A Diabetes Outcome Progression Trial Research Articles

Prior event rate ratio adjustment produced estimates consistent with randomized trial: a diabetes case study

ObjectivesElectronic health records (EHR) provide a valuable resource for assessing drug side-effects, but treatments are not randomly allocated in routine care creating the potential for bias. We conduct a case study using the Prior Event Rate Ratio (PERR) Pairwise method to reduce unmeasured confounding bias in side-effect estimates for two second-line therapies for type 2 diabetes, thiazolidinediones, and sulfonylureas. Study Design and SettingsPrimary care data were extracted from the Clinical Practice Research Datalink (n = 41,871). We utilized outcomes from the period when patients took first-line metformin to adjust for unmeasured confounding. Estimates for known side-effects and a negative control outcome were compared with the A Diabetes Outcome Progression Trial (ADOPT) trial (n = 2,545). ResultsWhen on metformin, patients later prescribed thiazolidinediones had greater risks of edema, HR 95% CI 1.38 (1.13, 1.68) and gastrointestinal side-effects (GI) 1.47 (1.28, 1.68), suggesting the presence of unmeasured confounding. Conventional Cox regression overestimated the risk of edema on thiazolidinediones and identified a false association with GI. The PERR Pairwise estimates were consistent with ADOPT: 1.43 (1.10, 1.83) vs. 1.39 (1.04, 1.86), respectively, for edema, and 0.91 (0.79, 1.05) vs. 0.94 (0.80, 1.10) for GI. ConclusionThe PERR Pairwise approach offers potential for enhancing postmarketing surveillance of side-effects from EHRs but requires careful consideration of assumptions.

Evaluating associations between the benefits and risks of drug therapy in type 2 diabetes: a joint modeling approach.

ObjectivePrecision medicine drug therapy seeks to maximize efficacy and minimize harm for individual patients. This will be difficult if drug response and side effects are positively associated, meaning that patients likely to respond best are at increased risk of side effects. We applied joint longitudinal–survival models to evaluate associations between drug response (longitudinal outcome) and the risk of side effects (survival outcome) for patients initiating type 2 diabetes therapy.Study design and settingParticipants were randomized to metformin (MFN), sulfonylurea (SU), or thiazolidinedione (TZD) therapy in the A Diabetes Outcome Progression Trial (ADOPT) drug efficacy trial (n=4,351). Joint models were parameterized for 1) current HbA1c response (change from baseline in HbA1c) and 2) cumulative HbA1c response (total HbA1c change).ResultsWith MFN, greater HbA1c response did not increase the risk of gastrointestinal events (HR per 1% absolute greater current response 0.82 [95% CI 0.67, 1.01]; HR per 1% higher cumulative response 0.90 [95% CI 0.81, 1.00]). With SU, greater current response was associated with an increased risk of hypoglycemia (HR 1.41 [95% CI 1.04, 1.91]). With TZD, greater response was associated with an increased risk of edema (current HR 1.45 [95% CI 1.05, 2.01]; cumulative 1.22 [95% CI 1.07, 1.38]) but not fracture.ConclusionJoint modeling provides a useful framework to evaluate the association between response to a drug and the risk of developing side effects. There may be great potential for widespread application of joint modeling to evaluate the risks and benefits of both new and established medications.

Sex and BMI Alter the Benefits and Risks of Sulfonylureas and Thiazolidinediones in Type 2 Diabetes: A Framework for Evaluating Stratification Using Routine Clinical and Individual Trial Data.

