Thomas Almdal

Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials

Objective To assess the effect of targeting intensive glycaemic control versus conventional glycaemic control on all cause mortality and cardiovascular mortality, non-fatal myocardial infarction, microvascular complications, and severe hypoglycaemia in patients with type 2 diabetes. Design Systematic review with meta-analyses and trial sequential analyses of randomised trials. Data sources Cochrane Library, Medline, Embase, Science Citation Index Expanded, LILACS, and CINAHL to December 2010; hand search of reference lists and conference proceedings; contacts with authors, relevant pharmaceutical companies, and the US Food and Drug Administration. Study selection Randomised clinical trials comparing targeted intensive glycaemic control with conventional glycaemic control in patients with type 2 diabetes. Published and unpublished trials in all languages were included, irrespective of predefined outcomes. Data extraction Two reviewers independently assessed studies for inclusion and extracted data related to study methods, interventions, outcomes, risk of bias, and adverse events. Risk ratios with 95% confidence intervals were estimated with fixed and random effects models. Results Fourteen clinical trials that randomised 28 614 participants with type 2 diabetes (15 269 to intensive control and 13 345 to conventional control) were included. Intensive glycaemic control did not significantly affect the relative risks of all cause (1.02, 95% confidence interval 0.91 to 1.13; 28 359 participants, 12 trials) or cardiovascular mortality (1.11, 0.92 to 1.35; 28 359 participants, 12 trials). Trial sequential analyses rejected a relative risk reduction above 10% for all cause mortality and showed insufficient data on cardiovascular mortality. The risk of non-fatal myocardial infarction may be reduced (relative risk 0.85, 0.76 to 0.95; P=0.004; 28 111 participants, 8 trials), but this finding was not confirmed in trial sequential analysis. Intensive glycaemic control showed a reduction of the relative risks for the composite microvascular outcome (0.88, 0.79 to 0.97; P=0.01; 25 600 participants, 3 trials) and retinopathy (0.80, 0.67 to 0.94; P=0.009; 10 793 participants, 7 trials), but trial sequential analyses showed that sufficient evidence had not yet been reached. The estimate of an effect on the risk of nephropathy (relative risk 0.83, 0.64 to 1.06; 27 769 participants, 8 trials) was not statistically significant. The risk of severe hypoglycaemia was significantly increased when intensive glycaemic control was targeted (relative risk 2.39, 1.71 to 3.34; 27 844 participants, 9 trials); trial sequential analysis supported a 30% increased relative risk of severe hypoglycaemia. Conclusion Intensive glycaemic control does not seem to reduce all cause mortality in patients with type 2 diabetes. Data available from randomised clinical trials remain insufficient to prove or refute a relative risk reduction for cardiovascular mortality, non-fatal myocardial infarction, composite microvascular complications, or retinopathy at a magnitude of 10%. Intensive glycaemic control increases the relative risk of severe hypoglycaemia by 30%.

Glycaemic control of Type 1 diabetes in clinical practice early in the 21st century: an international comparison

Improving glycaemic control in people with Type 1 diabetes is known to reduce complications. Our aim was to compare glycaemic control among people with Type 1 diabetes using data gathered in regional or national registries.

Comparison of metformin and insulin versus insulin alone for type 2 diabetes: systematic review of randomised clinical trials with meta-analyses and trial sequential analyses

Objectives To compare the benefits and harms of metformin and insulin versus insulin alone as reported in randomised clinical trials of patients with type 2 diabetes. Design Systematic review of randomised clinical trials with meta-analyses and trial sequential analyses. Data sources The Cochrane Library, Medline, Embase, Science Citation Index Expanded, Latin American Caribbean Health Sciences Literature, and Cumulative Index to Nursing and Allied Health Literature until March 2011. We also searched abstracts presented at the American Diabetes Association and European Association for the Study of Diabetes Congresses, contacted relevant trial authors and pharmaceutical companies, hand searched reference lists of included trials, and searched the US Food and Drug Administration website. Review methods Two authors independently screened titles and abstracts for randomised clinical trials comparing metformin and insulin versus insulin alone (with or without placebo) in patients with type 2 diabetes, older than 18 years, and with an intervention period of at least 12 weeks. We included trials irrespective of language, publication status, predefined outcomes, antidiabetic interventions used before randomisation, and reported outcomes. Results We included 26 randomised trials with 2286 participants, of which 23 trials with 2117 participants could provide data. All trials had high risk of bias. Data were sparse for outcomes relevant to patients. Metformin and insulin versus insulin alone did not significantly affect all cause mortality (relative risk 1.30, 95% confidence interval 0.57 to 2.99) or cardiovascular mortality (1.70, 0.35 to 8.30). Trial sequential analyses showed that more trials were needed before reliable conclusions could be drawn regarding these outcomes. In a fixed effect model, but not in a random effects model, severe hypoglycaemia was significantly more frequent with metformin and insulin than with insulin alone (2.83, 1.17 to 6.86). In a random effects model, metformin and insulin resulted in reduced HbA1c, weight gain, and insulin dose, compared with insulin alone; trial sequential analyses showed sufficient evidence for a HbA1c reduction of 0.5%, lower weight gain of 1 kg, and lower insulin dose of 5 U/day. Conclusions There was no evidence or even a trend towards improved all cause mortality or cardiovascular mortality with metformin and insulin, compared with insulin alone in type 2 diabetes. Data were limited by the severe lack of data reported by trials for patient relevant outcomes and by poor bias control.

