Clinical Studies

UKPDS AT A GLANCE

• The UKPDS (United Kingdom Prospective Diabetes Study) compared intensive glucose control with conventional control in a randomized trial.

• A total of 5,102 patients were included and followed for a mean of up to 13 years; 42% of the patients were female.

• Patients were stratified to treatment groups based on their ideal bodyweight.

• Patients who were not overweight were assigned intensive treatment with insulin, sulphonylurea or diet (conventional treatment or control group). Overweight patients were randomized to the above treatment with the additional possibility of metformin.

• Investigators found that the risk of any diabetes-related outcome was 12% lower in patients who were assigned to the intensive blood-glucose control group versus those who were in the conventional control group (P=.029).

• Reporting in the Lancet, the UKPDS Study Group said that the majority of risk reduction of the diabetes-related endpoint was attributable to a 25% reduced risk in macrovascular outcomes.

UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet. 1998;837-858.

DPP AT A GLANCE

• The DPP (Diabetes Prevention Program) Trial evaluated treatment with metformin, lifestyle modification or placebo with regard to their ability to delay or prevent the onset of diabetes in high-risk, nondiabetic patients with elevated glucose.

• This trial was designed to enroll half of the patients from an ethnic minority, 68% were women and the average age was 51 years. A total of 3,234 patients were randomized to placebo, metformin twice daily or a lifestyle modification intervention with a goal of ≥7% weight loss and ≥150 minutes of physical activity weekly. The average follow-up was 2.8 years.

• Investigators reported that 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. Lifestyle intervention reduced the incidence of diabetes by 58% (95% CI, 0.48-0.66); metformin by 31% (95% CI, 0.17-0.43) as compared to placebo. The lifestyle intervention was significantly more effective than metformin.

• The Diabetes Prevention Program Research Group wrote that to prevent one case of diabetes during 3 years, 6.9 patients would have to participate in lifestyle intervention and 13.9 would have to be treatment with metformin. Both treatments reduced the incidence of diabetes in those at high risk. The lifestyle intervention was more effective.

Knowler WC, Barrett-Conner E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

LALES AT A GLANCE

• The LALES (Los Angeles Latino Eye Study) was a population-based and cross-sectional study of eye disease that measured the outcomes of visual impairment, blindness, cataract, glaucoma, DR and AMD.

• Patients were mostly Mexican-American (80%). All 6,357 Latinos were aged ≥40 years, and were from six census tracts in La Puente, Calif.

• All patients had detailed interviews and eye assessments (visual acuity measurement; intraocular pressure and visual fields; fundus and optic disc photography; a detailed anterior and posterior segment exam) and measurements of blood pressure, HbA1c and blood glucose levels that noted demographic, behavioral and ocular risk factors. The assessments also uncovered health-related and vision-related quality of life.

• Investigators concluded that developing Latino-targeted programs for evaluating and treating eye diseases is important, especially among older patients. The burden of visual impairment on Latinos may be decreased through better education and employment efforts.

• Three percent of patients enrolled were visually impaired; 0.4% were blind. The prevalence of visual impairment was higher among Latinos than in whites, but comparable to the prevalence among African-Americans.

• Of 1,217 diabetic patients, one in 5 were diagnosed during the study. DR was found in 46.9%, and macular edema was found in 10%. Out of the 10% with macular edema, 60% needed laser treatment to correct it.

• Investigators said that the prevalence of DR is high among Latinos of primarily Mexican ancestry, and the longer a patient had diabetes, the higher their risk of developing DR.

• Relatively high rates of early AMD were found, however, the corresponding rates of advanced AMD were not high.

• Open-angle glaucoma prevalence is high among Latinos of primarily Mexican ancestry. The prevalence was 4.74% (95 CI, 4.22%-5.30%). The prevalence of ocular hypertension was 3.56% (95% CI, 3.12%-4.06%).

•  Valid assessment of self-reported visual functioning was obtained using the NEI-VFQ-25, the investigators concluded.

• Poorer binocular presenting visual acuity was associated with lower self-reported visual functioning, and a 5-point difference in NEI-VFQ-25 scores was found to be associated with a two-line difference in visual acuity. This was a visual impairment-related difference.

• The association between binocular visual acuity and self-reported visual function was not impacted by the visual impairment definition (including or excluding 20/40).

• In this study, the most common type of lens opacities were cortical opacities. High rates of visual impairment from lens opacities suggests that programs that increase access to cataract surgery for older Latinos could help to reduce the burden of visual impairment in the United States.

• The study, which was the largest and the most epidemiological study of its kind, lasted 5 years, and was funded by the National Institutes of Health, the National Eye Institute and the Nationall Center on Minority Health and Health Disparities.

Varma R, Paz H, Azen SP, et al. The Los Angeles Latino Eye Study. Ophthalmology. 2004;111:1121-1306.

