Treatment Strategies for Diabetes and Obesity: Update 2013 Christopher Sorli, MD/PhD, FACE Chair, Department of Diabetes, Endocrinology and Metabolism Billings Clinic Billings, MT

Pathogenesis of Type 2 Diabetes HGP=hepatic glucose production. Islet  -cell Impaired Insulin Secretion IncreasedHGP Decreased Glucose Uptake Metformin SUs Insulin

NHANES Advances in Therapy, but Falling Short of Goals  1980s 1990s 2000s  HbA 1c (%) SU / Insulin Metformin (1995) TZDs (1999) Incretins (2004) Pre-DCCT9.0% 7.7NHANES NHANES NHANES Future 6.0% ? 1997: ADA lowered T2DM diagnosis from FPG ≥140 mg/dLto ≥126 mg/dL 2003: ADA eliminated HbA 1c “action point” of <8% from guidelines SU=sulfonylurea; TZDs=thiazolidinediones; T2DM=type 2 diabetes. Koro CE, et al. Diabetes Care. 2004;27:17-20; Hoerger TJ, et al. Diabetes Care. 2008;31: : ADA added HbA 1c goal of <6% for “individual patients” to guidelines General ADA Target: <7% 1998: UKPDS results published 2008: ACCORD, ADVANCE, VADT, and UKPDS 80 published

Type 2 Diabetes Evolving Treatment Strategies

Mortality intensive standard HR = 1.22 (95% CI = ) p = 0.04

NHANES Advances in Therapy, but Falling Short of Goals  1980s 1990s 2000s  HbA 1c (%) SU / Insulin Metformin (1995) TZDs (1999) Incretins (2004) Pre-DCCT9.0% 7.7NHANES NHANES NHANES Future 6.0% ? SU=sulfonylurea; TZDs=thiazolidinediones; T2DM=type 2 diabetes. Koro CE, et al. Diabetes Care. 2004;27:17-20; Hoerger TJ, et al. Diabetes Care. 2008;31: General ADA Target: <7% 2009: ADA added “less stringent” HbA 1c goal for patients with significant comorbidities or risk of hypoglycemia, or short life expectancy

Group A 1 C Targets Intensification Thresholds A1CA1C> 50% of SMBG Results/4 Days Intensive < 6%> 5.9% Fasting > 100 (5.6) OR 2 Hr PP > 140 (7.8) Even if the A 1 C is <6.0 Rx was reduced in the presence of significant hypoglycemia.

Mortality Primary outcome (composite nonfatal MI, nonfatal stroke, CVD death)

Diabetes Management Strategies Making Sense of ACCORD Mortality vs Treatment A1c 10 x less 10 x more Death Rate vs Drop in A1c No drop in A1c = higher death rate

Pathogenesis of Type 2 Diabetes HGP=hepatic glucose production. Islet  -cell Impaired Insulin Secretion IncreasedHGP Decreased Glucose Uptake

The Ominous Octet Islet  -cell Impaired Insulin Secretion NeurotransmitterDysfunction Decreased Glucose Uptake Islet  -cellIncreased Glucagon Secretion IncreasedLipolysis Increased Glucose Reabsorption IncreasedHGP Decreased Incretin Effect

Metabolic syndromeHyperglycemia Failing  -cell Functional  -cell Heine RJ, Spijkerman AM Insulin resistance Type 2 Diabetes: A Heterogeneous Disorder CVD Cancer Retinopathy Neuropathy Nephropathy 70-80% of population 20-30% of population

DIABETES/OBESITY Management Strategies Insulin Resistance Metabolic Syndrome Energy Storage Insulin Supply Beta Cell Dysfunction Hyperglycemia Insulin Resistance β cell function Years of Diabetes/Metabolic Syndrome Relative Function 100 (%) β cell mass Adapted from IDC, Minneapolis, MN Macrovascular Risk/ Cancer Risk Prevention! Intensive managment of Insulin resistance β cell dysfunction CVD risks Damage Control! Less intensive glycemic goals Avoid hypoglycemia

