Dose Of Sulfonylurea Research Articles

Safety and Effectiveness of Sodium-Glucose Co-transporter 2 Inhibitors on Glycemic Control in Patients with Type 2 Diabetes Mellitus Fasting during Ramadan: A Review.

This review evaluates the current evidence on the safety and efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with type 2 diabetes mellitus (T2DM) fasting during Ramadan. All studies included in the review were conducted in Asia and the Middle East. Overall, the evidence suggests that SGLT2 inhibitors are a safe and effective treatment option for most T2DM patients fasting during Ramadan. The average incidence of symptomatic hypoglycemia is 12.5%, but ranges from 0.7% to 27%, depending on the study population and concomitant use of other medications. The risk of hypoglycemia is increased when SGLT2 inhibitors are used in combination with insulin and/or sulfonylureas. Therefore, patients taking SGLT2 inhibitors in combination with insulin and/or sulfonylureas can take steps to mitigate this risk, such as having their insulin and/or sulfonylurea doses adjusted and being closely monitored for hypoglycemia. Patients taking SGLT2 inhibitors may be at increased risk of dehydration. To mitigate the risk of dehydration, patients should be advised to consume adequate fluids during the fast-breaking hours. Further research is warranted to validate these findings and extend their applicability to high-risk populations and other regions of the world.

PSUN269 Suboptimal Sulfonylurea Therapeutic Response in a Patient with MODY-3 with a Rare HNF1A Pathogenic Genetic Variant

Abstract Maturity-onset diabetes of the young (MODY) is a rare non-autoimmune type of diabetes, seen in 1-6% of patients with diabetes, caused by a single gene variant defect that ultimately impairs pancreatic b-cell insulin secretion. MODY-3, caused by mutations in HNF1A gene, accounts for most MODY cases. Misdiagnosis of MODY as type 1 diabetes (T1DM) or young-onset type 2 diabetes (T2DM) due to their overlapping features is common, leading to suboptimal pharmacologic management. When pharmacologic therapy is indicated, patients with MODY-3 typically present an excellent response to sulfonylurea monotherapy. We describe a case of a young adult woman diagnosed with MODY-3, previously treated as T1DM, with an atypical suboptimal response to sulfonylurea therapy possibly attributed to a rare HNF1A pathogenic genetic variant. A 24-year-old female with a BMI of 21, diagnosed with diabetes at age 13 managed as T1DM on insulin, underwent genetic analysis at age 23 after her 14-year-old sister was found to have MODY-3. DNA sequencing revealed heterozygous HNF1A gene with pathogenic variant c.365A>G (p.Tyr122Cys). Sulfonylurea therapy was initiated with the goal to lower the insulin regimen. Additional workup revealed a new HbA1C 12%, new-onset microalbuminuria, positive glutamic acid decarboxylase (GAD) antibody (0.22 nmol/L), negative islet cell antibody, and zinc transporter-8 antibody (ZnT8), in addition to normal C-peptide level of 1.5ng/mL. Upon follow-up visit, sulfonylurea dose was doubled, and basal and pre-prandial insulin were lowered and discontinued, respectively. Although the HbA1C improved to 9.8%, the patient admitted to self-resuming previous basal and pre-prandial insulin regimen after consistently having hyperglycemia 300 mg/dL when following last pharmacologic adjustments. MODY usually has autosomal-dominant inheritance although de novo mutations can occur. The molecular diagnosis aims at tailoring the choice of the most appropriate treatment to improve blood glucose control, reduce the risk of hypoglycemia, and prevent long-term micro and macrovascular complications. Typically, patients with MODY-3 are highly sensitive to monotherapy with sulfonylureas especially when shorter diabetes duration, lower BMI, and lower HbA1C are present at the time of genetic diagnosis. Although our patient's HbA1C level improved once sulfonylurea therapy was initiated, HbA1C remains above the goal level and discontinuation of insulin regimen has not been able to be achieved despite increasing sulfonylurea dose. Similar cases of MODY-3 with atypical sulfonylurea therapeutic response have been reported and attributed to the presence of novel HNF1A genetic variants. Moreover, studies have predicted that about 50% of MODY-3 patients require insulin therapy as the disease progresses. Nonetheless, more research is needed to elucidate possible additional contributing factors to a suboptimal sulfonylurea therapeutic response in MODY-3 cases. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Effects of Hydroxychloroquine on Progression of Diabetic Retinopathy in Subjects with Rheumatoid Arthritis and Type 2 Diabetes Mellitus.

