This review summarizes the clinical development of a family of ultra-rapid-acting recombinant hum... more This review summarizes the clinical development of a family of ultra-rapid-acting recombinant human insulin formulations. These formulations use ethylenediaminetetraacetic acid (EDTA) to chelate zinc and thereby destabilize NEW INSULINS AND INSULIN THERAPY S-41
Aim Many countries require individuals with diabetes to adhere to standards regarding blood gluco... more Aim Many countries require individuals with diabetes to adhere to standards regarding blood glucose testing in order to be granted or retain a driving licence. Currently, interstitial glucose results may not be used. The aim of this study was to determine whether interstitial glucose measurements using flash glucose-sensing technology can provide additional information to augment safe driving. Methods Sensor data from two European studies (NCT02232698 and NCT02082184) of the FreeStyle Libre Glucose Monitoring System ™ in insulin-treated Type 1 and Type 2 diabetes, 241 and 224 participants respectively, were used to determine the frequency of a low interstitial sensor glucose result (< 3.9 mmol/l) up to 4 h subsequent to a daytime (07:00-21:00 h) capillary blood glucose result ≥ 5 mmol/l. Results Within 4 h of a capillary blood glucose result ≥ 5 mmol/l a sensor glucose result of < 3.9 mmol/l occurred on 22.0% of occasions (2573 of 11 706 blood glucose readings) for those with Type 1 diabetes, and 8.4% of occasions (699/8352) for those with Type 2 diabetes; 13.8% (1610/11 628) and 4.4% (365/8203) within 2 h, and 10.0% (1160/ 11 601) and 3.1% (254/8152) within 1.5 h. Analysis of sensor glucose results 5-7 mmol/l demonstrated the glucose trend arrow descending on 14.7% (1163/7894, Type 1 diabetes) and 9.4% (305/3233, Type 2 diabetes) of occasions. Conclusions Sensor-based glucose information with directional arrows has the potential to support assessment of safe glucose levels associated with driving and offers distinct advantages over blood glucose testing for individuals with Type 1 and Type 2 diabetes to concord with driving safety standards.
Aims: Dapagliflozin, a highly selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), redu... more Aims: Dapagliflozin, a highly selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycaemia and weight in patients with type 2 diabetes (T2DM) by increasing urinary glucose excretion. Long-term glycaemic control, body composition and bone safety were evaluated in patients with T2DM after 102 weeks of dapagliflozin treatment. Materials and methods: This randomized, double-blind, placebo-controlled study (NCT00855166) enrolled patients with T2DM (mean: age 60.7 years; HbA1c 7.17%; BMI 31.9 kg/m 2 ; body weight 91.5 kg) inadequately controlled on metformin. Patients (N=182) were randomly assigned 1:1 to receive dapagliflozin 10 mg/day or placebo added to open-label metformin for a 24-week doubleblind treatment period followed by a 78-week site-and patient-blinded extension period. At week 102, changes from baseline in HbA1c, weight, waist circumference, total body fat mass as measured by Dual-Energy X-ray Absorptiometry (DXA), serum markers of bone turnover, bone mineral density (BMD) as measured by DXA, and adverse events were evaluated. Results: 140 patients (76.9%) completed the study. Over 102 weeks, dapagliflozin-treated patients showed reductions in HbA1c by −0.30%, weight by −4.54 kg, waist circumference by −5.0 cm and fat mass by −2.80 kg without increase in rate of hypoglycaemia. Compared with placebo, no meaningful changes from baseline in markers of bone turnover or BMD were identified over 102 weeks. One fracture occurred in each treatment group. The frequency of UTI and genital infection was similar in both treatment groups. Conclusions: Over 102 weeks, dapagliflozin improved glycaemic control, and reduced weight and fat mass, without affecting markers of bone turnover or BMD in patients with T2DM inadequately controlled on metformin.
adjunct therapy with sodium-glucose cotransporter 2 inhibitors in patients with type 1 diabetes h... more adjunct therapy with sodium-glucose cotransporter 2 inhibitors in patients with type 1 diabetes have become available and regulatory submissions are on the way, with decisions expected early next year. These drugs have the potential of addressing common side effects of insulin therapy such as glycemic variability, weight gain, or hypoglycemia. This must be balanced against notable untoward effects such as increased risk for genital mycotic infections or diabetic ketoacidosis. Mealtime insulin should ideally be absorbed very quickly after injection to counteract the rise in blood glucose with food consumption. Regarding the next-generation mealtime insulin Fiasp (NovoNordisk), it is now available in several markets and more data from the clinical Onset trial program with FiAsp were published or presented during the last year. As we outlined in the previous yearbook, these insulins where thought to be of particular value in insulin pump therapy. However, when the results of the Onset 5 FiAsp pump trial were presented during the 2017 ATTD meeting, the results were controversial. While we are still waiting for the eventual publication of this study, Eli Lilly initiated the PRONTO-Pump phase 3 trial to evaluate the compatibility and safety of their ultrarapid formulation LY 900014 or trepostinil lispro compared with insulin lispro in February 2018. Although clinical data of Adocia's ultra-rapid insulin-known as BioChaperone Lispro-was originally developed together with Lilly, this collaboration was terminated as we reported in last year's article. While initial data for treatment in people with type 1 and type 2 diabetes (T1D and T2D) have now been published, Adocia is still left without a partner to help get BioChaperone Lispro through critical phase 3 trials. Adocia won