DRUGS FOR THE TREATMENT OF DIABETES MELLITUS

DRUGS FOR THE TREATMENT OF DIABETES MELLITUS

TYPES OF INSULIN PREPARATIONS
1. Ultra-short-acting 2. Short-acting (Regular) 3. Intermediate-acting 4. Long-acting

Short-acting (regular) insulins
e.g. Humulin R, Novolin R Uses Designed to control postprandial hyperglycemia & to treat emergency diabetic ketoacidosis Physical characteristics Clear solution at neutral pH Chemical structure Hexameric analogue Route & time of administration S.C. 30 – 45 min before meal I.V. in emergency (e.g. diabetic ketoacidosis) Onset of action 30 – 45 min ( S.C ) Peak serum levels 2 – 4 hr Duration of action 6 – 8 hr Usual administration 2 – 3 times/day or more Ultra-Short acting insulins e.g. Lispro, aspart, glulisine Similar to regular insulin but designed to overcome the limitations of regular insulin Clear solution at neutral pH Monomeric analogue S.C. 5 min (no more than 15 min) before meal I.V. in emergency (e.g. diabetic ketoacidosis) 0 – 15 min ( S.C ) 30 – 90 min 3 – 4 hr 2 – 3 times / day or more

3. Intermediate - acting insulins
e.g. isophane (NPH) Turbid suspension Injected S.C.(Only) Onset of action hr Peak serum level hr Duration of action hr Insulin mixtures 75/ /30 50/50 ( NPH / Regular )

3. Intermediate - acting insulins (contd.)
Lente insulin Turbid suspension Mixture of 30% semilente insulin 70% ultralente insulin Injected S.C. (only) Onset of action hr Peak serum level hr Duration of action hr

3. Intermediate - acting insulins (contd.)
Lente and NPH insulins Are roughly equivalent in biological effects. They are usually given once or twice a day. N.B: They are not used during emergencies (e.g. diabetic ketoacidosis).

4. Long – acting insulins e.g.Insulin glargine Onset of action 2 hr
Absorbed less rapidly than NPH&Lente insulins. Duration of action upto 24 hr Designed to overcome the deficiencies of intermediate acting insulins Advantages over intermediate-acting insulins: Constant circulating insulin over 24hr with no pronounced peak. Safer than NPH&Lente insulins due to reduced risk of hypoglycemia(esp.nocturnal hypoglycemia). Clear solution that does not require resuspention before administration.

Profile of Insulin Glargine vs NPH

Methods of Adminisration
Insulin Syringes Pre-filled insulin pens External insulin pump Under Clinical Trials Oral tablets Inhaled aerosol Intranasal, Transdermal Insulin Jet injectors Ultrasound pulses

COMPLICATIONS OF INSULIN THERAPY
1. Severe Hypoglycemia (< 50 mg/dl )– Life threatening Overdose of insulin Excessive (unusual) physical exercise A meal is missed How it is treated ? 2. Weight gain 3. Local or systemic allergic reactions (rare) 4. Lipodystrophy at injection sites 5. Insulin resistance 6. Hypokalemia

Severe insulin reaction (Diabetic Ketoacidosis)
(Hypoglycemic Shock) Diabetic coma (Diabetic Ketoacidosis) Onset Rapid Slow- Over several days Insulin Excess Too little Acidosis & dehydration No Ketoacidosis Signs and symps B.P. Normal or elevated Subnormal or in shock Respiration Normal or shallow Deep & air hunger Skin Pale & Sweating Hot & dry CNS Tremors, mental confusion, sometimes convulsions General depression Blood sugar Lower than 70 mg/100cc Elevated above 200 mg/100cc Ketones Normal Elevated

Oral Hypoglycemics All taken orally in the form of tablets. Pts with type11 diabetes have two physiological defects: Abnormal insulin secretion Resistance to insulin action in target tissues associated with decreased number of insulin receptors

Oral Anti-Diabetic Agents
Sulfonylureas Drugs other than Sulfonylurea

Sulfonylureas (Oral Hypoglycemic drugs)
First generation Second generation Short acting Intermediate acting Long acting Short acting Long acting Glyburide (Glibenclamide) Glimepiride Tolbutamide Acetohexamide Tolazamide Chlorpropamide Glipizide