The choice of therapy for type 2 diabetes after metformin is guided by overall estimates of glycemic response and side effects seen in large cohorts. A stratified approach to therapy would aim to improve on this by identifying subgroups of patients whose glycemic response or risk of side effects differs markedly. We assessed whether simple clinical characteristics could identify patients with differing glycemic response and side effects with sulfonylureas and thiazolidinediones. We studied 22,379 patients starting sulfonylurea or thiazolidinedione therapy in the U.K. Clinical Practice Research Datalink (CPRD) to identify features associated with increased 1-year HbA1c fall with one therapy class and reduced fall with the second. We then assessed whether prespecified patient subgroups defined by the differential clinical factors showed differing 5-year glycemic response and side effects with sulfonylureas and thiazolidinediones using individual randomized trial data from ADOPT (A Diabetes Outcome Progression Trial) (first-line therapy, n = 2,725) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) (second-line therapy, n = 2,222). Further replication was conducted using routine clinical data from GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) (n = 1,977). In CPRD, male sex and lower BMI were associated with greater glycemic response with sulfonylureas and a lesser response with thiazolidinediones (both P < 0.001). In ADOPT and RECORD, nonobese males had a greater overall HbA1c reduction with sulfonylureas than with thiazolidinediones (P < 0.001); in contrast, obese females had a greater HbA1c reduction with thiazolidinediones than with sulfonylureas (P < 0.001). Weight gain and edema risk with thiazolidinediones were greatest in obese females; however, hypoglycemia risk with sulfonylureas was similar across all subgroups. Patient subgroups defined by sex and BMI have different patterns of benefits and risks on thiazolidinedione and sulfonylurea therapy. Subgroup-specific estimates can inform discussion about the choice of therapy after metformin for an individual patient. Our approach using routine and shared trial data provides a framework for future stratification research in type 2 diabetes.

Time to be cautious about prescribing sulfonylureas?

Type 2 diabetes increases the risk of cardiovascular disease (CVD) and reducing this disease burden through glycaemic control has long been the principal objective of treating the disease. No treatment has yet succeeded in reaching this objective. There are concerns that sulfonylurea (SU) medications may increase, rather than decrease this risk. SUs have been central to the management of type 2 diabetes for many decades. Every month, more than 600 000 prescriptions for SUs are dispensed in England and current National Institute for Health and Care Excellence (NICE) guidelines recommend them for second-line use after metformin. The American College of Endocrinologists downgraded this role for SUs in 2009 and the European Association for the Study of Diabetes (EASD) did likewise in 2012. There are three major concerns regarding SUs. Firstly their widely acknowledged and indisputable tendency to cause hypoglycaemia. Second is the belief that they accelerate beta pancreatic cell failure. This was demonstrated by their marked lack of durability in maintaining glycaemic control in the UK Prospective Diabetes Study (UKPDS) and ADOPT (A Diabetes Outcome Progression Trial) study. This was highlighted by Ralph de Fronzo in his 2008 American Diabetes Association’s Banting lecture, in which he declared that: ‘Sulfonylureas are not recommended because, after an initial improvement in glycaemic control, they are associated with a progressive rise in HbA1c and progressive loss of beta cell function’. 1 The third and most worrying concern regarding SUs relates to questions regarding their cardiovascular safety. These questions have remained unanswered for more than 40 years. The University Group …

Effect of Rosiglitazone on Bone Quality in a Rat Model of Insulin Resistance and Osteoporosis

OBJECTIVERosiglitazone (RSG) is an insulin-sensitizing drug used to treat type 2 diabetes mellitus. The A Diabetes Outcome Progression Trial (ADOPT) shows that women taking RSG experienced more fractures than patients taking other type 2 diabetes drugs. These were not osteoporotic vertebral fractures but, rather, occurred in the limbs. The purpose of this study was to investigate how RSG treatment alters bone quality, which leads to fracture risk, using the Zucker fatty rat as a model.RESEARCH DESIGN AND METHODSA total of 61 female 4-month-old rats were divided into six groups. One Sham group was a control and another was administered oral RSG 10 mg/kg/day. Four ovariectomized (OVX) groups were dosed as follows: controls, RSG 10 mg/kg, alendronate (ALN, injected at 0.7 mg/kg/week), and RSG 10 mg/kg plus ALN. After 12 weeks of treatment, bone quality was evaluated by mechanical testing. Microarchitecture, bone mineral density (BMD), cortical bone porosity, and bone remodeling were also measured.RESULTSOVX RSG 10 mg/kg rats had lower vertebral BMD and compromised trabecular architecture versus OVX controls. Increased cortical bone porosity and decreased mechanical properties occurred in these rats. ALN treatment prevented decreased BMD and architectural and mechanical properties in the OVX model. Reduced bone formation, increased marrow adiposity, and excess bone resorption were observed in RSG-treated rats.CONCLUSIONSRSG decreases bone quality. An unusual finding was an increase in cortical bone porosity induced by RSG, consistent with its effect on long bones of women. ALN, an inhibitor of bone resorption, enhanced mechanical strength and may provide an approach to partially counter the deleterious skeletal effects of RSG.

