Kåre I. Birkeland

Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial

BACKGROUND Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes. METHODS We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993. FINDINGS Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups. INTERPRETATION Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.

The effects of acute and chronic exercise on PGC‐1α, irisin and browning of subcutaneous adipose tissue in humans

Irisin was first identified as a peroxisome proliferator‐activated receptor γ co‐activator‐1α (PGC‐1α) dependent myokine with the potential to induce murine brown‐fat‐like development of white adipose tissue. In humans, the regulatory effect of training on muscle FNDC5mRNA expression and subsequently irisin levels in plasma is more controversial. We recruited 26 inactive men (13 normoglycaemic and normal weight, controls; and 13 slightly hyperglycaemic and overweight, pre‐diabetes group) aged 40–65 years for a 12‐week intervention of combined endurance and strength training with four sessions of training per week. Before and after the 12‐week intervention period, participants were exposed to an acute endurance workload of 45 min at 70% of VO2max, and muscle biopsies were taken prior to and after exercise. Skeletal muscle mRNA for PGC1A and FNDC5 correlated and both PGC1A and FNDC5mRNA levels increased after 12 weeks of training in both control and pre‐diabetes subjects. Circulating irisin was reduced in response to 12 weeks of training, and was increased acutely (~1.2‐fold) just after acute exercise. Plasma concentration of irisin was higher in pre‐diabetes subjects compared with controls. There was little effect of 12 weeks of training on selected browning genes in subcutaneous adipose tissue. UCP1mRNA did not correlate with FNDC5 expression in subcutaneous adipose tissue or skeletal muscle or with irisin levels in plasma. We observed no enhancing effect of long‐term training on circulating irisin levels, and little or no effect of training on browning of subcutaneous white adipose tissue in humans.

Metformin in patients with non-alcoholic fatty liver disease: A randomized, controlled trial

Objective. The antidiabetic agent metformin is regularly discussed as a promising treatment for non-alcoholic fatty liver disease (NAFLD), which is characterized by insulin resistance. However, the evidence for its beneficial effects is limited, and conflicting reports have been published. The purpose of this study was to conduct a randomized, double-blind, placebo-controlled trial to test whether metformin improves liver histology in patients with non-alcoholic fatty liver disease. Material and methods. Forty-eight patients with biopsy-proven NAFLD were randomized to treatment with metformin (n=24) or placebo (n=24) for 6 months. A second liver biopsy was obtained in all subjects who completed the trial (n=44). Data analyses are restricted to this group (per-protocol analyses). The primary outcome was changes in histologically assessed liver steatosis. Secondary outcomes were changes in NAFLD activity (NAS)-score, liver steatosis assessed by computed tomography (CT), liver transaminases, body-weight, metabolic variables and inflammatory markers. Results. No significant differences between treatment with metformin or placebo were observed for changes in liver steatosis, assessed either histologically or by CT, NAS-score, liver transaminases or on markers of insulin resistance or inflammation. In contrast, beneficial effects of metformin were observed on changes in body-weight (p<0.001), serum levels of cholesterol (p=0.004), LDL-cholesterol (p<0.001), glucose (p=0.032) and on HbA1c (p=0.020). Conclusions. Treatment with metformin for 6 months was no better than placebo in terms of improvement in liver histology in patients with NAFLD. Nevertheless, the use of metformin could still be beneficial in this group as it is associated with a reduction in serum levels of lipids and glucose. (ClinicalTrials.gov number, NCT00303537)

Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)