The study was conducted to investigate the effects of hydroxychloroquine, an anti-inflammatory drug, which was recently approved and used as an add on oral antidiabetic drug for uncontrolled Type 2 Diabetes Mellitus (DM) on an adequate dose of sulfonylurea and metformin on the progression of diabetic retinopathy (DR) in subjects with Rheumatoid Arthritis and Type 2 Diabetes Mellitus. The primary objective was to evaluate the effect of hydroxychloroquine on the onset of Diabetic Retinopathy (DR) and progression of the disease. Best-corrected visual acuity (BCVA) charts with 3 or more lines worsening of visual acuity and the development of clinically significant macular edema (CSME) were added as secondary objectives as described in the Early Treatment Diabetic Retinopathy Study (ETDRS). This retrospective analysis was done from medical records of all Rheumatoid Arthritis (RA) patients who also had T2DM and were treated with hydroxychloroquine (HCQ) 400 mg OD or 200 mg BID (N=65) and received ophthalmologic care at an endocrinology clinic in India up to a mean follow-up of 3.5±0.5 years and matched subjects taking any other disease-modifying antirheumatic drugs (DMARD) and pioglitazone (N=34). Baseline characteristics were similar in both the groups, with matched glycated haemoglobin (9.1 % and 9.2 % respectively, p=0.127). In both groups, over 3.5 years, HbA1c was reduced significantly. No new cases of DR were detected in the HCQ group, whereas 2 patients had developed DR in the pioglitazone group. At the base line visit, mild non-proliferative Diabetic Retinopathy (NPDR) was present in 18 eyes and 14 eyes in the HCQ and pioglitazone groups, respectively. Progression to moderate NPDR over 3.5 years occurred in 2 out of 18 (11 %) eyes in the HCQ group and 8 out of 14 (57 %) eyes in the pioglitazone group, respectively, representing a significant relative risk reduction (p=.001). No patients had progressed from mild NPDR to severe NPDR in the HCQ group, whereas 2 eyes had progressed from mild NPDR to severe NPDR in the pioglitazone group. None of the patients in either arm developed diabetic macular oedema. Progression of DR from mild to moderate NPDR or severe NPDR may be delayed by HCQ. Large scale randomised prospective clinical trial is required to establish the risk-benefit profiles of HCQ in T2DM.ct.

Dapagliflozin Improves Body Fat Patterning, and Hepatic and Pancreatic Fat in Patients With Type 2 Diabetes in North India.

Excess hepatic and pancreatic fat may contribute to hyperglycemia. The objective of this study was to examine the effect of dapagliflozin (an SGLT2 inhibitor) on anthropometric profile, liver, and pancreatic fat in patients with type 2 diabetes mellitus (T2DM). This is an observational interventional paired study design without a control group. Patients (n = 30) were given dapagliflozin 10 mg/day (on top of stable dose of metformin and/or sulfonylureas) for 120 days. Changes in anthropometry (circumferences and skinfold thickness), surrogate markers of insulin resistance, body composition, liver, and pancreatic fat (as measured by magnetic resonance imaging (MRI)-derived proton density fat fraction [FF]) were evaluated. After 120 days of treatment with dapagliflozin, a statistically significant reduction in weight, body mass index (BMI), body fat, circumferences, and all skinfold thickness was seen. A statistically significant reduction in blood glucose, glycated hemoglobin A1c, hepatic transaminases, fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR), and postprandial C-peptide was noted, while HOMA-β, postprandial insulin sensitivity, and fasting adiponectin were statistically significantly increased. There was no change in lean body mass. Compared to baseline there was a statistically significant decrease in mean liver FF (from 15.2% to 10.1%, P < .0001) and mean pancreatic FF (from 7.5% to 5.99%, P < .0083). Reduction in liver fat was statistically significant after adjustment for change in body weight. Dapagliflozin, after 120 days of use, reduced pancreatic and liver fat and increased insulin sensitivity in Asian Indian patients with T2DM.

The use of SGLT2 inhibitors in achieving glycaemic control in maturity-onset diabetes of the young type 3.

SummaryMaturity-onset diabetes of the young type 3 (MODY3) accounts for approximately 50% of cases of MODY. First-line treatment with sulfonylureas has been well established for individuals with MODY3. In contrast, the use of sodium-glucose co-transporter 2 (SGLT2) inhibitors in the treatment of individuals with MODY3 remains unclear. This case illustrates the in vivo effect of an SGLT2 inhibitor in a 30-year-old woman with MODY3 with poor glycaemic control despite the treatment with supramaximal doses of sulfonylurea and metformin. The addition of a SGLT2 inhibitor resulted in a rapid improvement in glycaemic control without any hypoglycaemic episodes. This case suggests that SGLT2 inhibitors may be an effective and potent treatment option in addition to sulfonylureas for individuals with MODY3.Learning pointsMaturity-onset diabetes of the young type 3 (MODY3) arises from mutations in the hepatocyte nuclear factor-1alpha gene, which controls the expression of sodium-glucose co-transporter 2 (SGLT2) in the kidneys.Paradoxically, despite individuals with MODY3 having reduced expression of SGLT2, SGLT2 inhibitors induce higher glycosuria in individuals with MODY3 compared to individuals with type 2 diabetes mellitus.SGLT2 inhibitors may be an effective treatment for achieving glycaemic control in individuals with MODY3.

Deintensification of Treatment With Sulfonylurea and Insulin After Severe Hypoglycemia Among Older Adults With Diabetes