its first claim against Eli Lilly & Company regarding a disputed milestone payment, and additional claims will be assessed in another hearing, but a decision is not expected until 2019 and the future of the program remains unclear at this time. While the two ultra-long-acting basal insulin analogs, Toujeo (Sanofi) and Tresiba (Novo Nordisk) have now been on the market for several years, we are entering a time during which the efficacy in reducing the risk for hypoglycemia with the ultra-longacting insulins is studied in direct head-to-head randomized controlled trials and also with different methodologies including continuous glucose monitoring. As our review concludes, uncertainty still remains whether there are any clinically meaningful differences between the two at the present time. The first biosimilar insulin (BioIns)-an insulin glargine developed by Eli Lilly and Boehringer Ingelheim called Abasaglar in the EU and Basaglar in the United States (which was approved in the United States, but not as BioIns) has been on the market now for 1 to 2 years in the EU and the United States. It appears as if this BioIns has gained more market acceptance in the United States than in the EU; it is preferred over the originator insulin glargine in major U.S. formularies, which has induced significant reductions in the sales of the originator insulin. The observed decrease in prices varies between countries, with a maximum of up to 30%. Most likely, a plethora of BioInsparticularly insulin glargines-will be on the market within a few years, which might generate some confusion at the levels of both patients and health-care professionals. As we approach the centennial celebration of insulin discovery, the current scientific progress and controversies around the molecule remain thought-provoking. Key Articles Reviewed for the Article Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 1 diabetes. The SWITCH 1 randomized clinical trial
The Journal of Clinical Endocrinology and Metabolism, Feb 1, 1993
The adrenergic regulation of adipose tissue lipolysis and glucose metabolism was investigated in ... more The adrenergic regulation of adipose tissue lipolysis and glucose metabolism was investigated in situ during a standardized mental stress test in 11 nonobese, healthy subjects, using microdialysis of the extracellular water space in sc adipose tissue. Microdialysis probes were inserted in the abdominal sc fat, and were perfused using solvents with or without adrenoceptor blocking agents. The tissue dialysate concentrations of glycerol (lipolysis index) glucose, lactate, and pyruvate were determined. The glycerol concentration in adipose tissue increased markedly during the stress test and decreased in the poststress period. A similar kinetic pattern was observed in blood. In situ administration of the nonselective beta-adrenoceptor blocking agent propranolol almost completely prevented the stress-induced increase in adipose tissue glycerol levels, whereas a nonselective alpha-adrenoceptor blocking agent (phentolamine) was ineffective in this respect. Plasma levels of glucose and lactate remained unaltered during and after the stress test; at the same time plasma pyruvate decreased moderately. By contrast, glucose, lactate, and pyruvate in adipose tissue increased by 25-30% during or after the stress (P &lt; 0.05). The increase in lactate and pyruvate in adipose tissue after the stress was completely off-set by alpha-adrenoceptor blockade in situ, whereas beta-adrenoceptor blockade in situ did not influence the kinetic pattern of these metabolites. It is concluded that the lipolytic activity in human adipose tissue is markedly enhanced during mental stress, owing to adrenergic mechanisms that are mediated via beta-adrenoceptors. After mental stress, adipose tissue glucose utilization is decreased and routed toward nonoxidative pathways. The latter seems to involve adrenergic effects that are mediated via alpha-adrenoceptors.
den). Adipose zinc-a2-glycoprotein is a catabolic marker in cancer and noncancerous states. J Int... more den). Adipose zinc-a2-glycoprotein is a catabolic marker in cancer and noncancerous states. J Intern Med 2012; 271: 414-420. Objective. Zinc-a2-glycoprotein (ZAG) has been proposed as a tumour-derived cancer cachexia factor. However, ZAG is produced by some normal tissues, including white adipose tissue (WAT), and high serum ZAG levels are present in nonmalignant conditions. We determined whether human WAT contributes to serum ZAG levels and how serum and WAT-secreted ZAG levels correlate with catabolism in patients with cancer and in obese subjects undergoing a very low-calorie diet (VLCD) for 11 days. Design ⁄ subjects. ZAG levels in serum and in conditioned medium from WAT ⁄ adipocytes were determined by enzyme-linked immunosorbent assay. ZAG release from WAT in vivo was determined in 10 healthy subjects. The correlation between ZAG and cachexia was studied in 34 patients with newly diagnosed gastrointestinal cancer. The impact of a VLCD on ZAG release and serum levels was assessed in 10 obese women. Results. ZAG was released from abdominal WAT and adipocytes in vitro. However, the arteriovenous differences in vivo showed that there was no significant contribution of WAT to the circulating levels. WAT-secreted but not serum ZAG correlated positively with poor nutritional status but not with fat mass (or body mass index) in patients with gastrointestinal cancer. In obese subjects on a VLCD, ZAG secretion from WAT increased significantly whereas serum levels remained unaltered. Conclusions. ZAG is released from human WAT, but this tissue does not contribute significantly to the circulating levels. WAT-secreted ZAG correlates with nutritional status but not with fat mass in both cancer and nonmalignant conditions. Adipose ZAG is therefore a local factor activated primarily by the catabolic state per se.
adjunct therapy with sodium-glucose cotransporter 2 inhibitors in patients with type 1 diabetes h... more adjunct therapy with sodium-glucose cotransporter 2 inhibitors in patients with type 1 diabetes have become available and regulatory submissions are on the way, with decisions expected early next year. These drugs have the potential of addressing common side effects of insulin therapy such as glycemic variability, weight gain, or hypoglycemia. This must be balanced against notable untoward effects such as increased risk for genital mycotic infections or diabetic ketoacidosis. Mealtime insulin should ideally be absorbed very quickly after injection to counteract the rise in blood glucose with food consumption. Regarding the next-generation mealtime insulin Fiasp (NovoNordisk), it is now available in several markets and more data from the clinical Onset trial program with FiAsp were published or presented during the last year. As we outlined in the previous yearbook, these insulins where thought to be of particular value in insulin pump therapy. However, when the results of the Onset 5 FiAsp pump trial were presented during the 2017 ATTD meeting, the results were controversial. While we are still waiting for the eventual publication of this study, Eli Lilly initiated the PRONTO-Pump phase 3 trial to evaluate the compatibility and safety of their ultrarapid formulation LY 900014 or trepostinil lispro compared with insulin lispro in February 2018. Although clinical data of Adocia's ultra-rapid insulin-known as BioChaperone Lispro-was originally developed together with Lilly, this collaboration was terminated as we reported in last year's article. While initial data for treatment in people with type 1 and type 2 diabetes (T1D and T2D) have now been published, Adocia is still left without a partner to help get BioChaperone Lispro through critical phase 3 trials. Adocia won its first claim against Eli Lilly & Company regarding a disputed milestone payment, and additional claims will be assessed in another hearing, but a decision is not expected until 2019 and the future of the program remains unclear at this time. While the two ultra-long-acting basal insulin analogs, Toujeo (Sanofi) and Tresiba (Novo Nordisk) have now been on the market for several years, we are entering a time during which the efficacy in reducing the risk for hypoglycemia with the ultra-longacting insulins is studied in direct head-to-head randomized controlled trials and also with different methodologies including continuous glucose monitoring. As our review concludes, uncertainty still remains whether there are any clinically meaningful differences between the two at the present time. The first biosimilar insulin (BioIns)-an insulin glargine developed by Eli Lilly and Boehringer Ingelheim called Abasaglar in the EU and Basaglar in the United States (which was approved in the United States, but not as BioIns) has been on the market now for 1 to 2 years in the EU and the United States. It appears as if this BioIns has gained more market acceptance in the United States than in the EU; it is preferred over the originator insulin glargine in major U.S. formularies, which has induced significant reductions in the sales of the originator insulin. The observed decrease in prices varies between countries, with a maximum of up to 30%. Most likely, a plethora of BioInsparticularly insulin glargines-will be on the market within a few years, which might generate some confusion at the levels of both patients and health-care professionals. As we approach the centennial celebration of insulin discovery, the current scientific progress and controversies around the molecule remain thought-provoking. Key Articles Reviewed for the Article Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 1 diabetes. The SWITCH 1 randomized clinical trial
R. has received honoraria and travel grants from Medtronic. T.B. has received consulting fees and... more R. has received honoraria and travel grants from Medtronic. T.B. has received consulting fees and honoraria from Medtronic and Abbott. D.K. has received honoraria from and served on advisory boards for Medtronic, Roche, and LifeScan. M.P. has served on advisory boards for Medtronic, Abbott, and D-Medical. Abbreviations: CGM, continuous glucose monitoring; SMBG, self-monitoring of blood glucose. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
OBJECTIVE-To compare the effect of bedtime NPH insulin or preprandial regular insulin combined wi... more OBJECTIVE-To compare the effect of bedtime NPH insulin or preprandial regular insulin combined with glibenclamide on metabolic control in non-insulindependent diabetes mellitus (NIDDM) patients with secondary failure to sulfonylurea therapy. RESEARCH DESIGN AND M E T H O D S-Eighty NIDDM patients were randomized to treatment with either three preprandial doses of regular insulin (daytime insulinization, group D) or a bedtime dose of NPH insulin (nocturnal insulinization, group N), both regimens being combined with 10.5 mg of glibenclamide. Metabolic profiles were obtained at 0, 6, and 16 weeks. RESULTS-Glycemic control had improved significantly in both groups after 4 months. Fasting blood glucose was significantly lower compared with baseline in both groups. The mean change ± SD in group D was-2.8 ± 3.5 mmol/1 and in group N-6.4 ± 3.0 mmol/1, the reduction being more pronounced in group N compared with group D (P < 0.0001). HbA lc was lowered similarly, from 9.2 ± 1.4 to 7.1 ± 1.2% in group D (P < 0.0001) and from 9.1 ± 1.1 to 7.5 ± 1.5% in group N (P < 0.0001). The total daily insulin doses were similar, 29 ± 11 U in group D and 26 ± 9 U in group N, and the circulating insulin levels during daytime were higher in group D than in group N. Total serum cholesterol and triglycerides were similarly and significantly lowered compared with baseline in both groups. Weight gain was more pronounced in group D (3.4 ± 0.3 kg) than in group N (1.9 ± 1.9 kg; D vs. N, P < 0.002), and the change was inversely correlated with the initial weight but not with the improvement in HbA lc. CONCLUSIONS-The two insulin regimens exert similar effects on glucose metabolism and serum lipids in NIDDM patients on combination therapy. Weight gain is more pronounced in patients given insulin during the daytime when preprandial doses of short-acting insulin are used.
. Pancreatic autoantibodies were determined in 49 patients with Sjögren's syndrome and relate... more . Pancreatic autoantibodies were determined in 49 patients with Sjögren's syndrome and related to functional parameters. Pancreatic duct autoantibodies (PDA) were detected in the sera of three patients, and all showed abnormal exocrine pancreatic function. Islet cell antibodies (ICA) were not detected in the sera of the 49 patients, including two individuals with diabetes mellitus. In conclusion, PDA occur in patients with Sjögren's syndrome, and may be associated with exocrine pancreatic dysfunction.