History of Diabetes Therapy: What More Could We Possibly Want? Animal Insulin ’s Sulfonylurea Human Insulin Metformin Lispro Glitazones Glinides Aspart Exenatide Pramlintide Detemir Sitagliptin Bromocriptine Saxagliptin 2013 Liraglutide SGLT-2 inhib 11-β-HSD1 inhib The End of Protocol Driven Therapy Weekly Exenatide Degludec Glucagon R antangonists

Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 3. ANTI-HYPERGLYCEMIC THERAPY Glycemic targets  HbA1c < 7.0% (mean PG  mg/dl [ mmol/l]) - Pre-prandial PG <130 mg/dl (7.2 mmol/l) - Post-prandial PG <180 mg/dl (10.0 mmol/l) - Individualization is key:  Tighter targets ( %) - younger, healthier  Looser targets ( % + ) - older, comorbidities, hypoglycemia prone, etc. - Avoidance of hypoglycemia PG = plasma glucose Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Figure 1 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] (Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Weight -Majority of T2DM patients overweight / obese -Intensive lifestyle program -Metformin -GLP-1 receptor agonists -? Bariatric surgery -Consider LADA in lean patients Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Adapted Recommendations: When Goal is to Avoid Weight Gain Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Stomach Islet GI Tract Brain Hypothalmus Hind Brain Peptide Therapeutics: Incretins (GLP-1 and GIP) Visceral Fat Cell Vagal Afferents Leptin Amylin Insulin GLP-1 Glicentin Oxyntomodulin Ghrelin GIP Adiponectin Visfatin Resistin Glucagon CCK Adapted from Badman MK and Flier JS; Science 2006: 307, PYY 3-36 Incretins (injectables) Exenatide – Bydureon, Byetta Liraglutide - Victoza DPP-IV Inhibitors (orals) Sitagliptin – Januvia Linagliptin – Tradjenta Saxagliptin - Onglyza Incretins (injectables) Exenatide – Bydureon, Byetta Liraglutide - Victoza DPP-IV Inhibitors (orals) Sitagliptin – Januvia Linagliptin – Tradjenta Saxagliptin - Onglyza

Incretins: GLP-1 Agonists vs. DPP-IV Inhibitors Pharmacology vs Physiology DPP-IV – increases endogenous GLP-1 GLP-1 agonist – super physiologic effect …Not quite that simple Differential Effects: Glycemic Control Energy Balance

T2DM – Treatment Strategies Islet  -cell Impaired Insulin Secretion NeurotransmitterDysfunction Decreased Glucose Uptake Islet  -cellIncreased Glucagon Secretion IncreasedLipolysis Increased Glucose Reabsorption IncreasedHGP Decreased Incretin Effect GLP-1 > DPP IV (A1c, FPG,  -cell function) GLP-1 > DPP-IV

Incretins (Exenatide): Sustained Efficacy- Improved Beta Cell Function Buse et.al., Oct 2012, EASD, Berlin

T2DM – Treatment Strategies Islet  -cell Impaired Insulin Secretion NeurotransmitterDysfunction Decreased Glucose Uptake Islet  -cellIncreased Glucagon Secretion IncreasedLipolysis Increased Glucose Reabsorption IncreasedHGP Decreased Incretin Effect GLP-1 > DPP IV (A1c, FPG,  -cell function) GLP-1 (weight loss) GLP-1 > DPP-IV

Incretin Therapy Effect on Energy Homeostasis

T2DM– Treatment Strategies Islet  -cell Impaired Insulin Secretion NeurotransmitterDysfunction Decreased Glucose Uptake Islet  -cellIncreased Glucagon Secretion IncreasedLipolysis Increased Glucose Reabsorption IncreasedHGP Decreased Incretin Effect GLP-1 > DPP IV (A1c, FPG,  -cell function) GLP-1 (weight loss) GLP-1 > DPP-IV GLP-1 > DPP IV (glucagon inhibition, FPG, Prandial control) GLP-1 > DPP IV (Glucagon inhibition, FPG, Prandial control)