusions Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin.
STENO (multiple risk factor control)
|
Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes
Peter Gæde, M.D., Pernille Vedel, M.D., Ph.D., Nicolai Larsen, M.D., Ph.D., Gunnar V.H. Jensen, M.D., Ph.D., Hans-Henrik Parving, M.D., D.M.Sc., and Oluf Pedersen, M.D., D.M.Sc.
ABSTRACT
Background Cardiovascular morbidity is a major burden in patients with type 2 diabetes. In the Steno-2 Study, we compared the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease in patients with type 2 diabetes and microalbuminuria.
Methods The primary end point of this open, parallel trial was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation. Eighty patients were randomly assigned to receive conventional treatment in accordance with national guidelines and 80 to receive intensive treatment, with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of cardiovascular disease with aspirin.
Results The mean age of the patients was 55.1 years, and the mean follow-up was 7.8 years. The decline in glycosylated hemoglobin values, systolic and diastolic blood pressure, serum cholesterol and triglyceride levels measured after an overnight fast, and urinary albumin excretion rate were all significantly greater in the intensive-therapy group than in the conventional-therapy group. Patients receiving intensive therapy also had a significantly lower risk of cardiovascular disease (hazard ratio, 0.47; 95 percent confidence interval, 0.24 to 0.73), nephropathy (hazard ratio, 0.39; 95 percent confidence interval, 0.17 to 0.87), retinopathy (hazard ratio, 0.42; 95 percent confidence interval, 0.21 to 0.86), and autonomic neuropathy (hazard ratio, 0.37; 95 percent confidence interval, 0.18 to 0.79).
Conclusions A target-driven, long-term, intensified intervention aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent.