Type 2 Diabetes Management: Case 3: Initiation and Intensification - - PDF document

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Type 2 Diabetes Management: Case 3: Initiation and Intensification of Insulin 1

Type 2 Diabetes Management

Case 3: Initiation and Intensification of Insulin

• M. Susan Burke, MD, FACP

Clinical Associate Professor of Medicine Sidney Kimmel Medical College at Thomas Jefferson University Senior Advisor , Lankenau Medical Associates Lankenau Medical Center Wynnewood, PA Ellen H. Miller, MD Professor of Science Education & Medicine Hofstra Northwell School of Medicine Senior Medical Director North Shore - LIJ CareConnect East Hills, NY

Case 3: Barbara

52-year-old woman with 6-year history of T2DM

• Also has hypertension and dyslipidemia, both controlled on medications;

no history of CVD

• Takes metformin 1,500 mg QD and glimepiride 8 mg QD
• A1C was 8.2%, but has increased to 9.1%; patient reports compliance

with antihyperglycemic medications, but has experienced several episodes of dizziness and fatigue over past month

• Weight = 186 lb, height = 5’7” (BMI = 29.1 kg/m2)

ADA/EASD Position Statement

Inzucchi SE et al. Diabetes Care. 2015;38:140-149. Used for Educational Purposes Only. *AACE guidelines: Garber AJ et al. Endocr Pract. 2016;22:84-113

When to Consider Insulin in a Person with Type 2 Diabetes

• Consider as initial therapy in T2DM if A1C >9% or symptomatic
• When a combination of non-insulin antihyperglycemic medications are unable to

achieve A1C target

• Unacceptable side effects and/or contraindications to non-insulin medications
• Advanced hepatic or renal disease or other comorbidities precluding use of
• ther agents
• Special considerations (steroids, infection, pregnancy)
• Hyperglycemia in a hospitalized patient
• “Severely” uncontrolled diabetes*

Nathan DM et al. Diabetes Care. 2009;32:193-203. Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379.

• ADA. Diabetes Care. 2014:37(Suppl 1):S14-S80.

* Random Glucose >300 mg/dL, A1C >10%, Ketonuria, Symptomatic polyuria/polydipsia, weight loss

ADA/EASD Position Statement

Initiation and Adjustment of Insulin Regimens: Basal Insulin (Analog or NPH)

Add 1 rapid insulin injection before largest meal Change to premixed insulin twice daily

Basal Insulin

(usually with metformin +/-

• ther noninsulin agent)

If not controlled after FBG target is reached (or if dose >0.5 U/kg/day), treat PPG excursions with mealtime insulin, (consider initial GLP-1 RA Trial)

• Start: 10 U/day or 0.1-0.2 U/kg/day
• Adjust: 10%-15% or 2-4 U once-twice weekly to reach FBG target
• For hypo: Determine and address cause; ↓ dose by 4 U 10%-20%

Inzucchi SE et al. Diabetes Care. 2015;38:140-149. *AACE guidelines: Garber AJ et al. Endocr Pract. 2016;22:84-113.

Insulin Preparations: Onset and Duration of Action

Insulin preparation Onset of action Peak Duration of action Glargine (U-100) 45 min – 4 hr Minimal – depends on dose Up to 22 hr Glargine (U-300) ~6 hr Minimal – depends on dose >24 hr Detemir 45 min – 4 hr Minimal – depends on dose Up to 22 hr Degludec (U-100/U-200) 1 hr Minimal – depends on dose >42 hr Degludec/aspart 70/30 Rapid after injection Minimal – depends on dose >24 hr

Analogue Biphasic / Premixed Insulin

Insulin preparation Onset of action Prandial Peak Duration of action 75% NPL / 25% Lispro ~15 min 1-2 hr 10-16 50% NPL / 50% Lispro ~15 min 1-2 hr 10-16 70% Aspart protamine / 30% Aspart ~15min 4-10 hr 15-18

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Type 2 Diabetes Management: Case 3: Initiation and Intensification of Insulin 2

Time-Action Profiles of Human Insulins and Insulin Analogs

Rosenstock J et al. eds. Textbook of Type 2 Diabetes. 2003:131-154. Plank J et al. Diabetes Care. 2005;28:1107-1112. Rave K et al. Diabetes Care. 2005;28:1077-1082; Afrezza (insulin human). Prescribing information. Available at: http://products.sanofi.us/afrezza/afrezza.html.

2 4 6 8 10 12 14 16 18 20 22 24

Plasma insulin levels Regular Insulin NPH Time Course of Action (Hour) Glargine (basal) Aspart, Glulisine, Lispro Detemir (basal) Inhaled insulin

Long-acting Insulins

Adapted from Hirsch I. N Engl J Med. 2005;352:174-183.