Using videophotometric capillaroscopy and laser Doppler fluxmetry, we have investigated skin micr... more Using videophotometric capillaroscopy and laser Doppler fluxmetry, we have investigated skin microvascular reactivity in the fingers of 14 diabetic patients with severe, late complications 20 months after combined kidney and pancreas transplantation. The results were compared with those obtained in 20 diabetic patients awaiting pancreas transplantation and in 19 healthy subjects. The capillary blood cell velocity at rest (P < 0.01) and during postocclusive reactive hyperemia (P < 0.05) was significantly lower in both patient groups than in the healthy controls. However, the time to peak capillary blood cell velocity during hyperemia was normal in the post-transplantation group (NS) but significantly prolonged in the pretransplantation group (P < 0.01). The ability to decrease flow during venous stasis-the so called venoarte-riolar reflex-was strongly impaired in the pretransplantation group (P < 0.001) but less so in the post-transplantation group (P <0.05) as compared to healthy controls. It may be concluded that diabetic patients, after combined kidney and pancreas transplantation, show a tendency towards better microvascular reactivity than those awaiting transplantation.
Objectives. To estimate the total direct medical costs to society for patients with type 2 diabet... more Objectives. To estimate the total direct medical costs to society for patients with type 2 diabetes in Sweden and to investigate how different factors, for example diabetic late complications, affect costs. Design. Cross-sectional data regarding health care utilization, clinical characteristics and quality of life, were collected at a single time-point. Data on resource use cover the 6-month period prior to this time point. Setting. Patient recruitment and data collection were performed in nine primary care centres in three main regions in Sweden. Subjects. Only patients with an age at diabetes diagnosis $ 30 years (type 2 diabetes) were included (n = 777). Results. The total annual direct medical costs for the Swedish diabetes type 2 population were estimated at about 7 billion SEK (Swedish Kronor) in 1998 prices, which is about 6% of the total health care expenditures and more than four times higher than the former Swedish estimate obtained when using diabetes as main diagnosis for calculating costs. The annual per patient cost was about 25 000 SEK. The largest share of this cost was hospital inpatient care. Costs increased with diabetes duration and were higher for patients treated with insulin compared to those treated with oral hypoglycaemic drugs or with life style modification only. Patients with both macroand microvascular complications had more than three times higher costs compared with patients without such complications. Conclusions. Type 2 diabetes is a serious and expensive disease and the key to reducing costs seems to be intensive management and control in order to prevent and delay the associated late complications.
Scandinavian Journal of Clinical & Laboratory Investigation, 1990
The kinetic pattern of subcutaneous adipose tissue extracellular glucose following glucose ingest... more The kinetic pattern of subcutaneous adipose tissue extracellular glucose following glucose ingestion was investigated in vivo with a microdialysis technique in normal-weight (n = 21) and obese subjects (n = 18) before and after a 7-day fast (n = 9). A dialysis probe (4 x 0.5 mm) was implanted subcutaneously, and was continuously perfused (5 microliters/min). The tissue dialysate glucose concentration was determined in 15-min samples before and during a period of 180 min after a 75-g oral glucose load. A comparison was made between the tissue dialysate concentrations and the venous blood glucose levels. In all study groups the increase in subcutaneous tissue dialysate glucose following glucose ingestion paralleled that in blood, with a time-lag of up to 15 min. In the normal-weight subjects the maximum relative increase in abdominal adipose tissue dialysate glucose was 25% higher (p less than 0.005) than the corresponding blood glucose level, and the total relative glucose level (area under curve, AUC) in abdominal fat was 20% (p less than 0.01) higher than in blood. In contrast, the kinetics of gluteal subcutaneous tissue dialysate and blood glucose levels were similar. In the obese patients before the fasting period the maximum relative glucose level in abdominal fat was almost twice as high as in blood (p less than 0.005), and the total glucose level (AUC) was 50% higher than the blood glucose AUC (p less than 0.005). After the fast, on the other hand, almost identical relative dynamics of abdominal subcutaneous tissue and blood glucose levels were found.(ABSTRACT TRUNCATED AT 250 WORDS)
Aims To evaluate the effect of adding insulin to sulphonylurea (SU) and the effect of SU withdraw... more Aims To evaluate the effect of adding insulin to sulphonylurea (SU) and the effect of SU withdrawal on glycaemic control in Type 2 diabetic patients who failed on treatment with SU alone. Method One hundred and seventy-®ve patients were included in a placebocontrolled multicentre study. During phase I (4 months), premixed insulin was added to glibenclamide therapy; during phase II (1±4 months, depending on response) the insulin dose was ®xed, while placebo or glibenclamide replaced the open SU therapy. Insulin sensitivity (KITT), beta-cell function (C-peptide) and metabolic control (HbA 1c) were monitored. Results HbA 1c improved from 9.65% to 7.23% (P < 0.0001) during phase I. A high HbA 1c value (P < 0.0001) and a high KITT-value (P = 0.045) at baseline were associated with a bene®cial response to combination treatment. During phase II, glycaemic control was unchanged in the control (glibenclamide) group. In the placebo group, after SU withdrawal, fasting blood glucose (FBG) increased by 10% or more within 4 weeks in 79% of the patients. Patients (67 of 112) with an FBG increase >40% during phase II were de®ned as`SU responders' by protocol. In a multivariate analysis only a long duration of diabetes was associated with SU response. There were more GAD-antibodypositive patients among non-responders (18% vs. 4%, P = 0.0263). Conclusions Poor glycaemic control in combination with preserved insulin sensitivity and lack of GAD antibodies predicts a bene®cial response to combination therapy, which can be achieved in 75% of patients with SU failure.