Practice guidelines recommend deintensification of hypoglycemic agents among older adults with diabetes who are at high risk of hypoglycemia, yet real-world treatment deintensification practices are not well characterized. To examine the incidence of sulfonylurea and insulin deintensification after a hypoglycemia-associated emergency department (ED) visit or hospitalization among older adults with diabetes and to identify factors associated with deintensification of treatment. This retrospective cohort study included a random sample of 20% of nationwide fee-for-service US Medicare beneficiaries aged 65 years and older with concurrent Medicare parts A, B, and D coverage between January 1, 2007, and December 31, 2017. Individuals with diabetes who had at least 1 hypoglycemia-associated ED visit or hospitalization were included. Data were analyzed from August 1, 2020, to August 1, 2021. Baseline medication for the treatment of diabetes (sulfonylurea, insulin, or both). Incidence of treatment deintensification (yes or no) in the 100 days after a severe hypoglycemic episode requiring an ED visit or hospitalization, with treatment deintensification defined as (1) a decrease in sulfonylurea dose, (2) a change from long-acting to short-acting sulfonylurea (glipizide), (3) discontinuation of sulfonylurea, or (4) discontinuation of insulin based on pharmacy dispensing claims. Among 76 278 distinct Medicare beneficiaries who had a hypoglycemia-associated ED visit or hospitalization, the mean (SD) age was 76.6 (7.6) years. Of 106 293 total hypoglycemic episodes requiring hospital attention, 69 084 (65.0%) occurred among women, 26 056 (24.5%) among Black individuals; 4761 (4.5%) among Hispanic individuals; 69 704 (65.6%) among White individuals; and 5772 (5.4%) among individuals of other races and ethnicities (comprising Asian, North American Native, unknown race or ethnicity, and unspecified race or ethnicity). A total of 32 074 episodes (30.2%) occurred among those receiving sulfonylurea only, 60 350 (56.8%) occurred among those receiving insulin only, and 13 869 (13.0%) occurred among those receiving both sulfonylurea and insulin. Treatment deintensification rates were highest among individuals receiving both sulfonylurea and insulin therapies at the time of their hypoglycemic episode (6677 episodes [48.1%]), followed by individuals receiving sulfonylurea only (14 192 episodes [44.2%]) and insulin only (14 495 episodes [24.0%]). Treatment deintensification rates increased between 2007 and 2017 (sulfonylurea only: from 41.4% to 49.7%; P < .001 for trend; insulin only: from 21.3% to 25.9%; P < .001 for trend; sulfonylurea and insulin: from 45.9% to 49.6%; P = .005 for trend). Lower socioeconomic status (as indicated by the receipt of low-income subsidies) was associated with lower odds of deintensification, regardless of baseline hypoglycemic regimen (sulfonylurea only: adjusted odds ratio [AOR], 0.74 [95% CI, 0.70-0.78]; insulin only: AOR, 0.71 [95% CI, 0.68-0.75]; sulfonylurea and insulin: AOR, 0.72 [95% CI, 0.66-0.78]). A number of patient factors were associated with higher odds of treatment deintensification: higher frailty (eg, ≥40% probability of needing assistance with activities of daily living among those receiving sulfonylurea and insulin: AOR, 1.50; 95% CI, 1.32-1.71), chronic kidney disease (eg, sulfonylurea and insulin: AOR, 1.29; 95% CI, 1.19-1.40), a history of falls (eg, sulfonylurea and insulin: AOR, 1.20; 95% CI, 1.09-1.33), and depression (eg, sulfonylurea and insulin: AOR, 1.11; 95% CI, 1.02-1.20). In this cohort study, deintensification of sulfonylurea and/or insulin therapy within 100 days after a hypoglycemia-associated ED visit or hospitalization occurred in fewer than 50% of older adults with diabetes; however, these deintensification rates may be increasing over time, and deintensification of insulin was likely underestimated because of challenges in capturing changes to insulin dosing using administrative claims data. These results suggest that greater efforts are needed to identify individuals at high risk of hypoglycemia to encourage appropriate treatment deintensification in accordance with current evidence.

Molecular Genetics, Clinical Characteristics, and Treatment Outcomes of KATP-Channel Neonatal Diabetes Mellitus in Vietnam National Children’s Hospital

BackgroundNeonatal diabetes mellitus (NDM) is defined as insulin-requiring persistent hyperglycemia occurring within the first 6 months of life, which can result from mutations in at least 25 different genes. Activating heterozygous mutations in genes encoding either of the subunits of the ATP-sensitive K+ channel (KATP channel; KCNJ11 or ABCC8) of the pancreatic beta cell are the most common cause of permanent NDM and the second most common cause of transient NDM. Patients with NDM caused by KATP channel mutations are sensitive to sulfonylurea (SU) treatment; therefore, their clinical management can be improved by replacing insulin with oral agents.Patients and MethodsSeventy patients were diagnosed with NDM between May 2008 and May 2021 at Vietnam National Children’s Hospital, and molecular genetic testing for all genes known to cause NDM was performed at the Exeter Genomic Laboratory, UK. Patients with ABCC8 or KCNJ11 mutations were transferred from insulin to oral SU. Clinical characteristics, molecular genetics, and annual data relating to glycemic control, SU dose, severe hypoglycemia, and side effects were collected. The main outcomes of interest were SU dose, SU failure (defined as permanent reintroduction of daily insulin), and glycemic control (HbA1c).ResultsFifty-four of 70 patients (77%) with NDM harbored a genetic mutation and of these; 27 (50%) had activating heterozygous mutations in ABCC8 or KCNJ11. A total of 21 pathogenic mutations were identified in the 27 patients, including 13 mutations in ABCC8 and 8 mutations in KCNJ11. Overall, 51% had low birth weight (below 3rd percentile), 23 (85%) were diagnosed before 3 months of age, and 23 (85%) presented with diabetic ketoacidosis. At diagnosis, clinical and biochemical findings (mean ± SD) were pH 7.16 ± 0.16; , 7.9 ± 7.4 mmol/L; BE, −17.9 ± 9.1 mmol/L; HbA1C, 7.98% ± 2.93%; blood glucose, 36.2 ± 12.3 mmol/L; and C-peptide median, 0.09 (range, 0–1.61 nmol/l). Twenty-six patients were successfully transferred from insulin to SU therapy. In the remaining case, remission of diabetes occurred prior to transfer. Glycemic control on SU treatment was better than on insulin treatment: HbA1c and blood glucose level decreased from 7.58% ± 4.63% and 19.04 ± 14.09 mmol/L when treated with insulin to 5.8 ± 0.94% and 6.87 ± 3.46 mmol/L when treated with SU, respectively.ConclusionsThis is the first case series of NDM patients with ABCC8/KCNJ11 mutations reported in Vietnam. SU is safe in the short term for these patients and more effective than insulin therapy, consistent with all studies to date. This is relevant for populations where access to and cost of insulin are problematic, reinforcing the importance of genetic testing for NDM.

