John G. Cooper

A 52-week, multinational, open-label, parallel-group, noninferiority, treat-to-target trial comparing insulin detemir with insulin glargine in a basal-bolus regimen with mealtime insulin aspart in patients with type 2 diabetes

OBJECTIVE This trial compared the efficacy and safety profiles of the insulin analogues detemir and glargine as the basal insulin component of a basal-bolus regimen in patients with type 2 diabetes mellitus (T2DM) who were being treated with oral antidiabetic drugs (OADs) or insulin with or without OADs. METHODS This was a multinational, 52-week, openlabel, parallel-group, noninferiority, treat-to-target trial. Patients with a diagnosis of T2DM for > or = 12 months who had been receiving an OAD or insulin, with or without OADs, for > 4 months were randomized in a 2:1 ratio to receive detemir or glargine. According to the approved labeling, detemir could be administered once or twice daily, and glargine was administered once daily. Insulin aspart was given at mealtimes. Insulin secretagogues and a-glucosidase inhibitors were discontinued at study entry, and existing OADs were continued. Doses of detemir and glargine were titrated to achieve a prebreakfast (and predinner for detemir administered twice daily) plasma glucose target of < or = 6.0 mmol/L. Patients monitored their plasma glucose levels before breakfast and dinner on the 3 days before each of 13 scheduled visits, recorded their insulin doses on 1 of these 3 days, and recorded their 10-point self-monitored plasma glucose (SMPG) at baseline and after 24 and 52 weeks. The primary efficacy end point was glycosylated hemoglobin (HbA(1c)) at 52 weeks; secondary efficacy end points included changes in fasting plasma glucose (FPG), postprandial plasma glucose, insulin doses, and weight change at 52 weeks. Safety end points included the frequency of hypoglycemia and adverse events (AEs). RESULTS The intention-to-treat population included 319 patients (58.0% male, 42.0% female; 78.4% white; mean age, 58 years; mean weight, 92.8 kg; mean duration of diabetes, 13.6 years). At study entry, 46.1% of patients were receiving insulin and > or = 1 OAD, 35.4 were receiving insulin only, and 18.5% were receiving > or = 1 OAD only. At 52 weeks, there was no significant difference between detemir and glargine in terms of mean HbA(1c) (7.19% and 7.03%, respectively; mean difference, 0.17% [95% CI, -0.07 to 0.40]) or the mean decrease in HbAlc from baseline (-1.52% and -1.68%). The reduction in HbA(1c) was not significantly affected by whether detemir was administered once or twice daily. There were no significant differences between groups in terms of mean FPG (7.05 and 6.68 mmol/L) or the mean change in FPG from baseline (-2.56 and -2.92 mmol/L; mean difference, 0.36; 95% CI, -0.26 to 0.99). The overall shape of the 10-point SMPG profiles was not significantly different between groups. Mean weight gain at 52 weeks was significantly lower with detemir than with glargine (2.8 vs 3.8 kg; mean difference, -1.04; 95% CI, -2.08 to -0.01; P < 0.05). Doses of basal and prandial insulins at the end of the study were not significantly different between groups. Major hypoglycemic episodes were reported by 4.7% and 5.7% of patients in the respective treatment groups. There was no significant difference in the risk of hypoglycemia between groups. The proportion of patients with AEs and the number of AEs per patient were comparable between groups (185/214 patients [86.4%] reporting 743 AEs and 88/105 patients [83.8%] reporting 377 AEs). CONCLUSIONS when used as indicated as part of a basal-bolus regimen in patients with T2DM who had previously received other insulin and/or OAD regimens, detemir was noninferior to glargine in its effects on overall glycemic control. Both basal insulins were associated with clinically relevant reductions in hyperglycemia. Both were well tolerated, with no significant difference in the frequency of hypoglycemia or AEs.