Safety of PPAR agonists.

The thiazolidinediones pioglitazone and rosiglitazone were introduced into global markets in 1999–2000; we now have over 10 years of experience with them. The safety issues that it was fashionable to focus on at that time were abnormalities of liver function as a result of the rare but serious side effects of troglitazone, the thiazolidinedione then on the market. This turned out to be irrelavent for other thiazolidinediones without the antioxidant structure of troglitazone and has long since been forgotten in clinical practice. Many practicing clinicians felt concern, however, with the mechanisms of action of these drugs, namely to influence gene expression (1). Although the chemical effects are quite specific, in terms of binding to peroxisome proliferator–activated receptors (PPARs), concern over unknown problems in longer-term use prevented their prescription by some. However, even at the time of marketing approval, the issue of fluid retention was a recognized problem of PPAR agonists as a class, and simple clinical logic implied that this might be an issue with regard to cardiac failure, leading to licensing cautions even at the time of approval (2–4). Troglitazone was already being investigated for preservation of β-cell function at that time, and a study set up to address the issue for rosiglitazone, A Diabetes Outcome Progression Trial (ADOPT), subsequently identified another safety issue—that of bone fractures in people taking thiazolidinediones (5). Before this, but receiving little attention, a suggestion appeared that rosiglitazone was associated with an adverse cardiovascular (CV) profile specifically in regard to myocardial ischemia, this becoming a headline issue after a later publication of an integrated trial-level analysis in New England Journal of Medicine (4,6) and resulting in a further regulatory review in the summer of 2010. This article addresses four issues: 1 ) evidence for genotoxicity with thiazolidinediones; 2 ) our knowledge about …

Should the algorithm for the treatment of type 2 diabetes be evidence-based?

Keywords Beta cell function.Cardiovascularcomplications.Glycaemic control.Guidelines.Nephropathy.Sulfonylureas.Treatment.Trials.Type 2 diabetesAbbreviationsADOPT A Diabetes Outcome Progression TrialADVANCE Action in Diabetes and Vascular Disease:Preterax and Diamicron-MR ControlledEvaluationUKPDS UK Prospective Diabetes StudyTo the Editor: InarecentissueofDiabetologia, Schernthanerand colleagues [1] state that the last consensus statementfrom the ADA and EASD released in October 2008 [2]wasnot based strongly enough on clinical evidence, and raisesome concerns about the role of sulfonylureas in treatingtype 2 diabetes.Trialsevaluatingdrugsforthetreatmentoftype2diabeteswiththehighestdegreeofevidencearesparse,andtothebestof my knowledge include only the UK Prospective DiabetesStudy (UKPDS) [3, 4], A Diabetes Outcome ProgressionTrial (ADOPT) [5], Action in Diabetes and VascularDisease: Preterax and Diamicron-MR Controlled Evaluation(ADVANCE) [6] and PROspective pioglitAzone ClinicalTrial In macroVascular Events (PROactive) [7]. The firstthree of these studies in which sulfonylureas were usedfound in favour of their beneficial effect in the long-term,either on glycaemic control, beta cell function or cardiovas-cular events.Concerning beta cell function, Schernthaner et al.advocate the positive results with rosiglitazone in ADOPT[5]. However, it is worth considering that after 5 years, betacell function was identical between the rosiglitazone- andglibenclamide (known as glyburide in the USA andCanada)-treated groups, and higher than in the metformin-treated group. UKPDS data also demonstrated a similareffect on beta cell function after 6 years, comparingmetformin vs sulfonylureas [8].Concerning cardiovascular events, in the most recenttrial, namely ADVANCE [6], based on modified-releasegliclazide (gliclazide MR) with normalisation of HbA

Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) clinical trials

Aims/hypothesisObservational and mechanistic studies have suggested a possible relationship between treatment with metformin and decreased incidence of cancer in participants with type 2 diabetes. We extracted data for malignancies from the ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) randomised controlled clinical trials, in which the efficacy and/or safety of metformin was assessed in comparison with sulfonylureas and rosiglitazone.MethodsNeoplasm occurrences were collected as adverse events in these studies. We reviewed and re-analysed the individual participant data in both studies for serious adverse events, malignancies reported as adverse events and related neoplasms of special interest.ResultsIn ADOPT, 50 participants (3.4%) on metformin and 55 (3.8%) on each of rosiglitazone and glibenclamide (known as glyburide in the USA and Canada) developed serious adverse event malignancies (excluding non-melanoma skin cancers). This corresponds to 1.03, 1.12 and 1.31 per 100 person-years, giving hazard ratios for metformin of 0.92 (95% CI 0.63–1.35) vs rosiglitazone and 0.78 (0.53–1.14) vs glibenclamide. In RECORD, on a background of sulfonylurea, 69 (6.1%) participants developed malignant neoplasms in the metformin group, compared with 56 (5.1%) in the rosiglitazone group (HR 1.22 [0.86–1.74]). On a background of metformin, 74 (6.7%) participants in the sulfonylurea group developed malignant neoplasms, compared with 57 (5.1%) in the rosiglitazone group (HR 1.33 [0.94–1.88]).Conclusions/interpretationThe malignancy rates in these two randomised controlled clinical trials do not support a view that metformin offers any particular protection against malignancy compared with rosiglitazone. However, they do not refute the possibility of a difference compared with sulfonylureas.

Effect of Rosiglitazone, Metformin, and Glyburide on Bone Biomarkers in Patients with Type 2 Diabetes

An increase in bone fractures has been observed in women taking thiazolidinediones. The objective of the study was to examine whether changes in circulating bone biomarkers provide insight into the underlying mechanisms responsible for the increase in bone fractures in female participants randomized to rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT). Paired stored baseline and 12-month serum samples were available from 1605 participants (689 women, 916 men) in ADOPT, a long-term clinical trial comparing the effects of rosiglitazone, glyburide, and metformin on glycemic control in patients with type 2 diabetes. This subset was well matched to the total ADOPT study population. In women a marker of osteoclast activity, C-terminal telopeptide (for type 1 collagen), increased by 6.1% with rosiglitazone compared with reductions of 1.3% (P = 0.03 vs. rosiglitazone) and 3.3% (P = 0.002 vs. rosiglitazone) with metformin and glyburide, respectively. In men, C-terminal telopeptide was unchanged on rosiglitazone (-1.0%) and fell on metformin (-12.7%; P < 0.001) and glyburide (-4.3%, P = NS). Markers of osteoblast activity, procollagen type 1 N-propeptide (P1NP) and bone alkaline phosphatase, were reduced for women and men in almost all treatment groups, with the greatest changes in the metformin group (P1NP in females, -14.4%; P1NP in males, -19.3%), intermediate for rosiglitazone (P1NP in females, -4.4%; P1NP in males, -14.4%), and smallest for glyburide (P1NP in males, +0.2%; bone alkaline phosphatase in females, -11.6%). Commonly measured bone biomarkers suggest that changes in bone resorption may be partly responsible for the increased risk of fracture in women taking thiazolidinediones.

Rosiglitazone Decreases C-Reactive Protein to a Greater Extent Relative to Glyburide and Metformin Over 4 Years Despite Greater Weight Gain

OBJECTIVEC-reactive protein (CRP) is closely associated with obesity and cardiovascular disease in both diabetic and nondiabetic populations. In the short term, commonly prescribed antidiabetic agents have different effects on CRP; however, the long-term effects of those agents are unknown.RESEARCH DESIGN AND METHODSIn A Diabetes Outcome Progression Trial (ADOPT), we examined the long-term effects of rosiglitazone, glyburide, and metformin on CRP and the relationship among CRP, weight, and glycemic variables in 904 subjects over 4 years.RESULTSBaseline CRP was significantly correlated with homeostasis model assessment of insulin resistance (HOMA-IR), A1C, BMI, waist circumference, and waist-to-hip ratio. CRP reduction was greater in the rosiglitazone group by −47.6% relative to glyburide and by −30.5% relative to metformin at 48 months. Mean weight gain from baseline (at 48 months) was 5.6 kg with rosiglitazone, 1.8 kg with glyburide, and −2.8 kg with metformin. The change in CRP from baseline to 12 months was correlated positively with change in BMI in glyburide (r = 0.18) and metformin (r = 0.20) groups but not in the rosiglitazone (r = −0.05, NS) group. However, there was no longer a significant correlation between change in CRP and change in HOMA-IR, A1C, or waist-to-hip ratio in any of the three treatment groups.CONCLUSIONSRosiglitazone treatment was associated with durable reductions in CRP independent of changes in insulin sensitivity, A1C, and weight gain. CRP in the glyburide and metformin groups was positively associated with changes in weight, but this was not the case with rosiglitazone.

