Efficacy and safety of givosiran for acute hepatic porphyria: Final results of the randomized phase III ENVISION trial.

BACKGROUND & AIMS: Acute hepatic porphyria (AHP) is caused by defects in hepatic heme biosynthesis, leading to disabling acute neurovisceral attacks and chronic symptoms. In ENVISION (NCT03338816), givosiran treatment for 6 months reduced attacks and other disease manifestations compared with placebo. Herein, we report data from the 36-month final analysis of ENVISION. METHODS: Ninety-four patients with AHP (age ≥12 years) and recurrent attacks were randomized 1:1 to monthly double-blind subcutaneous givosiran 2.5 mg/kg (n = 48) or placebo (n = 46) for 6 months. In the open-label extension (OLE) period, 93 patients received givosiran 2.5 or 1.25 mg/kg for 6 months or more before transitioning to 2.5 mg/kg. Endpoints were exploratory unless otherwise noted. RESULTS: During givosiran treatment, the median annualized attack rate (AAR) was 0.4. Through Month 36, annualized days of hemin use remained low in the continuous givosiran group (median, 0.0 to 0.4) and decreased in the placebo crossover group (16.2 to 0.4). At end of OLE, in the continuous givosiran and placebo crossover groups, 86% and 92%, respectively, had 0 attacks. AAR was lower than historical AAR in 98% and 100%, respectively (post hoc analysis), and there were 0 days of hemin use in 88% and 90%, respectively. The 12-item short-form health survey physical and mental component summary scores increased by 8.6 and 8.1, respectively (continuous givosiran) and 9.4 and 3.2, respectively (placebo crossover). EQ-5D health-related questionnaire scores increased by 18.9 (continuous givosiran) and 9.9 (placebo crossover). Lower urinary delta-aminolevulinic acid and porphobilinogen levels were sustained. Safety findings demonstrated a continued positive risk/benefit profile for givosiran. CONCLUSIONS: Long-term monthly givosiran treatment provides sustained and continued improvement in clinical manifestations of AHP. GOV IDENTIFIER: NCT03338816. EUDRACT NUMBER: 2017-002432-17. IMPACT AND IMPLICATIONS: Acute hepatic porphyria (AHP) is a group of rare, chronic, multisystem disorders associated with overproduction and accumulation of neurotoxic heme intermediates (delta-aminolevulinic acid and porphobilinogen), sometimes resulting in recurrent acute attacks and long-term complications. Givosiran, a small-interfering RNA that prevents accumulation of delta-aminolevulinic acid and porphobilinogen, is approved for the treatment of AHP. These final 36-month results of ENVISION, a phase III study of givosiran in patients with AHP and recurrent attacks, show that long-term monthly treatment with givosiran leads to continuous and sustained reductions in annualized attack rate and use of hemin over time, as well as improved quality of life, with an acceptable safety profile. These results are important for physicians, patients, families, and caregivers who are grappling with this debilitating and potentially life-threatening disease with few effective and tolerable treatment options.

Cohort profile: the Funen Diabetes Database-a population-based cohort of patients with diabetes in Denmark.

PURPOSE: Detailed population-based data are essential to understanding the epidemiology of diabetes and its clinical course. This article describes the Funen Diabetes Database (FDDB). The purpose of the FDDB was to serve as a shared electronic medical record system for healthcare professionals treating patients with diabetes. The cohort can also be used for research. PARTICIPANTS: The FDDB covers a geographical area of almost 500 000 Danish inhabitants. It currently includes 3691 patients with type 1 diabetes, 19 085 patients with type 2 diabetes, 292 patients with other types of diabetes and 5992 patients with an unknown type of diabetes. Patients have been continuously enrolled from general practitioners and endocrinology departments in the Funen area in Denmark since 2003. Patients undergo a clinical work-up at their first diabetes contact and during follow-up visits. The information collected includes type of diabetes contact, blood pressure, height, weight, lifestyle factors (smoking, exercise), laboratory records (eg, haemoglobin A1c and cholesterol levels), results from foot examinations (eg, pulse, cutaneous sensitivity and ankle brachial index), results from eye examinations (eg, degree of retinopathy assessed by retinal photo and eye examination), glucose-lowering drugs and diabetic complications. FINDINGS TO DATE: The FDDB cohort was followed for a total of 212 234 person-years up to 2016. A cross-sectional study described the prevalence of diabetic retinopathy and its associated risk factors. The clinical outcomes of patients with type 1 diabetes, type 2 diabetes and latent autoimmune diabetes in adults have been assessed. Linkage to population-based medical registries with complete follow-up has enabled the collection of extensive continuous data on general practice contacts, diagnoses and procedures from hospital contacts, medication use and mortality. FUTURE PLANS: The FDDB serves as a strong data resource that will be used in future studies of diabetes epidemiology with focus on occurrence, risk factors, treatment, complications and prognosis.

