The Experts below are selected from a list of 5868 Experts worldwide ranked by ideXlab platform
Laurent Azoulay - One of the best experts on this subject based on the ideXlab platform.
-
Sulfonylureas as initial treatment for type 2 diabetes and the risk of adverse cardiovascular events a population based cohort study
British Journal of Clinical Pharmacology, 2019Co-Authors: Kristian B Filion, Antonios Douros, Laurent Azoulay, Hui Yin, Samy SuissaAbstract:Aims Sulfonylureas are recommended as second-line treatment in the management of type 2 diabetes. However, they are still commonly used also as first-line treatment instead of metformin. Given the controversial cardiovascular safety of Sulfonylureas, we aimed to determine if their use as first-line treatment is associated with adverse cardiovascular events among patients with newly treated type 2 diabetes compared with metformin. Methods We conducted a population-based cohort study of patients with newly treated type 2 diabetes using the UK's Clinical Practice Research Datalink. Initiators of metformin and sulfonylurea monotherapy were matched on high-dimensional propensity score, and Cox proportional hazards models were used to compare the rate of cardiovascular events (myocardial infarction, ischaemic stroke, cardiovascular death, and all-cause mortality) with Sulfonylureas vs metformin. Results Our cohort included 94 750 patients initiating treatment for type 2 diabetes, 17 612 on a sulfonylurea and 77 138 on metformin. After matching, sulfonylurea monotherapy, compared with metformin monotherapy, was not associated with an increased risk of myocardial infarction (hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 0.85-1.25) but was associated with increased risks of ischaemic stroke (HR: 1.25, 95% CI: 1.002-1.56), cardiovascular death (HR: 1.25, 95% CI: 1.06-1.47), and all-cause mortality (HR: 1.60, 95% CI: 1.45-1.76). This represents an additional 2.0 ischaemic strokes, 3.5 cardiovascular deaths, and 21.4 all-cause deaths per 1,000 patients per year with Sulfonylureas. Conclusions Initiating treatment of type 2 diabetes with a sulfonylurea rather than metformin is associated with higher rates of ischaemic stroke, cardiovascular death, and all-cause mortality.
-
pharmacologic differences of Sulfonylureas and the risk of adverse cardiovascular and hypoglycemic events
Diabetes Care, 2017Co-Authors: Kristian B Filion, Antonios Douros, Laurent Azoulay, Hui Yin, Samy SuissaAbstract:OBJECTIVE Sulfonylureas have been associated with an increased risk of cardiovascular adverse events and hypoglycemia, but it is unclear if these risks vary with different agents. We assessed whether the risks of acute myocardial infarction, ischemic stroke, cardiovascular death, all-cause mortality, and severe hypoglycemia differ between Sulfonylureas grouped according to pancreas specificity and duration of action. RESEARCH DESIGN AND METHODS Using the U.K. Clinical Practice Research Datalink, linked with the Hospital Episodes Statistics and the Office for National Statistics databases, we conducted a cohort study among patients with type 2 diabetes initiating monotherapy with Sulfonylureas between 1998 and 2013. Adjusted hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, comparing use of pancreas-nonspecific, long-acting Sulfonylureas (glyburide/glimepiride) to pancreas-specific, short-acting Sulfonylureas (gliclazide/glipizide/tolbutamide). RESULTS The cohort included 17,604 sulfonylurea initiators (mean [SD] follow-up 1.2 [1.5] years). Compared with specific, short-acting Sulfonylureas (15,741 initiators), nonspecific, long-acting Sulfonylureas (1,863 initiators) were not associated with an increased risk of acute myocardial infarction (HR 0.86; CI 0.55–1.34), ischemic stroke (HR 0.92; CI 0.59–1.45), cardiovascular death (HR 1.01; CI 0.72–1.40), or all-cause mortality (HR 0.81; CI 0.66–1.003), but with an increased risk of severe hypoglycemia (HR 2.83; CI 1.64–4.88). CONCLUSIONS The nonspecific, long-acting Sulfonylureas glyburide and glimepiride do not have an increased risk of cardiovascular adverse events compared with the specific, short-acting Sulfonylureas gliclazide, glipizide, and tolbutamide. However, nonspecific, long-acting Sulfonylureas glyburide and glimepiride have an increased risk of severe hypoglycemia.
