Therapy of Type 2 Diabetes Mellitus: UPDATE

Glycemic Goals in the Care of Patients with Type Glycemic Goals in the Care of Patients with Type 2 Diabetes- 2013 ADA and AACE Guidelines:2 Diabetes- 2013 ADA and AACE Guidelines:

Room For Improvement Room For Improvement

(Be HAPPY/ Avoid Burnout, While Caring for Patients with DM)(Be HAPPY/ Avoid Burnout, While Caring for Patients with DM)

Stan Schwartz MD, FACP, FACEAffiliate, Main Line Health System

Clinical Associate Professor of Medicine, Emeritus, U of Pa.

Part 5

8-10x

2-4x

3

82WEEK WEIGHT Dec.-Not correlated to nausea

exenatide

Effect on hypothalamus,

Slower gastric emptying,

Not related to nausea

DPP-4 Inhibitors and CV Events:A Meta-analysisDPP-4 Inhibitors and CV Events:A Meta-analysis

52% reduction in risk for CV events compared to other oral agents or placebo.52% reduction in risk for CV events compared to other oral agents or placebo.Patil HR, et al. Am J Cardiol. 2012;110(6):826-833.

First AuthorDPP4i Comparator

Risk RatioM-H, Random, 95% CI

Risk RatioM-H, Random, 95% CIEvents Total Events Total Weight

Aschner 1 528 3 522 3.7% 0.33 (0.03, 3.16)

Bosi E 1 300 2 294 3.3% 0.49 (0.04, 5.37)

Chan 10 65 12 26 37.7% 0.33 (0.16, 0.67)

Defronzo 2 264 0 64 2.1% 1.23 (0.06, 25.54)

Foley 0 546 0 546 Not estimable

Foley Je 0 29 0 30 Not estimableNCT00316082 4 291 3 74 8.6% 0.34 (0.08, 1.48)NCT00374907 0 20 1 16 1.9% 0.27 (0.01, 6.21)

NCT00698932 4 284 0 284 2.2% 9.00 (0.49, 166.39)

NCT00918879 0 107 0 106 Not estimable

NCT01263496 5 391 0 83 2.3% 2.36 (0.13, 42.22)

Pfuntzer 2 335 7 328 7.7% 0.28 (0.06, 1.34)

Pi-Sunyer 0 262 0 92 Not estimable

Rosenstock 11 306 3 95 11.9% 1.14 (0.32, 4.00)

Rosenstock J 0 396 0 202 Not estimable

Schweitzer 2 169 2 166 4.9% 0.98 (0.14, 6.89)

Schweitzer A 0 526 2 254 2.0% 0.10 (0.00, 2.01)

Williams-Herman 3 179 11 364 11.7% 0.55 (0.16, 1.96)

Total (95% CI) 4998 3546 100.0% 0.48 (0.31,0.75)

Total events 45 46

Heterogeneity: Tau2 = 0.00; Chi2 = 11.22, df = 12 (P = 0.51); I2 = 0%Test for overall effect: Z = 3.28 (P = 0.001)

0.001

DPP4i better0.1 1 10 1000

DPP4i worse

SavorN Engl J Med. 2013 Oct 3;369(14):1317-1326. Epub 2013 Sep 2.Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus.Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I; the SAVOR-TIMI 53 Steering Committee and Investigators.

SavorN Engl J Med. 2013 Oct 3;369(14):1317-1326. Epub 2013 Sep 2.Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus.Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I; the SAVOR-TIMI 53 Steering Committee and Investigators.

