The Year in Diabetes Mellitus: 2019• Rybelsus for type 2 diabetes • SGLT2 inhibitors and...

©2019 MFMER | slide-1

The Year in Diabetes Mellitus: [email protected]


Disclosure • Product Support:

Dexcom, Roche Diabetes, Tandem Diabetes

• Consulting: Novo Nordisk• Educational session for

Libre use: reimbursed by Endo Society March 2019


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


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 %


Dassau et al. Diabetes Care 2014


• 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


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


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


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).


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


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


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.


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


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


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)


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


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


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


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. ———


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.


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.


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.


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


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


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


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]


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


NEJM On line June 11, 2019


Background



Lancet 2018; 392: 1519–29


Perkovic et al. NEJM 2019


Empagliflozin, Dapagliflozin and Canagliflozin have benefical effects on CV and renal end points

Caution

DKAGenital infection


Wiviott et al. NEJM 2019:380;348


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).”


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).

https://www.healio.com/cardiology/chd-prevention/news/online/%7b7f8c0980-0315-4b53-a5f2-e750cf3b5c7d%7d/declare-timi-58-dapagliflozin-reduces-hf-hospitalization-in-type-2-diabetes


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


Baqsimi PI


Herold K et al. NEJM 2019:381;603


ZnT8 Abs and DR3-DR4+ were markers for success


The Year in Diabetes Mellitus: 2019• Rybelsus for type 2 diabetes • SGLT2 inhibitors and...

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