-
Sulfonylureas as initial treatment for type 2 diabetes and the risk of severe hypoglycemia
The American Journal of Medicine, 2017Co-Authors: Laurent Azoulay, Kristian B Filion, Hui Yin, Samy SuissaAbstract:Abstract Purpose The magnitude of the risk of severe hypoglycemia associated with Sulfonylureas as the initial treatment for type 2 diabetes in the real-world setting is unknown. We assessed the risk of severe hypoglycemia associated with initiating monotherapy with sulfonylurea compared with metformin for the treatment of type 2 diabetes. Methods By using the UK Clinical Practice Research Datalink and Hospital Episode Statistics linked to the Office for National Statistics, we identified a cohort of patients with type 2 diabetes who initiated Sulfonylureas or metformin monotherapy between April 1, 1998, and December 31, 2012, with follow-up until December 31, 2013. Sulfonylurea users were matched one-to-one to metformin users by high-dimensional propensity scores. Hazard ratios (HRs) and 95% confidence intervals (CIs) of severe hypoglycemia, defined as requiring hospitalization, were estimated using Cox proportional hazards models comparing Sulfonylureas with metformin monotherapy. Results The study cohort consisted of 14,012 initiators of Sulfonylureas matched to 14,012 initiators of metformin. The mean treated follow-up time was 1.41 (standard deviation, 1.84) years. Use of sulfonylurea was associated with an elevated incidence of severe hypoglycemia compared with metformin as the initiating monotherapy for type 2 diabetes (incidence rate, 2.4/1000 person-years; 95% CI, 1.90-2.90; HR, 4.53; 95% CI, 2.76-7.45). Conclusions Sulfonylureas, when prescribed as the initiating monotherapy for the treatment of type 2 diabetes, is associated with a 4.5-fold increase in the risk of severe hypoglycemia. Given the negative consequences of this outcome, clinicians should consider alternative hypoglycemic agents when metformin is not tolerated or contraindicated.
-
the combination of dpp 4 inhibitors versus Sulfonylureas with metformin after failure of first line treatment in the risk for major cardiovascular events and death
Canadian Journal of Diabetes, 2015Co-Authors: Hui Yin, Laurent AzoulayAbstract:Abstract Objective To determine whether the combination of dipeptidyl-peptidase 4 (DPP-4) inhibitors vs. Sulfonylureas with metformin after failure of first-line treatment is associated with a decreased risk for major adverse cardiovascular events (myocardial infarction and stroke) and for all-cause mortality. Method Using the UK Clinical Practice Research Datalink, a cohort of patients newly treated with metformin or sulfonylurea monotherapy between January 1, 1988, and December 31, 2011, was identified and was followed until December 31, 2012. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models to compare the DPP-4 inhibitor-metformin combination to the sulfonylurea-metformin combination so as to study the risk for a composite endpoint consisting of myocardial infarction, stroke and all-cause mortality. The models were adjusted for high-dimensional propensity score deciles. Results The cohort consisted of 11,807 patients that included 2286 on a DPP-4 inhibitor-metformin combination and 9521 on a sulfonylurea-metformin combination. The crude incidence rates (95% CIs) of the composite endpoint were 1.2% (0.8% to 1.7%) and 2.2% (1.9% to 2.5%) per year for the DPP-4 inhibitor-metformin and sulfonylurea-metformin combinations, respectively. In the high-dimensional propensity score-adjusted model, the use of the DPP-4 inhibitor-metformin combination was associated with a 38% decreased risk for the composite endpoint (adjusted HR: 0.62; 95% CI 0.40 to 0.98), compared with the sulfonylurea-metformin combination. Conclusions The use of a DPP-4 inhibitor combination with metformin, compared with a sulfonylurea-metformin combination, was associated with decreased risks for major cardiovascular events and all-cause mortality.
Samy Suissa - One of the best experts on this subject based on the ideXlab platform.
-
Sulfonylureas as initial treatment for type 2 diabetes and the risk of adverse cardiovascular events a population based cohort study
British Journal of Clinical Pharmacology, 2019Co-Authors: Kristian B Filion, Antonios Douros, Laurent Azoulay, Hui Yin, Samy SuissaAbstract:Aims Sulfonylureas are recommended as second-line treatment in the management of type 2 diabetes. However, they are still commonly used also as first-line treatment instead of metformin. Given the controversial cardiovascular safety of Sulfonylureas, we aimed to determine if their use as first-line treatment is associated with adverse cardiovascular events among patients with newly treated type 2 diabetes compared with metformin. Methods We conducted a population-based cohort study of patients with newly treated type 2 diabetes using the UK's Clinical Practice Research Datalink. Initiators of metformin and sulfonylurea monotherapy were matched on high-dimensional propensity score, and Cox proportional hazards models were used to compare the rate of cardiovascular events (myocardial infarction, ischaemic stroke, cardiovascular death, and all-cause mortality) with Sulfonylureas vs metformin. Results Our cohort included 94 750 patients initiating treatment for type 2 diabetes, 17 612 on a sulfonylurea and 77 138 on metformin. After matching, sulfonylurea monotherapy, compared with metformin monotherapy, was not associated with an increased risk of myocardial infarction (hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 0.85-1.25) but was associated with increased risks of ischaemic stroke (HR: 1.25, 95% CI: 1.002-1.56), cardiovascular death (HR: 1.25, 95% CI: 1.06-1.47), and all-cause mortality (HR: 1.60, 95% CI: 1.45-1.76). This represents an additional 2.0 ischaemic strokes, 3.5 cardiovascular deaths, and 21.4 all-cause deaths per 1,000 patients per year with Sulfonylureas. Conclusions Initiating treatment of type 2 diabetes with a sulfonylurea rather than metformin is associated with higher rates of ischaemic stroke, cardiovascular death, and all-cause mortality.