* Good for pts with renal impairment
FIRST GENERATION SULPHONYLUREA COMPOUNDS Tolbutamide(Orinase) short-acting Acetohexamide (Dymelor) intermediate-acting Tolazamide (Tolinase)intermediate-acting Chlorpropamide (Diabenase) long- acting Absorption Well Slow Metabolism Yes Metabolites Inactive* Active +++ ** Active ++ ** Inactive ** Half-life 4 - 5 hrs 6 – 8 hrs 7 hrs 24 – 40 hrs Duration of action Short (6 – 8 hrs) Intermediate (12 – 20 hrs) (12 – 18 hrs) Long ( 20 – 60 hrs) Excretion Urine * Good for pts with renal impairment ** Pts with renal impairment can expect long t1/2

SECOND GENERATION SULPHONYLUREA COMPOUNDS
Glipizide (Glucotrol) Short- acting Glibenclamide (Glyburide) Long-acting Glimepiride (Amaryl) Absorption Well Metabolism Yes Metabolites Inactive Half-life 3 – 4 hrs Less than 3 hrs 5 - 9 hrs Duration of action 10 – 16 hrs 12 – 24 hrs Excretion Urine

MECHANISM OF ACTION OF SULPHONYLUREAS
1) Release of insulin from β-cells 2) Reduction of serum glucagon concentration 3) Potentiation of insulin action on target tissues

Block ATP-Sensitive Pottasium Channels in beta cells of the pancreas
Decrease potassium permeability into cells resulting in depolarization Calcium entry into cells result in insulin secretion

SIDE EFFECTS OF SULPHONYLUREAS
1) Nausea, vomiting, abdominal pain, diarrhea 2) Hypoglycemia 3) Dilutional hyponatremia & water intoxication (Chlorpropamide) 4) Disulfiram-like reaction with alcohol (Chlorpropamide) 5) Weight gain

SIDE EFFECTS OF SULPHONYLUREAS (contd.)
6) Blood dyscrasias (not common; less than 1% of patients) - Agranulocytosis - Haemolytic anaemia - Thrombocytopenia 7) Cholestatic obstructive jaundice (uncommon) 8) Dermatitis (Mild) 9) Muscle weakness, headache, vertigo (not common) 10) Increased cardio-vascular mortality with longterm use ??

CONTRAINDICATIONS OF SULPHONYLUREAS
1) Type 1 DM ( insulin dependent) 2) Parenchymal disease of the liver or kidney 3) Pregnancy, lactation 4) Major stress

DRUGS THAT AUGMENT THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS
WARFARIN SULFONAMIDES SALICYLATES PHENYLBUTAZONE PROPRANOLOL ALCOHOL CHLORAMPHENICOL FLUCONAZOLE

DRUGS THAT ANTAGONIZE THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS
DIURETICS (THIAZIDE, FUROSEMIDE) DIAZOXIDE CORTICOSTEROIDS ORAL CONTRACEPTIVES PHENYTOIN, PHENOBARB., RIFAMPIN ALCOHOL ( chronic pts )

Drugs other than Sulfonylurea
Meglitinides Biguanides α-Glucosidase Inhibitors Thiazolidinediones Repaglinide Nateglinide Metformin Acarbose Rosiglitazone Pioglitazone

MEGLITINIDES e.g. Repaglinide(Prandin), Nateglinide(Starlix) PHARMACOKINETICS Taken orally Rapidly absorbed ( Peak approx. 1hr ) Metabolized by liver t1/2 = 1 hr Duration of action 4-5 hr

MEGLITINIDES (Contd.) MECHANISM OF ACTION Bind to the same KATP Channel as do Sulfonylureas, to cause insulin release from β-cells.

MEGLITINIDES (Contd.) CLINICAL USE Approved as monotherapy and in combination with metformin in type 2 diabetes Taken before each meal, 3 times / day Does not offer any advantage over sulfonylureas; Advantage: Pts. allergic to sulfur or sulfonylurea SIDE EFFECTS: Hypoglycemia Wt gain ( less than SUs ) Caution in pts with renal & hepatic impairement.

