What we learned from the UKPDS
Between its inception in 1977 and 2018 – the 20th anniversary of the publication of its primary findings – the UKPDS has generated an astonishing 93 original research papers. Here, we give an overview of all these papers, showcasing the vast breadth and depth of knowledge obtained from this seminal trial.
The primary findings: blood glucose and blood pressure
On 12th September 1998, the UKPDS investigators published five papers covering their primary findings. The two papers in The Lancet showed that intensive glycemic control with sulfonylureas or insulin significantly reduced the risk for microvascular outcomes, albeit with an increased hypoglycemic risk, but not macrovascular outcomes, and that metformin treatment in obese patients reduced the risk for combined micro- and macrovascular outcomes, as well as diabetes-related and all-cause mortality [1,2].
The three papers in The BMJ showed that controlling blood pressure in patients with type 2 diabetes resulted in a significant reduction in micro- and macrovascular outcomes and in mortality, irrespective of the specific medication used, and had a favorable cost–effectiveness ratio [3–5].
And in 2008, the team published two papers in The New England Journal of Medicine revealing what had happened over the 10 years after the randomized treatment period, when patients resumed standard clinical care. This revealed a “legacy” effect of the period of tight glucose control, with patients formerly in the intensive group continuing to have a significantly reduced risk for microvascular complications, in addition to which the previously nonsignificant reduction in macrovascular outcomes attained significance . There was no such effect for blood pressure, however .
Characterizing patients with newly diagnosed diabetes
The UKPDS enrolled 3867 patients, presenting the investigators with a unique opportunity to characterize a large number of people with newly diagnosed diabetes. They learned the following.
- Participants were more likely to be male, but the female participants were more obese .
- Being a UK study, 83% of the participants were unsurprisingly of European ethnicity.
- However, Asian and Afro-Caribbean participants were younger than the Europeans, and Afro-Caribbeans had the highest fasting plasma glucose levels and more severely impaired beta‐cell function, although they were more insulin-sensitive .
About their diet
- Participants on the whole consumed less fat relative to the general UK population, but more protein, with carbohydrate intake being on a par.
- Energy intake appeared to be reduced relative to the general population, but the investigators suspected this to be an effect of inaccurate self-reporting .
- Forty percent of men and 53% of women had hypertension, going by the then accepted threshold of 160/95 mmHg, but only 23% and 42%, respectively, had previously been diagnosed, and just 12% and 26% were taking antihypertensive medication .
About biochemical factors
- The majority of participants had markedly reduced insulin sensitivity and only moderately impaired beta-cell function, in line with the high prevalence of obesity, although a minority were lean with significant beta-cell impairment .
- The participants, particularly the female ones, had a poorer lipid profile than people without diabetes, characterized by high triglycerides and low levels of high-density lipoprotein cholesterol .
- They had elevated levels of albumin in the urine .
- Leptin levels did not differ by ethnicity, but correlated positively with fasting plasma insulin concentrations .
And their association with existing complications
- Existing micro- and macrovascular complications were not associated with each other and were individually associated with specific risk factors; for example, stroke with hypertension and retinopathy with hyperglycemia .
- Markers of renal damage were associated with the degree of hyperglycemia (in the case of urinary N-acetylglucosaminidase excretion) and hypertension (in the case of urinary albumin excretion) .
|Did you know?|
The investigators had to change the numbering system on the UKPDS publications, for obvious practical reasons.
“If you look at all the early ones, we started using Roman numerals,” says UKPDS investigator David Matthews (University of Oxford, UK). “We’d have been in deep trouble now!”
The progression of type 2 diabetes
The UKPDS participants underwent comprehensive assessments at baseline and every 3 years during the 10-year randomized phase of the study. The fact that the glucose and blood pressure targets were considerably more relaxed than they are nowadays gave the investigators insights into the natural history of type 2 diabetes:
- Diabetes progressed irrespective of efforts to control blood glucose, with the proportion of patients achieving control with their allocated monotherapy declining over time .
- Likewise, nearly half of patients taking sulfonylureas required an additional medication within 6 years of starting treatment .
- However, urinary albumin excretion barely changed over 3 years in the dietary intervention group, suggesting that diabetic nephropathy is a slowly evolving process .
The influence of baseline factors
- Ethnicity did not influence glycemic control during follow-up, but Caucasian patients put on the most weight while Afro-Caribbeans had the largest increases in systolic blood pressure but more favorable changes in lipid profiles .
- Age at diagnosis had variable effects on the likelihood of complications being present at baseline and occurring during follow-up. For example, myocardial infarction and neuropathy were more likely to be present in older patients at baseline, whereas retinopathy was not but occurred more frequently in older patients during follow-up .
The role of autoantibodies
Although type 2 diabetes is not perceived as an autoimmune process, a substantial proportion of patients do have islet autoantibodies, potentially identifying patients who actually have latent autoimmune diabetes in adults (LADA). Several UKPDS publications focused on the predictive power of autoantibodies and found the following:
- Autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase were most common in younger patients (21–34% of those ≤65 years) and these patients had a relatively low BMI and a high level of glycated hemoglobin (HbA1c), consistent with autoimmune-driven disease.