A Comprehensive Analysis of Hungarian MODY Patients-Part I: Gene Panel Sequencing Reveals Pathogenic Mutations in HNF1A, HNF1B, HNF4A, ABCC8 and INS Genes.

Maturity-onset diabetes of the young (MODY) has about a dozen known causal genes to date, the most common ones being HNF1A, HNF4A, HNF1B and GCK. The phenotype of this clinically and genetically heterogeneous form of diabetes depends on the gene in which the patient has the mutation. We have tested 450 Hungarian index patients with suspected MODY diagnosis with Sanger sequencing and next-generation sequencing and found a roughly 30% positivity rate. More than 70% of disease-causing mutations were found in the GCK gene, about 20% in the HNF1A gene and less than 10% in other MODY-causing genes. We found 8 pathogenic and 9 likely pathogenic mutations in the HNF1A gene in a total of 48 patients and family members. In the case of HNF1A-MODY, the recommended first-line treatment is low dose sulfonylurea but according to our data, the majority of our patients had been on unnecessary insulin therapy at the time of requesting their genetic testing. Our data highlights the importance of genetic testing in the diagnosis of MODY and the establishment of the MODY subtype in order to choose the most appropriate treatment.

A Review on Drug Related Problems in Type 2 DM with Combination of Sulfonylureas and Biguanides

Increased drug related problems in diabetic patients treated with combinations of high doses of sulfonylureas and metformin was recently reported. This review article is aimed towards the assessment of drug related problems in patients treated with low-doses of sulfonylureas and biguanides. Sulphonylureas the second most commonly used antidiabetic drugs after metformin; there have been concerns regarding the cardiovascular safety of sulfonylureas. These safety concerns initiated with the University Group Diabetes Program conducted in the 1960s, found a sulfonylurea, tolbutamide, where tolbutamide is a first-generation sulfonylurea and was associated with an increased risk of all-cause and cardiovascular problems compared with placebo. Indeed, sulfonylureas have been associated with known cardiovascular risk factors like weight gain, fluid retention, and hypoglycemia. Phenformin, a biguanide, was related to lactic acidosis and withdrawn from use after causing increased risk factors within the University Group Diabetes Program since then, a more modern biguanide, metformin, has risen to its current place because the leading oral therapy for diabetes supported its relative lack of hazard from lactic acidosis and evidence especially from a subgroup of participants in the UK Prospective Diabetes Study, that it can reduce cardiovascular risk and other drug related problems. But there are certain studies showing that combination treatment with metformin and sulfonylurea is more effective, than drugs alone in enabling glycemic control in type 2 diabetes. However, safety of such combinations deserves further investigation. Keywords: Type2 diabetes mellitus, T2DM, drug related problems, sulfonylureas, biguanides.

Efficacy and Safety of Ertugliflozin in Patients With Type 2 Diabetes Mellitus and Established Cardiovascular Disease Treated With Metformin and Sulfonylurea

Abstract Introduction: Ertugliflozin (ERTU), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is approved as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM). Aim: As a pre-specified sub-study of the Phase 3 VERTIS CV trial (NCT01986881), the efficacy and safety of ERTU were assessed in patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD) inadequately controlled with metformin and sulfonylurea (SU). Methods: Patients with T2DM, established ASCVD, and HbA1c 7.0–10.5% on stable metformin (≥1500 mg/day) and SU doses as defined per protocol were randomized to once-daily ERTU (5 mg or 15 mg) or placebo. The primary sub-study objectives were to assess the effect of ERTU on HbA1c compared with placebo and to evaluate safety and tolerability during 18-week follow-up. Key secondary endpoints included proportion of patients achieving HbA1c &amp;lt;7%, fasting plasma glucose (FPG), body weight, and systolic blood pressure. Changes from baseline at Week 18 for continuous efficacy endpoints were assessed using a constrained longitudinal data analysis model. Results: Of the 8246 patients enrolled in the VERTIS CV trial, 330 patients were eligible for this sub-study (ERTU 5 mg, n=100; ERTU 15 mg, n=113; placebo, n=117). Patients had a mean (SD) age of 63.2 (8.4) years, T2DM duration 11.4 (7.4) years, estimated glomerular filtration rate 83.5 (17.8) mL/min/1.73 m2, and HbA1c 8.3% (1.0) (67.4 [10.6] mmol/mol). At Week 18, ERTU 5 mg and 15 mg were each associated with a significantly greater least squares mean (95% CI) HbA1c reduction from baseline versus placebo; the placebo-adjusted differences for ERTU 5 mg and 15 mg were –0.7% (–0.9, –0.4) and –0.8% (–1.0, –0.5), respectively (P&amp;lt;0.001). A higher proportion of patients in each ERTU group achieved HbA1c &amp;lt;7% relative to placebo (P&amp;lt;0.001). ERTU significantly reduced FPG and body weight (P&amp;lt;0.001, for each dose versus placebo), but not systolic blood pressure. Adverse events were reported in 48.0%, 54.9%, and 47.0% of patients in the ERTU 5 mg, 15 mg, and placebo groups, respectively. Genital mycotic infections were experienced by significantly higher proportions of male patients who received ERTU 5 mg and 15 mg (4.2% and 4.8%, respectively) versus placebo (0.0%; P≤0.05) and by a numerically, but not significantly, higher proportion of female patients who received ERTU 15 mg (10.3%) compared with placebo (3.8%) (P=0.36). The incidences of symptomatic hypoglycemia were 11.0% (5 mg), 12.4% (15 mg), and 7.7% (placebo), and of severe hypoglycemia 2.0% (5 mg), 1.8% (15 mg), and 0.9% (placebo). Conclusion: Among patients with T2DM and ASCVD, ERTU (5 mg and 15 mg) added to metformin and SU for 18 weeks improved glycemic control (HbA1c and FPG) and reduced body weight, and was generally well tolerated with a safety profile consistent with the SGLT2 inhibitor class.

