Post on 23-Jan-2020
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The Year in Diabetes Mellitus: 2019Kudva.yogish@mayo.edu
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Disclosure • Product Support:
Dexcom, Roche Diabetes, Tandem Diabetes
• Consulting: Novo Nordisk• Educational session for
Libre use: reimbursed by Endo Society March 2019
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Learning Objectives • Hybrid Closed Loop testing in DCLP3 Trial• Rybelsus for type 2 diabetes • SGLT2 inhibitors and diabetes related
complications • Expanded indication for Dapagliflozin• Baqsimi to treat hypoglycemia • Immunosuppression to prevent type 1 diabetes
in high risk normoglycemic individuals
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Learning Objectives • Hybrid Closed Loop testing in DCLP3 Trial• Rybelsus for type 2 diabetes • SGLT2 inhibitors and diabetes related
complications • Expanded indication for Dapagliflozin• Baqsimi to treat hypoglycemia • Immunosuppression to prevent type 1 diabetes
in high risk normoglycemic individuals
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Question In the Experimental cohort of the DCCT, glucose control achieved is best stated as follows: • A. TIR 52 % and time < 70 mg/dl=13 %• B. TIR 64 % and time < 54 mg/dl=5 % • C. TIR 31 % and time > 180 mg/dl =64 %• D. TIR 34 % and time > 180 mg/dl =34 %
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Question In the Experimental cohort of the DCCT, glucose control achieved is best stated as follows: • A. TIR 52 % and time < 70 mg/dl=13 %• B. TIR 64 % and time < 54 mg/dl=5 % • C. TIR 31 % and time > 180 mg/dl =64 %• D. TIR 34 % and time > 180 mg/dl =34 %
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Dassau et al. Diabetes Care 2014
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• NIDDK Grant UC4 DK108483
• Material Support by Tandem Diabetes Care, including: t:slim X2 insulin pumps with
Control-IQ technology and related supplies
Dexcom G6 CGM supplies Accu-Chek Guide glucometer
STUDY FUNDING
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DEVELOPMENT of UVA’s AP TECHNOLOGY
from ResearchDiAs
(UVA, 2012)Sensor: Dexcom Seven plus
or G4;Insulin Pump: Roche or
Tandem
to MobileinControl
(TypeZero, 2015)Sensor: Dexcom G4 or G5;
Insulin Pump: Roche or Tandem
to EmbeddedControl-IQ(Tandem, 2017)
Sensor: Dexcom G6Insulin Pump: t:slim X2
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THE iDCL TRIAL: TESTING EMBEDDED CLOSED LOOP CONTROL
OBJECTIVE: In a Randomized Controlled Trial, assess safety and efficacy of long-term Closed-Loop Control (CLC) using t:slim X2 with Control-IQ technology (Tandem Diabetes Care), compared to Sensor-Augmented Pump (SAP) Therapy; Generate safety and efficacy data that can satisfy FDA
requirements.
NIH Grant PI: Boris Kovatchev, PhD (University of Virginia);
Protocol Chair: Sue Brown, MD (University of Virginia);
Study Coordination: Jaeb Center for Health Research, Tampa, Florida.
Clinicaltrials.gov: NCT03563313
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THE iDCL TRIAL CLINICAL SITES
o University of Virginia (Sue Brown, MD/Stacey Anderson, MD);
o Sansum Diabetes Research Institute (Jordan Pinsker, MD);o Mount Sinai School of Medicine (Carol Levy, MD);o Mayo Clinic (Yogish Kudva, MD);o Joslin Diabetes Center/Harvard University (Lori Laffel,
MD/Francis Doyle III, PhD);o Barbara Davis Diabetes Center (Paul Wadwa, MD);o Stanford University (Bruce Buckingham, MD).