- The majority of these patients became insulin-dependent within 6 years .
- Autoantibodies to protein tyrosine phosphatase IA-2 were very rare but highly predictive of insulin dependence .
- Autoantibody-positive patients initially responded well to intensive pharmacologic treatment, despite the rapid progression to insulin dependence .
- The SOX‐13 autoantigen did not distinguish between type 1 diabetes patients (from the Fremantle Diabetes Study) and UKPDS participants and is likely a “non‐specific marker of tissue damage associated with chronic hyperglycaemia” .
Control of blood glucose
The UKPDS used the only three classes of antidiabetes medication that were available at the time, in addition to dietary intervention, and the continued progression of diabetes in most patients meant that many ended up on combination therapy.
- Three months of dietary intervention resulted in near normalization of blood glucose and corresponding improvements in lipid profiles, but only for 16% of patients, and this was related to energy restriction rather than to bodyweight [27,28].
- Acarbose significantly improved glycemic control over 3 years versus placebo, whether given alongside diet, metformin, insulin, a sulfonylurea, or a combination .
- Adding metformin to a sulfonylurea improved glycemic control during 3 years of treatment without resulting in more hypoglycemia .
- And the same was true when adding insulin to a sulfonylurea during 6 years of treatment .
Comparative efficacy over time
- After 1 year of follow-up, efficacy and hypoglycemic risk appeared similar for sulfonylureas and insulin, although both were associated with weight gain relative to diet alone .
- Changes in fasting plasma glucose correlated with changes in HbA1c, regardless of treatment allocation .
- The medications (including metformin) had comparable efficacy at the 3-, 6-, and 9-year reports, but only a minority of patients achieved glycemic control and by 6 years up to two-thirds of the patients had required intensification of therapy merely to achieve glucose levels below 15 mmol/L [34–36].
- Hypoglycemia rates were generally low, but were elevated in patients taking sulfonylureas and highest of all in those using insulin .
Associations with diabetes subtypes
- Two papers strengthened the evidence that LADA and type 1 diabetes are closely related, with the HLA-DRB1 and HLA-DQB1 susceptibility genes and variation within the insulin gene region conferring susceptibility to both subtypes [38,39].
- In line with this, HLA-DRB1 and HLA-DQB1 were most common in younger UKPDS participants and were associated with the presence of islet autoantibodies .
- The butyrylcholinesterase gene K variant and variants in the sarco(endo)plasmic reticulum Ca2+-transport ATPase gene were associated with type 2 diabetes [41,42].
- But variants in the beta‐cell ATP‐sensitive K‐channel genes SUR1 and Kir6.2 were not linked to diabetes .
- MODY3 variants and a mutation in the tRNALeu(UUR) gene were very rare contributors to type 2 diabetes risk in the UKPDS population [44,45].
- The insulin receptor substrate-1 gene was associated with insulin resistance in people with diabetes, whereas the β3-adrenergic-receptor gene was associated with obesity .
Associations with complications
- Variants in the paraoxonase 2 gene had “at best, a small effect” on the risk for developing renal dysfunction .
- But one variant of the angiotensin-converting enzyme gene was associated with more severe microalbuminuria and another with an increased risk for myocardial infarction, with the effect strongest in people with low cholesterol levels [48,49].
|Did you know?|
Many UKPDS publications, including the landmark 1998 papers, were attributed to the “UKPDS Group,” with no individual authors mentioned.
“But that’s damaging to people’s CVs,” says Matthews. “So you’ll see that Group disappears and we bother to put people’s names on, which I think is right, and I think the original papers should have had a large number of authors on them.
“That would have been the better thing to do, because I don’t think that anonymity helps anyone. People need to take responsibility for what they’ve written.”
The long-term consequences of diabetes
A vital factor underpinning the importance of the UKPDS was simply that no one had previously monitored such a large cohort of patients with newly diagnosed diabetes for so long, so seemingly simple questions like how many patients develop nephropathy over time were unanswered.
Incidence and progression of microvascular complications
- Evidence of retinopathy was already present in around a third of UKPDS participants at baseline, and was associated with higher blood glucose and blood pressure .
- The overall prevalence of nephropathy was around 7%, but this rose to 25% during 10 years of follow-up, with around 2–3% of patients annually developing the first signs of nephropathy or progressing to a more severe stage .
The effects of blood glucose and blood pressure control
The mission statement of the UKPDS was to examine the effect of blood glucose (and later blood pressure) control on the incidence of micro- and macrovascular complications of diabetes. This resulted in the landmark papers published in 1998 and 2008, but also in a large number of other publications looking at additional factors influencing patients’ risk for these outcomes. Two notable papers in The BMJ in 2000 [52,53] looked at the relationships between cumulative blood glucose and blood pressure exposure during follow-up and outcomes, irrespective of treatment allocation.
- There was a linear relationship between systolic blood pressure and outcomes, with higher pressure conferring greater risk for both microvascular outcomes and myocardial infarction (the most frequent macrovascular outcome).