Time after SC injection (hours) 4 8 16 24 Intermediate-acting insulin: NPH Long-acting insulin: Detemir, Glargine Glargine U-300 Degludec U-100 or U-200

Insulin Glargine U-300

• Once-daily long-acting basal insulin
• FDA approved 02/25/2015
• Trials comparing glargine U-300 with glargine U-100
• Similar rates of glucose control and HbA1C reduction
• Lower rates of nocturnal and severe hypoglycemia with U-300
• U-300 has longer duration of action compared with U-100
• U-300 has flatter pharmacokinetic profile compared with U-100

Riddle MC et al. Diabetes Care. 2014;37:2755-2762; Yki-Järvinen H et al. Diabetes Care. 2014;7:3235-3243; Bolli GB et al. Diabetes Obes Metab. 2015;17:386-394.

Insulin Degludec

• New-generation ultra-long-acting basal insulin analog
• FDA approved 09/25/2015
• Meta-analysis of treat-to-target trials (2,899 people randomized to insulin degludec and

1,431 randomized to insulin glargine)

• Lower hypoglycemia* in T2DM RR = 0.83 [95% CI: 0.74; 0.94]
• 86% reduction in insulin-naive patients
• Lower nocturnal hypoglycemia** in T2DM RR: 0.68 [95% CI: 0.57; 0.82]
• Lower hypoglycemia rate in elderly
• Improved treatment satisfaction and quality of life
• FLEX Study: time of daily dosing can be varied without compromising glycemic

control with A1C reduction comparable to fixed time glargine

Evans M, McEwan P. J Comp Eff Res. 2015:1-8. [Epub ahead of print]. Ratner R et al. Diabetes Obes Metab. 2013;15:175-184. Meneghini L et al. Diabetes Care.2013;36:858-864. * Plasma glucose <3.1 mmol/L, irrespective of symptoms, or if the hypoglycemia was severe – requiring assistance from a third party); ** Nocturnal hypoglycemia was defined as occurring between 00:00 and 05:59.

Ultra-long Basal Insulins: Place in Therapy

Patients needing less fluctuation of insulin levels

• Includes those with:
• Nocturnal hypoglycemia
• Renal impairment, elderly
• Variable schedules/lifestyle: shift workers, college students
• Complaints of variability of fasting glucose levels
• Adherence issues: can dose within 8 hours if dose was missed

Insulin Glargine Follow-on (Biosimilar) Agent

• FDA approved first follow-on insulin glargine agent in

December 2015

• Also referred to as biosimilar
• Long-acting alternative form of currently available

insulin glargine with the same protein sequence and similar glucose-lowering

• Injected once daily, subcutaneously using a prefilled pen formulation
• May be priced competitively
• Availability for use in US: late 2016

FDA news release, 12-16-15. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm477734.htm.

SLIDE 3

Type 2 Diabetes Management: Case 3: Initiation and Intensification of Insulin 3

Case 3: Barbara – cont’d

• She has not met her A1C goal of <7% despite 56 units
• f glargine daily and metformin 1000 BID
• She has had several episodes of nocturnal

hypoglycemia in the last month, so she started to reduce her glargine dose on her own What are some reasons she hasn’t gotten to goal?

ADA/EASD Position Statement Options when Basal Insulin +/- OADs Don’t Achieve Target Glycemia

• Start: 4U, 0.1 U/kg, or 10% basal dose

If A1C <8%, consider ↓ basal by same amount

• Adjust: ↑ dose by 1-2 U or 10%-15% once-

twice weekly until SMBG target reached

• For hypo: Determine and address cause;

↓ corresponding dose by 2-4 U 10%-20% Add 1 rapid insulin* injection before largest meal Change to premixed insulin* twice daily

If not controlled after FBG target is reached (or if dose >0.5 U/kg/day), treat PPG excursions with mealtime insulin, (consider initial GLP-1 RA trial)

• Start: 4 U, 0.1 U/kg, or 10% basal dose/meal‡

If HbA1C <8%, consider ↓ basal by same amount

• Adjust: ↑ dose by 1-2 U or 10%-15% once-twice

weekly until SMBG target reached

• For hypo: Determine and address cause;

↓ corresponding dose by 2-4 U 10%-20% Add ≥2 rapid insulin* injection before largest meal (“basal-bolus” ‡)

• Start: Divide current basal dose into 2/3 AM,

1/3 PM or ½ AM, ½ PM

• Adjust: ↑ dose by 1-2 U or 10%-15% once-twice

weekly until SMBG target reached.

• For hypo: Determine and address cause;

↓ corresponding dose by 2-4 U 10%-20%

If not controlled, consider basal- bolus If not controlled, consider basal- bolus

high mod. more flexible 3+ 2 Inzucchi SE et al. Diabetes Care. 2015;38:140-149. *AACE guidelines: Garber AJ et al. Endocr Pract. 2016;22:84-113. less flexible

DULA is approved only with prandial insulin; EXN QW is not approved with any insulin4,5

a Added to DEG (26 wk; n = 177); DEG is not approved by the US FDA b Added to GLAR (30 wk; n = 637) c Added to GLAR (26 wk; n = 566) d P <0.05 between groups e Rates of severe hypoglycemia were low across groups f Lower levels of nocturnal hypoglycemia

• 1. Mathieu et al. Diabetes Obes Metab. 2014;16:636-44.
• 2. Diamant et al. Diabetes Care. 2014;37:2763-73.
• 3. Rosenstock et al. Diabetes Care. 2014;37:2317-25.
• 4. Eli Lilly and Co. Trulicity (dulaglutide) prescribing information.

http://pi.lilly.com/us/trulicity-uspi.pdf.