Background -Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose co-transporter-2 inhibitor (SGLT-2i) empagliflozin in type 2 diabetes patients with atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose lowering drugs (oGLDs) in six countries to determine if these benefits are seen in real-world practice, and across SGLT-2i class. Methods -Data were collected via medical claims, primary care/hospital records and national registries from the US, Norway, Denmark, Sweden, Germany and the UK. Propensity score for SGLT-2i initiation was used to match treatment groups. Hazard ratios (HRs) for HHF, death and their combination were estimated by country and pooled to determine weighted effect size. Death data were not available for Germany. Results -After propensity matching, there were 309,056 patients newly initiated on either SGLT-2i or oGLD (154,528 patients in each treatment group). Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42% and 5% of the total exposure time in the SGLT-2i class, respectively. Baseline characteristics were balanced between the two groups. There were 961 HHF cases during 190,164 person-years follow up (incidence rate [IR] 0.51/100 person-years). Of 215,622 patients in the US, Norway, Denmark, Sweden, and UK, death occurred in 1334 (IR 0.87/100 person-years), and HHF or death in 1983 (IR 1.38/100 person-years). Use of SGLT-2i, versus oGLDs, was associated with lower rates of HHF (HR 0.61; 95% CI 0.51-0.73; p<0.001); death (HR 0.49; 95% CI 0.41-0.57; p<0.001); and HHF or death (HR 0.54; 95% CI 0.48-0.60, p<0.001) with no significant heterogeneity by country. Conclusions -In this large multinational study, treatment with SGLT-2i versus oGLDs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of T2D patients in real-world practice (NCT02993614). Clinical Trial Registration -URL: ClinicalTrials.gov; Unique Identifier: NCT02993614.Background: Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose cotransporter-2 inhibitor (SGLT-2i) empagliflozin in patients with type 2 diabetes mellitus who have atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose-lowering drugs in 6 countries to determine if these benefits are seen in real-world practice and across SGLT-2i class. Methods: Data were collected via medical claims, primary care/hospital records, and national registries from the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom. Propensity score for SGLT-2i initiation was used to match treatment groups. Hazard ratios for HHF, death, and their combination were estimated by country and pooled to determine weighted effect size. Death data were not available for Germany. Results: After propensity matching, there were 309 056 patients newly initiated on either SGLT-2i or other glucose-lowering drugs (154 528 patients in each treatment group). Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42%, and 5% of the total exposure time in the SGLT-2i class, respectively. Baseline characteristics were balanced between the 2 groups. There were 961 HHF cases during 190 164 person-years follow-up (incidence rate, 0.51/100 person-years). Of 215 622 patients in the United States, Norway, Denmark, Sweden, and the United Kingdom, death occurred in 1334 (incidence rate, 0.87/100 person-years), and HHF or death in 1983 (incidence rate, 1.38/100 person-years). Use of SGLT-2i, versus other glucose-lowering drugs, was associated with lower rates of HHF (hazard ratio, 0.61; 95% confidence interval, 0.51–0.73; P<0.001); death (hazard ratio, 0.49; 95% confidence interval, 0.41–0.57; P<0.001); and HHF or death (hazard ratio, 0.54; 95% confidence interval, 0.48–0.60; P<0.001) with no significant heterogeneity by country. Conclusions: In this large multinational study, treatment with SGLT-2i versus other glucose-lowering drugs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of patients with type 2 diabetes mellitus in real-world practice. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02993614.

The Efficacy and Safety of Insulin Degludec Given in Variable Once-Daily Dosing Intervals Compared With Insulin Glargine and Insulin Degludec Dosed at the Same Time Daily: A 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes

OBJECTIVE The requirement to inject current basal insulin analogs at a fixed time each day may complicate adherence and compromise glycemic control. This trial evaluated the efficacy and safety of varying the daily injection time of insulin degludec (IDeg), an ultra-long-acting basal insulin. RESEARCH DESIGN AND METHODS This 26-week, open-label, treat-to-target trial enrolled adults (≥18 years) with type 2 diabetes who were either insulin naïve and receiving oral antidiabetic drugs (OADs) (HbA1c = 7–11%) or previously on basal insulin ± OAD(s) (HbA1c = 7–10%). Participants were randomized to 1) once-daily (OD) IDeg in a prespecified dosing schedule, creating 8–40-h intervals between injections (IDeg OD Flex; n = 229); 2) once-daily IDeg at the main evening meal (IDeg OD; n = 228); or 3) once-daily insulin glargine at the same time each day (IGlar OD; n = 230). The primary outcome was noninferiority of IDeg OD Flex to IGlar OD in HbA1c reduction after 26 weeks. RESULTS After 26 weeks, IDeg OD Flex, IDeg OD, and IGlar OD improved HbA1c by 1.28, 1.07, and 1.26% points, respectively (estimated treatment difference [IDeg OD Flex − IGlar OD]: 0.04% points [–0.12 to 0.20], confirming noninferiority). No statistically significant differences in overall or nocturnal hypoglycemia were found between IDeg OD Flex and IGlar OD. Comparable glycemic control and rates of hypoglycemia were seen with IDeg OD Flex and IDeg OD. Adverse event profiles were similar across groups. CONCLUSIONS The use of extreme dosing intervals of 8–40 h demonstrates that the daily injection time of IDeg can be varied without compromising glycemic control or safety.