Inheritance of Mildly Activating ABCC8 Mutation From a Mother With MODY Causes Permanent Neonatal Diabetes Mellitus (NDM) in Two Siblings Who Also Carry a Second Inactivating Mutation: Genetic Testing Allows for Improved Treatment With Sulfonylureas (SU)

Background: Heterozygous activating mutations in KCNJ11 or ABCC8 are the most common cause of neonatal diabetes (NDM). ABCC8 (SUR1) mutations more often cause transient NDM. Inactivating ABCC8 mutations can cause congenital hyperinsulinism (HI), but very rarely will such mutations be inherited together. Mildly activating KATP mutations can also be a cause of MODY, but even if genetic testing is considered, many commercial testing panels do not include these genes, despite the significant difference in treatment that can result due to sulfonylurea (SU) responsiveness.Clinical Case: The proband was diagnosed with DM at 11 months old and fortuitously treated with SU for 3 years. He was switched to insulin and had poor DM control thereafter. Sister was diagnosed at 3.5 months old and had poor DM control on insulin. Mother was diagnosed with DM at 27 years old and treated with various medications including insulin. Genetic testing revealed that mother carried ABCC8 mutation R1380C previously described to cause transient NDM and/or later-onset DM consistent with her phenotype. Both children inherited this mutation from her and inherited a variant (L1148R) from their father without diabetes that has been reported in association with HI. The L1148R allele may reduce cell surface expression thereby increasing the relative expression and pathogenic effect of the R1380C allele that has not previously been described to cause permanent NDM.We assessed SU responsiveness by measuring maximal beta-cell function through combined mixed meal and arginine testing. Mother exhibited easily detectable C-peptide levels at baseline that improved by SU treatment. In contrast, the children displayed almost undetectable baseline beta-cell function with variable response to SU: the sister who had been chronically poorly controlled on insulin therapy displayed barely improved C-peptide production, while her brother who had previously been treated with SU as an infant had markedly improved beta-cell function on SU. Within two months of continued treatment with high doses of SU only, he was able to start lowering his SU dose with improved glycemia. His sister was started on high-dose SU in addition to insulin, but continued to have difficulty adhering to her treatment regimen. Her blood sugar improved after the addition of long-acting GLP-1 agonist (liraglutide) but she later became pregnant and returned to insulin only. Her glycemic control improved when re-started on SU after pregnancy. The mother exhibited excellent DM on a lower dose of exclusive SU therapy.Clinical Lesson: Genetic testing can dramatically alter management and must be pursued in both NDM and family members with diabetes later in life. Careful assessment of clinical characteristics along with genetic testing for segregation patterns in family members can greatly improve understanding of the causality of previous uncharacterized variants.

Efficacy and Safety of Ertugliflozin in Patients with Type2 Diabetes Inadequately Controlled by Metformin and Sulfonylurea: A Sub-Study of VERTIS CV.

IntroductionVERTIS CV is the cardiovascular outcome trial for the sodium–glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin. A sub-study was conducted to assess the efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus (T2DM) inadequately glycemic-controlled on metformin and a sulfonylurea (SU).MethodsPatients with T2DM, established atherosclerotic cardiovascular disease (ASCVD), and an HbA1c of 7.0–10.5% on stable metformin (≥ 1500 mg/day) and moderate to high SU doses were randomly assigned to once-daily ertugliflozin (5 or 15 mg) or placebo. The primary sub-study objectives were to assess the effect of ertugliflozin on HbA1c compared with placebo and to evaluate safety following 18 weeks of treatment. Key secondary endpoints included changes in fasting plasma glucose (FPG), body weight (BW), blood pressure (BP), and the proportion of patients achieving HbA1c < 7%.ResultsOf the 8246 patients enrolled in VERTIS CV, 330 were eligible for this sub-study (ertugliflozin 5 mg, n = 100; ertugliflozin 15 mg, n = 113; placebo, n = 117). This subgroup had a mean (SD) age of 63.2 (8.4) years and T2DM duration of 11.4 (7.4) years. At week 18, ertugliflozin 5 mg and 15 mg were each associated with significantly greater least squares (LS) mean reductions from baseline in HbA1c relative to placebo (placebo-adjusted LS mean [95% CI] − 0.66% [− 0.89, − 0.43] and − 0.75% [− 0.98, − 0.53], respectively, p < 0.001 for each dose vs placebo). Ertugliflozin significantly reduced FPG and BW compared with placebo (p < 0.001), but not systolic BP. Adverse events were reported in 48.0%, 54.9%, and 47.0% of patients in the ertugliflozin 5 mg and 15 mg, and placebo groups. The incidences of symptomatic hypoglycemia were 11.0% (5 mg), 12.4% (15 mg), and 7.7% (placebo), and of severe hypoglycemia 2.0% (5 mg), 1.8% (15 mg), and 0.9% (placebo).ConclusionsIn patients with T2DM and ASCVD, ertugliflozin added to metformin and SU improved glycemic control, reduced BW, and was generally well tolerated.Trial RegistrationVERTIS CV ClinicalTrials.gov identifier, NCT01986881.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01033-x.