Increased Mortality in Patients Hospitalized with Primary Hyperparathyroidism during the Period 1977–1993 in Denmark

The aim of the present study was to determine whether patients with the incident hospital diagnosis of primary hyperparathyroidism (PHPT) in Denmark during the period 1977–1993 had an increased mortality from cardiovascular disease and cancer compared to the rest of the Danish population. In a random sample of half of the Danish population, all patients with an incident hospital diagnosis of PHPT were identified in the National Hospital Patients Register. The mortality in the cohort was analyzed and compared with the background population. A cohort of 1578 patients was identified. Follow-up of 1179 women and 376 men, who did not die in the same month as the incident PHPT diagnosis, was made through 1993. Of these, 312 (20%) died within the follow-up period. The standard mortality ratio (SMR) for women was 1.7 (95% confidence interval [95% CI]: 1.5–1.9). SMR for men was 1.6 (95% CI: 1.3–2.0). In women an increased mortality from ischemic heart disease, cerebrovascular disease, and cancer was found. In men an increased mortality from cerebrovascular disease and cancer was found.

Social support and self-management behaviour among patients with Type 2 diabetes

Diabet. Med. 29, 654–661 (2012)

Glucagon increases hepatic efficacy for urea synthesis

The effect of glucagon on the relation between urea synthesis and blood amino acid concentration was studied in seven healthy volunteers. Alanine was given as prime-continuous infusions and, after 1 hr for equilibration, the urea nitrogen synthesis rate was measured in two periods of about 2 hrs as urinary excretion corrected for accumulation and intestinal hydrolysis. During one of the periods, glucagon was infused to obtain a constant concentration of 200-1200 ng/l. The spontaneous urea synthesis during the alanine infusion was 86-141 mmol/hr and linearly related to the alanine concentrations of 1.33-2.99 mmol/l. The hepatic clearance of alanine-nitrogen to urea-nitrogen, assessed by the ratio between the increase in the urea synthesis rate and alanine concentration, was 23 +/- 4 l/hr (mean +/- S.D.). Glucagon increased the rate of urea synthesis by 35 +/- 11 mmol/hr (p less than 0.02) and decreased the alanine concentration by 0.22 +/- 0.06 mmol/l (p less than 0.01). Glucagon increased the hepatic nitrogen clearance to an average of 42 +/- 13 l/hr (p less than 0.01). The difference between infusion of amino-nitrogen and appearance of urea-nitrogen was +15 +/- 10 mmol/hr during alanine infusion alone and -11 +/- 25 mmol/hr during exogenous glucagon. The loss of nitrogen could be accounted for by depletion of non-alanine amino acids from the blood. Glucagon increases the efficacy of urea synthesis, which may be of importance for catabolism by changing the hepatic contribution to nitrogen homeostasis.

Effect of Hyperglycemia on Mitochondrial Respiration in Type 2 Diabetes

AIM Skeletal muscle mitochondrial content is reduced in type 2 diabetes mellitus (T2DM). Whether hyperglycemia inhibits mitochondrial biogenesis and/or function is unknown. This study examined the effect of different levels of glycemia on skeletal muscle mitochondrial function in patients with T2DM. PATIENTS AND METHODS Eleven patients with T2DM [9 males, 2 females; age, 52.8 +/- 2.5 yr (mean +/- se); body mass index, 30.2 +/- 1.1 kg/m(2)] in poor glycemic control were treated with insulin aspart and NPH insulin for a median period of 46 d (range, 31-59). Mitochondrial respiration and citrate synthase activity (a marker of mitochondrial content) were measured before and after treatment. Eleven healthy subjects (age, 53.3 +/- 2.7 yr; body mass index, 30.6 +/- 1.1 kg/m(2)) were included as controls. RESULTS Hemoglobin A1c (9.1 +/- 0.5 to 7.5 +/- 0.3%; P < 0.001) and fasting plasma glucose (12.7 +/- 1.1 to 6.5 +/- 0.3 mmol/liter; P < 0.001) were reduced after treatment. Mitochondrial respiration per milligram muscle was lower in T2DM compared to controls [substrates for complex I, 24% lower (P < 0.05); substrates for complex I+II, 17% lower (P < 0.05)]. Mitochondrial respiration and citrate synthase activity did not differ before and after improvements in glycemic control, but mitochondrial respiration correlated with fasting plasma glucose before (r(2) = 0.53; P < 0.05) but not after treatment [r(2) = 0.0024; not significant (NS)]. Mitochondrial respiration normalized to mitochondrial content did not differ between control subjects and patients with T2DM. DISCUSSION Mitochondrial respiration and content was not improved after significant improvements in glycemic control. However, severe hyperglycemia inhibited respiration reversibly, but moderate hyperglycemia and mitochondrial function were not correlated.