Increased insulin sensitivity and fibrinolytic capacity after dietary intervention in obese women with polycystic ovary syndrome

In overweight women with polycystic ovary syndrome (PCOS), increased insulin resistance has been observed. Since abdominal obesity is associated with impaired fibrinolytic capacity and elevated levels of plasminogen activator inhibitor (PAI-1) and since PAI-1 seems to be related to insulin resistance, we investigated the possible effects of dietary intervention on lipids, fibrinolysis, coagulation, and insulin sensitivity in obese PCOS women. Nine women aged 22 to 39 years (median weight, 97 kg) ate a protein-rich very—low-calorie diet (VLCD) (Nutrilett, Nycomed Pharma, Oslo, Norway; 421 kcal/d) for 4 weeks (part 1). After significant reductions of body fat (13%, P < .01), two of nine women achieved regular menstruation and became pregnant. Six of the remaining women continued on a conventional low-calorie diet (1,000 to 1,500 kcal/d) for the next 20 weeks (part 2), during which time they were generally able to preserve the body fat loss obtained in part 1 of the study. During part 1, significant reductions of total serum cholesterol (29%, P = .001) and fasting triglyceride ([TG] 31%, P < .05) levels were observed, as well as significant reductions of fasting glucose (6%, P < .05) and insulin (20%, P < .05). Insulin sensitivity (glucose disposal rate [GDR]) was increased by 93% (P < .05). After finishing part 2, insulin sensitivity was still significantly increased (86%, P < .05) and PAI-1 activity was significantly reduced (54%, P < .05). Moreover, overall fibrinolytic activity was significantly improved (serum d-dimer concentration increased by 75%, P < .05). In conclusion, through intensive dietary intervention with adequate loss of weight it is possible to change an unfavorable atherothrombogenic risk profile in overweight (PCOS) women. Most convincingly, significantly increased insulin sensitivity and fibrinolytic capacity were observed.

Effect of rhepo administration on serum levels of stfr and cycling performance

PURPOSE We assessed the possibility of using soluble transferrin receptor (sTfR) as an indicator of doping with recombinant erythropoietin (rhEPO). METHODS A double-blind, placebo-controlled study was conducted with the administration of 5,000 U of rhEPO (N = 10) or placebo (N = 10) three times weekly (181-232 U x kg(-1) x wk-1) for 4 wk to male athletes. We measured hematocrit and the concentration of hemoglobin, sTfR, ferritin, EPO, and quantified the effects on performance by measuring time to exhaustion and maximal oxygen uptake (VO2max) on a cycle ergometer. RESULTS Hematocrit increased from 42.7 +/- 1.6% to 50.8 +/- 2.0% in the EPO group, and peaked 1 d after treatment was stopped. In the EPO group, there was an increase in sTfR (from 3.1 +/- 0.9 to 6.3 +/- 2.3 mg x L(-1) , P < 0.001) and in the ratio between sTfR and ferritin (sTfR-ferritin(-1)) (from 3.2 +/- 1.6 to 11.8 +/- 5.1, P < 0.001). The sTfR increase was significant after 1 wk of treatment and remained so for 1 wk posttreatment. Individual values for sTfR throughout the study period showed that 8 of 10 subjects receiving rhEPO, but none receiving placebo, had sTfR levels that exceeded the 95% confidence interval for all subjects at baseline (= 4.6 mg x L(-1)). VO2max increased from 63.6 +/- 4.5 mL x kg(-1) x min(-1) before to 68.1 +/- 5.4 mL x kg(-1) x min(-1) 2 d post rhEPO administration (7% increase, P = 0.001) in the EPO group. Hematocrit, sTfR, sTfR-ferritin(-1), and VO2max did not change in the placebo group. CONCLUSION Serum levels of sTfR may be used as an indirect marker of supranormal erythropoiesis up to 1 wk after the administration of rhEPO, but the effects on endurance performance outlast the increase in sTfR.