BIGUANIDES e.g. Metformin (Glucophage) PHARMACOKINETICS Given orally
Not bind to plasma proteins Not metabolized Excreted unchanged in urine t 1/2 2 hr

BIGUANIDES (Contd.) MECHANISM OF ACTION
1. Increase peripheral glucose utilization 2. Inhibits gluconeogenesis 3. Impaired absorption of glucose from the gut

Reduction of hepatic glucose production through activation of the enzyme AMP-activated protein kinase (AMPK)

Advantages of Metformin over SUs
Does not cause hypoglycemia ( why ? ) Does not result in wt gain ( why ? ) ( Ideal for obese pts )

BIGUANIDES (Contd.) SIDE EFFECTS 1. Metallic taste in the mouth
2. Gastrointestinal (anorexia, nausea, vomiting, diarrhea, abdominal discomfort) 3. Vitamin B 12 deficiency (prolonged use) 4. Lactic acidosis ( rare – 01/ 30,000-exclusive in renal & hepatic failure)

BIGUANIDES (Contd.) CONTRAINDICATIONS 1. Hepatic impairment
2. Renal impairment 3. Alcoholism 4. Heart failure

BIGUANIDES (Contd.) INDICATIONS Obese patients with type 11 diabetes
2. Alone or in combination with sulfonylureas

α-GLUCOSIDASE INHIBITORS
e.g. Acarbose (Precose), Miglitol (Glyset) PHARMACOKINETICS Given orally Not absorbed from intestine except small amount t1/ hr Excreted with stool

(Contd.) MECHANISM OF ACTION Competitively Inhibits intestinal alpha-glucosidases and delays carbohydrate absorption, reducing postprandial increase in blood glucose

α-GLUCOSIDASE INHIBITORS (Contd.)
MECHANISM OF ACTION Acarbose

α-GLUCOSIDASE INHIBITORS (Contd.)
MECHANISM OF ACTION

(Contd.) SIDE EFFECTS Flatulence Loose stool or diarrhea Abdominal pain Alone does not cause hypoglycemia

(Contd.) INDICATIONS Patients with Type 11 inadequately controlled by diet with or without other agents( SU, Metformin) Can be combined with insulin may be helpful in obese Type 11 patients (similar to metformin)

THIAZOLIDINEDIONE DERIVATIVES
New class of oral antidiabetics e.g.: Rosiglitazone (Avandia) Pioglitazone (Actos)

(Contd.) PHARMACOKINETICS 99% absorbed Metabolized by liver 99% of drug binds to plasma proteins Half-life 3 – 4 h Eliminated via the urine 64% and feces 23%

(Contd.) MECHANISM OF ACTION Increase target tissue sensitivity to insulin by: reducing hepatic glucose output & increase glucose uptake & oxidation in muscles & adipose tissues. They do not cause hypoglycemia (similar to metformin and acarbose ) .

(Contd.) ADVERSE EFFECTS Mild to moderate edema Wt gain Headache Myalgia Hepatotoxicity ?

(Contd.) INDICATIONS Type 11 diabetes alone or in combination with metformin or sulfonylurea or insulin in patients resistant to insulin treatment.

New Drugs Incretins GLP1 analogues: Exenatide (Byetta)
DPP4 Inhibitors: Sitagliptin (Januvia) Medication affecting the incretin system has been a big advancement in targeting an unmet area in the diabetes physiology. We now have Exenatide, an incretin analog; and now the DDP4 inhibitor, sitagliptin, to help prevent the breakdown of these incretin hormones which all go into more detail soon. We also have an amylin analog and we are now administering insulin by a different route. I will not be going over inhale insulin today, but if you have any pharmacy related questions, feel free to ask me during our lunch session.

Role of Incretin in Glucose Homeostasis
INtestine seCRETion INsulin Definition: gut derived factors that increase glucose stimulated insulin secretion Two hormones: (1) glucagon-like peptide-1 (GLP-1) (2) glucose-dependent insulinotropic polypeptide (GIP) 2 GI hormones, GIP and GLP-1 are responsible for most of the incretin effect. Those of you that don’t know, INCRETIN, is actually a mnemonic.