-
pharmacologic differences of Sulfonylureas and the risk of adverse cardiovascular and hypoglycemic events
Diabetes Care, 2017Co-Authors: Kristian B Filion, Antonios Douros, Laurent Azoulay, Hui Yin, Samy SuissaAbstract:OBJECTIVE Sulfonylureas have been associated with an increased risk of cardiovascular adverse events and hypoglycemia, but it is unclear if these risks vary with different agents. We assessed whether the risks of acute myocardial infarction, ischemic stroke, cardiovascular death, all-cause mortality, and severe hypoglycemia differ between Sulfonylureas grouped according to pancreas specificity and duration of action. RESEARCH DESIGN AND METHODS Using the U.K. Clinical Practice Research Datalink, linked with the Hospital Episodes Statistics and the Office for National Statistics databases, we conducted a cohort study among patients with type 2 diabetes initiating monotherapy with Sulfonylureas between 1998 and 2013. Adjusted hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, comparing use of pancreas-nonspecific, long-acting Sulfonylureas (glyburide/glimepiride) to pancreas-specific, short-acting Sulfonylureas (gliclazide/glipizide/tolbutamide). RESULTS The cohort included 17,604 sulfonylurea initiators (mean [SD] follow-up 1.2 [1.5] years). Compared with specific, short-acting Sulfonylureas (15,741 initiators), nonspecific, long-acting Sulfonylureas (1,863 initiators) were not associated with an increased risk of acute myocardial infarction (HR 0.86; CI 0.55–1.34), ischemic stroke (HR 0.92; CI 0.59–1.45), cardiovascular death (HR 1.01; CI 0.72–1.40), or all-cause mortality (HR 0.81; CI 0.66–1.003), but with an increased risk of severe hypoglycemia (HR 2.83; CI 1.64–4.88). CONCLUSIONS The nonspecific, long-acting Sulfonylureas glyburide and glimepiride do not have an increased risk of cardiovascular adverse events compared with the specific, short-acting Sulfonylureas gliclazide, glipizide, and tolbutamide. However, nonspecific, long-acting Sulfonylureas glyburide and glimepiride have an increased risk of severe hypoglycemia.
-
Sulfonylureas as initial treatment for type 2 diabetes and the risk of severe hypoglycemia
The American Journal of Medicine, 2017Co-Authors: Laurent Azoulay, Kristian B Filion, Hui Yin, Samy SuissaAbstract:Abstract Purpose The magnitude of the risk of severe hypoglycemia associated with Sulfonylureas as the initial treatment for type 2 diabetes in the real-world setting is unknown. We assessed the risk of severe hypoglycemia associated with initiating monotherapy with sulfonylurea compared with metformin for the treatment of type 2 diabetes. Methods By using the UK Clinical Practice Research Datalink and Hospital Episode Statistics linked to the Office for National Statistics, we identified a cohort of patients with type 2 diabetes who initiated Sulfonylureas or metformin monotherapy between April 1, 1998, and December 31, 2012, with follow-up until December 31, 2013. Sulfonylurea users were matched one-to-one to metformin users by high-dimensional propensity scores. Hazard ratios (HRs) and 95% confidence intervals (CIs) of severe hypoglycemia, defined as requiring hospitalization, were estimated using Cox proportional hazards models comparing Sulfonylureas with metformin monotherapy. Results The study cohort consisted of 14,012 initiators of Sulfonylureas matched to 14,012 initiators of metformin. The mean treated follow-up time was 1.41 (standard deviation, 1.84) years. Use of sulfonylurea was associated with an elevated incidence of severe hypoglycemia compared with metformin as the initiating monotherapy for type 2 diabetes (incidence rate, 2.4/1000 person-years; 95% CI, 1.90-2.90; HR, 4.53; 95% CI, 2.76-7.45). Conclusions Sulfonylureas, when prescribed as the initiating monotherapy for the treatment of type 2 diabetes, is associated with a 4.5-fold increase in the risk of severe hypoglycemia. Given the negative consequences of this outcome, clinicians should consider alternative hypoglycemic agents when metformin is not tolerated or contraindicated.
Marie R Griffin - One of the best experts on this subject based on the ideXlab platform.