NHANES AT A GLANCE

• The NHANES (National Health and Nutrition Examinations Survey) is information from a series of studies that assessed the health and nutritional status of US adults and children. Information was collected through interviews and physical examinations.

• The series is comprised of NHANES I, II (1976-1980) and III (1988-1994).

• Current statistics (listed below) include data from 4,115 adults and 4,018 children from 1999 to 2000. It also included data from 4,390 adults and 4,258 children from 2001 to 2002.

• The study was stratified and multistaged, and the patient population was comprised of a probability sample of civilian, noninstitutionalized US citizens.

• Results from the 1999-2002 portion of the NHANES study that dealt with children estimated that 16% of people aged 6 to 19 years are overweight. This is a 45% increase from the prevalence in 1998 to 1994.

• From 1960 to 1980, the prevalence of overweight children was steady, however, it was nearly doubled between 1976 and 1980.

• Non-Hispanic black children have a 21% prevalence of overweight, and Mexican-American adolescents, aged 12 to 19 years, are 23% more likely to be overweight when compared to non-Hispanic whites. They are 14% likely to be overweight.

• Investigators concluded that overweight adolescents are at an increased risk of becoming overweight adults.

• In the portion of the data that dealt with adults, investigators identified that one-third of all adults, aged ≥20 years, are classified as obese. This includes over 60 million people.

• The prevalence of obesity in women (33%) is higher than in men (28%), and the population with the highest prevalence of obesity is non-Hispanic black women (49%). Following behind this group is Mexican-American women (38%), and non-Hispanic white women (31%).

• Only 37% of patients reached the goal of HbA1c <7%. Values were >8% in 37% of patients.

• Only 36% had normal blood pressure, while 40% had elevated levels. Over 50% of patients had total cholesterol 200 mg/dL. Seven percent of patients achieved the recommended goals for HbA1c, blood pressure and total cholesterol.

• Authors noted that there continues to be disparities by sex and between racial/ethnic groups in the prevalence of overweight and obesity.

NHANES was conducted by the National Center for Health Statistics, CDC. To access materials that are related to NHANES II and NHANES III, please visit http://www.cdc.gov/nchs/nhanes.htm or http://archive.nlm.nih.gov/proj/dxpnet/nhanes/nhanes.ph

The North West Diabetes Foot Care Study AT A GLANCE

• The North West Diabetes Foot Care Study was established to predict neuropathic foot ulcers risk in 9,710 diabetic patients followed for 2 years.

• The population-based, prospective analysis was carried out in six community health care districts in the North West United Kingdom. Investigators analyzed diabetic foot screening methods to determine which ones were the most effective.

• Three sensory modalities to determine a NDS were used: vibration with a 128-Hz tuning fork, pinprick with a Neurotip device and hot-cold rods. The score of 0 was normal and 1 was abnormal. Most of the screenings were performed at a podiatry clinic or by a patient’s general practitioner.

• Of the 7,410 people who were available for follow-up, investigators confirmed that ulcers were either developed or undeveloped in 6,613 patients.

• They found that the annual incidence of foot ulceration to be 2.2%, and determined NDS as the best baseline predictor for ulceration.

• A score of <6 translated to a 1.1% annual ulcer incidence and a score of >6 translated to a 6.3% annual ulcer incidence.

• Investigators concluded that in most cases (55%) ulcers were caused by footwear pressure. Other causes were trauma (15%), fissure and self-injury.

Abbott CA, Carrington AL, Ashe H, et al. The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabetic Med. 2002;19:377-384.

DETAIL AT A GLANCE

• The DETAIL (Diabetics Exposed to Telmisartan and Enalapril) prospective, multicenter, double-blind, double-dummy, parallel-group study was comprised of 250 randomized patients.

• The angiotensin-converting enzyme (ACE) inhibitor enalapril, along with the angiotensin-receptor blocker (ARB) telmisartan were studied in type 2 diabetic patients with early nephropathy and hypertension.

• Patients, mean age 60 years, received either 80mg telmisartan or 20 mg enalpapril for 5 years. Twenty-seven percent of patients were female.

• The primary endpoint was considered to be the change in glomerular filtration rate (GFR) from baseline. This was the first time that a study directly measured GFR to measure the progression of kidney disease.

• GFR was evaluated by the investigators at 1, 2, 3, 4, and 5 years: They observed a change of -17.9mL/min/1.73m2 for patients assigned telmisartan versus -14.8 mL/min/1.73m2 for patients who took enalapril. Investigators said the difference was not statistically significant.

• Results indicated that telmisartan provided comparable renoprotective effects to enalapril.

• Investigators also commented that both groups only had a 5% cardiovascular mortality rate, and both experienced a decrease in their blood pressure throughout the study. 