This review summarizes the clinical development of a family of ultra-rapid-acting recombinant hum... more This review summarizes the clinical development of a family of ultra-rapid-acting recombinant human insulin formulations. These formulations use ethylenediaminetetraacetic acid (EDTA) to chelate zinc and thereby destabilize NEW INSULINS AND INSULIN THERAPY S-41
Aim Many countries require individuals with diabetes to adhere to standards regarding blood gluco... more Aim Many countries require individuals with diabetes to adhere to standards regarding blood glucose testing in order to be granted or retain a driving licence. Currently, interstitial glucose results may not be used. The aim of this study was to determine whether interstitial glucose measurements using flash glucose-sensing technology can provide additional information to augment safe driving. Methods Sensor data from two European studies (NCT02232698 and NCT02082184) of the FreeStyle Libre Glucose Monitoring System ™ in insulin-treated Type 1 and Type 2 diabetes, 241 and 224 participants respectively, were used to determine the frequency of a low interstitial sensor glucose result (< 3.9 mmol/l) up to 4 h subsequent to a daytime (07:00-21:00 h) capillary blood glucose result ≥ 5 mmol/l. Results Within 4 h of a capillary blood glucose result ≥ 5 mmol/l a sensor glucose result of < 3.9 mmol/l occurred on 22.0% of occasions (2573 of 11 706 blood glucose readings) for those with Type 1 diabetes, and 8.4% of occasions (699/8352) for those with Type 2 diabetes; 13.8% (1610/11 628) and 4.4% (365/8203) within 2 h, and 10.0% (1160/ 11 601) and 3.1% (254/8152) within 1.5 h. Analysis of sensor glucose results 5-7 mmol/l demonstrated the glucose trend arrow descending on 14.7% (1163/7894, Type 1 diabetes) and 9.4% (305/3233, Type 2 diabetes) of occasions. Conclusions Sensor-based glucose information with directional arrows has the potential to support assessment of safe glucose levels associated with driving and offers distinct advantages over blood glucose testing for individuals with Type 1 and Type 2 diabetes to concord with driving safety standards.
Aims: Dapagliflozin, a highly selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), redu... more Aims: Dapagliflozin, a highly selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycaemia and weight in patients with type 2 diabetes (T2DM) by increasing urinary glucose excretion. Long-term glycaemic control, body composition and bone safety were evaluated in patients with T2DM after 102 weeks of dapagliflozin treatment. Materials and methods: This randomized, double-blind, placebo-controlled study (NCT00855166) enrolled patients with T2DM (mean: age 60.7 years; HbA1c 7.17%; BMI 31.9 kg/m 2 ; body weight 91.5 kg) inadequately controlled on metformin. Patients (N=182) were randomly assigned 1:1 to receive dapagliflozin 10 mg/day or placebo added to open-label metformin for a 24-week doubleblind treatment period followed by a 78-week site-and patient-blinded extension period. At week 102, changes from baseline in HbA1c, weight, waist circumference, total body fat mass as measured by Dual-Energy X-ray Absorptiometry (DXA), serum markers of bone turnover, bone mineral density (BMD) as measured by DXA, and adverse events were evaluated. Results: 140 patients (76.9%) completed the study. Over 102 weeks, dapagliflozin-treated patients showed reductions in HbA1c by −0.30%, weight by −4.54 kg, waist circumference by −5.0 cm and fat mass by −2.80 kg without increase in rate of hypoglycaemia. Compared with placebo, no meaningful changes from baseline in markers of bone turnover or BMD were identified over 102 weeks. One fracture occurred in each treatment group. The frequency of UTI and genital infection was similar in both treatment groups. Conclusions: Over 102 weeks, dapagliflozin improved glycaemic control, and reduced weight and fat mass, without affecting markers of bone turnover or BMD in patients with T2DM inadequately controlled on metformin.
adjunct therapy with sodium-glucose cotransporter 2 inhibitors in patients with type 1 diabetes h... more adjunct therapy with sodium-glucose cotransporter 2 inhibitors in patients with type 1 diabetes have become available and regulatory submissions are on the way, with decisions expected early next year. These drugs have the potential of addressing common side effects of insulin therapy such as glycemic variability, weight gain, or hypoglycemia. This must be balanced against notable untoward effects such as increased risk for genital mycotic infections or diabetic ketoacidosis. Mealtime insulin should ideally be absorbed very quickly after injection to counteract the rise in blood glucose with food consumption. Regarding the next-generation mealtime insulin Fiasp (NovoNordisk), it is now available in several markets and more data from the clinical Onset trial program with FiAsp were published or presented during the last year. As we outlined in the previous yearbook, these insulins where thought to be of particular value in insulin pump therapy. However, when the results of the Onset 5 FiAsp pump trial were presented during the 2017 ATTD meeting, the results were controversial. While we are still waiting for the eventual publication of this study, Eli Lilly initiated the PRONTO-Pump phase 3 trial to evaluate the compatibility and safety of their ultrarapid formulation LY 900014 or trepostinil lispro compared with insulin lispro in February 2018. Although clinical data of Adocia's ultra-rapid insulin-known as BioChaperone Lispro-was originally developed together with Lilly, this collaboration was terminated as we reported in last year's article. While initial data for treatment in people with type 1 and type 2 diabetes (T1D and T2D) have now been published, Adocia is still left without a partner to help get BioChaperone Lispro through critical phase 3 trials. Adocia won