- The lowest risk was observed at blood pressures below 120 mmHg .
- The same was true for blood glucose, although the effect was stronger for microvascular outcomes, with the effect on myocardial infarction plateauing at an HbA1c of 9–10%.
- The lowest risk was observed at HbA1c levels below 6% .
- Baseline levels also played a part, with lower baseline glucose equating to lower risk during follow-up, despite a similar deterioration in glycemic control as seen for higher baseline glucose .
- The protective effects against macrovascular outcomes, largely myocardial infarction, were confirmed in a meta-analysis also involving the ACCORD, ADVANCE, and VADT trials .
- A more recent individual participant data meta-analysis involving the same trials confirmed the same for nephropathy and retinopathy .
- The effects of both approaches were additive, ie, patients receiving both intensive glucose control and intensive blood pressure control did better than those allocated to one or neither .
- Effects to achieve tight glucose or blood pressure did not impair patients’ quality of life, but developing microvascular complications or hypoglycemia did [58,59].
Intensive treatment and retinopathy
As the most frequent microvascular outcome, retinopathy was explored in more detail in two other papers.
- Blood pressure control markedly reduced the risk for all measures of retinopathy and its severity, up to and including blindness .
- The duration of hyperglycemia was as important as its severity for predicting the risk for photocoagulation .
Other influences on…
- The development of renal impairment and albuminuria were both associated with baseline systolic blood pressure, urinary albumin, plasma creatinine, and Indian-Asian ethnicity, but the individual endpoints were also associated with distinct sets of other risk factors, suggesting the two are “not linked inexorably” in diabetes patients .
- Besides blood pressure and glucose, not smoking was “somewhat counter-intuitively” associated with an increased risk of both the development and progression of retinopathy, and older age and male sex were associated with progression .
- The need for photocoagulation was very rare – just 2.6% over 9 years of follow-up – although the risk was markedly higher among patients with retinopathy at baseline; baseline micro-aneurysms were highly predictive of progression during follow-up [64,65].
…peripheral vascular disease
- Pre-existing cardiovascular disease and current smoking were the strongest independent predictors of peripheral vascular disease, but older age, higher HbA1c, higher systolic blood pressure, and lower high-density lipoprotein cholesterol were also predictive .
- Of the ethnic groups in the UKPDS, people of Afro-Caribbean ethnicity had the lowest risk for most vascular endpoints and Asian Indians had the highest risk over the long-term [67,68].
- For metabolic factors, neither hyperinsulinemia nor insulin sensitivity at baseline were significantly associated with macrovascular risk, but hyperglycemia was, as was the presence of the metabolic syndrome [69–71].
- Stroke risk was associated with baseline age, male sex, hypertension, and atrial fibrillation .
- Coronary heart disease was likewise associated with high blood pressure, and also with high levels of low-density lipoprotein cholesterol, triglycerides, fasting plasma glucose, and HbA1c. There was also a relationship with low levels of high-density lipoprotein cholesterol, and with a history of smoking .
- Subclinical myocardial infarction at baseline was associated with fatal myocardial infarction during follow-up, as were older age, higher blood pressure, higher urine albumin level, and higher HbA1c levels; the last factor was also associated with fatal (vs nonfatal) stroke [74,75].
- The predictive power of the cardiovascular risk marker homocysteine might be underestimated by half over 10 years, because of intra-individual variation in levels over time .
The predictive models that emerged
The wealth of data from the UKPDS allowed the investigators to develop predictive models to help guide the management of patients with type 2 diabetes. They released the following:
- The UKPDS Risk Engine, for predicting coronary heart disease and stroke [77,78].
- The UKPDS Outcomes Model: seven equations to predict cardiovascular disease, cerebrovascular disease, amputation, blindness, nephropathy, risk factor progression, and mortality .
- The investigators validated the model using the post-trial follow-up data, and then further developed the model to include these follow-up data [80,81].
- The trial data were also used to produce a method to estimate life expectancy in people with type 2 diabetes .
The economics of diabetes management
The UKPDS investigators produced the following data relating to healthcare economics:
- Inpatient and non-inpatient costs for a range of diabetes complications including nonfatal and fatal stroke and myocardial infarction, heart failure, and blindness in one eye – calculated from the original randomized trial and then updated based on the post-trial monitoring data [83,84].
- The finding that intensive blood glucose control increased treatment costs, but also reduced the cost of complications and extended the time patients spent free of those complications .
- That the total costs of blood pressure treatment were less for the beta blocker atenolol than for the angiotensin-converting enzyme inhibitor captopril but the treatments were equally effective .
- The treatments used in the UKPDS to control blood glucose and blood pressure had acceptable costs per quality-adjusted life–year, with metformin actually reducing costs while extending life expectancy [87,88].
- Extrapolated to the population of England, the costs of intensively treating all diabetes patients with the trial medications were equivalent to “a small fraction of the NHS's spending plans” .