Diagnosing diabetes mellitus in patients with porphyria cutanea tarda.

The prevalence of diabetes mellitus is increased in patients with porphyria cutanea tarda. Different tests are available for diagnosing and screening for type II diabetes mellitus, however choosing the most suitable test is challenging. The pitfalls in the different tests along with the interfering comorbidities and treatments concerning patients with porphyria cutanea tarda complicate diagnosing these patients with diabetes mellitus. HbA1c, fasting glucose, or oral glucose tolerance are the current available tests, with HbA1c as first choice. Measuring HbA1c requires no fasting, however HbA1c can be false low if the patient is treated with phlebotomy or has liver cirrhosis or chronic hepatitis. Instead fasting glucose and oral glucose tolerance tests can be used if the patient is not acutely ill. If either of the tests give a result in the diagnostic range, the test should be repeated if the patient has no clinical symptoms of diabetes. Diagnosing diabetes mellitus is important for the purpose of early intervention, and this review provides the knowledge needed to diagnose this special patient group properly.

Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans: a randomised trial.

AIMS/HYPOTHESIS: Metformin is believed to reduce glucose levels primarily by inhibiting hepatic glucose production. Recent data indicate that metformin antagonises glucagon-dependent glucose output, suggesting that compensatory mechanisms protect against hypoglycaemia. Here, we examined the effect of metformin on glucose metabolism in humans after a glycogen-depleting fast and the role of reduced-function alleles in OCT1 (also known as SLC22A1). METHODS: In a randomised, crossover trial, healthy individuals with or without reduced-function alleles in OCT1 were fasted for 42 h twice, either with or without prior treatment with 1 g metformin twice daily. Participants were recruited from the Pharmacogenomics Biobank of the University of Southern Denmark. Treatment allocation was generated by the Good Clinical Practice Unit, Odense University Hospital, Denmark. Variables of whole-body glucose metabolism were assessed using [3-(3)H]glucose, indirect calorimetry and measurement of substrates and counter-regulatory hormones. The primary outcome was endogenous glucose production (EGP). RESULTS: Thirty-seven individuals were randomised. Thirty-four completed the study (12 had none, 13 had one and nine had two reduced-function alleles in OCT1). Three were excluded from the analysis because of early dropout. Metformin significantly stimulated glucose disposal rates and non-oxidative glucose metabolism with no effect on glucose oxidation. This increase in glucose utilisation was explained by a concomitant increase in glycolytic flux and accompanied by increased EGP, most likely mediated by increased plasma lactate, glucagon and cortisol levels. There was no effect of reduced-function OCT1 alleles on any of these measures. All individuals completed the glycogen-depleting fast without hypoglycaemia. CONCLUSIONS/INTERPRETATION: Metformin stimulates glycolytic glucose utilisation and lactate production in the glycogen-depleted state. This may trigger a rise in glucose counter-regulatory hormones and subsequently an increase in EGP, which protects against hypoglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT01400191 FUNDING: Danish Research Council for Health and Disease (0602-02695B) and Odense University Hospital Free Research Fund, 2012.

Steady-state pharmacokinetics of metformin is independent of the OCT1 genotype in healthy volunteers.

PURPOSE: The aim of the study was to determine the steady-state pharmacokinetics of metformin in healthy volunteers with different numbers of reduced-function alleles in the organic cation transporter 1 gene (OCT1). METHODS: The study was conducted as part of a randomized cross-over trial. Thirty-four healthy volunteers with known OCT1 genotypes (12 with two wild-type alleles, 13 with one and 9 with two reduced-function alleles) were included. In one of the study periods, they were titrated to steady-state with 1 g metformin twice daily. RESULTS: Neither AUC(0-12), C(max) nor Cl(renal) were statistically significantly affected by the number of reduced-function alleles (0, 1 or 2) in OCT1: (AUC(0-12): 0, 1, 2: 14, 13 and 14 h ng/L (P = 0.61)); (C(max): 0, 1, 2: 2192, 1934 and 2233 ng/mL, (P = 0.26)) and (Cl(renal): 0, 1, 2: 31, 28 and 30 L/h (P = 0.57)) CONCLUSIONS: In a cohort of healthy volunteers, we found no impact of different OCT1 genotypes on metformin steady-state pharmacokinetics.