-
hospitalization for heart failure among patients with diabetes mellitus and reduced kidney function treated with metformin versus Sulfonylureas a retrospective cohort study
Journal of the American Heart Association, 2021Co-Authors: Tadarro L Richardson, Adriana M Hung, Robert A Greevy, Carlos G Grijalva, Amber J Hackstadt, Marie R GriffinAbstract:Background Metformin and sulfonylurea are commonly prescribed oral medications for type 2 diabetes mellitus. The association of metformin and Sulfonylureas on heart failure outcomes in patients wit...
-
hospitalization for lactic acidosis among patients with reduced kidney function treated with metformin or Sulfonylureas
Diabetes Care, 2020Co-Authors: Adriana M Hung, Robert A Greevy, Marie R Griffin, Jonathan Chipman, Amber J Hackstadt, Patricia Y Chu, Carlos G GrijalvaAbstract:OBJECTIVE To compare the risk of lactic acidosis hospitalization between patients treated with metformin versus Sulfonylureas following development of reduced kidney function. RESEARCH DESIGN AND METHODS This retrospective cohort combined data from the National Veterans Health Administration, Medicare, Medicaid, and the National Death Index. New users of metformin or Sulfonylureas were followed from development of reduced kidney function (estimated glomerular filtration rate [eGFR] RESULTS The weighted cohort included 24,542 metformin and 24,662 sulfonylurea users who developed reduced kidney function (median age 70 years, median eGFR 55.8 mL/min/1.73 m2). There were 4.18 (95% CI 3.63, 4.81) vs. 3.69 (3.19, 4.27) lactic acidosis hospitalizations per 1,000 person-years among metformin and sulfonylurea users, respectively (adjusted hazard ratio [aHR] 1.21 [95% CI 0.99, 1.50]). Results were consistent for both primary discharge diagnosis (aHR 1.11 [0.87, 1.44]) and laboratory-confirmed lactic acidosis (1.25 [0.92, 1.70]). CONCLUSIONS Among veterans with diabetes who developed reduced kidney function, occurrence of lactic acidosis hospitalization was uncommon and not statistically different between patients who continued metformin and those patients who continued Sulfonylureas.
-
association of treatment with metformin vs sulfonylurea with major adverse cardiovascular events among patients with diabetes and reduced kidney function
JAMA, 2019Co-Authors: Christianne L Roumie, Adriana M Hung, Robert A Greevy, Carlos G Grijalva, Tom A Elasy, Jonathan Chipman, Jea Young Min, Amber J Hackstadt, Marie R GriffinAbstract:Importance Before 2016, safety concerns limited metformin use in patients with kidney disease; however, the effectiveness of metformin on clinical outcomes in patients with reduced kidney function remains unknown. Objective To compare major adverse cardiovascular events (MACE) among patients with diabetes and reduced kidney function who continued treatment with metformin or a sulfonylurea. Design, Setting, and Participants Retrospective cohort study of US veterans receiving care within the national Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016. There were 174 882 persistent new users of metformin and Sulfonylureas who reached a reduced kidney function threshold (estimated glomerular filtration rate Exposures New users of metformin or sulfonylurea monotherapy who continued treatment with their glucose-lowering medication after reaching reduced kidney function. Main Outcomes and Measures MACE included hospitalization for acute myocardial infarction, stroke, transient ischemic attack, or cardiovascular death. The analyses used propensity score weighting to compare the cause-specific hazard of MACE between treatments and estimate cumulative risk accounting for the competing risks of changing therapy or noncardiovascular death. Results There were 67 749 metformin and 28 976 sulfonylurea persistent monotherapy users; the weighted cohort included 24 679 metformin and 24 799 sulfonylurea users (median age, 70 years [interquartile range {IQR}, 62.8-77.8]; 48 497 men [98%]; and 40 476 white individuals [82%], with median estimated glomerular filtration rate of 55.8 mL/min/1.73 m2[IQR, 51.6-58.2] and hemoglobin A1clevel of 6.6% [IQR, 6.1%-7.2%] at cohort entry). During follow-up (median, 1.0 year for metformin vs 1.2 years for sulfonylurea), there were 1048 MACE outcomes (23.0 per 1000 person-years) among metformin users and 1394 events (29.2 per 1000 person-years) among sulfonylurea users. The cause-specific adjusted hazard ratio of MACE for metformin was 0.80 (95% CI, 0.75-0.86) compared with Sulfonylureas, yielding an adjusted rate difference of 5.8 (95% CI, 4.1-7.3) fewer events per 1000 person-years of metformin use compared with sulfonylurea use. Conclusions and Relevance Among patients with diabetes and reduced kidney function persisting with monotherapy, treatment with metformin, compared with a sulfonylurea, was associated with a lower risk of MACE.