GLP-1 and GIP Are Incretin Hormones
Released from L cells in ileum and colon1,2 Stimulates insulin from beta cells in a glucose-dependent manner1 Inhibits gastric emptying1,2 Reduces food intake and body weight2 Inhibits glucagon secretion from alpha cells in a glucose-dependent manner1 Deficient in type 2 diabetes Released from K cells in duodenum1,2 Minimal effects on gastric emptying2 No significant effects on satiety or body weight2 Does not appear to inhibit glucagon secretion from alpha cells1,2 Normal levels but decreased responsiveness in type 2 diabetes GLP-1 and GIP Are Incretin Hormones GLP-1 and GIP are the currently identified incretin hormones. An incretin is a hormone with the following characteristics1: It is released from the intestine in response to ingestion of food, particularly glucose. The circulating concentration of the hormone must be sufficiently high to stimulate the release of insulin. The release of insulin in response to physiological levels of the hormone occurs only when glucose levels are elevated (glucose-dependent). GIP and GLP-1 are hormones that fulfill these 3 characteristics, qualifying them as incretins.1 In the fasting state, GIP and GLP-1 circulate at very low levels. Their levels rapidly increase after food ingestion and play a role in the release of insulin.2,3 GLP-1 stimulates insulin response from beta cells in a glucose-dependent manner and suppresses glucagon secretion from alpha cells in a glucose-dependent manner. GIP also potentiates insulin release from beta cells in a glucose-dependent manner.4 Other effects of GLP-1 and GIP are summarized on the slide. 1. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606. 2. Drucker DJ. Diabetes Care. 2003;26:2929–2940. References: 1. Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept. 2005;128:87–91. 2. Gautier JF, Fetita S, Sobngwi E, Salaün-Martin C. Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. Diabetes Metab. 2005;31:233–242. 3. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab. 2004;287:E199–E206. 4. Meier JJ, Nauck MA. Glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.

Incretins: The medications
GLP1 analogues:Exenatide (Byetta) DPP4 Inhibitors:Sitagliptin (Januvia)

New Therapies: Incretin System
o n 12, 12.2 New Therapies: Incretin System 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 Mechanism of Action of Sitagliptin This illustration describes the mechanism of action of sitagliptin. 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. X DPP-4 enzyme Glucose- dependent Exenatide  Hepatic glucose production  Glucagon (GLP-1) Sitagliptin Inactive GLP-1 Inactive GIP GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

GLP-1 ANALOGS Stable analog not cleaved by DDP-4
Exendin-4 in saliva of Gila Monster lizard is 50% similar to human GLP-1 Exenatide ( Byetta) is a synethic form of this

Incretin Physiology GLP-1 GIP
Stimulates glucose-dependent insulin secretion from beta cells Suppresses glucagon release from alpha cells Slows gastric emptying & reduces food intake Degraded by DPP-4 enzyme GIP Increases glucose-dependent insulin release 1. Incretins are intestinal hormones released in response to meals that assist in regulating insulin release in a glucose-dependent manner. 2. Currently, there are 2 incretin hormones: -GLP-1 (glucagon-like peptide-1) -GIP (glucose-dependent insulinotropic polypeptide) 3. GLP-1 binds to receptors located on islet cells, stomach, heart, hypothalamus. GLP-1 half-life < 2 minutes. 4. T2DM pts are still responsive to GLP-1 actions. 5. GIP binds to receptors located on islet beta-cells. Half-life 5-7 minutes. 6. DM pts are resistant to GIP’s actions. ? if this is due to reduced GIP receptor expression or reduced GIP receptor sensitivity. This might be cause of diminished “incretin effect” in T2DM pts. 1. Drucker DJ, Nauck MA. Lancet 2006;368: 2. Nauck MA. Am J Med 2009;122(Suppl 1):S3-S10