Long-term Follow-up of Glycemic and Neurological Outcomes in an International Series of Patients With Sulfonylurea-Treated ABCC8 Permanent Neonatal Diabetes.

ABCC8 mutations cause neonatal diabetes mellitus that can be transient (TNDM) or, less commonly, permanent (PNDM); ∼90% of individuals can be treated with oral sulfonylureas instead of insulin. Previous studies suggested that people with ABCC8-PNDM require lower sulfonylurea doses and have milder neurological features than those with KCNJ11-PNDM. However, these studies were short-term and included combinations of ABCC8-PNDM and ABCC8-TNDM. We aimed to assess the long-term glycemic and neurological outcomes in sulfonylurea-treated ABCC8-PNDM. We studied all 24 individuals with ABCC8-PNDM diagnosed in the U.K., Italy, France, and U.S. known to transfer from insulin to sulfonylureas before May 2010. Data on glycemic control, sulfonylurea dose, adverse effects including hypoglycemia, and neurological features were analyzed using nonparametric statistical methods. Long-term data were obtained for 21 of 24 individuals (median follow-up 10.0 [range 4.1-13.2] years). Eighteen of 21 remained on sulfonylureas without insulin at the most recent follow-up. Glycemic control improved on sulfonylureas (presulfonylurea vs. 1-year posttransfer HbA1c 7.2% vs. 5.7%, P = 0.0004) and remained excellent long-term (1-year vs. 10-year HbA1c 5.7% vs. 6.5%, P = 0.04), n = 16. Relatively high doses were used (1-year vs. 10-year dose 0.37 vs. 0.25 mg/kg/day glyburide, P = 0.50) without any severe hypoglycemia. Neurological features were reported in 13 of 21 individuals; these improved following sulfonylurea transfer in 7 of 13. The most common features were learning difficulties (52%), developmental delay (48%), and attention deficit hyperactivity disorder (38%). Sulfonylurea treatment of ABCC8-PNDM results in excellent long-term glycemic control. Overt neurological features frequently occur and may improve with sulfonylureas, supporting early, rapid genetic testing to guide appropriate treatment and neurodevelopmental assessment.

Randomised cross-over trial of vildagliptin and pioglitazone as add-on therapy in patients with type 2 diabetes: predicting Which One is Right Here (WORTH) study protocol

IntroductionThere is emerging evidence for stratified glucose-lowering responses to certain oral medications for type 2 diabetes (T2D) by individual characteristics. The objective of this study was to test whether glycaemic...

127-LB: Characteristics of INS-MODY Participants in a National Diabetes Registry

Introduction: Maturity onset diabetes of the young (MODY) may represent 2-5% of diabetes under 30-35 years. Rarely MODY may be due to mutation in the INS gene. HNF1A mutations are well described causes of MODY and may be treated with low dose sulfonylurea. Our aim was to compare clinical features and treatment of INS-MODY with HNF1A-MODY cohort population. Methods: Participants enrolled through the U.S. Monogenic Diabetes Registry, with Sanger or next-generation sequencing completed with causal mutations found in INS or HNF1A, diagnosed after 13 months of age. Those with neonatal diabetes due to INS were excluded. Results: Each group shared similar demographics (Table 1). Common presenting symptoms in each group included polyuria, polydipsia, weight loss, fatigue (Table 1). In the INS cohort, all showed residual c-peptide. None reported DKA. The majority had used insulin, though there were a variety of treatment modalities, even among those with the same mutation (Figure 1). For HNF1A cohort, over 60% had been on insulin or sulfonylurea, with 40% having discontinued insulin. Conclusion: Review of treatments in INS cohort consist of multiple agents with majority using insulin at some point. If clinical suspicion of MODY, genetic testing may help inform treatment. It appears that some variants of INS-MODY lead to a progressive disease eventually requiring insulin therapy and early insulin may improve outcomes. Disclosure M. McCauley: None. S. Korkmaz: None. L.R. Letourneau-Freiberg: None. R.N. Naylor: None. S.W. Greeley: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104942, P30DK0205950); National Center for Advancing Translational Sciences (UL1TR002389)

Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial

Oral semaglutide is the first oral glucagon-like peptide-1 (GLP-1) receptor agonist for glycaemic control in patients with type 2 diabetes. Type 2 diabetes is commonly associated with renal impairment, restricting treatment options. We aimed to investigate the efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment. This randomised, double-blind, phase 3a trial was undertaken at 88 sites in eight countries. Patients aged 18 years and older, with type 2 diabetes, an estimated glomerular filtration rate of 30-59 mL/min per 1·73 m2, and who had been receiving a stable dose of metformin or sulfonylurea, or both, or basal insulin with or without metformin for the past 90 days were eligible. Participants were randomly assigned (1:1) by use of an interactive web-response system, with stratification by glucose-lowering medication and renal function, to receive oral semaglutide (dose escalated to 14 mg once daily) or matching placebo for 26 weeks, in addition to background medication. Participants and site staff were masked to assignment. Two efficacy-related estimands were defined: treatment policy (regardless of treatment discontinuation or rescue medication) and trial product (on treatment without rescue medication) in all participants randomly assigned. Endpoints were change from baseline to week 26 in HbA1c (primary endpoint) and bodyweight (confirmatory secondary endpoint), assessed in all participants with sufficient data. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on ClinicalTrials.gov, number NCT02827708, and the European Clinical Trials Registry, number EudraCT 2015-005326-19, and is now complete. Between Sept 20, 2016, and Sept 29, 2017, of 721 patients screened, 324 were eligible and randomly assigned to oral semaglutide (n=163) or placebo (n=161). Mean age at baseline was 70 years (SD 8), and 168 (52%) of participants were female. 133 (82%) participants in the oral semaglutide group and 141 (88%) in the placebo group completed 26 weeks on treatment. At 26 weeks, oral semaglutide was superior to placebo in decreasing HbA1c (estimated mean change of -1·0 percentage point (SE 0·1; -11 mmol/mol [SE 0·8]) vs -0·2 percentage points (SE 0·1; -2 mmol/mol [SE 0·8]); estimated treatment difference [ETD]: -0·8 percentage points, 95% CI -1·0 to -0·6; p<0·0001) and bodyweight (estimated mean change of -3·4 kg [SE 0·3] vs -0·9 kg [SE 0·3]; ETD, -2·5, 95% CI -3·2 to -1·8; p<0·0001) by the treatment policy estimand. Significant differences were seen for the trial product estimand: mean change in HbA1c -1·1 percentage points (SE 0·1; -12 mmol/mol [SE 0·8] versus -0·1 percentage points (SE 0·1; -1 mmol/mol [SE 0·8]; ETD -1·0 percentage points, 95% CI -1·2 to -0·8; p<0·0001); mean change in bodyweight -3·7 kg (SE 0·3) versus -1·1 kg (SE 0·3; ETD -2·7 kg, 95% CI -3·5 to -1·9; p<0·0001). More patients taking oral semaglutide than placebo had adverse events (120 [74%] of 163 vs 105 [65%] of 161), and discontinued treatment as a result (24 [15%] vs eight [5%]). Gastrointestinal events, mainly mild-to-moderate nausea, were more common with oral semaglutide than with placebo. Three deaths occurred during the treatment period that were not condsidered to be treatment related, one in the semaglutide group and two in the placebo group. Oral semaglutide was effective in patients with type 2 diabetes and moderate renal impairment, potentially providing a new treatment option for this population. Safety, including renal safety, was consistent with the GLP-1 receptor agonist class. Novo Nordisk A/S.

1008-P: Efficacy of Dulaglutide on Renal Functions in the Real-World Clinical Practice for Diabetes in Japan

Aims: Efficacy of a GLP-1 receptor agonist, dulaglutide, on renal functions in type 2 diabetic patients under the real-world clinical practice in Japan was retrospectively examined. Subjects: 154 patients with type 2 diabetes treated with dulaglutide (0.75 mg once weekly) in our clinic (mean administration period 540.7 ± 332 days; mean age 58.1 years; mean duration of diabetes 10.5 years). Methods: Dulaglutide was added to the conventional antidiabetes drugs. The dose of sulfonylurea was reduced by 50-67% and all the DPP-4 inhibitors were discontinued. The annual changes in eGFR between 1 year before and 2 years after the administration of dulaglutide were retrospectively analyzed in 2 groups divided by the baseline eGFR; eGFR&amp;lt;90 ml/min/1.73m2 group and eGFR≧90 group. Changes in HbA1c levels and body weight were also evaluated. Results: eGFR in the eGFR&amp;lt;90 group (n = 90) rapidly declined (-5.4 ± 7.8/year) before the administration of dulaglutide (p &amp;lt;0.001). However, the decline was moderate after the administration of dulaglutide (-1.2 ± 7.1/year after 1 year, p = 0.134; -1.1 ± 5.8/year between 1 and 2 years, p = 0.179). In contrast, eGFR in the eGFR≧90 group (n = 57) was not declined before the administration of dulaglutide (+ 1.4 ± 6.6/year, p = 0.318), and significantly decreased after the administration of dulaglutide (-2.9 ± 10.0/year after 1 year, p = 0.036; -2.5 ± 6.8/year between 1 and 2 years, p = 0.048). HbA1c levels were 8.70 ± 1.76% at baseline, -1.32 ± 1.69% at 1 year (p &amp;lt;0.001, n = 86), -1.19 ± 1.56% at 2 years (p &amp;lt;0.001, n = 39). Body weight were 71.3 ± 15.2 kg at baseline, -1.86 ± 3.38 kg at 1 year (p &amp;lt;0.001, n = 86), -2.04±3.33 kg at 2 years (p=0.001, n=39). Conclusions: These observations suggest that dulaglutide may ameliorate renal hyperfiltration and protect renal functions. Disclosure S.T. Sato: None. T. Tosaki: Research Support; Self; Daiichi Sankyo Company, Limited, Sanofi K.K. Speaker's Bureau; Self; Astellas Pharma Inc., Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. M. Kondo: None. Y. Yamada: None. A. Inagaki: None. S. Tsunekawa: None. T. Himeno: None. Y. Kato: Speaker's Bureau; Self; Merck &amp; Co., Inc. J. Nakamura: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd., Merck Sharp &amp; Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceu. Co. Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. H. Kamiya: Speaker's Bureau; Self; Astellas Pharma Inc., Eli Lilly Japan K.K., MSD K.K., Novartis Pharma K.K., Novo Nordisk Oharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K.K.