-
kidney function decline in metformin versus sulfonylurea initiators assessment of time dependent contribution of weight blood pressure and glycemic control
Pharmacoepidemiology and Drug Safety, 2013Co-Authors: Adriana M Hung, Christianne L Roumie, Robert A Greevy, Carlos G Grijalva, Xulei Liu, Harvey J Murff, Marie R GriffinAbstract:Background and objective We recently reported that kidney function declined faster among initiators of Sulfonylureas compared to metformin; however, sulfonylurea compared to metformin use was also associated with increases in body mass index (BMI) and systolic blood pressure (SBP). We sought to determine if differences between Sulfonylureas and metformin on kidney function decline were mediated by differential effects on BMI, SBP, or glucose control.
-
comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus a cohort study
Annals of Internal Medicine, 2012Co-Authors: Christianne L Roumie, Adriana M Hung, Robert A Greevy, Carlos G Grijalva, Xulei Liu, Harvey J Murff, Tom A Elasy, Marie R GriffinAbstract:Background The effects of Sulfonylureas and metformin on outcomes of cardiovascular disease (CVD) in type 2 diabetes are not well-characterized. Objective To compare the effects of Sulfonylureas and metformin on CVD outcomes (acute myocardial infarction and stroke) or death. Design Retrospective cohort study. Setting National Veterans Health Administration databases linked to Medicare files. Patients Veterans who initiated metformin or sulfonylurea therapy for diabetes. Patients with chronic kidney disease or serious medical illness were excluded. Measurements Composite outcome of hospitalization for acute myocardial infarction or stroke, or death, adjusted for baseline demographic characteristics; medications; cholesterol, hemoglobin A1c, and serum creatinine levels; blood pressure; body mass index; health care utilization; and comorbid conditions. Results Among 253 690 patients initiating treatment (98 665 with sulfonylurea therapy and 155 025 with metformin therapy), crude rates of the composite outcome were 18.2 per 1000 person-years in sulfonylurea users and 10.4 per 1000 person-years in metformin users (adjusted incidence rate difference, 2.2 [95% CI, 1.4 to 3.0] more CVD events with Sulfonylureas per 1000 person-years; adjusted hazard ratio [aHR], 1.21 [CI, 1.13 to 1.30]). Results were consistent for both glyburide (aHR, 1.26 [CI, 1.16 to 1.37]) and glipizide (aHR, 1.15 [CI, 1.06 to 1.26]) in subgroups by CVD history, age, body mass index, and albuminuria; in a propensity score-matched cohort analysis; and in sensitivity analyses. Limitation Most of the veterans in the study population were white men; data on women and minority groups were limited but reflective of the Veterans Health Administration population. Conclusion Use of Sulfonylureas compared with metformin for initial treatment of diabetes was associated with an increased hazard of CVD events or death. Primary funding source Agency for Healthcare Research and Quality and the U.S. Department of Health and Human Services.
Frances M Ashcroft - One of the best experts on this subject based on the ideXlab platform.
-
permanent neonatal diabetes combining Sulfonylureas with insulin may be an effective treatment
Diabetic Medicine, 2018Co-Authors: Shivani Misra, Frances M Ashcroft, Andrew T Hattersley, Natascia Vedovato, E Cliff, E De Franco, Nick OliverAbstract:BACKGROUND Permanent neonatal diabetes caused by mutations in the KCNJ11 gene may be managed with high-dose Sulfonylureas. Complete transfer to Sulfonylureas is not successful in all cases and can result in insulin monotherapy. In such cases, the outcomes of combining Sulfonylureas with insulin have not been fully explored. We present the case of a woman with diabetes due to a KCNJ11 mutation, in whom combination therapy led to clinically meaningful improvements. CASE A 22-year-old woman was found to have a KCNJ11 mutation (G334V) following diagnosis with diabetes at 3 weeks. She was treated with insulin-pump therapy, had hypoglycaemia unawareness and suboptimal glycaemic control. We assessed the in vitro response of the mutant channel to tolbutamide in Xenopus oocytes and undertook sulfonylurea dose-titration with C-peptide assessment and continuous glucose monitoring. In vitro studies predicted the G334V mutation would be sensitive to sulfonylurea therapy [91 ± 2% block (n = 6) with 0.5 mM tolbutamide]. C-peptide increased following a glibenclamide test dose (from 5 to 410 pmol/l). Glibenclamide dose-titration was undertaken: a lower glibenclamide dose did not reduce blood glucose levels, but at 1.2 mg/kg/day insulin delivery was reduced to 0.1 units/h. However, when insulin was stopped, hyperglycaemia ensued. Glibenclamide was further increased (2 mg/kg/day), but once-daily long-acting insulin was still required to maintain glycaemia. This resulted in improved HbA1c of 52 mmol/mol (6.9%), restoration of hypoglycaemia awareness and reduced glycaemic variability. CONCLUSION In people with KCNJ11 mutations causing permanent neonatal diabetes, and where complete transfer is not possible, consideration should be given to dual insulin and sulfonylurea therapy. This article is protected by copyright. All rights reserved.