Glucose Homeostasis: Nondiabetic, Fed State
Brain Food Intake Gastric Emptying Liver Stomach Rate of glucose appearance Postprandial Glucagon Plasma Glucose GUT Alpha GLP-1 BG levels increase after a meal GLP-1 secreted from L-cells of ileum GLP-1 binds to receptors on islet cells causing: insulin production and release inhibits production of glucagon from pancreatic alpha cells Slows gastric emptying and decreases food intake through neural mechanisms **Amylin is cosecreted with insulin and slows gastric emptying, decreases appetite and inhibits glucagon release through neural mechanisms. Pancreas Rate of glucose disappearance L-cells Glucose Disposal Beta Insulin Amylin Muscle & Adipose Tissue Edelman SV, Weyer C. Diabetes Tech Therapeutics 2002;4:

doses of 0.6 mg, 1.2 mg, or 1.8 mg (6 mg/mL, 3 mL
Incretin Mimetic Byetta® For diabetes type 2 patients on metformin, TZD, sulfonylurea or combination. Injectable pen ((5mcg and 10mcg ) Mimics GLP-1 (resistance to the effects of DDP4) Decreases liver glucose release Increases insulin release Slows digestion (caution if dx w/ gastroparesis) Decreases appetite -> weight loss Inject 1 hour before meals twice a day GI side effects GLP-1 agonist/incretin mimetic Byetta comes in an injectable pen similar to insulin pens. Byetta works by mimicking a homone GLP-1 normally produced in our intestines. (Refer to previous slide in regards to Januvia) The main side effects of this medication are GI related. It should not be used in patients with significant GI problems/gastroparesis. It may also slow the absorption of oral medications. Liraglutide (Victoza) Novo Nordisk. Longer duration so once daily administration. Solution for subcutaneous injection, pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg (6 mg/mL, 3 mL

Injectible Symlin (Amylin Pharmaceuticals)
Acts on CNS  Appetite Slows gastric emptying Inhibits glucagon secretion Really flattens postprandial BGs

Amylin the Hormone Reported in 1987 37-amino acid peptide
Neuroendocrine hormone Amylin, a neuroendocrine hormone that is co-located and co-secreted from beta cells, plays a critical role in the appearance of glucose in the circulation after a meal.

Amylin: Co-Secreted With Insulin
Meal Insulin Amylin 30 600 25 This is a 24-hour plasma profile of insulin and amylin in healthy subjects without diabetes. Both peptides are co-secreted by beta cells in response to nutrient intake. SLIDE BACKGROUND: Data presented are mean values. In the peripheral circulation, the insulin-to-amylin molar ratio is approximately 20:1. When secreted by the pancreas, the insulin:amylin molar ratio is approximately 50:1. This higher ratio is seen in the portal circulation but falls to approximately 20:1 in the peripheral circulation since insulin, not amylin, is extracted by the liver. 20 400 Plasma Amylin (pM) Plasma Insulin (pM) 15 200 10 5 7 AM Noon 5 PM Midnight Time (24 h) Healthy subjects, n = 6; Mean Data from Kruger D, et al. Diabetes Educ 1999; 25:

Amylin: Deficient in Diabetes
Meal 20 15 Without Diabetes The graph illustrates postprandial amylin concentrations in subjects without diabetes, insulin-using type 2 diabetes, and type 1 diabetes. Diabetes manifests with beta-cell failure, which results in absolute or relative deficiency of both insulin and amylin. Type 1 diabetes: Beta-cell destruction resulting in absolute insulin and amylin deficiency. Type 2 diabetes: Insulin and amylin secretory capacity depends on where the patient is in the natural history of his/her disease with regards to beta-cell function. Though insulin-using patients in this study had normal fasting amylin concentrations, postprandial amylin secretion was clearly abnormal. Plasma Amylin (pM) 10 Insulin-Using Type 2 5 Type 1 -30 30 60 90 120 150 180 Time After Meal (min) Without diabetes, n = 27 Insulin-using type 2, n = 12 Type 1, n = 190; Mean data Kruger D, et al. Diabetes Educ 1999; 25:

