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Ominous Octect Pathophysiological Contributions
to Hyperglycemia in Type 2 Diabetes
7.Brain- Inc. Appetite Insulin Resistance, Decrea
se , GLP-1
8.Kidney-
HYPERGLYCEMIA
3.Muscle
4.Liver
6.Fat- increased lipolysis,
inc FFA
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Mechanism of Incretins
S e c t i o n 12, 12.2
Incretin Mimetic
Glucose dependent
? Insulin (GLP-1andGIP)
? Glucose uptake by peripheral tissue
Ingestion of food
Pancreas
Release of active incretins GLP-1 and GIP
Beta cells Alpha cells
? Blood glucose in fasting and postprandial states
GI tract
X
Glucose- dependent
DPP-4 enzyme
DPP-4 inhibitor
? 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-1glucagon-like peptide-1 GIPglucose-depende
nt insulinotropic polypeptide.
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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

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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

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) 133145.
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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) 133145.
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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
  ß-cell growth/replication, slows gastric
  emptying, and decreases food intake.

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GLP-1 Agonists
Mechanism of Action
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GLP-1 Agonists

• Contraindications
• 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 lt30 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

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GLP-1 Agonists

• Medications
• 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
  ß-cell growth/replication, slows gastric
  emptying, and decreases food intake.

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GLP-1 Agonists

• Most Common Side Effects
• Adverse reactions include Nausea , constipation,
  nervousness, headache, vomiting, weakness,
  fatigue