Impact of ethnicity on gestational diabetes identified with the WHO and the modified International Association of Diabetes and Pregnancy Study Groups criteria: a population-based cohort study

Objective The International Association of Diabetes and Pregnancy Study Groups (IADPSG) recently proposed new criteria for diagnosing gestational diabetes mellitus (GDM). We compared prevalence rates, risk factors, and the effect of ethnicity using the World Health Organization (WHO) and modified IADPSG criteria. Methods This was a population-based cohort study of 823 (74% of eligible) healthy pregnant women, of whom 59% were from ethnic minorities. Universal screening was performed at 28±2 weeks of gestation with the 75 g oral glucose tolerance test (OGTT). Venous plasma glucose (PG) was measured on site. GDM was diagnosed as per the definition of WHO criteria as fasting PG (FPG) ≥7.0 or 2-h PG ≥7.8 mmol/l; and as per the modified IADPSG criteria as FPG ≥5.1 or 2-h PG ≥8.5 mmol/l. Results OGTT was performed in 759 women. Crude GDM prevalence was 13.0% with WHO (Western Europeans 11%, ethnic minorities 15%, P=0.14) and 31.5% with modified IADPSG criteria (Western Europeans 24%, ethnic minorities 37%, P< 0.001). Using the WHO criteria, ethnic minority origin was an independent predictor (South Asians, odds ratio (OR) 2.24 (95% confidence interval (CI) 1.26–3.97); Middle Easterners, OR 2.13 (1.12–4.08)) after adjustments for age, parity, and prepregnant body mass index (BMI). This increased OR was unapparent after further adjustments for body height (proxy for early life socioeconomic status), education and family history of diabetes. Using the modified IADPSG criteria, prepregnant BMI (1.09 (1.05–1.13)) and ethnic minority origin (South Asians, 2.54 (1.56–4.13)) were independent predictors, while education, body height and family history had little impact. Conclusion GDM prevalence was overall 2.4-times higher with the modified IADPSG criteria compared with the WHO criteria. The new criteria identified many subjects with a relatively mild increase in FPG, strongly associated with South Asian origin and prepregnant overweight.

Weight loss, cardiovascular risk factors, and quality of life after gastric bypass and duodenal switch: a randomized trial.