its first claim against Eli Lilly & Company regarding a disputed milestone payment, and additional claims will be assessed in another hearing, but a decision is not expected until 2019 and the future of the program remains unclear at this time. While the two ultra-long-acting basal insulin analogs, Toujeo (Sanofi) and Tresiba (Novo Nordisk) have now been on the market for several years, we are entering a time during which the efficacy in reducing the risk for hypoglycemia with the ultra-longacting insulins is studied in direct head-to-head randomized controlled trials and also with different methodologies including continuous glucose monitoring. As our review concludes, uncertainty still remains whether there are any clinically meaningful differences between the two at the present time. The first biosimilar insulin (BioIns)-an insulin glargine developed by Eli Lilly and Boehringer Ingelheim called Abasaglar in the EU and Basaglar in the United States (which was approved in the United States, but not as BioIns) has been on the market now for 1 to 2 years in the EU and the United States. It appears as if this BioIns has gained more market acceptance in the United States than in the EU; it is preferred over the originator insulin glargine in major U.S. formularies, which has induced significant reductions in the sales of the originator insulin. The observed decrease in prices varies between countries, with a maximum of up to 30%. Most likely, a plethora of BioInsparticularly insulin glargines-will be on the market within a few years, which might generate some confusion at the levels of both patients and health-care professionals. As we approach the centennial celebration of insulin discovery, the current scientific progress and controversies around the molecule remain thought-provoking. Key Articles Reviewed for the Article Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 1 diabetes. The SWITCH 1 randomized clinical trial
The Journal of Clinical Endocrinology and Metabolism, Feb 1, 1993
The adrenergic regulation of adipose tissue lipolysis and glucose metabolism was investigated in ... more The adrenergic regulation of adipose tissue lipolysis and glucose metabolism was investigated in situ during a standardized mental stress test in 11 nonobese, healthy subjects, using microdialysis of the extracellular water space in sc adipose tissue. Microdialysis probes were inserted in the abdominal sc fat, and were perfused using solvents with or without adrenoceptor blocking agents. The tissue dialysate concentrations of glycerol (lipolysis index) glucose, lactate, and pyruvate were determined. The glycerol concentration in adipose tissue increased markedly during the stress test and decreased in the poststress period. A similar kinetic pattern was observed in blood. In situ administration of the nonselective beta-adrenoceptor blocking agent propranolol almost completely prevented the stress-induced increase in adipose tissue glycerol levels, whereas a nonselective alpha-adrenoceptor blocking agent (phentolamine) was ineffective in this respect. Plasma levels of glucose and lactate remained unaltered during and after the stress test; at the same time plasma pyruvate decreased moderately. By contrast, glucose, lactate, and pyruvate in adipose tissue increased by 25-30% during or after the stress (P &lt; 0.05). The increase in lactate and pyruvate in adipose tissue after the stress was completely off-set by alpha-adrenoceptor blockade in situ, whereas beta-adrenoceptor blockade in situ did not influence the kinetic pattern of these metabolites. It is concluded that the lipolytic activity in human adipose tissue is markedly enhanced during mental stress, owing to adrenergic mechanisms that are mediated via beta-adrenoceptors. After mental stress, adipose tissue glucose utilization is decreased and routed toward nonoxidative pathways. The latter seems to involve adrenergic effects that are mediated via alpha-adrenoceptors.
den). Adipose zinc-a2-glycoprotein is a catabolic marker in cancer and noncancerous states. J Int... more den). Adipose zinc-a2-glycoprotein is a catabolic marker in cancer and noncancerous states. J Intern Med 2012; 271: 414-420. Objective. Zinc-a2-glycoprotein (ZAG) has been proposed as a tumour-derived cancer cachexia factor. However, ZAG is produced by some normal tissues, including white adipose tissue (WAT), and high serum ZAG levels are present in nonmalignant conditions. We determined whether human WAT contributes to serum ZAG levels and how serum and WAT-secreted ZAG levels correlate with catabolism in patients with cancer and in obese subjects undergoing a very low-calorie diet (VLCD) for 11 days. Design ⁄ subjects. ZAG levels in serum and in conditioned medium from WAT ⁄ adipocytes were determined by enzyme-linked immunosorbent assay. ZAG release from WAT in vivo was determined in 10 healthy subjects. The correlation between ZAG and cachexia was studied in 34 patients with newly diagnosed gastrointestinal cancer. The impact of a VLCD on ZAG release and serum levels was assessed in 10 obese women. Results. ZAG was released from abdominal WAT and adipocytes in vitro. However, the arteriovenous differences in vivo showed that there was no significant contribution of WAT to the circulating levels. WAT-secreted but not serum ZAG correlated positively with poor nutritional status but not with fat mass (or body mass index) in patients with gastrointestinal cancer. In obese subjects on a VLCD, ZAG secretion from WAT increased significantly whereas serum levels remained unaltered. Conclusions. ZAG is released from human WAT, but this tissue does not contribute significantly to the circulating levels. WAT-secreted ZAG correlates with nutritional status but not with fat mass in both cancer and nonmalignant conditions. Adipose ZAG is therefore a local factor activated primarily by the catabolic state per se.
