Type 2 diabetes treatment: Old and New Emily Szmuilowicz, MD, MS Assistant Professor of Medicine Division of Endocrinology Northwestern University

Factors in deciding between therapies Treatment goals (and how far from goal) Costs Adverse effects, especially hypoglycemia. Need for flexibility, eating patterns Patterns of blood glucose before/after eating Patient characteristics

GLYCEMIC GOALS Diabetes treatment

Treatment goals American Diabetes Association. Standards of Medical Care in Diabetes  Diabetes Care 2015; 38 (S1)

Relationship between “A1c” and blood glucose Nathan D et al., for the A1c-Derived Average Glucose (ADAG) Study Group. Diabetes Care 2008

TREATMENT OPTIONS Diabetes treatment

Lifestyle modifications Increasing physical activity Nutrition therapy Weight loss

diabetesmanager.pbworks.com. Accessed Treatment options

Medications: Metformin How it works AdvantagesDisadvantagesCost ↓ liver glucose production Helps body use insulin better Extensive clinical experience Rare hypoglycemia Likely  CVD events (UKPDS) Weight neutral/loss GI side effects Lactic acidosis risk (rare) Vitamin B12 deficiency Multiple contraindications: CKD, acidosis, hypoxia, dehydration, etc. Low A1c ↓ 1.0–2.0%

Medications: Sulfonylureas (glipizide, glimepiride) How they work AdvantagesDisadvantagesCost  Insulin release from pancreas Extensive experience  microvascular complication (UKPDS) Hypoglycemia Weight gain Low A1c ↓ 1.0–2.0%

Medications: Meglitinides (repaglinide, nateglinide) Mechanism/ Action AdvantagesDisadvantagesCost  Insulin release from pancreas  glucose after eating Flexibility Short duration of action Hypoglycemia Weight gain Multiple daily doses High A1c ↓ %* *repaglinide more effective than nateglinide

Medications: Incretin mimetics Ahren B. Nature Reviews Drug Discovery 2009; 8: 369. GLP-1 analogs x DPP-4 inhibitors +

Medications: GLP-1 analogs (exenatide, liraglutide, dulaglutide) How they work AdvantagesDisadvantagesCost  insulin  glucagon slows gastric emptying  satiety No hypoglycemia Weight loss ? Cardiovascular protective actions GI side effects (nausea/vomiting) Injection Unknown long-term safety ?pancreatitis thyroid c-cell tumors in rodents High A1c ↓ %

Medications: DPP-4 inhibitors (sitagliptin, linagliptin, saxagliptin) Mechanism/ Action AdvantagesDisadvantagesCost  insulin  glucagon No hypoglycemia Well tolerated modest efficacy ?pancreatitis Severe joint pain ?  risk of heart failure (saxagliptin) Unknown long- term safety High A1c ↓ %

Medications: Thiazolidinediones (pioglitazone,rosiglitazone) How they work AdvantagesDisadvantagesCost Helps body use insulin better (  insulin sensitivity) no hypoglycemia durability improves HDL ? ↓ heart attack (pioglit.) weight gain fluid retention/ heart failure bone fractures  LDL (rosiglit.) ? ↑ heart attack (rosiglit.) ? ↑ bladder cancer (pioglit.) High A1c ↓ 0.5–1.4%

Medications: SGLT2 inhibitors (canagliflozin, empagliflozin, dapagliflozin, etc) How they work AdvantagesDisadvantagesCost  glucose excretion by kidneys  blood glucose  weight  BP Low risk of hypoglycemia  genital mycotic infections, urinary tract infections ? long-term safety of chronic glucosuria hypotension “Euglycemic DKA”  fractures / ↓bone density hypotension High A1c ↓ 0.5 –0.7 %

Medications: Insulin Insulin therapy frequently required due to progressive loss of pancreas (“beta-cell”) function Initial therapy if: –  glucose (e.g., >300 mg/dL) or HbA1c (e.g. >10%) – Significant hyperglycemic symptoms – Necessary when catabolic symptoms or ketonuria (reflects profound insulin deficiency) If no evidence of T1DM, may be possible to taper insulin partially or entirely after symptoms relieved and glucotoxicity resolved

Medications: Insulin Mechanism/A ction AdvantagesDisadvantagesCost ↓ glucose release by the liver moves glucose from blood into muscle/fat Universally effective No dose limit ↓ microvascular disease improved cholesterol Hypoglycemia Weight gain Injection (1 – 4+) Training requirements “Stigma” (for patients)  A1c ↓ 1.0 – 3.5%

Physiologic insulin delivery DeWitt DE et al. JAMA 2003; 289: 2254.

Insulin delivery options

Insulin delivery options

Insulin delivery options

PUTTING IT ALL TOGETHER Diabetes treatment

Treatment of T2DM American Diabetes Association. Standards of Medical Care in Diabetes  Diabetes Care 2015; 38 (S1)