HOMA-beta in the UKPDS and ADOPT. Is the natural history of type 2 diabetes characterised by a progressive and inexorable loss of insulin secretory function? Maybe? Maybe not?

Introduction In 1995 the investigators of the United Kingdom Prospective Diabetes Study (UKPDS) published the results of 6 years of therapy with a variety of blood glucose-lowering drugs in patients with 2DM. Although the major goal of the study was to evaluate the relationship between glycaemic control and the development of diabetic complications, the report contained metabolic data which have had a substantial impact on general views as to the pathophysiology of 2DM. Specifically, using HOMA-beta, a surrogate estimate of pancreatic beta-cell function based on measurements of fasting plasma glucose and insulin concentrations, it was concluded that approximately 50% of insulin secretory capacity had been lost in these patients prior to initiation of the study. Following enrolment, there was a progressive deterioration of glycaemic control over the next 6 years in all groups, including those assigned to ‘intensive’ glycaemic intervention. beta-cell function as estimated by HOMA-beta also decreased continuously over the study period, leading the authors to conclude that ‘progressively increasing hyperglycaemia, associated with decreasing beta-cell function, was a marked feature irrespective of the therapy used.’ HOMA-beta has continued to be used as an estimate of beta-cell function in the years following the publication of the UKPDS report, with essentially similar conclusions as to the progressive loss of insulin secretory function over the natural history of 2DM. For example, HOMA-beta was used in the recent study 3 A Diabetes Outcome Progression Trial (ADOPT) to assess changes in beta-cell function over time in patients with 2DM assigned to monotherapy with rosiglitazone, metformin or glyburide. The major conclusion of ADOPT was that although the three drugs differed in length of time for monotherapy to fail, the data were consistent with the UKPDS results in that the initial improvement in glycaemic control was followed by a progressive increase in glycated haemoglobin and fasting plasma glucose concentration. The effect of treatment on the estimate of beta-cell function was somewhat more complicated than reported by the UKPDS, consisting of an initial improvement following initiation of drug treatment, but after this ‘levels of beta-cell function declined in all three groups.’ The notion of a progressive and inexorable loss of beta-cell function as part of the natural history of 2DM has been buttressed by results suggesting that in order to attain glycaemic control in patients with 2DM over time additional pharmacological agents must continually be added. This point was initially made in one of the reports of the UKPDS, but is echoed in the findings of the ADOPT study. The remainder of this analysis will be devoted to consideration of the appropriateness of HOMA-beta as an assessment of insulin secretory function, as well as the notion that glycaemic control inexorably declines with duration of 2DM.

GlaxoSmithKline responds to the consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes

To the Editor: GlaxoSmithKline regrets the recommendation [1] of the recent consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes against the use of rosiglitazone for treatment of type 2 diabetes, because it is contrary to scientific evidence. The evidence regarding a possible association of rosiglitazone with increased risk of cardiovascular ischaemic morbidity remains inconclusive. Data from clinical trials assessing cardiovascular outcomes are inconsistent with hypotheses of increases in the rates of myocardial ischaemia or death that have arisen from meta-analyses. No long-term clinical trial has confirmed an increased risk of cardiovascular ischaemia with rosiglitazone. Moreover, data from two large head-to-head clinical trials—A Diabetes Outcome Progression Trial (ADOPT) [2] and the interim report of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial [3]— show that, apart from the well-documented risk of heart failure with thiazolidinediones, rosiglitazone has a cardiovascular risk profile comparable to the recommended tier 1 glucose-lowering medicines, metformin and sulfonylurea. The consensus statement contains multiple unexplained inconsistencies regarding the evidence underlying its conclusions and recommendations. Data from long-term clinical trials, which provide gold-standard evidence, sometimes appear to receive less weight than conclusions from hypothesisgenerating meta-analyses. This circumstance is difficult to understand, particularly in light of a recent comment by the corresponding author of the consensus statement [4] that ‘the vagaries of meta-analyses make them unreliable’. Furthermore, the consensus statement cites data in an inconsistent manner. Meta-analyses critical of rosiglitazone are mentioned repeatedly, while analyses reporting no increase in cardiovascular ischaemic risk with rosiglitazone versus other established glucose-lowering medications are overlooked (such as those performed by Lago et al. [5] and the US Food and Drug Administration [FDA] [6]). A metaanalysis [7] that reported a statistically significant increase in a composite endpoint of cardiovascular hospitalisation or mortality with the combination of sulfonylureas and metformin—a tier 1 recommended option—is not mentioned in the consensus statement. The authors of the consensus statement write that ‘the overarching principle in selecting a particular intervention will be its ability to achieve and maintain glycaemic goals’ [1]. Rosiglitazone has been shown to provide glycaemic control for up to 5 years—significantly longer than the most commonly used oral glucose-lowering medications, sulfonylurea and metformin [2]. GlaxoSmithKline strongly believes that rosiglitazone has a place in the therapeutic armamentarium for type 2 diabetes when used appropriately. Diabetologia (2009) 52:986–987 DOI 10.1007/s00125-009-1301-3

Rosiglitazone-Associated Fractures in Type 2 Diabetes

OBJECTIVE—The purpose of this study was to examine possible factors associated with the increased risk of fractures observed with rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT). RESEARCH DESIGN AND METHODS—Data from the 1,840 women and 2,511 men randomly assigned in ADOPT to rosiglitazone, metformin, or glyburide for a median of 4.0 years were examined with respect to time to first fracture, rates of occurrence, and sites of fractures. RESULTS—In men, fracture rates did not differ between treatment groups. In women, at least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74 per 100 patient-years), metformin in 30 patients (5.1%, 1.54 per 100 patient-years), and glyburide in 21 patients (3.5%, 1.29 per 100 patient-years). The cumulative incidence (95% CI) of fractures in women at 5 years was 15.1% (11.2–19.1) with rosiglitazone, 7.3% (4.4–10.1) with metformin, and 7.7% (3.7–11.7) with glyburide, representing hazard ratios (95% CI) of 1.81 (1.17–2.80) and 2.13 (1.30–3.51) for rosiglitazone compared with metformin and glyburide, respectively. The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and fractures were seen predominantly in the lower and upper limbs. No particular risk factor underlying the increased fractures in female patients who received rosiglitazone therapy was identified. CONCLUSIONS—Further investigation into the risk factors and underlying pathophysiology for the increased fracture rate in women taking rosiglitazone is required to relate them to preclinical data and better understand the clinical implications of and possible interventions for these findings.

Thiazolidinediones and Fracture Risk in Diabetic Women

Diabetic patients have higher BMD but greater risk for fragility fractures than do nondiabetics. Could diabetes medications account for this finding? In two studies, researchers investigated whether thiazolidinediones (TZDs) were linked to elevated fracture incidence. In the original A Diabetes Outcome Progression Trial (ADOPT) — a comparison of the glucose-controlling effects of rosiglitazone (a TZD), glyburide, and metformin — a relatively high rate of fractures among rosiglitazone users was identified unexpectedly. In a supplementary …

