Clinical trial risk in type-2 diabetes: importance of patient history.

PURPOSE: To determine the risk of clinical trial failure for drugs developed for type-2 diabetes. METHODS: Drugs were investigated by reviewing phase I to phase III studies that were conducted between 1998 and February 2013. The clinical trial success rates were calculated and compared to the industry standard. The drugs were classified into GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors and "Other". The exclusion criteria for drugs in this study: Drugs that were started in phase I studies prior to January 1998 for this indication and drugs whose primary indications were not for the control of blood glucose levels. RESULTS: Data was extracted from clinicaltrials.gov; there were a total of 131 drug candidates that fit our specified criteria, of which 8 received FDA approval. The cumulative success rate for molecules developed for type-2 diabetes is 10%. Small molecules were more successful than biologics. A strong disparity was observed in phase III, with studies that utilised treatment naïve patients having a 40% success rate, compared to an 83% success rate in patients who have had previous anti-hyperglycemic exposure. CONCLUSIONS: 1 in 10 drugs that enter clinical testing in this disease will be approved. The DPP-4 inhibitor class of drugs had the highest success rate of all drug classes with a 63% cumulative success rate; while treatment naïve patients carried the greatest clinical trial risk.

Implementation of the glucommander method of adjusting insulin infusions in critically ill patients.

BACKGROUND: Intensive glycemic control has been associated with reduced morbidity and mortality in critically ill patients. Web-based, patient-specific insulin nomograms may facilitate improved glucose control. OBJECTIVE: To compare 2 algorithms for individualizing insulin infusion therapy (a web-based system [Glucommander method] and a standard paper-based nomogram) in a cardiovascular surgery intensive care unit (ICU). METHODS: In this prospective, before-after cohort study, measures of glycemic control for 50 patients receiving insulin according to the Glucommander system were compared with a control group (n = 50) who received insulin according to the standard paper-based nomogram used in the cardiovascular surgery ICU. RESULTS: There was no significant difference between the 2 groups with respect to time to target blood glucose (5.1-8.0 mmol/L), percentage of time within the target range, or mean amplitude of glucose excursion. Patients in the intervention group spent less time above the target range (p = 0.007) and more time below the target range (p < 0.001), and the mean glucose was lower in this group compared with the control group (7.9 versus 8.6 mmol/L, p = 0.002). The percentage of blood glucose measurements below 4 mmol/L was higher in the intervention group than in the control group (3.7% versus 1.4%, p = 0.003). Satisfaction surveys revealed that the program was well accepted by the nursing staff in the cardiovascular surgery ICU. CONCLUSIONS: A web-based insulin nomogram was an easy-to-use instrument for achieving tighter glucose control for patients in the cardiovascular surgery ICU. Use of the Glucommander system led to lower mean blood glucose but an increase in episodes of hypoglycemia.

Cost-effectiveness of using recombinant human thyroid-stimulating hormone before radioiodine ablation for thyroid cancer: the Canadian perspective.

OBJECTIVES: Radioiodine ablation for the treatment of thyroid cancer is traditionally performed after preparing patients by inducing hypothyroidism. Exogenous stimulation of thyroid-stimulating hormone (TSH) using recombinant human TSH (rhTSH) avoids hypothyroidism and hastens the clearance of radioiodine from the patient. These advantages are achieved without jeopardizing the success rate of remnant ablation. An economic analysis was performed to place the increased acquisition cost of rhTSH in the context of the health benefits achieved and the earlier discharge from radioprotection. METHODS: Markov modeling, using 17 individual weekly cycles, was used to assess the incremental cost per quality-adjusted life-year (QALY) associated with exogenous stimulation. Clinical inputs were largely sourced from a multicenter, randomized, controlled trial comparing remnant ablation success after either rhTSH or hypothyroid preparation. The model applied Canadian unit costs, taking a societal perspective. Additional costs associated with rhTSH were considered in the context of the clinical benefits and cost offsets. These included avoidance of hypothyroidism, increased work productivity, earlier administration of ablation after surgery, and earlier discharge from the radio-protective ward because of faster radioiodine clearance following rhTSH preparation. The model duration avoided the need for discounting. RESULTS: The additional benefits of rhTSH (0.0576 QALY) are obtained with an incremental cost of CDN$87, generating an incremental cost per QALY of CDN$1520. Deterministic one-way and two-way sensitivity analyses demonstrated the result to be robust. CONCLUSIONS: The use of rhTSH before radioiodine ablation represents a reasonable allocation of costs, with the benefits to patients, hospitals, and society as a whole, obtained at modest cost.

Effect of a low-glycemic index or a high-cereal fiber diet on type 2 diabetes: a randomized trial.