Glucose effectiveness and insulin sensitivity measurements derived from the non-insulin-assisted minimal model and the clamp techniques are concordant.

BACKGROUND: We investigated the concordance between glucose effectiveness (SG) and insulin sensitivity (SI), derived from the unmodified dynamic non-insulin-assisted intravenous glucose tolerance test (IVGTT) implemented by SG(MM) and SI(MM); simulation analysis and modelling/conversational interaction (SAAM/CONSAM) versus the eu/hyperglycaemic basal insulinaemic and the euglycaemic hyperinsulinaemic clamp (SG(CLAMP) and SI(CLAMP)). METHODS: Twenty-seven of 30 normoglycaemic subjects completed a (1) euglycaemic hyperinsulinaemic clamp, (2) 6-h eu/hyperglycaemic near-normoinsulinaemic pancreatic clamp with hyperglycaemia present over the final 2 h of the clamp (Day 2 study), (3) identical clamp to (2) but with euglycaemia maintained over the entire 6 h (Day 3 study) and (4) IVGTT. SG(CLAMP) was calculated in two ways based on data from study (2) alone (Day 2 SG(CLAMP210-240')) or from data from study day (2) and (3) (Day 2-3 SG(CLAMP330-360')). RESULTS: SG(MM) was unrelated to the magnitude of endogenous insulin release (AIR). The single-day (Day 2) and two-day (Day 2 and 3) SG(CLAMP) protocols correlated (r = 0.72, p = 0.003), but SG(CLAMP210-240') was significantly (p = 0.001) higher than SG(CLAMP330-360'). Employing the Day 2 and 3 SG(CLAMP) protocol, the whole body SG(CLAMP330-360') was similar to SG(MM) (1.80 ± 0.82 versus 1.73 ± 0.58 dL/min) and correlated (r = 0.45, p < 0.02). SG(CLAMP210-240') did not correlate with SG(MM) (r = 0.24). SI(MM) and SI(CLAMP) were similar (0.093 ± 0.060 versus 0.087 ± 0.029 dL/min per mU/L) and correlated (r = 0.76, p < 0.001). CONCLUSIONS: The time-dependent increase in glucose disposal observed during a prolonged 6-h clamp significantly influences the estimation of SG(CLAMP), and significant concordance coefficients are observed between SG(MM), and SG(CLAMP330-360'), and SI(MM) and SI(CLAMP).

Hepatic autoregulation: response of glucose production and gluconeogenesis to increased glycogenolysis.

The effect of increased glycogenolysis, simulated by galactose's conversion to glucose, on the contribution of gluconeogenesis (GNG) to hepatic glucose production (GP) was determined. The conversion of galactose to glucose is by the same pathway as glycogen's conversion to glucose, i.e., glucose 1-phosphate --> glucose 6-phosphate --> glucose. Healthy men (n = 7) were fasted for 44 h. At 40 h, hepatic glycogen stores were depleted. GNG then contributed approximately 90% to a GP of approximately 8 micromol.kg(-1).min(-1). Galactose, 9 g/h, was infused over the next 4 h. The contribution of GNG to GP declined from approximately 90% to 65%, i.e., by approximately 2 micromol.kg(-1).min(-1). The rate of galactose conversion to blood glucose, measured by labeling the infused galactose with [1-(2)H]galactose (n = 4), was also approximately 2 micromol.kg(-1).min(-1). The 41st h GP rose by approximately 1.5 micromol.kg(-1).min(-1) and then returned to approximately 9 micromol.kg(-1).min(-1), while plasma glucose concentration increased from approximately 4.5 to 5.3 mM, accompanied by a rise in plasma insulin concentration. Over 50% of the galactose infused was accounted for in blood glucose and hepatic glycogen formation. Thus an increase in the rate of GP via the glycogenolytic pathway resulted in a concomitant decrease in the rate of GP via GNG. While the compensatory response to the galactose administration was not complete, since GP increased, hepatic autoregulation is operative in healthy humans during prolonged fasting.

Effects of troglitazone in young first-degree relatives of patients with type 2 diabetes.