• The study was the first to supply comparative evidence from over 5 years in regards to the renoprotective effects of ARBs versus ACE inhibitors among the type 2 diabetes population with early nephropathy.

Barnett A, et al. Comparison of Angiotensin-II receptor blocker and angiotensin-converting enzyme inhibition in subjects with type 2 diabetes and nephropathy. N Engl J Med. 2004;351:12-20.

IRMA-2 AT A GLANCE

• The IRMA-2 (Irbesartan in Type 2 Diabetes with Microalbuminuria-2) study enrolled 590 hypertensive patients with type 2 diabetes and microalbuminuria and randomized them to receive daily doses of irbesartan or placebo.

• Patients, who took 150mg/day, 300mg/day or placebo, were followed for 2 years in order to test the effect of the drug on slowing the progression to diabetic nephropathy.

• A primary outcome of time to onset of diabetic nephropathy was evaluated, and characteristics of participants across all groups were similar at the start of the study.

• Out of patients receiving 300mg/day, 5.2% reached the endpoint; 9.7% in the 150mg/day group (hazard ratios, 0.30) (95% CO, 0.34-1.08; P=.08) and 14.9% in the placebo group also reached the endpoint (95% CI, 0.14-0.61; P<.001).

• Investigators concluded that irbesartan is renoprotective independent of its blood pressure-lowering effects in type 2 diabetic patients with microalbuminuria. 

Parving HH, Lehnert H, Brochner-Mortensen J, et al. The Effect of Irbesartan on the Development of Diabetic Neuphropathy in Patients with Type 2 Diabetes. N Engl J Med. 2001;345:870-878.

Palmer AJ, Annemans L, Roze S, et al. Cost-effectiveness of early irbesartan treatment versus control or late irbesartan treatment in patients with type 2 diabetes, hypertension, and renal disease. Diabetes Care. 2004;27:1897-1903.

IDNT AT A GLANCE

• Comparing irbesartan with the calcium-channel antagonist amlodipine on the progression of nephropathy in patients with type 2 diabetes, the IDNT (Irbesartan in Diabetic Nephropathy Trial) enrolled 1,715 patients.

• Investigator wanted to see if the two classes of drugs slowed nephropathy independently of lowering blood pressure.

• Patients were hypertensive and had type 2 diabetes and nephropathy, and they were randomized to receive 300mg/daily irbesartan, 10mg/day amlodipine or placebo.

• A target blood pressure of 135/85 mm/Hg was assigned.

• Doubling of baseline serum creatinine concentrtion, development of end stage renal disease or death from any cause consisted of the primary composite endpoint.

• Risk of the primary endpoint was 20% lower in patients who took irbesartan versus those who took placebo (P=.02) and 23% lower versus those who took amlodipine (P=.006).

• Risk of doubling the serum creatinine also varied between the groups: Patients in the irbesartan group had a 33% lower concentration versus placebo (P=.003) and 37% versus amlodipine (P<.001).

• Investigators concluded that irbesartan is an effective treatment against nephropathy progression in type 2 diabetes. This effect is independent from blood pressure reductions.

Lewis EJ, Hunsicker LF, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860.

DCCT AT A GLANCE

• DCCT (Diabetes Control and Complications Trial) was initiated 20 years ago.

• A total of 1,441 patients were studied to compare the effects of intensive control versus conventional control on blood glucose levels.

• Patients had type 1 diabetes, and were enrolled from 29 US and Canadian medical centers.

• Duration of diabetes ranged from 1 year to 15 years, and the average age of patients was 27 years. They were randomly assigned to either the intensive or conventional control groups.  

• Initial results from the study showed that a 76% reduction was seen in diabetic retinopathy when patients had intensive glucose control. This same group also slowed their progression of diabetic nephropathy by 50% and saw a 60% reduction in diabetic neuropathy.

• Intensive treatment did produce unwanted side effects, however, that included increased risk for hypoglycemia, modest weight-gain, and a doubling in the cost of managing diabetes.

National Institute of Diabetes and Digestive and Kidney Diseases. Diabetes Control and Complications Trial. National Institutes of Health; 2001. NIH Publication 02-3874.

EDIC AT A GLANCE

• The EDIC (Epidemiology of Diabetes Interventions and Complications) study was a multicenter, longitudinal, observational study that enrolled patients from DCCT.

• Investigators studied the micro- and macrovascular long-term effects of prior separation of glycemic level of the population for 10 years.

• Each year, patients were screened for nephropathy, and received Doppler ultrasound measurements of ankle/arm blood pressure and well as a resting electrocardiogram. 

• After an average of 6 years, patients treated with intensive therapy had a lower risk for developing neuropathy versus patients who did not receive intensive therapy. This trend was also seen after 8 years of treatments.

• Investigators also noticed that HbA1c levels across patients in the intensive treatment group were lower than in conventional treatment group patients.