Amylin: Mechanism of Action
Inhibits inappropriately high postprandial glucagon secretion Slows gastric emptying Promotes satiety and reduces caloric intake Extensive preclinical studies have demonstrated that amylin’s mechanism of action include inhibition of inappropriately high postprandial glucagon secretion, slowing of gastric emptying, and the promotion of satiety and reduced caloric intake. Pramlintide prescribing information, 2005

Pramlintide prescribing information, 2005
Amylin Analog Pramlintide (Symlin) Indication Type 1: as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy Type 2: with or without a concurrent sulfonylurea agent and/or metformin Dose Type 1: Start at 15 μg and titrated at 15 μg increments Maintenance dose of 30 μg or 60 μg Type 2: Start at 60 μg and increased to a dose of 120 μg as tolerated Immediately prior to each major meal (≥250 kcal or containing ≥30 g of carbohydrate Pramlintide prescribing information, 2005

Amylin Analog Pramlintide (Symlin) Adverse Reactions (> 5%) Nausea, Headache Anorexia, Vomiting, Abdominal Pain Fatigue, Dizziness Coughing Pharyngitis Comments Should not be used with other drugs that alter GI motility or gastric emptying Potential to delay absorption of concomitant oral medications If rapid onset is required (analgesics), consider 1 hour pre- or 2 hours post-SYMLIN dose Pramlintide prescribing information, 2005

Amylin Analog Pramlintide (Symlin) Advantages Weight loss Reduces glucose fluctuations Decreases insulin requirement REDUCE prandial insulin by 50% Disadvantages Injection only Multiple daily dosing Dose conversion (mcg to units) Error potential Pramlintide prescribing information, 2005

Dipeptidyl-Peptidase 4 Inhibitors
3/12/ :49 PM Agent in Class: Sitagliptin, Saxagliptin Mechanism of action: slows the inactivation of incretin hormones (glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide) Increases glucose-stimulated insulin secretion Causes glucose-stimulated glucagon suppression primarily lowers postprandial glucose levels but has also been shown to reduce fasting plasma glucose

Inhibition of DPP-IV Increases Active Portal GLP-1 and GIP
DPP-IV inhibitors exhibit both short term and long term actions of GLP-1 Augment glucose induced insulin secretion Inhibit glucagon secretion Slow gastric emptying Increase insulin biosynthesis Promote beta cell differentiation T ½=1-2mins

Dipeptidyl-Peptidase 4 Inhibitors
3/12/ :49 PM Dipeptidyl-Peptidase 4 Inhibitors Efficacy: Lower HbA1C by 0.8% Nonglycemic effect: weight neutral Adverse effects: well tolerated, no hypoglycemia when used as monotherapy. More recently reported to be associated with pancreatitis, ?causative? Available combination with metformin AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Diabetes Care, Vol 31(12):1-11, 2008

GLP-1 Modes of Action in Man
Upon ingestion of food… Slows gastric emptying GLP-1 is secreted from the L-cells in the jejunum and ileum Reduces food intake Suppresses glucagon secretion Stimulates insulin secretion Long term effects demonstrated in animals… Increases beta-cell cell mass and maintains beta-cell efficiency Drucker DJ. Curr Pharm Des 2001; 7: Drucker DJ. Mol Endocrinol 2003; 17:

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors
Sitagliptin (Januvia) 25, 50, 100 mg tablets Sitagliptin/metformin (Janumet) 50/500, 50/1000 mg Saxagliptin (Onglyza) 2.5, 5 mg Saxagliptin/metformin (Kombiglyze XR) 2.5/1000, 5/500, 5/1000 mg

Indications Diabetes Mellitus Type II MOA Inhibits the breakdown of GLP-1 by DPP-4 therefore increasing GLP-1 levels resulting in increased glucose-dependent insulin release and decreased level of circulating glucagon and hepatic glucose production

Where does it work? Image Obtained From: Diabetes 101: Overview of Drug Therapy by Jennifer Danielson, RPh, CDE

DPP-4 (cont) Patient Info N/V Hypoglycemia Weight neutral
Nasopharyngitis/URI Headache Onset: Reduction in postprandial serum glucose: 60 minutes