Exploring Treatment Strategies for Type 2 Diabetes

Perspectives on the News commentaries are now part of a new, free monthly CME activity. The Mount Sinai School of Medicine, New York, New York, is designating this activity for 2.0 AMA PRA Category 1 credits. If you wish to participate, review this article and visit www.diabetes.procampus.net to complete a posttest and receive a certificate. The Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians . This is the second in a series of articles based on presentations at the American Diabetes Association's 67th Scientific Sessions in June 2007, in Chicago, discussing approaches to the treatment of type 2 diabetes, contrasting the use of older therapies with the use of new agents to lower blood glucose levels. At a symposium on the use of insulin in treatment of type 2 diabetes, Rury Holman (Oxford, U.K.) reviewed the findings of the UK Prospective Diabetes Study (UKPDS) and A Diabetes Outcome Progression Trial (ADOPT) in terms of the performance of metformin, sulfonylureas, thiazolidinediones, and insulin. Among the newly diagnosed diabetic individuals entering the UKPDS, mean A1C fell from 9 to 7% with diet modification. At 1 year, mean A1C was 6% with insulin, sulfonylurea, and metformin treatment. After 3, 6, and 9 years in UKPDS, however, only ∼40, 40, and 30% of individuals receiving insulin maintained A1C <7%. Among those on sulfonylurea monotherapy, 45% had A1C <7% at 3 years, but the proportions decreased to 30 and 20% at 6 and 9 years, respectively, with 45, 35, and 15% of those receiving metformin monotherapy maintaining A1C <7% at these times. Holman characterized this inexorable increase as one of the principal challenges of glycemic treatment of individuals with type 2 diabetes. Interestingly, the widely used sulfonylurea glyburide was less …

Choice of monotherapy in newly diagnosed Type 2 diabetic patients: clinical perspective of ADOPT

A Diabetes Outcome Progression Trial (ADOPT) investigated the durability of the antihyperglycemic effects of rosiglitazone (RSG; maximum dose 4 mg twice daily), metformin (MET, maximum dose 1 g twice daily) and glyburide (or glibencamide [GB]; maximum dose 7.5 mg twice daily) in 4360 drug-naive patients with Type 2 diabetes mellitus. The therapeutic goal in the trial was a fasting plasma glucose level below 140 mg/dl (7.8 mmol/l) and the primary end point was the time from randomization to treatment failure, defined as an fasting plasma glucose above 180 mg/dl (10 mmol/l). The results showed a cumulative incidence of monotherapy failure at 5 years of 15% for RSG, 21% for MET and 34% for GB, equating to risk reductions in primary end point for RSG therapy of 32% relative to MET and 63% relative to GB (p < 0.001 for both comparisons). There were significant withdrawals from each of the study groups and when glycosylated hemoglobin was used as the measure of long-term glycemic control, the differences between groups were more modest. RSG also resulted in greater weight gain and, notably, a significantly increased fracture rate in the upper and lower limbs of women (9.3%) compared with MET (5.1%) and GB (3.5%). Overall, taking into account the modest glycemic benefit of RSG over MET, the cost difference between these treatments and safety concerns with RSG, MET remains the rational choice of initial treatment of Type 2 diabetes mellitus.

Counterpoint: A Diabetes Outcome Progression Trial (ADOPT): Good for Sulfonylureas?

A Diabetes Outcome Progression Trial (ADOPT) was conceived in the hope that the seemingly inexorable decline in islet B-cell function described with metformin, sulfonylureas, and insulin in the UK Prospective Diabetes Study (UKPDS) might be stopped or inhibited to a major degree by peroxisome proliferator–activated receptor-γ agonists, in particular rosiglitazone (1,2). It was already well recognized that the rapid early efficacy of sulfonylureas in lowering glucose was not retained to 12 months, and that metformin and thiazolidinediones had slow onset of action over months, so the design of the study necessarily had to enable decline of measures of blood glucose control to be assessed for a considerable period from 1 year onwards. However, the extent (degree and time) to which this early efficacy of the sulfonylureas in protecting against hyperglycemia would persist was not accurately known. The study also provided a good opportunity to compare durability of effect of the three classes of drugs directly in the context of some shorter-term studies since published (3). Metformin is currently well established as first-line therapy in people with type 2 diabetes, usually after lifestyle measures fail to achieve A1C levels <6.5%, although some consensus (as opposed to evidence-based) guidelines have suggested initiation immediately from diagnosis (4,5). This review will not challenge those ideas, although the evidence is not as strong as sometimes assumed. The exceptions to first-line metformin use are where metformin is contraindicated, perhaps where someone is not overweight, and where presentation glucose levels are high and the rapid effect of a sulfonylurea is needed. In situations where metformin is contraindicated, or as second-line add-on therapy to metformin when target levels are no longer met, the alternative choice to a sulfonylurea would be a thiazolidinedione or possibly a gliptin (it is assumed insulin would not usually …