Regional Anatomic Differences in Skeletal Muscle Mitochondrial Respiration in Type 2 Diabetes and Obesity

CONTEXT Previous studies on leg skeletal musculature have demonstrated mitochondrial dysfunction associated with type 2 diabetes mellitus (T2DM), but it is not known whether mitochondrial dysfunction is present in the upper extremities. OBJECTIVE The aim of the study was to compare mitochondrial respiration and markers of mitochondrial content in skeletal muscle of arm and leg in patients with T2DM and obese control subjects. PATIENTS Ten patients with T2DM (age, 52.3 +/- 2.7 yr; body mass index, 30.1 +/- 1.2 kg/m(2)) (mean +/- se) were studied after a 2-wk washout period of oral antihyperglycemic agents. Ten control subjects (age, 54.3 +/- 2.8 yr; body mass index, 30.4 +/- 1.2 kg/m(2)) with normal fasting and 2-h oral glucose tolerance test blood glucose levels were also included. MAIN OUTCOME MEASURE We measured mitochondrial respiration in saponin-treated skinned muscle fibers from biopsies of m. deltoideus and m. vastus lateralis using high-resolution respirometry. RESULTS In the arm, mitochondrial respiration and citrate synthase activity did not differ between groups, but mitochondrial respiration per milligram of muscle was significantly higher in the leg muscle of the control subjects compared to T2DM. Fiber type compositions in arm and leg muscles were not different between the T2DM and control group, and maximum rate of O(2) consumption did not differ between the groups. CONCLUSION The results demonstrate that reduced mitochondrial function in T2DM is only present in the leg musculature. This novel finding suggests that mitochondrial dysfunction is not a primary defect affecting all skeletal muscle but could be related to a decreased response to locomotor muscle use in T2DM.

Minor long-term changes in weight have beneficial effects on insulin sensitivity and β-cell function in obese subjects

SUMMARY

Glucagon Immunoneutralization in Diabetic Rats Normalizes Urea Synthesis and Decreases Nitrogen Wasting

To study the effect of glucagon neutralization on urea synthesis in diabetic rats, animals with newly induced (75 mg/kg streptozocin) experimental diabetes mellitus were divided into two groups. One group was given one weekly injection of nonimmune rabbit serum (n = 6), and the other group was given one weekly injection of a specific high-titer antibody against pancreatic glucagon (n = 6). Four weeks later, serum-treated diabetic rats had fasting glucagon concentrations 2–3 times higher than nondiabetic controls given one weekly injection of saline (control). Plasma glucagon binding capacity of diabetic rats given glucagon antibodies was 10–15 times higher than the glucagon concentration. A second group of nondiabetic controls were given nonimmune serum. Blood glucose concentration and urinary glucose output were identical in both groups of diabetic animals. Food intake doubled in both groups of diabetic rats. In control rats, the accumulated nitrogen balance, determined weekly for 4 wk, was positive at 81 ± 3.1 mmol/96 h; in serum-treated diabetic rats, the accumulated nitrogen balance was negative, −8.3 ± 2.4 mmol/96 h throughout the 4 wk, whereas it was higher at 4.7 ± 2.3 mmol/96 h in the glucagon antibody-treated diabetic rats (P < 0.05). The capacity of urea synthesis determined after 4 wk in both groups of nondiabetic controls was 8.4 ± 1.6 μmol · min−1 · 100 g−1 body wt; in the serum-treated diabetic group, it was 21.3 ± 1.9 μmol · min−1 · 100 g−1 body wt (P < 0.01 vs. control); and in the glucagon antibody–treated diabetic group, it was 8.6 ± 0.7 μmol · min−1 · 100 g−1 body wt (P < 0.01 vs. serum-treated diabetic). In the serum-treated diabetic group, the nitrogen content of muscle and heart fell significantly to 56 and 81% of control rats, respectively (P < 0.05). In the glucagon antibody–treated diabetic group, muscle and heart nitrogen content fell significantly less, i.e., to 67 and 88%, respectively (P < 0.05 vs. serum-treated diabetic). The results demonstrate that glucagon immunoneutralization in diabetic rats normalizes the capacity for hepatic aminonitrogen-to-urea conversion and reduces diabetic nitrogen loss by 25% without affecting hyperglycemia.