And there were several other one-off papers, covering subjects ranging from pregnancy to the appropriate use of aspirin, that do not entirely fit into a theme. The findings are summarized below:
- The 16 women who became pregnant during the UKPDS had very poor outcomes, with just eight of the pregnancies leading to live births; there were five miscarriages, two terminations, and one intrauterine death .
- Most patients with pre-existing cardiovascular disease were taking aspirin, but two-thirds of those without were not, despite being at high cardiovascular risk .
- Less than half of the patients who died during the trial had diabetes noted on their death certificates .
- There was no evidence that improving or not improving people’s health affected the quality of neighborhood in which they resided .
medwireNews is an independent medical news service provided by Springer Healthcare. © 2018 Springer Healthcare part of the Springer Nature group
- 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: 837–853 https://doi.org/10.1016/S0140-6736(98)07019-6
- UKPDS Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854–865 https://doi.org/10.1016/S0140-6736(98)07037-8
- UKPDS Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703–713 https://doi.org/10.1136/bmj.317.7160.703
- UKPDS Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes. BMJ 1998; 317: 713–720 https://doi.org/10.1136/bmj.317.7160.713
- UKPDS Group. Cost effectiveness analysis of improved blood pressure control in hypertensive patients with type 2 diabetes. BMJ 1998; 317: 720–726 https://doi.org/10.1136/bmj.317.7160.720
- Holman RR, Paul SK, Bethel MA, et al. 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Engl J Med 2008; 359: 1577–1589 https://www.nejm.org/doi/10.1056/NEJMoa0806470
- Holman RR, Paul SK, Bethel MA, et al. Long-Term Follow-up after Tight Control of Blood Pressure in Type 2 Diabetes. N Engl J Med 2008; 359: 1565–7156 https://www.nejm.org/doi/10.1056/NEJMoa0806359
- UKPDS Study Group. Characteristics of newly-presenting type 2 diabetic patients: male preponderance and obesity at different ages. Diabet Med 1988; 5: 154–159 https://doi.org/10.1111/j.1464-5491.1988.tb00963.x
- Meyer LC, Manley SE, Frighi V, et al. UK Prospective Diabetes Study. XII: Differences between Asian, Afro-Caribbean and white Caucasian type 2 diabetic patients at diagnosis of diabetes. Diabet Med 1994; 11: 670–677 https://doi.org/10.1111/j.1464-5491.1994.tb00331.x
- UKPDS Group. UKPDS 18: estimated dietary intake in type 2 diabetic patients randomly allocated to diet, sulphonylurea or insulin therapy. Diabet Med 1996; 13: 656–662 https://doi.org/10.1002/(SICI)1096-9136(199607)13:7%3C656::AID-DIA131%3E3.0.CO;2-5
- UKPDS Study Group. United Kingdom Prospective Diabetes Study. III. Prevalence of hypertension and hypotensive therapy in patients with newly diagnosed diabetes. A multicenter study. Hypertension 1985; 7: 11–13 https://www.ahajournals.org/doi/10.1161/01.HYP.7.6_Pt_2.II8
- UKPDS Study Group. Characteristics of newly presenting type 2 diabetic patients: estimated insulin sensitivity and islet beta-cell function. Diabet Med 1988; 5: 444–448 https://doi.org/10.1111/j.1464-5491.1988.tb01025.x
- UKPDS Group. U.K. Prospective Diabetes Study 27. Plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex. Diabetes Care 1997; 20: 1683–1687 https://doi.org/10.2337/diacare.20.11.1683
- Manley SE, Meyer LC, Neil HAW, et al. UK Prospective Diabetes Study (UKPDS). XI: Biochemical risk factors in type 2 diabetic patients at diagnosis compared with age-matched normal subjects. Diabet Med 1994; 11: 534–544 https://doi.org/10.1111/j.1464-5491.1994.tb02032.x
- UKPDS Group. UKPDS 20: plasma leptin, obesity, and plasma insulin in type 2 diabetic subjects. J Clin Endocrinol Metab 1997; 82: 654–657 https://doi.org/10.1210/jcem.82.2.3744
- UKPDS Study Group. UK Prospective Diabetes Study 6. Complications in newly diagnosed type 2 diabetic patients and their association with different clinical and biochemical risk factors. Diabet Res 1990; 13: 1–11 https://www.ncbi.nlm.nih.gov/pubmed/2097090
- UKPDS Study Group. UK Prospective Diabetes Study (UKPDS). IX: Relationships of urinary albumin and N-acetylglucosaminidase to glycaemia and hypertension at diagnosis of type 2 (non-insulin-dependent) diabetes mellitus and after 3 months diet therapy. Diabetologia 1993; 36: 835–842 https://link.springer.com/article/10.1007/BF00400359
