6.Fat- increased lipolysis, inc FFA ‘Ominous Octect: Pathophysiological Contributions to Hyperglycemia in Type 2 Diabetes - 1.Pancreatic insulin secretion 2.Pancreatic glucagon 5.Gut carbohydrate absorption 7.Brain- Inc. Appetite Insulin Resistance, Decrease , GLP-1 8.Kidney- HYPERGLYCEMIA Peripheral glucose uptake Hepatic production - 3.Muscle 4.Liver 6.Fat- increased lipolysis, inc FFA

Mechanism of Incretins 12, 12.2 Mechanism of Incretins Incretin Mimetic Glucose dependent  Insulin (GLP-1and GIP)  Glucose uptake by peripheral tissue Ingestion of food Pancreas Release of active incretins GLP-1 and GIP Beta cells Alpha cells GI tract  Blood glucose in fasting and postprandial states DPP-4 inhibitor X DPP-4 enzyme Glucose- dependent Mechanism of Action of Sitagliptin This illustration describes the mechanism of action of JANUVIA™ (sitagliptin phosphate). The incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon levels, along with higher insulin levels, lead to reduced hepatic glucose production and are associated with a decrease in blood glucose levels in the fasting and postprandial states. The effects of GLP-1 and GIP are glucose dependent. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly inactivates incretin hormones. Concentrations of the active intact hormones are increased by JANUVIA, thereby increasing and prolonging the action of these hormones.  Hepatic glucose production  Glucagon (GLP-1) Inactive GLP-1 Inactive GIP Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels  in response to a meal. Incretin Mimetics are resistant to DPP-4 inactivation Concentrations of the active intact hormones are increased by DPP-4 inhibition, thereby increasing and prolonging the actions of these hormones. GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

DPP-4 Inhibitors Sitagliptin(Januvia®) Linagliptin(Tradjenta®) Saxagliptin(Onglyza®) Alogliptin(Nesina®) Good safety profile Mechanism of action- Increases levels of native GLP-1 Treatment option for T2DM Favorable for use in combination with other anti-diabetic medications for synergistic effect (often initiated in combination with metformin) Stimulates insulin secretion in relation to food/ Decreases Hepatic Glucose release so low risk for hypoglycemia Potential for use as initial monotherapy in early stage T2DM based on mechanism of action https://www.nlm.nih.gov/medlineplus/druginfo/meds/a610003.html Not approved for type 1’s

SGLT-2 Inhibitors Canagliflozin (Invokana®) Dapagliflozin (Farxiga®) Empagliflozin (Jardiance®) Good safety profile Insulin-independent mechanism of action Treatment option for T1DM & T2DM Favorable for use in combination with other anti-diabetic medications for synergistic effect (often initiated in combination with metformin) Does not stimulate insulin secretion so low risk for hypoglycemia Potential for use as initial monotherapy in early stage T2DM based on mechanism of action Not approved for type 1’s Development and potential role of type-2 sodium-glucose transporter inhibitors for management of type 2 diabetes. Timothy CH, Simon WD. Diabetes Ther. 2011 September; 2(3): 133–145.

SGLT-2 Inhibitors HbA1C reduction of 0.5-0.9% Amount of glucose excretion in urine dependent on blood glucose concentration Greatest amount of glucose excretion when blood glucose levels are highest (post-prandial) Excretion of 80-90g of glucose/day Reduction in 300-400 calories/day in T2DM Significant weight loss Reduced hepatic glucose production Reversal of glucotoxicity Enhanced insulin sensitivity in muscle & liver Preserved pancreatic B-cell function Development and potential role of type-2 sodium-glucose transporter inhibitors for management of type 2 diabetes. Timothy CH, Simon WD. Diabetes Ther. 2011 September; 2(3): 133–145.

GLP-1 Agonists Medications: Byetta® (exenatide) Bydureon® (exenatide extended-release) Victoza® (liraglutide) Tanzeum® (albiglutide) Trulicity® (dulagutide) Indication: Treatment of type 2 diabetes (noninsulin dependent) to improve glycemic control Mechanism of Action: GLP-1 agonists are analogues of the natural hormone incretin which increases glucose-dependent insulin secretion, decreases inappropriate glucagon secretion, increases β-cell growth/replication, slows gastric emptying, and decreases food intake.

GLP-1 Agonists Mechanism of Action

GLP-1 Agonists Contraindications: Warnings/Precautions: Contraindicated in patients with prior severe hypersensitivity reactions to GLP-1 agonists or to any of the products components. Exenatide is not recommended for patients with severe renal impairment (GFR <30 ml/min), ESRD, or in patients on dialysis. Warnings/Precautions: GLP-1 agonists have been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, based on postmarketing data. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using these drugs; consider other antidiabetic therapies for these patients. Use GLP-1 agonists with caution in patients with renal impairment , pacreatitis, and/or history of thyroid carcinomas. Drug Interactions: Oral Medications: GLP-1 agonists slow gastric emptying and can reduce the rate of absorption of orally administered drugs. Use with caution with oral medications. Warfarin: Postmarketing reports show increased international normalized ratio (INR) sometimes associated with bleeding with concomitant use of warfarin. Monitor INR frequently until stable upon initiation or alteration of therapy. DO NOT TAKE IN COMBINATION WITH DPP-4 INHIBITORS

GLP-1 Agonists Medications: Indication: Mechanism of Action: Twice Daily Byetta® (exenatide) Once Daily Victoza® (liraglutide) Once Weekly Tanzeum® (albiglutide) Trulicity® (dulagutide) Bydureon® (exenatide extended-release) Indication: Treatment of type 2 diabetes (noninsulin dependent) to improve glycemic control Mechanism of Action: GLP-1 agonists are analogues of the natural hormone incretin which increases glucose- dependent insulin secretion, decreases inappropriate glucagon secretion, increases β-cell growth/replication, slows gastric emptying, and decreases food intake.

GLP-1 Agonists Most Common Side Effects: Adverse reactions include: Nausea , constipation, nervousness, headache, vomiting, weakness, fatigue