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A Diabetes Outcome Progression Trial (ADOPT): baseline characteristics of Type 2 diabetic patients in North America and Europe

To examine baseline characteristics of patients recruited into ADOPT, a multinational trial comparing three oral glucose-lowering monotherapies. Between April 2000 and June 2002, 4360 patients aged 30-75 years with Type 2 diabetes diagnosed for < 3 years and remaining on diet therapy alone with fasting plasma glucose levels (FPG) between 7.0 and 10.0 mmol/l were enrolled by 488 North American and European centres. Medical histories, anthropometric data and laboratory measurements were determined using common methodologies. The mean (SD) age of the patients was 57 (10) years, body mass index 32.2 (6.4) kg/m(2), HbA(1c) 7.4 (0.9)%; 58% were male, 88% Caucasian and 15% smoked. North American Caucasians (NAC) were younger, more obese, and more insulin resistant than European Caucasians (EUC), but had better pancreatic B-cell function. NAC had lower total, low-density lipoprotein- and high-density liporpotein-cholesterol concentrations with higher triglyceride concentrations and were more often on lipid-lowering treatment. They had lower blood pressure levels but were equally likely to be on antihypertensive treatment. Metabolic syndrome was more frequent and microalbuminuria less frequent in NAC. Within North America, NAC had lower HbA(1c) concentrations than Blacks, Hispanics and Asians despite similar or higher FPG and 30-min postchallenge glucose concentrations. Caucasian North American and European ADOPT patients differ with respect to adiposity, insulin resistance and metabolic syndrome prevalence. North American Blacks, Hispanics and Asians had lower HbA(1c) concentrations than NAC despite similar or higher glucose concentrations. These phenotypic differences may influence the progression of Type 2 diabetes and the response to initial oral glucose-lowering monotherapy.

Obesity Is a Major Determinant of the Association of C-Reactive Protein Levels and the Metabolic Syndrome in Type 2 Diabetes

The inflammatory factor C-reactive protein (CRP) and the fibrinolytic variables fibrinogen and plasminogen activator-1 (PAI-1) are associated with long-term cardiovascular morbidity. To determine the contribution of body adiposity (BMI), insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR], and glycemia (HbA(1c) [A1C]) to the levels of these inflammatory and fibrinolytic variables in recently diagnosed (<or=3 years), drug-naive, type 2 diabetic subjects (fasting plasma glucose <or=10 mmol/l), we examined a representative subgroup (n = 921) of the U.S. cohort in ADOPT (A Diabetes Outcome Progression Trial). The relationship between levels of CRP, fibrinogen, PAI-1 antigen and PAI-1 activity, and baseline variables including National Cholesterol Education Program Adult Treatment Panel III metabolic syndrome phenotype were explored. All four factors increased significantly with increasing numbers of metabolic syndrome components (P = 0.0136 to P < 0.0001). BMI (P < 0.0001) and HOMA-IR (P < 0.0001) but not A1C (P = 0.65) increased with increasing numbers of metabolic syndrome components. Adjustment of CRP levels for BMI eliminated the association between CRP and the number of metabolic syndrome components, while adjusting for HOMA-IR did not (P = 0.0028). The relationships of PAI-1 antigen and PAI-1 activity with the number of metabolic syndrome components were maintained after adjusting for BMI (P = 0.0002 and P = <0.0001, respectively) or HOMA-IR (P = 0.0008 and P = <0.0001, respectively), whereas that with fibrinogen was eliminated after adjusting for BMI but not after adjusting for HOMA-IR (P = 0.013). Adjustment for A1C had no effect on any of the relationships between the inflammatory and fibrinolytic factors and the metabolic syndrome. We conclude that in recently diagnosed, drug-naive type 2 diabetic subjects, markers of inflammation and fibrinolysis are strongly related to the number of metabolic syndrome components. Further, for CRP and fibrinogen this relationship is determined by body adiposity and not by insulin sensitivity or glucose control.