Epidemiology of Diabetes Interventions and Complications (EDIC). Design, implementation, and preliminary results of a long-term follow-up of the Diabetes Control and Complications Trial cohort. Diabetes Care. 1999;22:99-111.

BENEDICT AT A GLANCE

• BENEDICT (Bergamo Nephrologic Diabetes Complications Trial) was designed to determine the effectiveness of the angiotensin-converting enzyme (ACE) inhibitor trandolapril and the calcium antagonist verapamil on the incidence of microalbuminuria in type 2 diabetic patients with hypertension and normal urinary albumin excretion (UAE).

• A total of 1,204 type 2 diabetic patients, aged ≥40 years, were enrolled for a duration of ≤25 years, and were randomized to receive trandolapril (2mg/day) plus verapamil (180mg/day in a sustained-release formula); trandolapril alone (2mg/day); verapamil alone (240mg/day in a sustained-release formula); or placebo.

• The average UAE of patients was <20µg/minute and the average serum creatinine concentration was ≤1.5mg/dL at baseline.

• During the multicenter, double-blind, placebo-controlled study, 601 patients were treated with either an ACE inhibitor alone or in combination with verapamil; 603 were treated with either a calcium antagonist alone or in combination with trandolapril.

• The primary endpoint was the incidence of persistent microalbuminuria, where at least two of three overnight urine collections were ≥20µg/minute.

• Blood pressure and morning samples were analyzed at baseline, 1 week, 1 month, 3 months and every 3 months thereafter.

• A total of 30 of 300 patients in the placebo group developed microalbuminuria; 17 of 300 in the combination therapy group and 18 of 301 in the trandopapril only group.

• Delayed microalbuminuria, by a factor of 2.6, was seen in patients who received the combination therapy. When trandopapril was used alone, the delay factor was 2.1.

• An adjusted acceleration factor of 0.47 (95% CO, 0.26-0.83, P=.01) was seen in trandopapril use versus placebo.

• Microalbuminuria was not delayed in patients who used verapamil, and there was an adjusted acceleration factor of 0.83 (95% CI, 0.45-1.51; P=.54).

• Investigators concluded that the combination therapy of trandolapril plus verapamil in type 2 diabetic patients prodiced a significant reduction in the incidence of microalbuminuria. They saw a similar reduction among patients who took trandolapril alone. The estimated acceleration factor between the groups was 0.39 (95% CI, 0.19-0.8; P=.01). 

• Investigators concluded that trandolapril may be the best medication to protect against microalbuminuria, as well as control blood pressure.

Ruggeneti MD, Fassi A, Ilieva AP, et al. Preventing Microalbuminuria in Type 2 Diabetes. N Eng J Med. 2004;351:1941-1951.

ETDRS AT A GLANCE

• The ETDRS (Early Treatment Diabetic Retinopathy Study) enrolled 3,711 patients and followed them for 4 years to determine the risks and benefits of managing nonproliferative or early proliferative diabetic retinopathy (DR).

• The study was multicentered and randomized. Investigators assessed the effectiveness of argon laser photocoagulation and aspirin therapy on patients, all of whom were aged between 18 and 70 years.

• Patients were randomly assigned to have immediate photocoagulation in one eye, and had it deferred in the other eye until high-risk proliferative retinopathy was noted.

• Investigators concluded that aspirin had no effect on retinopathy progression in eyes that were deferred of photocoagulation.

• There were also no effects from aspirin on the risk of vitreous hemorrhage or vision. It did, however, decrease the risk of cardiovascular disease.

• Compared to patients with normal total cholesterol levels, those with elevated total cholesterol levels were significantly more likely to have retinal hard exudates.

• Investigators concluded that the progression of DR is negatively effected by hyperlipidemia because accumulation of retinal exudates may progress to vision loss from foveal lipid plaque. They also concluded that aspirin does not provide a clinical benefit to the progression of diabetic retinopathy. 

Fong DS, Ferris FL, Davis MD, et al. ETDRS Research Group: Causes of severe visual loss in the Early Treatment Diabetic Retinopathy Study (ETDRS Report No. 24) Am J Ophthalmol. 1999;127:137-141.

Fong DS, Barton FB, Bresnick GH, et al. ETDRS Research Group: Impaired color vision associated with diabetic retinopathy: Early Treatment Diabetic Retinopathy Study (ETDRS Report No. 15) Am J Ophthalmol. 1999;128:612-617.

Chew EY, Klein ML, Ferris FL III, et al. ETDRS Research Group: Association of elevated serum lipid levels with retinal hard exudates in diabetic retinopathy. (ETDRS Report No. 22) Arch Ophthalmol. 1996;114:1079-1084.

Ferris FL III: Early photocoagulation in patients with either type 1 or 2 diabetes. Tr Am Ophth Soc. 1996;94:505-537.