Risk of Cardiovascular Disease Events in Patients With Type 2 Diabetes Prescribed the Glucagon-Like Peptide 1 (GLP-1)Receptor Agonist Exenatide Twice Daily orOther Glucose-Lowering Therapies A retrospective analysis of the LifeLink database

JENNIE H. BEST, PHD, Diabetes Care 34:90–95, 20111

Exenatide and CV outcomes- 430,000 patients-near 40,000 on exenatide

Nausea StoryNausea Story Observations

– The most common AEs associated with exenatide (vs placebo) in three 30-week, placebo-controlled clinical trials were nausea (44% vs 18%), vomiting (13% vs 4%), diarrhea (13% vs 6%),

– 5 years later, monotherapy study was only 19%;

e.g.: learned how to use it- stop eating when full

– Both exenatide/liraglutide, nausea decreases over time

– Exenatide-QW 1/3 risk of nausea as liraglutide 1.8 mg/d

– Etiology- Oversensitive hypothalamic sensitivity Slower gastric emptying; patients keep eating after first sense of fullness High fiber, high fat meals

– In Hospital-

– TEACH PATIENTS TO STOP EATING AT FIRST SENSE OF FULLNESS!!

– Patients eat slowly, decreased speed of eating, decreased quantity of eating, less fatty meals

•The ~1 % hypothalamic nausea can be treated with metochlopromide/ ondansetron-Diabet Med. 2010 Oct;27(10):1168-73. doi: 10.1111/j.1464-5491.2010.03085.x.

Pancreatic Cancer- NOT

1.15 yr. Age difference, control to incretin2.Compared type 1 to type 2 pancreases3.Polyclonal nonspecific antibody vs monoclonal antibody (proves no GLP1 receptors on epithelium)4.Alpha cell hyperplasia Butler saw is not cell type leading to pancreatic cancer

Pancreatic Cancer- NOT

1.15 yr. Age difference, control to incretin2.Compared type 1 to type 2 pancreases3.Polyclonal nonspecific antibody vs monoclonal antibody (proves no GLP1 receptors on epithelium)4.Alpha cell hyperplasia Butler saw is not cell type leading to pancreatic cancer

Exenatide-QW carries same warning

GLP-1 Receptors on rodent C- cells, but not on Human C-CellsEndo, 2010ADA, 2013, EASD 2013

Patient Types/ SituationsPatient Types/ Situations0.Treat Late Post-Prandial Hypoglycemia1. Prevention / Delay of DM2. Cardiovascular- as above, likely reduced CV outcomes with

weight neutrality, no undue hypoglycemia

3. Guideline based4. Approach to Weight reduction in Diabetes5. Type 1/ Type 2 on insulin (on/off label)6. Discontinue Insulin7. Hospital/ stress/ steroid dm

12

Changes in Glycemia and Weight in3 Studies of Exenatide vs InsulinChanges in Glycemia and Weight in3 Studies of Exenatide vs Insulin

Glargine, Once Daily ExenatideInsulin Aspart, 70/30

1. Heine R, et al. Ann Intern Med. 2005;143:559-569. 2. Barnett AH, et al. Clin Ther. 2007;29:2333-2348.3. Nauck MA, et al. Diabetologia. 2007;50:259-267.

6

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9

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-1.4%-1.1%

Barnettet al2

Heine et al1

-0.9%

Naucket al3

-1.4%-1.1% -1.0%

Barnettet al2

Heineet al1

Naucket al3

-2

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+1.8 kg +2.3 kg +2.9 kg

-2.2 lb -2.5 kg-2.3 kg

4

ADA GOAL

ie: ALWAYS USE GLP-! BEFOREGO TO INSULIN

Weight Loss in Obese Non-Diabetics over 2 years with Lira-glutide

Weight Loss in Obese Non-Diabetics over 2 years with Lira-glutide

Incretins in Type-2 PatientsIncretins in Type-2 Patients

My Experience:Fewer patients need bolus insulin:

DPP-4 inh=~50%

GLP-1 RA=~ 20%

GLP-1 RAs in Type 1 DiabetesGLP-1 RAs in Type 1 Diabetes

Liraglutide Exenatide with a meal

Data Suggests: less dawn effect, less variability, decrease insulin doses, less hypoglycemiaRecent epiphany: I prescribe less pump therapy