• 5. US FDA. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA.

Addition of GLP-1 RAs vs Prandial Insulin to Basal Insulin

Outcome LIRA QD vs ASP QD1 EXN BID vs LIS TDS2 ALBI QW vs LIS TID3 Δ A1C (%) −0.71,a −0.41,a −1.12,b −1.12,b −0.83,c −0.73,c Δ Weight (kg) −2.8d 0.9 −2.5 2.1d −0.7d 0.8 Hypo (EPY)e 1.0d,f 8.2 2.1f 5.0 0.9 2.3 Nausea (%) LIRA > ASP (first 2 wk) 2.9 11 1

a Not US FDA approved b 26-week open-label, treat-to-target RCT; n = 1663 (insulin naïve) c 24-week open-label, treat-to-target RCT; n = 323 (insulin naïve) d P<0.001 vs iDegLira e P<0.001 vs iGlarLixi

• 1. Gough SC et al. Lancet Diabetes Endocrinol. 2014;2:885-893.
• 2. Rosenstock J et al. Diabetologia. 2014;57(suppl 1) [abstract 241].
• 3. US FDA. Drugs@FDA. www.accessdata.fda.gov/Scripts/cder/DrugsatFDA.

*Non-inferior to DEG, superior to LIRA

†Superior to GLAR

• ≤3 severe hypoglycemic episodes per group
• Lower rate of hypoglycemia (overall and nocturnal) for LIRA vs DEG or IDegLira1
• Lower rate of hypoglycemia (overall) for iGlarLixi than for GLAR2,e

Current GLP-1 RAs should not be mixed with or injected adjacent to insulin3 Outcome Δ A1C (%) Δ Weight (kg) IDegLira1,a,b −1.9* −0.5* DEG1,a,b −1.4* 1.6*,d LIRA1,b −1.3* −3.0*,d iGlarLixi2,a,c −1.8† −1.0† GLAR2,c −1.6† 0.5†,e

GLP-1 RA Fixed-Ratio Co-formulations: Emerging Basal Insulin GLP-1 RA + Prandial Insulin vs Basal Insulin + Prandial Insulina

• 1.4
• 1.5
• 1.2
• 2.0
• 1.0

0.0

• With GLP-RA vs basal insulin:
• Lower rates of nocturnal hypoglycemiab (and total hypoglycemiab with DULA 1.5 mg vs

basal insulin)

• Less weight gain
• Higher rates of GI adverse effects (nausea, vomiting, dyspepsia, diarrhea)

a BL A1C, 8.4%-8.53%; used with LIS TID (52 weeks; n=884); b BG ≤70 mg/dL and/or symptoms

Blonde L et al. Lancet. 2015;385:2057-2066.

DULA QW (1.5 mg) GLAR QD

P <0.05 for both DULA groups vs GLAR

DULA QW (0.75 mg) Δ A1C (%)

Concentrated Insulins: Guidance on How to Change to and from Formulations

• Dose differences in general:

U-300 glargine > U-100 glargine > U-100/U-200 degludec

Current Insulin Change to U100/U-200 Degludec Change to U-300 Glargine Change to U-100 Glargine U-100 Glargine Consider decreasing dose by 10% No dose change at initial change; will probably need to up-titrate

• U-300 Glargine

Decrease dose by 20%

• Decrease dose by 20%

U100/U-200 Degludec

• No dose change at initial

change; will probably need to up-titrate No dose change at initial change; will probably need to up-titrate Current Insulin Change to U100/U-200 Degludec Change to U-300 Glargine Change to U-100 Glargine

SLIDE 4

Type 2 Diabetes Management: Case 3: Initiation and Intensification of Insulin 4

Case 3: Barbara – cont’d

• Her glargine was changed to degludec at 50 units. She continued her

metformin at 500 BID and was started on 0.75 mg dulaglutide weekly

• Diet and exercise options were again reviewed with the patient. She

promised to walk several times a week with a friend

• Follow-up 3 months later: she did not report any hypoglycemic episodes.

Patient had lost 14 lb. Her A1C was 7.4%; her dulaglutide dose was increased to 1.5 mg/weekly What does the endocrinologist expect of the PCP regarding the

• ngoing management this patient?

Summary of Intensification

• f Treatments
• Hypoglycemia often limits intensification of insulin

regimen

• Consider metformin, TZDs, ultra-long acting insulins, SGLT-2

inhibitors, and incretin agents

• Per ADA guidelines, if basal insulin dose becomes

excessive, consideration should be given to use GLP-1 RA or bolus insulin with 1-3 meals daily