An estimated 29.1 million individuals in the United States have diabetes, and another 86 million adults have prediabetes.
Over the years, a number of landmark clinical studies have been published in the diabetes space and shaped how we treat the disease today. Here are 10 studies involving diabetes every pharmacist should know: 1. UGDP (1970)1
Launched in 1960, UGDP was one of the first large-scale, randomized clinical trials implemented in the United States. It aimed to evaluate the effectiveness of long-term antidiabetic medications in preventing or delaying vascular complications of diabetes.
A total of 823 patients 53 years, on average, were randomized into tolbutamide (a sulfonylurea), insulin standard, insulin variable, or placebo groups. Treatment with phenormin (a biguanuide) was added 18 months after recruitment was started for the other agents.
Because of an excess of cardiovascular (CV) deaths in patients treated with tolbutamide, investigators terminated this study aim before the end of follow-up. Approximately 2 years later, they also discontinued the recommendation that patients take phenformin because of higher all-cause and CV mortality.
The 2 insulin arms were continued to the end of patient follow-up, but neither were any more effective than placebo in prolonging life or delaying the onset and development of vascular complications. Conclusion
Neither insulin nor the oral hypoglycemic agents assessed provided greater protection against vascular complications than diet alone. Tolbutamide and phenformin were associated with higher mortality. 2. UKPDS (1998)2,3
Prompted by UGDP’s results, this was the largest and longest study ever conducted in type 2 diabetes (T2D) patients.
It recruited 5102 newly diagnosed T2D patients in 23 centers within the United Kingdom between 1977 and 1991. Patients were followed for 10 years, on average, to determine the effect of intensive glycemic control on the incidence of vascular complications and compare the advantages and disadvantages of different antidiabetic medications (metformin, sulfonylureas, insulin). Benefits of different blood pressure (BP) targets with ACE inhibitor or beta-blocker use were also assessed.
The results showed a 25% risk reduction in microvascular endpoints in the treatment-intensive group (median HbA1C 7%) versus the conventional-treatment group (HbA1C 7.9%). Although there was a trend towards reduced macrovascular complications, it didn’t reach statistical significance. The intensive group saw more hypoglycemic episodes and weight gain than the conventional group.
No differences were detected in the rates of myocardial infarction (MI) or diabetes-related death between participants assigned sulfonylureas or insulin therapies.
In the subgroup of overweight subjects, patients assigned to intensive therapy with metformin had decreased risks of diabetes-related complications and all-cause mortality versus diet alone; this wasn’t seen with insulin or sulfonylurea treatment.
Tight BP control reduced both diabetes-related morbidity and mortality, with each reaching statistical significance. Differences in BP were comparable between the different antihypertensives used. Conclusion
Intensive glycemic control (median HbA1C 7%) in T2D was associated with a reduction in microvascular complications, but there was no statistically significant effect on macrovascular disease or mortality. 3. ADVANCE (2009)4
This trial’s purpose was to build on information from UKPDS to determine whether a more intensive HbA1C goal ≤6.5% would provide additional benefit in reducing vascular disease risk and further investigate BP control benefit in diabetics.
This randomized, controlled trial of more than 11,000 T2D patients was conducted at 215 collaborating centers in 20 countries with a median 5-year follow-up duration.
At the end of the follow-up period, mean HbA1C values were 6.5% in the intensive-control group and 7.3% in the standard-control group. In the treatment-intense group, there was a statistically significant 10% reduction in a composite of macrovascular and microvascular events. The main contributor to this reduction was a 21% relative reduction in the risk of new or worsening nephropathy; there was no evidence of a reduction in macrovascular events.
There were no significant differences between the 2 groups in deaths, but hospitalization and severe hypoglycemia were more frequent in the intensive-control group.
For the BP analysis, use of perindopril and indapamide showed a reduction in the risks of major vascular events and death, regardless of initial BP. Conclusion
Intensive glycemic control targeting HbA1C ≤6.5% improved microvascular outcomes but had no impact on macrovascular outcomes in T2D patients. Increased hospitalized and severe hypoglycemia were potential complications of intensive control. 4. ACCORD (2008)5
This was designed to determine whether a therapeutic strategy targeting HbA1C <6% would reduce the rate of CV events (vs. HbA1C 7% to 7.9%) in adults with T2D and either established CV disease or additional CV risk factors.
A total of 10,251 men and women (median age 62 years, median HbA1C 8.1%) were randomly assigned to either the intensive-therapy group or the standard-therapy group.
Stable median HbA1C 6.4% and 7.5% were achieved in the 2 groups at 1 year and maintained throughout the follow-up period. After a median follow-up of 3.7 years, the trial was stopped early because intensive glycemic control was associated with increased all-cause and CV mortality. Compared with the standard-therapy group, the intensive-therapy group also had significantly higher rates of hypoglycemia, weight gain, and fluid retention. Conclusion
A more intensive glycemic target (HbA1C <6.0%) increased mortality versus standard control (7%, 7.9%). 5. VADT (2009)6,7
Several trials previously conducted in T2D patients examined the impact of intensive glycemic therapy on macrovascular and microvascular outcomes, but their results were mixed. VADT further compared the effects of intensive and standard glucose control on CV events.
From December 2000 to May 2003, 1791 patients (mean age 60.4 years, mean HbA1C 9.4%) were enrolled in the study, with follow-up ending on May 30, 2008. Participants were randomized to intensive or standard glucose control.