- Turner RC, Cull CA, Frighi V, Holman RR. Glycemic Control With Diet, Sulfonylurea, Metformin, or Insulin in Patients With Type 2 Diabetes Mellitus: Progressive Requirement for Multiple Therapies (UKPDS 49). JAMA 1999; 281: 2005–2012 https://jamanetwork.com/journals/jama/fullarticle/190204
- Matthews DR, Cull CA, Stratton IM, et al. UKPDS 26: Sulphonylurea failure in non-insulin-dependent diabetic patients over six years. Diabet Medicine 1998; 15: 297–303 https://doi.org/10.1002/(SICI)1096-9136(199804)15:4%3C297::AID-DIA572%3E3.0.CO;2-W
- Cull CA, Manley S, Frighi V, et al. UK Prospective Diabetes Study (UKPDS). X. Urinary albumin excretion over 3 years in diet-treated type 2, (non-insulin-dependent) diabetic patients, and association with hypertension, hyperglycaemia and hypertriglyceridaemia. Diabetologia 1993; 36: 1021–1029 https://link.springer.com/article/10.1007/BF02374494
- Davis TM, Cull CA, Holman RR. Relationship between ethnicity and glycaemic control, lipid profiles and blood pressure during the first nine years of Type 2 diabetes. Diabetes Care 2001; 24: 1167–1173 https://doi.org/10.2337/diacare.24.7.1167
- UKPDS Group. U.K. Prospective Diabetes Study 22. Effect of age at diagnosis on diabetic tissue damage during the first 6 years of NIDDM. Diabetes Care 1997; 20: 1435–1441 https://doi.org/10.2337/diacare.20.9.1435
- UKPDS Group. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. Lancet 1997; 350: 1288–1293 https://doi.org/10.1016/S0140-6736(97)03062-6
- Bottazzo GF, Bosi E, Cull CA, et al. IA-2 antibody prevalence and risk assessment of early insulin requirement in subjects presenting with type 2 diabetes. Diabetologia 2005; 48: 703–708 https://link.springer.com/article/10.1007%2Fs00125-005-1691-9
- Davis TME, Wright AD, Mehta ZM, et al. Islet autoantibodies in clinically diagnosed type 2 diabetes: prevalence and relationship with metabolic control. Diabetologia 2005; 48: 695–702 https://link.springer.com/article/10.1007%2Fs00125-005-1690-x
- Davis TM, Mehta Z, Mackay IR, et al. Autoantibodies to the islet cell antigen SOX-13 are associated with duration but not type of diabetes. Diabet Med 2003; 20: 198–204 https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1464-5491.2003.00897.x
- UKPDS Study Group. Response of fasting plasma glucose to diet therapy in newly-presenting Type 2 diabetic patients. Metabolism 1990; 39: 905–912 https://doi.org/10.1016/0026-0495(90)90299-R
- Manley SM, Stratton IM, Cull CA, et al. Effects of three months' diet after diagnosis of type 2 diabetes on plasma lipids and lipoproteins. Diabet Med 2000; 17: 518–523 https://doi.org/10.1046/j.1464-5491.2000.00320.x
- Holman RR, Cull CA, Turner RC. Randomised, double-blind trial of acarbose in type 2 diabetes shows improved glycaemic control over three years. Diabetes Care 1999; 22: 960–964 https://doi.org/10.2337/diacare.22.6.960
- UKPDS Group. UKPDS 28: a randomized trial of efficacy of early addition of metformin in sulfonylurea-treated type 2 diabetes. Diabetes Care 1998; 21: 87–92 https://doi.org/10.2337/diacare.21.1.87
- Wright A, Burden ACF, Paisey RB, et al. Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care 2002; 25: 330–336 https://doi.org/10.2337/diacare.25.2.330
- UKPDS Study Group. UK prospective study of therapies of maturity-onset diabetes. I. Effect of diet, sulphonylurea, insulin or biguanide therapy on fasting plasma glucose and body weight over one year. Diabetologia 1983; 24: 404–411 https://link.springer.com/article/10.1007%2FBF00257337
- UKPDS Study Group. U.K. prospective diabetes study. II. Reduction in HbA1c with basal insulin supplement, sulfonylurea, or biguanide therapy in maturity-onset diabetes. A multicenter study. Diabetes 1985; 34: 793–798 https://doi.org/10.2337/diab.34.8.793
- Holman RR, Cull CA, Fox C, Turner RC. Relative Efficacy of Randomly allocated Diet, Sulphonylurea, Insulin, or Metformin in Patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ 1995; 310: 83–88 https://doi.org/10.1136/bmj.310.6972.83
- UKPDS Group. United Kingdom Prospective Diabetes Study 24: a 6-year, randomized, controlled trial comparing sulfonylurea, insulin, and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy. Ann Intern Med 1998; 128: 165–175 http://annals.org/aim/article-abstract/711134/united-kingdom-prospective-diabetes-study-24-6-year-randomized-controlled?doi=10.7326%2f0003-4819-128-3-199802010-00001