DPP-4 (cont) CrCl 30-50 mL/min : 50 mg daily
Special Population Considerations: Renal Impairment: avoid combo drugs w/ metformin For sitagliptin: CrCl mL/min : 50 mg daily CrCl < 30 mL/min: 25 mg daily End Stage Renal Disease Requiring dialysis: 25 mg daily Geriatric: caution due to age related renal function decreases Cautions/Severe Adverse Reactions Acute pancreatitis Rash (Stevens-Johnson syndrome)

DPP-4 Inhibitors and Incretin Mimetics
Sitagliptin (Januvia®) Exenatide (Byetta®) Indication Management of type 2 diabetes mellitus - monotherapy - combo with metformin or TZD Management (adjunctive) of type 2 diabetes mellitus - metformin, sulfonylurea, and/or TZD Dose 100mg daily Avoid if creat clear<50ml/min Route: oral Initial: 5mcg bid within 60 minutes prior to a meal (morning and evening) After 1 month, may be increased to 10mcg bid CrCl < 30ml/min: not recommended Route: SC Injections are given to the thigh, abdomen, or upper arm. Exenatide is not recommended for patients with severe renal impairment or end-stage renal disease and has not been studied in patients with severe gastrointestinal disease. Sitagliptin prescribing information, Exenatide prescribing information, 2007.

DPP-4 Inhibitors and Incretin Mimetics
Sitagliptin (Januvia®) Exenatide (Byetta®) Adverse Reactions Monotherapy: nasopharyngitis Combination with TZDs: upper respiratory tract infxn, headache GI: abdominal pain, N/V/D Monotherapy: N/V/D Combination with sulfonylurea: hypoglycemia Anti-exenatide antibodies Weight loss Long-term unclear Comments Should NOT be used in type 1 diabetes or for treatment of diabetic ketoacidosis Patients who take exenatide in combination with SFU have an increased risk of hypoglycemia Long term data on weight loss is unclear, but it continues to decrease over time because people continue to eat less. However, the individual differences in the magnitude and the pattern of weight loss are large. Some patients lose dramatic amounts of weight, while others lose only a few pounds. More obese patients seem to lose the most weight. Some people do not lose weight in the beginning but lose weight later, while others lose a lot of weight initially and then their weight loss slows. Exenatide is contraindicated for patients with type 1 diabetes because the pharmacologic action of exenatide in part requires the presence of functional pancreatic ß cells. Sitagliptin prescribing information, Exenatide prescribing information, 2007.

Comparison: DPP-4 Inhibitors and Incretin Mimetics
DPP-4 Inhibitors (Sitagliptin) Incretin Mimetics (Exenatide) Advantages Route: oral No weight gain Promote b-cell proliferation Once daily dosing Weight loss independent of nausea and islet neogenesis Induces satiety, suppresses appetite Disadvantages Unwanted effects on immune function (possible safety issues) Less potent compared with injectable incretin mimetics Route: SC Twice daily dosing Dose-dependent nausea and vomiting Fixed dosing (Pen) Advantages: DPP-4 inhibitors have an advantage over the incretin mimetic, especially to the patient, because it is available PO. Compared older agents on the market, DDP-4 inhibitors and incretin mimetics have an advantage in terms of weight. Sitagliptin produces no weight gain (or weight lost) and exenatide produces a weight loss, independent from its nausea side effect. We have animal studies and 1 human study that I know of, that describes b-cell proliferation…however, we do not know the long term effects of this. Disadvantages: DPP-8 and -9 have a role in our immunity. DDP-4 agents are supposed to be specific enough not to affect our immune system. However, it is interesting to see, that in clinical trials, respiratory tract infections and nasopharyngitis are listed as side effects for sitagliptin. The data that we currently have suggests a slightly better A1C reduction with injectable incretin mimetics versus DDP-4s. (1) Nauck M, et al. Diabetologia 1986;29: (2) Triplitt C, et al. Pharmacotherapy 2006;26: (3) Drucker D, et al. Lancet 2006;368:

SGLT 2 inhibitors Glucokinase activators Glucagon receptor antagonists
Other new agents SGLT 2 inhibitors Glucokinase activators Glucagon receptor antagonists

DRUGS FOR THE TREATMENT OF DIABETES MELLITUS

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