adjunct therapy with sodium-glucose cotransporter 2 inhibitors in patients with type 1 diabetes h... more adjunct therapy with sodium-glucose cotransporter 2 inhibitors in patients with type 1 diabetes have become available and regulatory submissions are on the way, with decisions expected early next year. These drugs have the potential of addressing common side effects of insulin therapy such as glycemic variability, weight gain, or hypoglycemia. This must be balanced against notable untoward effects such as increased risk for genital mycotic infections or diabetic ketoacidosis. Mealtime insulin should ideally be absorbed very quickly after injection to counteract the rise in blood glucose with food consumption. Regarding the next-generation mealtime insulin Fiasp (NovoNordisk), it is now available in several markets and more data from the clinical Onset trial program with FiAsp were published or presented during the last year. As we outlined in the previous yearbook, these insulins where thought to be of particular value in insulin pump therapy. However, when the results of the Onset 5 FiAsp pump trial were presented during the 2017 ATTD meeting, the results were controversial. While we are still waiting for the eventual publication of this study, Eli Lilly initiated the PRONTO-Pump phase 3 trial to evaluate the compatibility and safety of their ultrarapid formulation LY 900014 or trepostinil lispro compared with insulin lispro in February 2018. Although clinical data of Adocia's ultra-rapid insulin-known as BioChaperone Lispro-was originally developed together with Lilly, this collaboration was terminated as we reported in last year's article. While initial data for treatment in people with type 1 and type 2 diabetes (T1D and T2D) have now been published, Adocia is still left without a partner to help get BioChaperone Lispro through critical phase 3 trials. Adocia won its first claim against Eli Lilly & Company regarding a disputed milestone payment, and additional claims will be assessed in another hearing, but a decision is not expected until 2019 and the future of the program remains unclear at this time. While the two ultra-long-acting basal insulin analogs, Toujeo (Sanofi) and Tresiba (Novo Nordisk) have now been on the market for several years, we are entering a time during which the efficacy in reducing the risk for hypoglycemia with the ultra-longacting insulins is studied in direct head-to-head randomized controlled trials and also with different methodologies including continuous glucose monitoring. As our review concludes, uncertainty still remains whether there are any clinically meaningful differences between the two at the present time. The first biosimilar insulin (BioIns)-an insulin glargine developed by Eli Lilly and Boehringer Ingelheim called Abasaglar in the EU and Basaglar in the United States (which was approved in the United States, but not as BioIns) has been on the market now for 1 to 2 years in the EU and the United States. It appears as if this BioIns has gained more market acceptance in the United States than in the EU; it is preferred over the originator insulin glargine in major U.S. formularies, which has induced significant reductions in the sales of the originator insulin. The observed decrease in prices varies between countries, with a maximum of up to 30%. Most likely, a plethora of BioInsparticularly insulin glargines-will be on the market within a few years, which might generate some confusion at the levels of both patients and health-care professionals. As we approach the centennial celebration of insulin discovery, the current scientific progress and controversies around the molecule remain thought-provoking. Key Articles Reviewed for the Article Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 1 diabetes. The SWITCH 1 randomized clinical trial
R. has received honoraria and travel grants from Medtronic. T.B. has received consulting fees and... more R. has received honoraria and travel grants from Medtronic. T.B. has received consulting fees and honoraria from Medtronic and Abbott. D.K. has received honoraria from and served on advisory boards for Medtronic, Roche, and LifeScan. M.P. has served on advisory boards for Medtronic, Abbott, and D-Medical. Abbreviations: CGM, continuous glucose monitoring; SMBG, self-monitoring of blood glucose. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
OBJECTIVE-To compare the effect of bedtime NPH insulin or preprandial regular insulin combined wi... more OBJECTIVE-To compare the effect of bedtime NPH insulin or preprandial regular insulin combined with glibenclamide on metabolic control in non-insulindependent diabetes mellitus (NIDDM) patients with secondary failure to sulfonylurea therapy. RESEARCH DESIGN AND M E T H O D S-Eighty NIDDM patients were randomized to treatment with either three preprandial doses of regular insulin (daytime insulinization, group D) or a bedtime dose of NPH insulin (nocturnal insulinization, group N), both regimens being combined with 10.5 mg of glibenclamide. Metabolic profiles were obtained at 0, 6, and 16 weeks. RESULTS-Glycemic control had improved significantly in both groups after 4 months. Fasting blood glucose was significantly lower compared with baseline in both groups. The mean change ± SD in group D was-2.8 ± 3.5 mmol/1 and in group N-6.4 ± 3.0 mmol/1, the reduction being more pronounced in group N compared with group D (P < 0.0001). HbA lc was lowered similarly, from 9.2 ± 1.4 to 7.1 ± 1.2% in group D (P < 0.0001) and from 9.1 ± 1.1 to 7.5 ± 1.5% in group N (P < 0.0001). The total daily insulin doses were similar, 29 ± 11 U in group D and 26 ± 9 U in group N, and the circulating insulin levels during daytime were higher in group D than in group N. Total serum cholesterol and triglycerides were similarly and significantly lowered compared with baseline in both groups. Weight gain was more pronounced in group D (3.4 ± 0.3 kg) than in group N (1.9 ± 1.9 kg; D vs. N, P < 0.002), and the change was inversely correlated with the initial weight but not with the improvement in HbA lc. CONCLUSIONS-The two insulin regimens exert similar effects on glucose metabolism and serum lipids in NIDDM patients on combination therapy. Weight gain is more pronounced in patients given insulin during the daytime when preprandial doses of short-acting insulin are used.
. Pancreatic autoantibodies were determined in 49 patients with Sjögren's syndrome and relate... more . Pancreatic autoantibodies were determined in 49 patients with Sjögren's syndrome and related to functional parameters. Pancreatic duct autoantibodies (PDA) were detected in the sera of three patients, and all showed abnormal exocrine pancreatic function. Islet cell antibodies (ICA) were not detected in the sera of the 49 patients, including two individuals with diabetes mellitus. In conclusion, PDA occur in patients with Sjögren's syndrome, and may be associated with exocrine pancreatic dysfunction.