At a median 5.6 years of follow-up, the intensive-therapy group had a lower HbA1C than the standard therapy group (6.9% vs. 8.4%), but no significant differences were found in time to first CV event. Minimal effects were seen in microvascular complications in the intensive-control group.
The most common adverse event was hypoglycemia, with significantly more episodes occurring in the intensive-therapy group than the standard-therapy group.
In a post-hoc analysis, intensive treatment resulted in a mortality benefit when initiated within 15 years of diabetes diagnosis, but was less beneficial and possibly harmful in those with longer-duration diabetes. Conclusion
Intensive glycemic control has minimal impact on both macrovascular and microvascular endpoints in T2D, although it may be beneficial in those with a shorter disease duration. 6. 10-Year Follow-Up Studies on UKPDS and VADT (2008, 2015)8,9
The 10-year UKPDS follow-up study examined 7 specified aggregate clinical outcomes on an intention-to-treat basis.
Despite loss of HbA1C differences between groups at 1 year, continued reduction in microvascular risk was observed during the 10 years of follow-up. Additionally, risk reductions in MI and all-cause death were observed. A continued benefit after metformin therapy was also seen among overweight patients.
In the 10-year VADT follow-up, the intensive-therapy group had a significantly lower risk in time to first major CV event than the standard-therapy group. No reductions were seen in the secondary endpoints of CV mortality and all-cause mortality. Conclusion
There was a CV benefit with intensive glycemic therapy at 10-year follow-up, but no reduction in CV mortality. 7. PROactive (2005)10
This prospective, randomized, controlled trial assessed the effect of pioglitazone on the secondary prevention of macrovascular events in high-risk T2D patients.
A total of 5238 T2D patients with evidence of macrovascular disease were assigned to pioglitazone or placebo to be taken in addition to their glucose-lowering drugs and other medications.
The primary endpoint (composite of all-cause mortality, nonfatal MI, stroke, acute coronary syndrome, and several other endpoints) didn’t reach statistical significance. The main secondary endpoint (composite of all-cause mortality, nonfatal MI, and stroke) was significantly lower in the pioglitazone group. Slightly more participants taking pioglitazone were hospitalized for heart failure (HF). Conclusion
In high-risk T2D patients, pioglitazone didn’t reduce the risk of the primary macrovascular endpoint. However, there was a significant reduction in the main CV secondary endpoint. 8. EMPA-REG OUTCOMES (2015)11
This was designed to examine the effects of empagliflozin on CV morbidity and mortality in T2D patients at high risk for CV events.
It randomized 7020 patients to daily oral empagliflozin 10 mg or 25 mg or placebo. The median treatment duration was 2.6 years, and median observation time was 3.1 years.
Empagliflozin was associated with a reduction in the primary outcome (composite of death from CV causes, nonfatal MI, or nonfatal stroke). It also resulted in significantly lower risk of death from CV causes, death from any cause, and HF hospitalization. Small reductions were seen in weight, waist circumference, and systolic and diastolic BP in those treated with empagliflozin versus placebo. Conclusion
Empagliflozin reduced the rate of CV events among T2D patients at high CV risk. 9. LEADER (2016)12
This multicenter, double-blind, placebo-controlled trial investigated the CV safety of liraglutide over a period of up to 5 years.
It enrolled more than 9000 adults from 410 sites in 32 countries. The primary composite outcome in the time-to-event analysis was the first occurrence of death from CV causes, nonfatal MI, or nonfatal stroke.
The liraglutide group had a statistically lower risk of the primary outcome. There was also a lower risk of death from CV causes, death from any cause, and microvascular events. Conclusion
T2D patients treated with liraglutide had significant reductions in CV events versus placebo. 10. The North American Comparator Trial (2013)13
This was conducted to determine differences in accuracy between the Contour Next EZ blood glucose monitoring system (BGMS) and 4 other BGMSs (Accu-Chek Aviva, FreeStyle Freedom Lite, One Touch Ultra 2, and True-Track).
Up to 3 capillary blood samples were collected from 146 subjects with and without diabetes. BGMS accuracy was compared using mean absolute relative difference (MARD) and other analyses.
Across tested glucose levels, Contour EZ had the lowest MARD (4.7%); Accu-Chek, FreeStyle, One Touch, and True-Track had MARD values of 6.3%, 18.3%, 23.4%, and 26.2%, respectively. For samples with glucose concentrations <70 mg/dL, Contour EZ also had the lowest MARD. Conclusion
Contour Next EZ meter was the most accurate BGMS assessed. References
- Meinert CL, et al. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results. Diabetes. 1970;19(suppl):789-830.
- 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;352:837-853.
- UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317(7160):703-713.
- Patel A, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24): 2560– 2572.
- Gerstein HC, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008. 358(24):2545-2559.
- Duckworth W, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129-139.
- Duckworth WC, et al. The duration of diabetes affects the response to intensive glucose control in type 2 subjects: the VA Diabetes Trial. J Diabetes Complications 2011;25(6):355-361.
- Holman RR, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577-1589.
- Hayward RA, et al. Follow-up of glycemic control and CV outcomes in type 2 diabetes. N Engl J Med. 2015;372(23):2197-2206.
- Dormandy JA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005. 366(9493):1279-1289.
- Zinman B, et al. Empagliflozin, CV outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015. 373(22):2117-2128.
- Marso SP, et al. Liraglutide and CV outcomes in type 2 diabetes. N Engl J Med. 2016 Jun 13.
- Halldorsdottir S, et al. Accuracy evaluation of five blood glucose monitoring systems: the orth American comparator trial. J Diabetes Sci Technol. 2013;7(5):1294-1304.