OBJECTIVE: Insulin resistance is a key characteristic of first-degree relatives of patients with type 2 diabetes. We therefore treated young, glucose-tolerant relatives with the insulin action enhancer troglitazone in order to determine the effects on insulin sensitivity, glucose metabolism, and glycogen synthase activity. RESEARCH DESIGN AND METHODS: Relatives were randomized in a double-blind manner and treated for 12 weeks with either 200 mg troglitazone or placebo. Before and after treatment, an oral glucose tolerance test (OGTT) and a euglycemic-hyperinsulinemic clamp (40 mU. m(-2). min(-1)) were performed, including 3-(3)H glucose infusion, glycolytic flux calculations, indirect calorimetry, and muscle biopsies. RESULTS: Twelve relatives received troglitazone and 12 placebo (aged 30.8 +/- 2.0 vs. 30.3 +/- 1.6 years, BMI 29.6 +/- 0.8 vs. 30.5 +/- 1.3 kg/m(2); means +/- SE). Area under the curve (AUC) for plasma glucose at the second OGTT was unchanged after troglitazone. In contrast, troglitazone reduced fasting (from 70.3 +/- 6.9 to 52.2 +/- 5.8 vs. 73.6 +/- 11.0 to 73.3 +/- 6.5 pmol/l, P < 0.02) and AUC plasma insulin (mean [CI] from 335.7 [230.9-488.1] to 277.4 [179.4-428.8] vs. 313.8 [218.2-451.2] to 353.9 [208.3-601.3] pmol/l, P < 0.05). Additionally, fasting plasma triglycerides were reduced by troglitazone (from 1.86 +/- 0.33 to 1.38 +/- 0.27 vs. 2.22 +/- 0.44 to 2.35 +/- 0.46 mmol/l, P < 0.01). Insulin-stimulated glucose disposal increased in the troglitazone group (from 208.3 +/- 23.7 to 263.5 +/- 30.4 vs. 197.1 +/- 20.0 to 200.8 +/- 20.8 mg. m(-2). min(-1), P < 0.02) mainly due to increased glucose storage (from 99.9 +/- 17.9 to 146.0 +/- 25.3 vs. 87.1 +/- 16.7 to 87.9 +/- 15.7 mg. m(-2). min(-1), P < 0.02), which took place without altering insulin-stimulated glycogen synthase activity. CONCLUSIONS: In glucose-tolerant first-degree relatives, treatment with troglitazone improved insulin sensitivity almost 50%, primarily due to increased glucose storage. It is suggested that the use of insulin action enhancers can be especially valuable in this group of subjects with a known high risk for developing type 2 diabetes.

The combined effect of triple therapy with rosiglitazone, metformin, and insulin aspart in type 2 diabetic patients.

OBJECTIVE: Type 2 diabetes is caused by reduced insulin secretion and insulin resistance in skeletal muscle and liver. We tested the combination therapy with insulin aspart, rosiglitazone, and metformin with the purpose of treating all three defects in order to test the hypothesis that this "triple therapy" will normalize glucose metabolism. RESEARCH DESIGN AND METHODS: Sixteen obese type 2 diabetic outpatients on human NPH or MIX (regular + NPH insulin) insulin twice daily were randomized to either triple therapy, i.e., insulin aspart (a rapid-acting insulin analog) at meals, metformin (which improves hepatic insulin sensitivity), and rosiglitazone (which improves peripheral insulin sensitivity), or to continue their NPH or MIX insulin twice daily for 6 months. Insulin doses were adjusted in both groups based on algorithms. HbA(1c), insulin dose, hypoglycemic episodes, insulin sensitivity (clamp), hepatic glucose production (tracer), and diurnal profiles of plasma glucose and insulin were used in evaluating treatment. RESULTS: In the triple therapy group, HbA(1c) declined from 8.8 to 6.8% (P < 0.01) without inducing severe hypoglycemic events. Postprandial hyperglycemia was generally avoided, and the diurnal profile of serum insulin showed fast and high peaks without any need to increase insulin dose. In the control group, the insulin dose was increased by 50%, but nevertheless both HbA(1c) and 24-h blood glucose profiles remained unchanged. Insulin sensitivity improved in both skeletal muscle and the liver in the triple therapy group, whereas no change was observed in the control group. CONCLUSIONS: We conclude that treatment of the three major pathophysiological defects in type 2 diabetic subjects by triple therapy significantly improved glucose metabolism in obese type 2 diabetic subjects.

Effects of free fatty acids per se on glucose production, gluconeogenesis, and glycogenolysis.