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STUDY DESIGN
0Week
Scre
enin
g &
Run
-In
Sensor Augmented Pump(no PLGS or CLC use)
Closed-Loop Control
Baseline HbA1c; Questionnaires
HbA1c;Questionnaires
26
Final HbA1c;Questionnaires
13R
ando
miz
atio
n 2:
1
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OUTCOMES
Primary Outcome:• Time in Target Range 70-180 mg/dL measured
by CGM
Additional Hierarchical Outcomes:• Time >180 mg/dL• Mean glucose by CGM• HbA1c• Time <70 mg/dL• Time <54 mg/dL
CGM outcomes measured over 26 weeks
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SYSTEM CONFIGURATION
• Study Pump: t:slimX2 with Control-IQ Algorithm
• Study CGM: Dexcom G6 with no calibration required:
UNIQUE ALGORITHM FEATURES:
Automated insulin correction boluses administered using CGM-based patient state estimation in addition to basal-rate modulation;
Dedicated hypoglycemia safety system which attenuates smoothly, or discontinues, insulin delivery using CGM and insulin-on-board information, and
Gradually intensified control overnight, sliding the algorithm target range down to achieve blood glucose levels of approximately 110-120mg/dL by the morning.
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ENROLLMENT CRITERIA
• Inclusion Criteria • Type 1 Diabetes for at least 1 year• Ages 14 years and older
• Exclusion Criteria• No other glucose lowering agents other than insulin
and metformin• No entry restrictions on:
• HbA1c• MDI or pump use• Severe hypoglycemia or DKA events
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Enrolled N=170
Randomized N= 168
STUDY FLOW CHART
Skipped Run-InN=83
Completed Run-In
N=85
Completed N= 168
CLC GroupN=112
SAP GroupN=56
2 wk
6 wk
13 wk
26 wk
In ClinicVisits
CLC GroupN=112
SAP GroupN=56
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BASELINE CHARACTERISTICSSAPN=56
CLCN=112
Mean Age (range)
33 yrs(14-63 yrs)
33 yrs(14-71 yrs)
Gender 54% F 48% F
Mean HbA1c(range)
7.4% (6.0%-9.0%)
7.4% (5.4%-10.6%)
MDI User 23% 20%
Current CGM User 71% 70%
Median T1D Duration(range)
15 yrs(1-53 yrs)
17 yrs(1-62 yrs)
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RESULTS
• Analyses conducted with a pre-specified hierarchical list of outcomes to maintain a type 1 error rate of 5%.
• All outcomes favored the CLC arm.
Outcome P valuePrimary Outcome:
Time in Range 70-180 mg/dL <0.0001Additional Outcomes
Time >180 mg/dL <0.0001Mean Glucose <0.0001HbA1c 0.0014Time <70 mg/dL <0.0001Time <54 mg/dL 0.02
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SUMMARY
• Study achieved all primary and main secondary efficacy outcomes without any severe hypoglycemic events
• Compared with sensor-augmented pump therapy, CLC system (Control-IQ) use for 6 months improved: Time in target range 70-180 mg/dL HbA1c Mean Glucose by CGM Hyperglycemia >180 mg/dL Hypoglycemia <70 mg/dL Hypoglycemia <54 mg/dL
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100% of participants completed the RCT and were actively using the system at the end of 6 months;
Benefit of the CLC Control-IQ system was realized in the first month and consistently sustained over six months;
Results are consistent across wide range of HbA1c (5.4-10.6%) and ages (14-71 years), including MDI participants;
Participants achieved CLC use rate of 92% over 6 months and reported high rates on ease of use, trust, and usefulness.
SUMMARY
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Learning Objectives • Hybrid Closed Loop testing in DCLP3 Trial• Rybelsus for type 2 diabetes • SGLT2 inhibitors and diabetes related
complications • Expanded indication for Dapagliflozin• Baqsimi to treat hypoglycemia • Immunosuppression to prevent type 1 diabetes
in high risk normoglycemic individuals
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RYBELSUS® is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1).Limitations of Use• Not recommended as first-line therapy for patients inadequately controlled on diet and exercise (1, 5.1).• Has not been studied in patients with a history of pancreatitis (1, 5.2).• Not indicated for use in patients with type 1 diabetes mellitus or treatment of diabetic ketoacidosis. ———
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DOSAGE AND ADMINISTRATION• Instruct patients to take RYBELSUS® at least 30 minutes before the first food, beverage, or other oral medications of the day with no more than 4 ounces of plain water only. Waiting less than 30 minutes, or taking with food, beverages (other than plain water) or other oral medications will lessen the effect of RYBELSUS®. Waiting more than 30 minutes to eat may increase the absorption of RYBELSUS®. • Swallow tablets whole. Do not cut, crush, or chew tablets.• Start RYBELSUS® with 3 mg once daily for 30 days. After 30 days on the 3 mg dose, increase the dose to 7 mg once daily.• Dose may be increased to 14 mg once daily if additional glycemic control is needed after at least 30 days on the 7 mg dose.