-
Sulfonylureas suppress the stimulatory action of Mg-nucleotides on Kir6.2/SUR1 but not Kir6.2/SUR2A KATP channels: a mechanistic study.
The Journal of general physiology, 2014Co-Authors: Peter Proks, Heidi De Wet, Frances M AshcroftAbstract:Sulfonylureas, which stimulate insulin secretion from pancreatic β-cells, are widely used to treat both type 2 diabetes and neonatal diabetes. These drugs mediate their effects by binding to the sulfonylurea receptor subunit (SUR) of the ATP-sensitive K+ (KATP) channel and inducing channel closure. The mechanism of channel inhibition is unusually complex. First, Sulfonylureas act as partial antagonists of channel activity, and second, their effect is modulated by MgADP. We analyzed the molecular basis of the interactions between the sulfonylurea gliclazide and Mg-nucleotides on β-cell and cardiac types of KATP channel (Kir6.2/SUR1 and Kir6.2/SUR2A, respectively) heterologously expressed in Xenopus laevis oocytes. The SUR2A-Y1206S mutation was used to confer gliclazide sensitivity on SUR2A. We found that both MgATP and MgADP increased gliclazide inhibition of Kir6.2/SUR1 channels and reduced inhibition of Kir6.2/SUR2A-Y1206S. The latter effect can be attributed to stabilization of the cardiac channel open state by Mg-nucleotides. Using a Kir6.2 mutation that renders the KATP channel insensitive to nucleotide inhibition (Kir6.2-G334D), we showed that gliclazide abolishes the stimulatory effects of MgADP and MgATP on β-cell KATP channels. Detailed analysis suggests that the drug both reduces nucleotide binding to SUR1 and impairs the efficacy with which nucleotide binding is translated into pore opening. Mutation of one (or both) of the Walker A lysines in the catalytic site of the nucleotide-binding domains of SUR1 may have a similar effect to gliclazide on MgADP binding and transduction, but it does not appear to impair MgATP binding. Our results have implications for the therapeutic use of Sulfonylureas.
-
switching from insulin to oral Sulfonylureas in patients with diabetes due to kir6 2 mutations
The New England Journal of Medicine, 2006Co-Authors: Ewan R Pearson, Frances M Ashcroft, Ethel Codner, Sarah E Flanagan, Isabelle Flechtner, Pal R Njolstad, Maciej T Malecki, Brian Larkin, I Klimes, Violeta IotovaAbstract:Background Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel, cause 30 to 58 percent of cases of diabetes diagnosed in patients under six months of age. Patients present with ketoacidosis or severe hyperglycemia and are treated with insulin. Diabetes results from impaired insulin secretion caused by a failure of the beta-cell KATP channel to close in response to increased intracellular ATP. Sulfonylureas close the KATP channel by an ATP-independent route. Methods We assessed glycemic control in 49 consecutive patients with Kir6.2 mutations who received appropriate doses of Sulfonylureas and, in smaller subgroups, investigated the insulin secretory responses to intravenous and oral glucose, a mixed meal, and glucagon. The response of mutant KATP channels to the sulfonylurea tolbutamide was assayed in xenopus oocytes. Results A total of 44 patients (90 percent) successfully discontinued insulin after receiving Sulfonylureas. The extent of ...
-
activating mutations in kir6 2 and neonatal diabetes new clinical syndromes new scientific insights and new therapy
Diabetes, 2005Co-Authors: Andrew T Hattersley, Frances M AshcroftAbstract:Closure of ATP-sensitive K(+) channels (K(ATP) channels) in response to metabolically generated ATP or binding of sulfonylurea drugs stimulates insulin release from pancreatic beta-cells. Heterozygous gain-of-function mutations in the KCJN11 gene encoding the Kir6.2 subunit of this channel are found in approximately 47% of patients diagnosed with permanent diabetes at transient neonatal diabetes > permanent neonatal diabetes > DEND syndrome channels. Sulfonylureas still close mutated K(ATP) channels, and many patients can discontinue insulin injections and show improved glycemic control when treated with high-dose sulfonylurea tablets. In conclusion, the finding that Kir6.2 mutations can cause neonatal diabetes has enabled a new therapeutic approach and shed new light on the structure and function of the Kir6.2 subunit of the K(ATP) channel.