- UKPDS Group. United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non-insulin-dependent diabetes mellitus. Ann Intern Med 1996; 124: 136–145 http://annals.org/aim/article-abstract/709358/united-kingdom-prospective-diabetes-study-17-9-year-update-randomized?doi=10.7326%2f0003-4819-124-1_Part_2-199601011-00011
- Wright AD, Cull CA, Macleod KM, Holman RR. Hypoglycemia in Type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73. J Diabetes Complications 2006; 20: 402–408 https://doi.org/10.1016/j.jdiacomp.2005.08.010
- Desai M, Zeggini E, Horton VA. An association analysis of the HLA gene region in latent autoimmune diabetes in adults. Diabetologia 2007; 50: 68–73 https://link.springer.com/article/10.1007%2Fs00125-006-0513-z
- Desai M, Zeggini E, Horton VA, et al. The Variable Number of Tandem Repeats Upstream of the Insulin Gene Is a Susceptibility Locus for Latent Autoimmune Diabetes in Adults. Diabetes 2006; 55: 1890–1894 https://doi.org/10.2337/db06-0089
- Horton VA, Stratton IM, Bottazzo GF, et al. Genetic heterogeneity of autoimmune diabetes: age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes (UKPDS 43). UK Prospective Diabetes Study (UKPDS) Group. Diabetologia 1999; 42: 608–616 https://link.springer.com/article/10.1007%2Fs001250051202
- Hashim Y, Shepherd D, Wiltshire S, et al. Butyrylcholinesterase K variant on chromsome 3q is associated with Type II diabetes in white Caucasian subjects. Diabetologia 2001; 44: 2227–2230 https://link.springer.com/article/10.1007%2Fs001250100033
- Varadi A, Lebel L, Hashim Y, et al. Sequence variants of the sarco(endo)plasmic reticulum Ca2+-transport ATPase 3 gene (SERCA3) are associated with Type 2 diabetes in Caucasians. Diabetologia 1999; 42: 1240–1243 https://link.springer.com/article/10.1007%2Fs001250051298
- Gloyn AL, Hashim Y, Ashcroft SJ, et al. Association studies of variants in promoter and coding regions of beta-cell ATP-sensitive K-channel genes SUR1 and Kir6.2 with Type 2 diabetes mellitus (UKPDS 53). Diabet Med 2001; 18: 206–212 https://doi.org/10.1046/j.1464-5491.2001.00449.x
- Cox RD, Sotham L, Hashim Y, et al. Hepatocyte nuclear factor-1alpha (the MODY3 gene) mutations in late onset Type 2 diabetes in the UK. Diabetes 1999; 42: 120–121 https://link.springer.com/article/10.1007%2Fs001250051127
- Saker PJ, Hattersley AT, Barrow B, et al. UKPDS 21: low prevalence of the mitochondrial transfer RNA gene (tRNA(Leu(UUR))) mutation at position 3243bp in UK Caucasian type 2 diabetic patients. Diabet Med 1997; 14: 42–45 https://doi.org/10.1002/(SICI)1096-9136(199701)14:1%3C42::AID-DIA295%3E3.0.CO;2-T
- Zhang Y, Wat N, Stratton IM, et al. UKPDS 19: Heterogeneity in NIDDM: separate contributions of IRS-1 and b3-adrenergic-receptor mutations to insulin resistance and obesity respectively with no evidence for glycogen synthase gene mutations. Diabetologia 1996; 39: 1505–1511 https://link.springer.com/article/10.1007%2Fs001250050605
- Calle R, McCarthy MI, Banerjee P, et al. Paraoxonase2 (PON2) Polymorphisms and Development of Renal Dysfunction in Type 2 Diabetes: UKPDS 76. Diabetologia 2006; 49: 2892–2899 https://link.springer.com/article/10.1007%2Fs00125-006-0436-8
- Dudley CRK, Keavney B, Stratton IM, Turner RC. U.K. Prospective Diabetes Study XV: Relationship of renin-angiotensin system gene polymorphisms with microalbuminuria in NIDDM. Kidney Int 1995; 48: 1907–1911 https://doi.org/10.1038/ki.1995.490
- Keavney BD, Dudley CRK, Stratton IM, et al. UK prospective diabetes study (UKPDS) 14: association of angiotensin-converting enzyme insertion/deletion polymorphism with myocardial infarction in NIDDM. Diabetologia 1995; 38: 948–952 https://link.springer.com/article/10.1007%2FBF00400584
- UKPDS Group. United Kingdom Prospective Diabetes Study, 30: diabetic retinopathy at diagnosis of non-insulin-dependent diabetes mellitus and associated risk factors. Arch Ophthalmol 1998; 116: 297–303 https://jamanetwork.com/journals/jamaophthalmology/fullarticle/261765
- Adler AI, Stevens RJ, Manley SE, et al. Development and progression of nephropathy in type 2 diabetes: The United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003; 63: 225–232 https://doi.org/10.1046/j.1523-1755.2003.00712.x
- Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000; 321: 412–419 https://www.bmj.com/content/321/7258/412
- Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of Type 2 diabetes: prospective observational study. BMJ 2000; 321: 405–412 https://www.bmj.com/content/321/7258/405
- Colagiuri S, Cull CA, Holman RR. Are Lower Fasting Plasma Glucose Levels at Diagnosis of Type 2 Diabetes Associated with Improved Outcomes? Diabetes Care 2002; 25: 1410–1417 https://doi.org/10.2337/diacare.25.8.1410
- Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 2009; 52: 2288–2298 https://link.springer.com/article/10.1007%2Fs00125-009-1470-0
- Zoungas S, Arima H, Gerstein HC, et al. Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials Lancet Diabetes Endocrinol 2017; 5: 431–437 https://doi.org/10.1016/S2213-8587(17)30104-3
- Stratton IM, Cull CA, Adler AI, et al. Additive effects of glycaemia and blood pressure exposure on risk of complications in type 2 diabetes: a prospective observational study (UKPDS 75). Diabetologia 2006; 49: 1761–1769 https://link.springer.com/article/10.1007%2Fs00125-006-0297-1
- UKPDS Group. Quality of life in type 2 diabetic patients is affected by complications but not by intensive policies to improve blood glucose or blood pressure control. Diabetes Care 1999; 22: 1125–1136 https://doi.org/10.2337/diacare.22.7.1125
- Clarke P, Gray A, Holman R. Estimating utility values for health states of type 2 diabetic patients using the EQ-5D. Med Decis Making 2002; 4: 340–349 https://doi.org/10.1177%2F0272989X0202200412
- Matthews DR, Stratton IM, Aldington SJ, et al. Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus. Arch Ophthalmol 2004; 122: 1631–1640 https://jamanetwork.com/journals/jamaophthalmology/fullarticle/416664
- Stevens RJ, Stratton IM, Holman RR. Modeling glucose exposure as a risk factor for photocoagulation in type 2 diabetes. J Diabetes Complications 2002; 16: 371–376 https://doi.org/10.1016/S1056-8727(02)00161-7
- Retnakaran R, Cull CA, Thorne KI, et al. Risk Factors for Renal Dysfunction in Type 2 Diabetes.
Diabetes 2006; 55: 1832–1839 https://doi.org/10.2337/db05-1620
- Stratton IM, Kohner EM, Aldington SJ, et al. UKPDS 50: risk factors for incidence and progression of retinopathy in Type II diabetes over 6 years from diagnosis. Diabetologia 2001; 44: 1546–1163 https://link.springer.com/article/10.1007%2Fs001250051594
- Kohner EM, Stratton IM, Aldington SJ, et al. Relationship between the severity of retinopathy and progression to photocoagulation in patients with Type 2 diabetes mellitus in the UKPDS (UKPDS 52). Diabet Med 2001; 18: 178–184 https://doi.org/10.1046/j.1464-5491.2001.00458.x
- Kohner EM, Stratton IM, Adlington SJ, Turner RC. Microaneurysms in the development of diabetic retinopathy. Diabetologia 1999; 42: 1107–1112 https://link.springer.com/article/10.1007%2Fs001250051278
- Adler AI, Stevens RJ, Neil A, et al. Hyperglycemia and Other Potentially Modifiable Risk Factors for Peripheral Vascular Disease in Type 2 Diabetes. Diabetes Care 2002; 25: 894–899 https://doi.org/10.2337/diacare.25.5.894
- UKPDS Group. Ethnicity and cardiovascular disease. The incidence of myocardial infarction in white, South Asian, and Afro-Caribbean patients with type 2 diabetes (U.K. Prospective Diabetes Study 32) Diabetes Care 1998; 21: 1271–1277 https://doi.org/10.2337/diacare.21.8.1271
- Davis TME, Coleman RL, Holman RR. Ethnicity and long-term vascular outcomes in Type 2 diabetes: a prospective observational study (UKPDS 83). Diabet Med 2014; 31: 200–207 https://doi.org/10.1111/dme.12353
- Adler AI, Neil AW, Manley SE, et al. Hyperglycemia and hyperinsulinemia at diagnosis of diabetes and their association with subsequent cardiovascular disease in the United Kingdom prospective diabetes study (UKPDS 47). https://doi.org/10.1016/S0002-8703(99)70035-9
- Adler AI, Levy JC, Matthews DR, et al. Insulin sensitivity at diagnosis of Type 2 diabetes is not associated with subsequent cardiovascular disease (UKPDS 67). Diabet Med 2004; 22: 306–311 https://doi.org/10.1111/j.1464-5491.2004.01418.x
- Cull CA, Jensen CC, Retnakaran R, Holman RR. Impact of the metabolic syndrome on macrovascular and microvascular outcomes in type 2 diabetes mellitus: United Kingdom Prospective Diabetes Study 78. Circulation 2007; 116: 2119–2126 https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.107.733428
- Davies TME, Millns H, Stratton IM, et al. Risk factors for stroke in non-insulin dependent diabetes mellitus. Arch Intern Med 1999; 159: 1097–1103 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/485034
- UKPDS Group. Risk factors for coronary artery disease in non-insulin dependent diabetes. BMJ 1998; 316: 823–828 https://doi.org/10.1136/bmj.316.7134.823
- Davis TME; Coleman RL; Holman RR. Prognostic Significance of Silent Myocardial Infarction in Newly-Diagnosed Type 2 Diabetes: UKPDS 79. Circulation 2013; 127: 980–987 https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.112.000908