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WARNINGS AND PRECAUTIONS ———• Pancreatitis: Has been reported in clinical trials. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed.• Diabetic Retinopathy Complications: Has been reported in a cardiovascular outcomes trial with semaglutide injection. Patients with a history of diabetic retinopathy should be monitored.• Hypoglycemia: When RYBELSUS® is used with an insulin secretagogue or insulin, consider lowering the dose of the secretagogue or insulin to reduce the risk of hypoglycemia.• Acute Kidney Injury: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions.• Hypersensitivity Reactions: Discontinue RYBELSUS® if suspected and promptly seek medical advice.
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ADVERSE REACTIONS ———The most common adverse reactions, reported in ≥5% of patients treated with RYBELSUS® are: nausea, abdominal pain, diarrhea, decreased appetite, vomiting and constipation.
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Results at Week 26 in a Trial of RYBELSUS® as Monotherapy in Adult Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise
Placebo RYBELSUS® 7 RYBELSUS® 14 mg
Intent-to-Treat (ITT) Population 178 175 175 HbA1c (%) Baseline (mean) 7.9 8.0 8.0 Change at week 26 -0.3 -1.2 -1.4
Difference from placebo [95% CI] −0.9 −1.1
Patients (%) achieving HbA1c <7% 31 69 77
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Results at Week 26 in a Trial of RYBELSUS® Compared to Sitagliptin 100 mg Once daily in Adult Patients with Type 2 Diabetes Mellitus In Combination with Metformin or Metformin with Sulfonylurea
R® 7 mg R® 14 mg Sitagliptin 100mg
Intent-to-Treat (ITT) Population 465 465 467
HbA1c (%) Baseline (mean) 8.4 8.3 8.3
Change at week 26 -1.0 -1.3 -0.8
Difference from sitagliptin [95% CI] -0.3 -0.5
Patients (%) achieving HbA1c <7% 44 56 32
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Results at Week 26 in a Trial of RYBELSUS® Compared to Empagliflozin in Adult Patients with Type 2 Diabetes Mellitus In Combination with Metformin
RYBELSUS® 14 mg Empagliflozin 25 mg Intent-to-Treat (ITT) Population (N)a 411 410 HbA1c (%)
Baseline (mean) 8.1 8.1
Change at week 26 -1.3 -0.9
Difference from empagliflozinb [95% CI] -0.4 [-0.6, -0.3]
Patients (%) achieving HbA1c <7% 67 40
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Results at Week 26 in a Trial of RYBELSUS® Compared to Liraglutide and Placebo in Adult Patients with Type 2 Diabetes Mellitus In Combination with Metformin or Metformin with SGLT-2i
Placebo Liraglutide 1.8 mg RYBELSUS® 14 mg
Intent-to-Treat (ITT) Population 142 284 285
HbA1c (%) Baseline (mean) 7.9 8.0 8.0
Change at week 26 -0.2 -1.1 -1. 2
Difference from placebo [95% CI] -1.1
[-1.2 ; -0.9]
Difference from liraglutide[95% CI] -0.1
[-0.3; 0.0]
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Results at Week 26 in a Trial of RYBELSUS® Compared to Placebo in Patients With Moderate Renal Impairment
Placebo RYBELSUS® 14 mg Intent-to-Treat (ITT) Population 161 163
HbA1c (%) Baseline (mean) 7.9 8.0
Change at week 26 -0.2 -1.0
Difference from placebo [95% CI] -0.8 [-1.0; -0.6]
Patients (%) achieving HbA1c <7% 23 58
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NEJM On line June 11, 2019
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Background
NEJM On line June 11, 2019
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NEJM On line June 11, 2019
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Lancet 2018; 392: 1519–29
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Lancet 2018; 392: 1519–29
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Lancet 2018; 392: 1519–29
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Learning Objectives • Hybrid Closed Loop testing in DCLP3 Trial• Rybelsus for type 2 diabetes • SGLT2 inhibitors and diabetes related
complications • Expanded indication for Dapagliflozin• Baqsimi to treat hypoglycemia • Immunosuppression to prevent type 1 diabetes
in high risk normoglycemic individuals
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Perkovic et al. NEJM 2019
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Perkovic et al. NEJM 2019
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Perkovic et al. NEJM 2019
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Perkovic et al. NEJM 2019
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Perkovic et al. NEJM 2019