Preoperative Octreotide Treatment in Newly Diagnosed Acromegalic Patients with Macroadenomas Increases Cure Short-Term Postoperative Rates: A Prospective, Randomized Trial

CONTEXT Surgery is the primary treatment of acromegaly. However, it often fails to cure the patient. New strategies that improve surgical outcome are needed. OBJECTIVE Our objective was to investigate whether 6-month preoperative treatment with octreotide improves the surgical outcome in newly diagnosed acromegalic patients. PATIENTS During a 5-yr period (1999-2004), all newly diagnosed acromegalic patients between 18 and 80 yr of age in Norway were screened and invited to participate in the study. A total of 62 patients was included in the Preoperative Octreotide Treatment of Acromegaly study. RESEARCH DESIGN AND METHODS After a baseline evaluation, patients were randomized directly to transsphenoidal surgery (n = 30) or pretreatment with octreotide (n = 32) 20 mg im every 28th day for 6 months before transsphenoidal surgery. Cure was evaluated 3 months postoperatively primarily by IGF-I levels. RESULTS According to the IGF-I criteria, 14 of 31 (45%) pretreated patients vs. seven of 30 (23%) patients with direct surgery were cured by surgery (P = 0.11). In patients with microadenomas (< or = 10 mm), one of five (20%) pretreated vs. three of five (60%) with direct surgery were cured (P = 0.52). In patients with macroadenomas, 13 of 26 (50%) pretreated vs. four of 25 (16%) with direct surgery were cured (P = 0.017). CONCLUSIONS Six-month preoperative octreotide treatment might improve surgical cure rate in newly diagnosed acromegalic patients with macroadenomas. These results have to be confirmed in future studies.

Efficacy and safety of insulin degludec in a flexible dosing regimen vs insulin glargine in patients with type 1 diabetes (BEGIN: Flex T1): a 26-week randomized, treat-to-target trial with a 26-week extension.

Objective: This study investigated the efficacy and safety of insulin degludec (IDeg) once daily (OD), varying injection timing day to day in subjects with type 1 diabetes. Research Design and Methods: This 26-week, open-label, treat-to-target, noninferiority trial compared IDeg forced flexible (Forced-Flex) OD (given in a fixed schedule with a minimum 8 and maximum 40 hours between doses) with IDeg or insulin glargine (IGlar) given at the same time daily OD. In the 26-week extension, all IDeg subjects were transferred to a free-flexible (Free-Flex) regimen, which allowed any-time-of-day dosing, and compared with subjects continued on IGlar. Results: After 26 treatment weeks, mean glycosylated hemoglobin was reduced with IDeg Forced- Flex (−0.40%), IDeg (−0.41%), and IGlar (−0.58%). IDeg Forced-Flex noninferiority was achieved. Fasting plasma glucose reductions were similar with IDeg Forced-Flex and IGlar but greater with IDeg (−2.54 mmol/L) than IDeg Forced-Flex (−1.28 mmol/L) (P = .021). At week 52, IDeg Free-Flex subjects had similar glycosylated hemoglobin but greater fasting plasma glucose reductions than IGlar subjects (−1.07 mmol/L) (P = .005). Confirmed hypoglycemia rates (plasma glucose <3.1 mmol/L or severe hypoglycemia) were similar at weeks 26 and 52. Nocturnal confirmed hypoglycemia was lower with IDeg Forced-Flex vs IDeg (37%; P = .003) and IGlar (40%; P = .001) at week 26 and 25% lower with IDeg Free-Flex vs IGlar (P = .026) at week 52. Conclusions: IDeg can be administered OD at any time of day, with injection timing varied without compromising glycemic control or safety vs same-time-daily IDeg or IGlar. This may improve basal insulin adherence by allowing injection-time adjustment according to individual needs.

Hyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred

AbstractHyperphosphatemic familial tumoral calcinosis (HFTC) is an autosomal recessive metabolic disorder characterized by extensive phenotypic and genetic heterogeneity. HFTC was shown recently to result from mutations in two genes: GALNT3, coding for a glycosyltransferase responsible for initiating O-glycosylation, and FGF23, coding for a potent phosphaturic protein. All GALNT3 mutations reported so far have been identified in patients of either Middle Eastern or African-American extraction, corroborating numerous historical reports of the disorder in Africa and in the Middle East. In the present study, we describe a patient of Northern European origin displaying typical features of HFTC. Mutation analysis revealed that this patient carries a homozygous novel nonsense mutation in GALNT3 predicted to result in the synthesis of a significantly truncated protein. The present results expand the spectrum of known mutations in GALNT3 and demonstrate the existence of HFTC-causing mutations in this gene outside the Middle Eastern and African-American populations.

The gap between guidelines and practice in the treatment of type 2 diabetes: A nationwide survey in Norway

AIMS In a nationwide sample of patients with type 2 diabetes we assessed the prevalence of complications and compliance with current guidelines. METHODS We recruited a randomly selected sample of 534 men and 441 women aged 18-75 years with type 2 diabetes. A single visit review of medical records, interview, physical examination and laboratory tests was collected. RESULTS The WHO criteria for the metabolic syndrome were met by 79% [74%, 84%]. Thirty percent [28%, 33%] had a history of cardiovascular disease, 13% [11%, 16%] had microalbuminuria, 15% [13%, 18%] had retinopathy, and 23% [21%, 26%] had peripheral neuropathy assessed by a monofilament test. Erectile dysfunction was common (43% [38%, 47%]). Two thirds met the national treatment target for glycaemia (HbA1c <7.5%), one-half the blood pressure target (BP <140/85mmHg), and one-third the target for lipids (total/HDL cholesterol <4). However, only 13% reached the combined targets for glucose, blood pressure and cholesterol control. CONCLUSIONS The classical microvascular complications of diabetes affected a minority of participants while the metabolic syndrome affected the majority. The gap between guidelines and current clinical practice was substantial given that only one of eight patients reached the combined goals for glycaemia, blood pressure and lipid control.

Quality of Care for Patients With Type 2 Diabetes in Primary Care in Norway Is Improving: Results of cross-sectional surveys of 33 general practices in 1995 and 2005

OBJECTIVE—To assess changes in the quality of care in Norway for patients with type 2 diabetes. RESEARCH DESIGN AND METHODS—Two cross-sectional surveys were examined that identified all patients (n = 1,470 in 1995 and n = 2,699 in 2005) with type 2 diabetes attending 33 general practices in 1995 and 2005. RESULTS—Between 1995 and 2005, there were significant improvements in the proportion of patients for whom important laboratory analyses, smoking habits, height, weight, and referral to eye examination were recorded. Mean A1C declined from 7.74 to 7.15%, systolic blood pressure from 150.0 to 140.4 mmHg, and cholesterol from 6.28 to 5.0 mmol/l (P < 0.001, age and sex adjusted). The 10-year risk of coronary heart disease for an average male patient declined from 42 to 29%. CONCLUSIONS—There have been substantial improvements in type 2 diabetes primary care in Norway that are potentially related to major improvements in health outcomes.

Preoperative octreotide treatment of acromegaly: long-term results of a randomised controlled trial