Using videophotometric capillaroscopy and laser Doppler fluxmetry, we have investigated skin micr... more Using videophotometric capillaroscopy and laser Doppler fluxmetry, we have investigated skin microvascular reactivity in the fingers of 14 diabetic patients with severe, late complications 20 months after combined kidney and pancreas transplantation. The results were compared with those obtained in 20 diabetic patients awaiting pancreas transplantation and in 19 healthy subjects. The capillary blood cell velocity at rest (P < 0.01) and during postocclusive reactive hyperemia (P < 0.05) was significantly lower in both patient groups than in the healthy controls. However, the time to peak capillary blood cell velocity during hyperemia was normal in the post-transplantation group (NS) but significantly prolonged in the pretransplantation group (P < 0.01). The ability to decrease flow during venous stasis-the so called venoarte-riolar reflex-was strongly impaired in the pretransplantation group (P < 0.001) but less so in the post-transplantation group (P <0.05) as compared to healthy controls. It may be concluded that diabetic patients, after combined kidney and pancreas transplantation, show a tendency towards better microvascular reactivity than those awaiting transplantation.
Objectives. To estimate the total direct medical costs to society for patients with type 2 diabet... more Objectives. To estimate the total direct medical costs to society for patients with type 2 diabetes in Sweden and to investigate how different factors, for example diabetic late complications, affect costs. Design. Cross-sectional data regarding health care utilization, clinical characteristics and quality of life, were collected at a single time-point. Data on resource use cover the 6-month period prior to this time point. Setting. Patient recruitment and data collection were performed in nine primary care centres in three main regions in Sweden. Subjects. Only patients with an age at diabetes diagnosis $ 30 years (type 2 diabetes) were included (n = 777). Results. The total annual direct medical costs for the Swedish diabetes type 2 population were estimated at about 7 billion SEK (Swedish Kronor) in 1998 prices, which is about 6% of the total health care expenditures and more than four times higher than the former Swedish estimate obtained when using diabetes as main diagnosis for calculating costs. The annual per patient cost was about 25 000 SEK. The largest share of this cost was hospital inpatient care. Costs increased with diabetes duration and were higher for patients treated with insulin compared to those treated with oral hypoglycaemic drugs or with life style modification only. Patients with both macroand microvascular complications had more than three times higher costs compared with patients without such complications. Conclusions. Type 2 diabetes is a serious and expensive disease and the key to reducing costs seems to be intensive management and control in order to prevent and delay the associated late complications.
Scandinavian Journal of Clinical & Laboratory Investigation, 1990
The kinetic pattern of subcutaneous adipose tissue extracellular glucose following glucose ingest... more The kinetic pattern of subcutaneous adipose tissue extracellular glucose following glucose ingestion was investigated in vivo with a microdialysis technique in normal-weight (n = 21) and obese subjects (n = 18) before and after a 7-day fast (n = 9). A dialysis probe (4 x 0.5 mm) was implanted subcutaneously, and was continuously perfused (5 microliters/min). The tissue dialysate glucose concentration was determined in 15-min samples before and during a period of 180 min after a 75-g oral glucose load. A comparison was made between the tissue dialysate concentrations and the venous blood glucose levels. In all study groups the increase in subcutaneous tissue dialysate glucose following glucose ingestion paralleled that in blood, with a time-lag of up to 15 min. In the normal-weight subjects the maximum relative increase in abdominal adipose tissue dialysate glucose was 25% higher (p less than 0.005) than the corresponding blood glucose level, and the total relative glucose level (area under curve, AUC) in abdominal fat was 20% (p less than 0.01) higher than in blood. In contrast, the kinetics of gluteal subcutaneous tissue dialysate and blood glucose levels were similar. In the obese patients before the fasting period the maximum relative glucose level in abdominal fat was almost twice as high as in blood (p less than 0.005), and the total glucose level (AUC) was 50% higher than the blood glucose AUC (p less than 0.005). After the fast, on the other hand, almost identical relative dynamics of abdominal subcutaneous tissue and blood glucose levels were found.(ABSTRACT TRUNCATED AT 250 WORDS)
Aims To evaluate the effect of adding insulin to sulphonylurea (SU) and the effect of SU withdraw... more Aims To evaluate the effect of adding insulin to sulphonylurea (SU) and the effect of SU withdrawal on glycaemic control in Type 2 diabetic patients who failed on treatment with SU alone. Method One hundred and seventy-®ve patients were included in a placebocontrolled multicentre study. During phase I (4 months), premixed insulin was added to glibenclamide therapy; during phase II (1±4 months, depending on response) the insulin dose was ®xed, while placebo or glibenclamide replaced the open SU therapy. Insulin sensitivity (KITT), beta-cell function (C-peptide) and metabolic control (HbA 1c) were monitored. Results HbA 1c improved from 9.65% to 7.23% (P < 0.0001) during phase I. A high HbA 1c value (P < 0.0001) and a high KITT-value (P = 0.045) at baseline were associated with a bene®cial response to combination treatment. During phase II, glycaemic control was unchanged in the control (glibenclamide) group. In the placebo group, after SU withdrawal, fasting blood glucose (FBG) increased by 10% or more within 4 weeks in 79% of the patients. Patients (67 of 112) with an FBG increase >40% during phase II were de®ned as`SU responders' by protocol. In a multivariate analysis only a long duration of diabetes was associated with SU response. There were more GAD-antibodypositive patients among non-responders (18% vs. 4%, P = 0.0263). Conclusions Poor glycaemic control in combination with preserved insulin sensitivity and lack of GAD antibodies predicts a bene®cial response to combination therapy, which can be achieved in 75% of patients with SU failure.
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