BACKGROUND Gastric bypass and duodenal switch are currently performed bariatric surgical procedures. Uncontrolled studies suggest that duodenal switch induces greater weight loss than gastric bypass. OBJECTIVE To determine whether duodenal switch leads to greater weight loss and more favorable improvements in cardiovascular risk factors and quality of life than gastric bypass. DESIGN Randomized, parallel-group trial. (ClinicalTrials.gov registration number: NCT00327912) SETTING 2 academic medical centers (1 in Norway and 1 in Sweden). PATIENTS 60 participants with a body mass index (BMI) between 50 and 60 kg/m(2). INTERVENTION Gastric bypass (n = 31) or duodenal switch (n = 29). MEASUREMENTS The primary outcome was the change in BMI after 2 years. Secondary outcomes included anthropometric measures; concentrations of blood lipids, glucose, insulin, C-reactive protein, and vitamins; and health-related quality of life and adverse events. RESULTS Fifty-eight of 60 participants (97%) completed the study. The mean reductions in BMI were 17.3 kg/m(2) (95% CI, 15.7 to 19.0 kg/m(2)) after gastric bypass and 24.8 kg/m(2) (CI, 23.0 to 26.5 kg/m(2)) after duodenal switch (mean between-group difference, 7.44 kg/m(2) [CI, 5.24 to 9.64 kg/m(2)]; P < 0.001). Total cholesterol concentration decreased by 0.24 mmol/L (CI, -0.03 to 0.50 mmol/L) (9.27 mg/dL [CI, -1.16 to 19.3 mg/dL]) after gastric bypass and 1.07 mmol/L (CI, 0.79 to 1.35 mmol/L) (41.3 mg/dL [CI, 30.5 to 52.1 mg/dL]) after duodenal switch (mean between-group difference, 0.83 mmol/L [CI, 0.48 to 1.18 mmol/L]; 32.0 mg/dL [CI, 18.5 to 45.6 mg/dL]; P ≤ 0.001). Reductions in low-density lipoprotein cholesterol concentration, anthropometric measures, fat mass, and fat-free mass were also greater after duodenal switch (P ≤ 0.010 for each between-group comparison). Both groups had reductions in blood pressure and mean concentrations of glucose, insulin, and C-reactive protein, with no between-group differences. The duodenal switch group, but not the gastric bypass group, had reductions in concentrations of vitamin A and 25-hydroxyvitamin D. Most Short Form-36 Health Survey dimensional scores improved in both groups, with greater improvement in 1 of 8 domains (bodily pain) after gastric bypass. From surgery until 2 years, 10 participants (32%) had adverse events after gastric bypass and 18 (62%) after duodenal switch (P = 0.021). Adverse events related to malnutrition occurred only after duodenal switch. LIMITATION Clinical experience was greater with gastric bypass than with duodenal switch at the study centers. CONCLUSION Duodenal switch surgery was associated with greater weight loss, greater reductions of total and low-density lipoprotein cholesterol concentrations, and more adverse events. Improvements in other cardiovascular risk factors and quality of life were similar after both procedures. PRIMARY FUNDING SOURCE South-Eastern Norway Regional Health Authority.

Insulin Degludec in Type 1 Diabetes: A randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine

OBJECTIVE Insulin degludec (IDeg) is a basal insulin that forms soluble multihexamers after subcutaneous injection, resulting in an ultra-long action profile. We assessed the efficacy and safety of IDeg formulations administered once daily in combination with mealtime insulin aspart in people with type 1 diabetes. RESEARCH DESIGN AND METHODS In this 16-week, randomized, open-label trial, participants (mean: 45.8 years old, A1C 8.4%, fasting plasma glucose [FPG] 9.9 mmol/L, BMI 26.9 kg/m2) received subcutaneous injections of IDeg(A) (600 μmol/L; n = 59), IDeg(B) (900 μmol/L; n = 60), or insulin glargine (IGlar; n = 59), all given once daily in the evening. Insulin aspart was administered at mealtimes. RESULTS At 16 weeks, mean A1C was comparable for IDeg(A) (7.8 ± 0.8%), IDeg(B) (8.0 ± 1.0%), and IGlar (7.6 ± 0.8%), as was FPG (8.3 ± 4.0, 8.3 ± 2.8, and 8.9 ± 3.5 mmol/L, respectively). Estimated mean rates of confirmed hypoglycemia were 28% lower for IDeg(A) compared with IGlar (rate ratio [RR]: 0.72 [95% CI 0.52–1.00]) and 10% lower for IDeg(B) compared with IGlar (RR: 0.90 [0.65–1.24]); rates of nocturnal hypoglycemia were 58% lower for IDeg(A) (RR: 0.42 [0.25–0.69]) and 29% lower for IDeg(B) (RR: 0.71 [0.44–1.16]). Mean total daily insulin dose was similar to baseline. The frequency and pattern of adverse events was similar between insulin treatments. CONCLUSIONS In this clinical exploratory phase 2 trial in people with type 1 diabetes, IDeg is safe and well tolerated and provides comparable glycemic control to IGlar at similar doses, with reduced rates of hypoglycemia.