OBJECTIVE Randomised studies have demonstrated a beneficial effect of pre-surgical treatment with somatostatin analogues (SSA) in acromegaly when evaluated early postoperatively. The objective of this study was to evaluate the long-term surgical cure rates. METHODS Newly diagnosed patients were randomised to direct surgery (n=30) or 6-month pretreatment with octreotide LAR (n=32). The patients were evaluated 1 and 5 years postoperatively. Cure was defined as normal IGF1 levels and by normal IGF1 level combined with nadir GH <2 mU/l in an oral glucose tolerance test, all without additional post-operative treatment. A meta-analysis using the other published randomised study with long-term analyses on preoperative SSA treatment was performed. RESULTS The proportion of patients receiving post-operative acromegaly treatment was equal in the two groups. When using the combined criteria for cure, 10/26 (38%) macroadenomas were cured in the pretreatment group compared with 6/25 (24%) in the direct surgery group 1 year postoperatively (P=0.27), and 9/22 (41%) vs 6/22 (27%) macroadenomas, respectively, 5 years postoperatively (P=0.34). In the meta-analysis, 16/45 (36%) macroadenomas were cured using combined criteria in the pretreatment group vs 8/45 (18%) in the direct surgery group after 6-12 months (P=0.06), and 15/41 (37%) vs 8/42 (19%), respectively, in the long-term (P=0.08). CONCLUSION This study does not prove a beneficial effect of SSA pre-surgical treatment, but in the meta-analysis a trend towards significance can be claimed. A potential favourable, clinically relevant response cannot be excluded.

Quality of care for patients with type 2 diabetes in general practice according to patients' ethnic background: a cross-sectional study from Oslo, Norway

BackgroundIn recent decades immigration to Norway from Asia, Africa and Eastern Europe has increased rapidly. The aim of this study was to assess the quality of care for type 2 diabetes mellitus (T2DM) patients from these ethnic minority groups compared with the care received by Norwegians.MethodsIn 2006, electronic medical record data were screened at 11 practices (49 GPs; 58857 patients). 1653 T2DM patients cared for in general practice were identified. Ethnicity was defined as self-reported country of birth. Chi-squared tests, one-way ANOVAs, multiple regression, linear mixed effect models and generalized linear mixed models were used.ResultsDiabetes was diagnosed at a younger age in patients from the ethnic minority groups (South Asians (SA): mean age 44.9 years, Middle East/North Africa (MENA): 47.2 years, East Asians (EA): 52.0 years, others: 49.0 years) compared with Norwegians (59.7 years, p < 0.001). HbA1c, systolic blood pressure (SBP) and s-cholesterol were measured in >85% of patients in all groups with minor differences between minority groups and Norwegians. A greater proportion of the minority groups were prescribed hypoglycaemic medications compared with Norwegians (≥79% vs. 72%, p < 0.001). After adjusting for age, gender, diabetes duration, practice and physician unit, HbA1c (geometric mean) for Norwegians was 6.9% compared to 7.3-7.5% in the minority groups (p < 0.05). The proportion with poor glycaemic control (HbA1c > 9%) was higher in minority groups (SA: 19.6%, MENA: 18.9% vs. Norwegians: 5.6%, p < 0.001. No significant ethnic differences were found in the proportions reaching the combined target: HbA1c ≤ 7.5%, SBP ≤ 140 mmHg, diastolic blood pressure (DBP) ≤ 85 mmHg and total s-cholesterol ≤5.0 mmol/L (Norwegians: 25.5%, SA: 24.9%, MENA: 26.9%, EA: 26.1%, others:17.5%).ConclusionsMean age at the time of diagnosis of T2DM was 8-15 years younger in minority groups compared with Norwegians. Recording of important processes of care measures is high in all groups. Only one in four of most patient groups achieved all four treatment targets and prescribing habits may be sub-optimal. Patients from minority groups have worse glycaemic control than Norwegians which implies that it might be necessary to improve the guidelines to meet the needs of specific ethnic groups.

Glycemic control and complications in patients with type 1 diabetes - a registry-based longitudinal study of adolescents and young adults.

The main aims of this study were to assess longitudinal glycemic control and the prevalence of retinopathy and nephropathy in young people (aged 14–30 yr) with type 1 diabetes in Norway.

Primary care diabetes in Norway

Usually patients with type 1 diabetes are treated by endocrinologists or specialists in internal medicine after the age of 16-18 years, and patients with type 2 diabetes in primary care. Quality of care has improved. A National Diabetes Strategy was launched in 2006. New national clinical guidelines will soon be published.