SUN-451 A Randomized-Withdrawal, Placebo-Controlled, Phase 3 Study to Assess the Efficacy and Safety of Selective Glucocorticoid Receptor Antagonist, Relacorilant, in Patients with Cushing Syndrome (GRACE Study)

Relacorilant is a highly selective glucocorticoid receptor antagonist (GRA) that modulates the effects of excess cortisol while showing no affinity for progesterone, mineralocorticoid, androgen, or estrogen receptors. In a phase 2 study, treatment with relacorilant showed improvement in glycemic and hypertension endpoints as well as other manifestations of cortisol excess in patients with endogenous Cushing syndrome (CS). Relacorilant was well tolerated, with no instances of drug-related hypokalemia or antiprogesterone effects. A multicenter phase 3 clinical trial of relacorilant is underway (GRACE Study: NCT03697109) that uses a randomized withdrawal (RW) design to evaluate efficacy and safety. Based on the mechanism of action of GRAs, clinical efficacy endpoints are being used. The study includes a 6-week (6wk) screening phase, followed by a 22wk open-label (OL) treatment phase, where eligible patients 18-80 years old with a confirmed biochemical diagnosis of endogenous CS, clinical signs and symptoms of CS, and either diabetes mellitus/impaired glucose tolerance (DM/IGT) or hypertension will receive relacorilant (100 mg/day, titrated to 400 mg/day, as tolerated). Those patients who complete the OL phase and meet clinical response criteria (assessed at OL wk22) are eligible to enter the blinded RW phase, where they will receive either placebo or relacorilant at the same dose they received at the end of the OL phase. During the RW phase, increases in antidiabetic and/or antihypertensive agents are allowed if there is a loss of response compared to OL wk22. Criteria for RW entry in the DM/IGT group include one of the following: ≥0.5% decrease in HbA1c from baseline, normalization or ≥50 mg/dL decrease in 2-hour OGTT glucose from baseline, or decrease in daily insulin or sulfonylurea dose and HbA1c unchanged or decreased. Criteria for RW entry in the hypertension group include one of the following: ≥5 mmHg decrease in mean systolic and/or diastolic blood pressure (SBP/DBP) without worsening of either, or a reduction in the number/dose of antihypertensives and no worsening of SBP/DBP. The primary efficacy endpoint in the DM/IGT group is the mean change from OL wk22 to RW wk12 in 2-hour OGTT glucose as compared between treatment groups. In the hypertension group, the primary endpoint is the proportion of patients with a loss of response with respect to hypertension from OL wk22 to RW wk12 as compared between treatment groups. Loss of response is defined as an increase in SBP or DBP ≥5 mmHg or any increase in dose or number of antihypertensive medications. Secondary efficacy endpoints include the proportion of patients meeting any DM/IGT and/or hypertension RW entry criteria at the end of the OL phase. Cushing Quality-of-Life and Global Clinical Response scores are also assessed. In conclusion, GRACE is enrolling participants in the first RW trial to assess relacorilant in the treatment of CS.

MON-121 Successful Transition from Insulin to Sulfonylurea for a 26 Year Old Female with Neonatal Diabetes Secondary to KCNJ11 Gene Mutation

Neonatal diabetes (NDM) is defined as diabetes that occurs in the first 6 months of life. Sporadic mutation is the main etiology of this type. ATP-sensitive potassium channels located in the beta cells of pancreas play a major role in insulin secretion and blood glucose hemostasis. Mutations that alter the function of these channels may lead to neonatal diabetes. We herein report a case of a 26 year old Irish female who was diagnosed with neonatal diabetes at the age of one month old and was labeled as type 1 diabetes mellitus, in which she was started on multiple daily injection of insulin with suboptimal control and frequent episodes of hypoglycemia. She has a positive family history of diabetes. Anti-GAD antibody and Islets cell antibody were both negative. However, at the age of 16 years, she underwent genetic testing and was diagnosed with KCNJ11 gene mutation. The gene is encoded for Kir6.2, which is a major subunit of ATP-sensitive potassium channels that lead to channels malfunction and development of diabetes. She was transferred to glibenclamide at the age of 16 but the trail was failed and restarted on insulin. Prior to the second trail of transition her HbA1C was 63 mmol/mol and her total daily dose of insulin was 50 units. At 23 years of age she was successfully shifted from insulin to high dose sulfonylurea (glibenclamide 15mg twice daily) with optimal control of blood glucose (HbA1C 44 mmol/mol), lower rates of hypoglycemic episodes and better quality of life.

The Effect of Proton Pump Inhibitors on Glycemic Control in Patients with Type 2 Diabetes.

Background: Type 2 diabetes patients have decreased pancreatic beta cell mass with a decline in beta cell function. Gastrin has increased beta cell proliferation in vitro and in animal studies. High gastric acid levels inhibit gastrin secretion. Proton pump inhibitors (PPIs) lower gastric acid, subsequently increasing gastrin levels. This may stimulate beta cell proliferation and function, and improve glycemic control. Studies with small numbers of type 2 diabetes patients have shown a slightly lower A1C in those taking PPI versus non-PPI users. Methods: This study was a retrospective multicenter electronic data analysis using data obtained from health care facilities within Veterans Integrated Service Network (VISN) 21. Patients were included if they had established care within VISN 21 and had type 2 diabetes with an A1C > 6.5%, were started on a PPI concurrently with stable doses of metformin or sulfonylurea (SFU) monotherapy, had at least two documented A1C values, and had a medication possession ratio >80% for metformin, SFU, or a PPI. Veterans were excluded if they were using insulin, combination antihyperglycemic therapy, or oral corticosteroids. A control group not using PPI was also identified. Results: There was a statistically significant decrease in A1C within each group. However, there was no statistically significant difference between the PPI and control group in the post-A1C. Conclusion: In patients with type 2 diabetes, A1C improved in both groups, but PPI addition did not affect glycemic control. Future randomized controlled trials are needed to determine the value of PPIs as a treatment option for patients with type 2 diabetes.