Insulin-independent effects of a physiological increase in free fatty acid (FFA) levels on fasting glucose production, gluconeogenesis, and glycogenolysis were assessed by administering [6,6-(2)H(2)]-glucose and deuteriated water ((2)H(2)O) in 12 type 1 diabetic patients, during 6-h infusions of either saline or a lipid emulsion. Insulin was either fully replaced (euglycemic group, n = 6), or underreplaced (hyperglycemic group, n = 6). During saline infusions, plasma FFA levels remained unchanged. Glucose concentrations decreased from 6.7 +/- 0.4 to 5.3 +/- 0.4 mmol/l and 11.9 +/- 1.0 to 10.5 +/- 1.0 mmol/l in the euglycemic and hyperglycemic group, respectively. Accordingly, glucose production declined from 84 +/- 5 to 63 +/- 5 mg x m(-2) x min(-1) and from 84 +/- 5 to 68 +/- 4 mg x m(-2) x min(-1), due to declining rates of glycogenolysis but unaltered rates of gluconeogenesis. During lipid infusions, plasma FFA levels increased twofold. In the euglycemic group, plasma glucose increased from 6.8 +/- 0.3 to 7.8 +/- 0.8 mmol/l. Glucose production declined less in the lipid study than in the saline study due to a stimulation of gluconeogenesis by 6 +/- 1 mg x m(-2) x min(-1) and a decline in glycogenolysis that was 6 +/- 2 mg x m(-2) x min(-1) less in the lipid study than in the saline study. In contrast, in the hyperglycemic group, there were no significant effects of elevated FFA on glucose production, gluconeogenesis, or glycogenolysis. In conclusion, a physiological elevation of plasma FFA levels stimulates glycogenolysis as well as gluconeogenesis and causes mild fasting hyperglycemia. These effects of FFA appear attenuated in the presence of hyperglycemia.

Is hepatic glucose production increased in type 2 diabetes mellitus?

Based on recent studies, including our own, using what we consider to be an appropriate technique to estimate rates of hepatic glucose production (HGP), this article can be summarized as follows: 1) HGP in the overnight fasted state is near normal in obese type 2 diabetes (T2D) subjects, i.e., it may be increased by a mean of 12% compared to matched control subjects. 2) Suppression of HGP by insulin shows a rightward shift of the dose response curve (reduced insulin sensitivity) but normal maximal suppression (no maximum velocity defect). 3) In the overnight fasted state, gluconeogenesis is responsible for two thirds of HGP in T2D subjects and is about 5% to 10% increased compared to healthy subjects. 4) Suppression of HGP during a meal is close to normal. 5) The slightly increased HGP values throughout the 24-hour period together with reduced metabolic clearance rate (peripheral insulin resistance) and increased carbohydrate intake is responsible for the increase in fasting plasma glucose values. 6) Hypothetically, the role of the liver in nondiabetic and T2D subjects may be to produce the amount of glucose needed for metabolism in peripheral tissues. If insulin-mediated glucose uptake in skeletal muscle is reduced, plasma glucose will increase due to the "nonsuppressed" HGP values. Plasma glucose continues to rise until glucose-mediated glucose uptake compensates completely for the reduction in insulin-mediated glucose uptake.

Effect of short-term hyperglycemia per se on nociceptive and non-nociceptive thresholds.

Previous animal and human studies have indicated that nociceptive thresholds are decreased by acute hyperglycemia. The results of these studies may be challenged due to methodological problems. We therefore conducted a double-blind, controlled, cross-over study on the effect of acute hyperglycemia on nociceptive and non-nociceptive thresholds in 10 type 1 (insulin-dependent) diabetic patients (diabetes < 5 years) without symptoms or clinical signs of peripheral neuropathy. During an overnight fast, blood glucose concentration was normalized by refract insulin injections. Then, blood glucose was kept at 6 mmol/l for 3 h by an intravenous infusion of glucose and insulin. On one study day, blood glucose was kept at 6 mmol/l for a further 3 h and on another day, blood glucose was elevated to 12 mmol/l during 0.5 h by additional glucose infusion and kept at that level for 2.5 h. Sensory testing was carried out twice during the initial 3 h with euglycemia and 3 times during the following period with either hyper- or euglycemia. The test procedure included determination of pain detection and pain tolerance thresholds to heat (wrists) and pressure (fingers) as well as detection thresholds to warmth/cooling (wrist), vibration (finger), and mechanical (wrist) stimulation. The changes in neither nociceptive nor non-nociceptive thresholds showed any statistically significant differences between the 2 study days. The pressure pain detection and tolerance thresholds showed, however, minor decreases at each of the test days, probably due to cutaneous sensitization caused by the repeated measurements. Compared to baseline, the pressure pain thresholds decreased significantly on the day with hyperglycemia. None of the other thresholds showed such changes.(ABSTRACT TRUNCATED AT 250 WORDS)