-
sulfonylurea stimulation of insulin secretion
Diabetes, 2002Co-Authors: Peter Proks, Fiona M Gribble, Frank Reimann, Nick Green, Frances M AshcroftAbstract:Sulfonylureas are widely used to treat type 2 diabetes because they stimulate insulin secretion from pancreatic beta-cells. They primarily act by binding to the SUR subunit of the ATP-sensitive potassium (K(ATP)) channel and inducing channel closure. However, the channel is still able to open to a limited extent when the drug is bound, so that high-affinity sulfonylurea inhibition is not complete, even at saturating drug concentrations. K(ATP) channels are also found in cardiac, skeletal, and smooth muscle, but in these tissues are composed of different SUR subunits that confer different drug sensitivities. Thus tolbutamide and gliclazide block channels containing SUR1 (beta-cell type), but not SUR2 (cardiac, smooth muscle types), whereas glibenclamide, glimepiride, repaglinide, and meglitinide block both types of channels. This difference has been exploited to determine residues contributing to the sulfonylurea-binding site. Sulfonylurea block is decreased by mutations or agents (e.g., phosphatidylinositol bisphosphate) that increase K(ATP) channel open probability. We now propose a kinetic model that explains this effect in terms of changes in the channel open probability and in the transduction between the drug-binding site and the channel gate. We also clarify the mechanism by which MgADP produces an apparent increase of sulfonylurea efficacy on channels containing SUR1 (but not SUR2).
Andrew T Hattersley - One of the best experts on this subject based on the ideXlab platform.
-
permanent neonatal diabetes combining Sulfonylureas with insulin may be an effective treatment
Diabetic Medicine, 2018Co-Authors: Shivani Misra, Frances M Ashcroft, Andrew T Hattersley, Natascia Vedovato, E Cliff, E De Franco, Nick OliverAbstract:BACKGROUND Permanent neonatal diabetes caused by mutations in the KCNJ11 gene may be managed with high-dose Sulfonylureas. Complete transfer to Sulfonylureas is not successful in all cases and can result in insulin monotherapy. In such cases, the outcomes of combining Sulfonylureas with insulin have not been fully explored. We present the case of a woman with diabetes due to a KCNJ11 mutation, in whom combination therapy led to clinically meaningful improvements. CASE A 22-year-old woman was found to have a KCNJ11 mutation (G334V) following diagnosis with diabetes at 3 weeks. She was treated with insulin-pump therapy, had hypoglycaemia unawareness and suboptimal glycaemic control. We assessed the in vitro response of the mutant channel to tolbutamide in Xenopus oocytes and undertook sulfonylurea dose-titration with C-peptide assessment and continuous glucose monitoring. In vitro studies predicted the G334V mutation would be sensitive to sulfonylurea therapy [91 ± 2% block (n = 6) with 0.5 mM tolbutamide]. C-peptide increased following a glibenclamide test dose (from 5 to 410 pmol/l). Glibenclamide dose-titration was undertaken: a lower glibenclamide dose did not reduce blood glucose levels, but at 1.2 mg/kg/day insulin delivery was reduced to 0.1 units/h. However, when insulin was stopped, hyperglycaemia ensued. Glibenclamide was further increased (2 mg/kg/day), but once-daily long-acting insulin was still required to maintain glycaemia. This resulted in improved HbA1c of 52 mmol/mol (6.9%), restoration of hypoglycaemia awareness and reduced glycaemic variability. CONCLUSION In people with KCNJ11 mutations causing permanent neonatal diabetes, and where complete transfer is not possible, consideration should be given to dual insulin and sulfonylurea therapy. This article is protected by copyright. All rights reserved.
-
loss of function cyp2c9 variants improve therapeutic response to Sulfonylureas in type 2 diabetes a go darts study
Clinical Pharmacology & Therapeutics, 2010Co-Authors: Kaixin Zhou, Andrew T Hattersley, Louise A Donnelly, Lindsay Burch, Roger Tavendale, Alex S F Doney, Graham P Leese, Mark I MccarthyAbstract:Sulfonylureas are metabolized mainly by the cytochrome p450 2C9 (CYP2C9) enzyme. Two CYP2C9 variants--*2 (Arg144Cys) and *3 (Ile359Leu)--are associated with reduced enzyme activity and impaired substrate metabolism. We identified 1,073 incident users of Sulfonylureas in Tayside, Scotland, and assessed the impact of the combined CYP2C9*2 and CYP2C9*3 genotypes on early and sustained sulfonylurea response. We found that patients with two copies of a loss-of-function allele were 3.4 times (P = 0.0009) more likely to achieve a treatment hemoglobin A(1c) (HbA(1c)) level <7% than patients with two wild-type CYP2C9 alleles. This corresponds to a 0.5% (P = 0.003) greater reduction in HbA(1c) concentration. In addition, *2 and *3 allele carriers were less likely to experience treatment failure with sulfonylurea monotherapy (P = 0.04; per-allele hazard ratio 0.79; 95% confidence interval 0.63-0.99). In conclusion, CYP2C9 loss-of-function alleles are associated with greater response to Sulfonylureas and decreased failure of therapy consistent with the pharmacokinetic role of CYP2C9.