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Perkovic et al. NEJM 2019
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Perkovic et al. NEJM 2019
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Empagliflozin, Dapagliflozin and Canagliflozin have benefical effects on CV and renal end points
Caution
DKAGenital infection
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Learning Objectives • Hybrid Closed Loop testing in DCLP3 Trial• Rybelsus for type 2 diabetes • SGLT2 inhibitors and diabetes related
complications • Expanded indication for Dapagliflozin• Baqsimi to treat hypoglycemia • Immunosuppression to prevent type 1 diabetes
in high risk normoglycemic individuals
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Wiviott et al. NEJM 2019:380;348
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Wiviott et al. NEJM 2019:380;348
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Wiviott et al. NEJM 2019:380;348
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Wiviott et al. NEJM 2019:380;348
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Wiviott et al. NEJM 2019:380;348
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Wiviott et al. NEJM 2019:380;348
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Wiviott et al. NEJM 2019:380;348
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Statement from HEALIO “The diabetes drug dapagliflozin has been approved by the FDA to reduce the risk for heart failure hospitalization among adults with type 2 diabetes who also have cardiovascular disease or multiple CV risk factors, according to a press release from AstraZeneca.The approval is based on results of the DECLARE-TIMI 58 trial. The trial, which included more than 17,000 patients with type 2 diabetes who were followed for a median of 4.2 years, demonstrated a 27% reduction in the rate of hospitalization for heart failure among participants assigned the SGLT2 inhibitor dapagliflozin (Farxiga) vs. those assigned placebo (HR = 0.73; 95% CI, 0.61-0.88).”
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The diabetes drug dapagliflozin has been approved by the FDA to reduce the risk for heart failure hospitalization among adults with type 2 diabetes who also have cardiovascular disease or multiple CV risk factors, according to a press release from AstraZeneca.The approval is based on results of the DECLARE-TIMI 58 trial. As Healiopreviously reported, that trial, which included more than 17,000 patients with type 2 diabetes who were followed for a median of 4.2 years, demonstrated a 27% reduction in the rate of hospitalization for heart failure among participants assigned the SGLT2 inhibitor dapagliflozin (Farxiga) vs. those assigned placebo (HR = 0.73; 95% CI, 0.61-0.88).
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Learning Objectives • Hybrid Closed Loop testing in DCLP3 Trial• Rybelsus for type 2 diabetes • SGLT2 inhibitors and diabetes related
complications • Expanded indication for Dapagliflozin• Baqsimi to treat hypoglycemia • Immunosuppression to prevent type 1 diabetes
in high risk normoglycemic individuals
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INDICATIONS AND USAGE --------------------------BAQSIMI™ is an antihypoglycemic agent indicated for the treatment of severe hypoglycemia in patients with diabetes ages 4 years and above.
Baqsimi PI
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Baqsimi PI
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Baqsimi PI
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Baqsimi PI
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Baqsimi PI
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Learning Objectives • Hybrid Closed Loop testing in DCLP3 Trial• Rybelsus for type 2 diabetes • SGLT2 inhibitors and diabetes related
complications • Expanded indication for Dapagliflozin• Baqsimi to treat hypoglycemia • Immunosuppression to prevent type 1 diabetes
in high risk normoglycemic individuals
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Herold K et al. NEJM 2019:381;603
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Herold K et al. NEJM 2019:381;603
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Herold K et al. NEJM 2019:381;603
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ZnT8 Abs and DR3-DR4+ were markers for success
Herold K et al. NEJM 2019:381;603