- Stevens RJ, Coleman RL, Adler AI, et al. Risk factors for myocardial infarction case fatality and stroke case fatality in type 2 diabetes: UKPDS 66. Diabetes Care 2004; 27: 201–207 https://doi.org/10.2337/diacare.27.1.201
- Clarke R, Lewington S, Donald A, et al. Underestimation of the importance of homocysteine as a risk factor for cardiovascular disease in epidemiological studies. J Cardiovasc Risk 2001; 8: 363–369 http://journals.sagepub.com/doi/pdf/10.1177/174182670100800605
- Stevens RJ, Kothari V, Adler AI, et al. The UKPDS Risk Engine: a model for the risk of coronary heart disease in type 2 diabetes. Clin Sci 2001; 101: 671–679 http://www.clinsci.org/content/101/6/671
- Kothari V, Stevens RJ, Adler AI, et al. Risk of Stroke in Type 2 Diabetes Estimated by the UK Prospective Diabetes Study Risk Engine. Stroke 2002; 33: 1776–1781 https://www.ahajournals.org/doi/full/10.1161/01.STR.0000020091.07144.C7
- Clarke PM, Gray AM, Briggs A, et al. A model to estimate the lifetime health outcomes of patients with type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS 68). Diabetologia 2004; 47: 1747–1759 https://link.springer.com/article/10.1007%2Fs00125-004-1527-z
- Leal J, Hayes AJ, Gray AM, et al. Temporal Validation of the UKPDS Outcomes Model Using 10-Year Post trial Monitoring Data. Diabetes Care 2013; 36: 1541–1546 https://doi.org/10.2337/dc12-1120
- Hayes AJ, Leal J, Gray AM, et al. UKPDS Outcomes Model 2: a new version of a model to simulate lifetime health outcomes of patients with type 2 diabetes mellitus using data from the 30 year United Kingdom Prospective Diabetes Study: UKPDS 82. Diabetologia 2013; 56: 1925–1933 https://link.springer.com/article/10.1007%2Fs00125-013-2940-y
- Stevens R, Adler A, Gray A, et al. Life-expectancy projection by modelling and computer simulation (UKPDS 46). Diabetes Res Clin Prac 2000; 50: S5–S13 https://doi.org/10.1016/S0168-8227(00)00214-X
- Clarke P, Gray A, Legood R, et al. The impact of diabetes-related complications on healthcare costs: results from the United Kingdom Prospective Diabetes Study (UKPDS Study No 65). Diabet Med 2003; 20:442–450. https://doi.org/10.1046/j.1464-5491.2003.00972.x
- Alva ML, Gray A, Mihaylova B, et al. The impact of diabetes-related complications on healthcare costs: new results from the UKPDS (UKPDS 84). Diabet Med 2015; 32: 459–466 https://doi.org/10.1111/dme.12647
- Gray A, Raikou M, McGuire A, et al. Cost effectiveness of an intensive blood glucose control policy in patients with type 2 diabetes: economic analysis alongside randomised controlled trial (UKPDS 41). BMJ 2000; 320: 1373–1378 https://doi.org/10.1136/bmj.320.7246.1373
- Gray A, Clarke P, Raikou M, et al. An economic evaluation of atenolol versus captopril in patients with Type 2 diabetes. Diabet Med 2001; 18: 438–444 https://doi.org/10.1046/j.1464-5491.2001.00485.x
- Clarke P, Gray A, Adler A, et al. Cost-effective analysis of intensive blood glucose control with metformin in overweight patients with type 2 diabetes (UKPDS 51). Diabetologia 2001; 44: 298–304 https://link.springer.com/article/10.1007%2Fs001250051617
- Clarke PM, Gray AM, Briggs A, et al. Cost-utility analyses of intensive blood glucose and tight blood pressure control in type 2 diabetes (UKPDS 72). Diabetologia 2005; 48: 868–877 https://link.springer.com/article/10.1007%2Fs00125-005-1717-3
- Gray A, Clarke P, Farmer A, et al. The economics of translating trial evidence into practice: costs of implementing more intensive glycaemic and blood pressure control in type 2 diabetes in England. BMJ 2002; 325: 860 https://doi.org/10.1136/bmj.325.7369.860
- Hadden DR, Cull CA, Croft DJ, Holman RR. Poor pregnancy outcome for women with Type 2 diabetes. Diabet Med 2003; 20: 506–507 https://doi.org/10.1046/j.1464-5491.2003.00955_2.x
- Cull CA, Neil HAW, Holman RR. Changing aspirin use in patients with Type 2 diabetes in the UKPDS. Diabet Med 2004; 21: 1368–1371 https://doi.org/10.1111/j.1464-5491.2004.01328.x
- Thomason MJ, Biddulph JP, Cull CA, Holman RR. Reporting of diabetes on death certificates using data from the UK Prospective Diabetes Study. Diabet Med 2005; 22: 1031–1036 https://doi.org/10.1111/j.1464-5491.2005.01584.x
- Arcaya M, Coleman RL, Razak F. Health selection into neighborhoods among patients enrolled in a clinical trial. Prev Med Rep 2017; 8: 51–54 https://doi.org/10.1016/j.pmedr.2017.07.003