-
effective treatment with oral Sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 sur1 mutations
Diabetes Care, 2008Co-Authors: Meena Rafiq, Sarah E Flanagan, Annmarie Patch, Beverley M Shields, Sian Ellard, Andrew T HattersleyAbstract:OBJECTIVE — Neonatal diabetes can result from mutations in the Kir6.2 or sulfonylurea receptor 1 (SUR1) subunits of the ATP-sensitive K channel. Transfer from insulin to oral Sulfonylureas in patients with neonatal diabetes due to Kir6.2 mutations is well described, but less is known about changing therapy in patients with SUR1 mutations. We aimed to describe the response to sulfonylurea therapy in patients with SUR1 mutations and to compare it with Kir6.2 mutations. RESEARCH DESIGN AND METHODS — We followed 27 patients with SUR1 mutations for at least 2 months after attempted transfer to Sulfonylureas. Information was collected on clinical features, treatment before and after transfer, and the transfer protocol used. We compared successful and unsuccessful transfer patients, glycemic control before and after transfer, and treatment requirements in patients with SUR1 and Kir6.2 mutations. RESULTS — Twenty-three patients (85%) successfully transferred onto Sulfonylureas without significant side effects or increased hypoglycemia and did not need insulin injections. In these patients, median A1C fell from 7.2% (interquartile range 6.6 – 8.2%) on insulin to 5.5% (5.3– 6.2%) on Sulfonylureas (P 0.01). When compared with Kir6.2 patients, SUR1 patients
-
Variation in TCF7L2 Influences Therapeutic Response to Sulfonylureas A GoDARTs Study
Diabetes, 2007Co-Authors: Ewan R Pearson, Andrew T Hattersley, Louise A Donnelly, Alex S F Doney, Mark I Mccarthy, Charlotte H. Kimber, Adrian L. Whitley, Andrew D. Morris, Colin N. A. PalmerAbstract:OBJECTIVE— There is considerable interindividual variation in sulfonylurea response in type 2 diabetes. Transcription factor 7-like 2 ( TCF7L2 ) variants have been identified to be strongly associated with type 2 diabetes risk, probably due to decreased β-cell function. We hypothesized that variation in TCF7L2 would influence response to Sulfonylureas but not metformin. We studied the effect of TCF7L2 rs12255372 and rs7903146 genotypes on glycemic response. RESEARCH DESIGN AND METHODS— The DARTS/MEMO (Diabetes Audit and Research Tayside/Medicines Monitoring Unit) collaboration database includes prescribing, biochemistry, and clinical phenotype of all patients with diabetes within Tayside, Scotland, from 1992. Of these, the TCF7L2 genotype was determined in 4,469 patients with type 2 diabetes recruited to GoDARTS (Genetics of Diabetes Audit and Research Tayside) between 1997 and July 2006. A total of 901 incident sulfonylurea users and 945 metformin users were identified. A logistic regression was used with treatment failure defined as an A1C >7% within 3–12 months after treatment initiation. Covariates included the TCF7L2 genotype, BMI, sex, age diagnosed, drug adherence, and drug dose. A1C pretreatment was available in a subset of patients (sulfonylurea n = 579; metformin n = 755). RESULTS— Carriers of the risk allele were less likely to respond to Sulfonylureas with an odds ratio (OR) for failure of 1.95 (95% CI 1.23–3.06; P = 0.005), comparing rs12255372 T/T vs. G/G. Including the baseline A1C strengthened this association (OR 2.16 [95% CI 1.21–3.86], P = 0.009). A similar, although slightly weaker, association was seen with rs7903146. No association was seen between metformin response and either single nucleotide polymorphism, after adjustment for baseline A1C. CONCLUSIONS— TCF7L2 variants influence therapeutic response to Sulfonylureas but not metformin. This study establishes that genetic variation can alter response to therapy in type 2 diabetes.
-
improved motor development and good long term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay early onset generalised epilepsy and neonatal diabetes associated with the v59m mutation in
Diabetologia, 2006Co-Authors: Annabelle S Slingerland, Andrew T Hattersley, R Nuboer, Mijna Haddersalgra, G J BruiningAbstract:Aims/hypothesis Activating mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the KATP channels in pancreatic beta cells are a common cause of neonatal diabetes. One-third of patients also have developmental delay, which probably results from mutated KATP channels in muscle, nerve and brain. Sulfonylureas, which bind to the sulfonylurea receptor 1 subunit of the KATP channel, can replace insulin injections in patients with KCNJ11 mutations. The aim of this study was to investigate the long-term outcome and impact on neurological features of sulfonylurea treatment.