CONTEXT: Clinical trials using antihyperglycemic medications to improve glycemic control have not demonstrated the anticipated cardiovascular benefits. Low-glycemic index diets may improve both glycemic control and cardiovascular risk factors for patients with type 2 diabetes but debate over their effectiveness continues due to trial limitations. OBJECTIVE: To test the effects of low-glycemic index diets on glycemic control and cardiovascular risk factors in patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: A randomized, parallel study design at a Canadian university hospital research center of 210 participants with type 2 diabetes treated with antihyperglycemic medications who were recruited by newspaper advertisement and randomly assigned to receive 1 of 2 diet treatments each for 6 months between September 16, 2004, and May 22, 2007. INTERVENTION: High-cereal fiber or low-glycemic index dietary advice. MAIN OUTCOME MEASURES: Absolute change in glycated hemoglobin A(1c) (HbA(1c)), with fasting blood glucose and cardiovascular disease risk factors as secondary measures. RESULTS: In the intention-to-treat analysis, HbA(1c) decreased by -0.18% absolute HbA(1c) units (95% confidence interval [CI], -0.29% to -0.07%) in the high-cereal fiber diet compared with -0.50% absolute HbA(1c) units (95% CI, -0.61% to -0.39%) in the low-glycemic index diet (P < .001). There was also an increase of high-density lipoprotein cholesterol in the low-glycemic index diet by 1.7 mg/dL (95% CI, 0.8-2.6 mg/dL) compared with a decrease of high-density lipoprotein cholesterol by -0.2 mg/dL (95% CI, -0.9 to 0.5 mg/dL) in the high-cereal fiber diet (P = .005). The reduction in dietary glycemic index related positively to the reduction in HbA(1c) concentration (r = 0.35, P < .001) and negatively to the increase in high-density lipoprotein cholesterol (r = -0.19, P = .009). CONCLUSION: In patients with type 2 diabetes, 6-month treatment with a low-glycemic index diet resulted in moderately lower HbA(1c) levels compared with a high-cereal fiber diet. Trial Registration clinicaltrials.gov identifier: NCT00438698.

18F-fluorodeoxyglucose positron emission tomography-computed tomography for suspected recurrent papillary thyroid cancer: early experience at Sunnybrook Health Sciences Centre.

OBJECTIVES: To report the initial experience with combined 18F-fluorodeoxyglucose positron emission tomography (FDG PET)/computed tomography (CT) imaging for suspected recurrent papillary differentiated thyroid cancer (DTC) at Sunnybrook Health Sciences Centre (SHSC), Toronto. DESIGN: Single institution retrospective study. METHODS: Consecutive patients from SHSC who underwent FDG PET/CT imaging for suspected recurrent DTC over a period of 2.5 years were identified and their charts reviewed. MAIN OUTCOME MEASURE: Qualitative appraisal of FDG PET/CT imaging in suspected recurrent DTC. RESULTS: Sixteen patients (14F, 2M) were identified accounting for 17 FDG PET/CT scans. Three scans (18%) in 3 different patients were reported as suspicious for recurrent disease in the neck (1-3 lesions) and were considered "positive". All were subsequently confirmed pathologically (4-13 positive lymph nodes post operatively). Prior conventional imaging was abnormal in two patients. Two patients had an elevated non-stimulated thyroglobulin (TG) < 10 ng/mL (4.9 and 9.4). The remaining patient had a TG < 0.3 ng/mL but was anti-TG antibody positive (84 IUx10-3/L). With a median follow up of 15 months (range 7-36) there were no false positive or negative scans. Incidental pathology (breast cancer, large bowel polyps) was identified on a further 2/17 scans (12%). CONCLUSIONS: FDG PET/CT imaging is able to detect recurrent DTC in patients with low TG levels. It can complement conventional imaging findings and exclude distant FDG-avid metastases prior to surgery. It may underestimate the number of positive lymph nodes in the neck. Occult pathology may be identified with whole body FDG PET/CT.

Management of type 2 diabetes mellitus. Role of thiazolidinediones.

OBJECTIVE: To review evidence supporting use of thiazolidinediones (TZDs) in management of type 2 diabetes mellitus (DM2). QUALITY OF EVIDENCE: A MEDLINE search found several randomized controlled trials (level I evidence). No systematic reviews of these trials were found in the Cochrane Library. MAIN MESSAGE: Thiazolidinediones lower hemoglobin AIc levels by as much as 1.0% to 1.5%. Effects can be seen in as little as 4 weeks, but full lowering takes 6 to 12 weeks. When used in combination with other diabetic agents, such as sulfonylureas and biguanides, TZDs' hypoglycemic effects appear to be complementary. Thiazolidinediones directly improve insulin sensitivity and recovery of pancreatic beta cell function. Nevertheless, there is no evidence indicating that TZDs are superior to other antidiabetic agents currently available or that TZDs reduce the long-term complications of DM2. CONCLUSION: Ongoing trials will further define the role of TZDs in management of diabetic patients. In current practice, cost is often a factor in the decision to prescribe TZDs.