OS 215: Reproduction and Hormonal Regulation LEC 09: Oral Diabetic Agents Exam # 7 | Dr. Cecilia A.

Jimeno | November 21, 2012

OUTLINE
I. Oral Diabetic Agents A. Sulfonylureas B. Megletinides C. Biguanides D. Alpha Glucosidase Inhibitors E. Thiazolidinediones F. Summary of Action of Oral ADAs G. Incretin-based Therapy H. Effectiveness of Diabetes Therapy II. Appendix

MOA of SU Bind to receptor in K channel (SUR1, check Fig. 3) Close K channel Depolarization Ca influx Vesicles attach to cell membrane Insulin release

Italicized- Dr. Jimeno, Bold emphasized points

I. ORAL DIABETIC AGENTS Oral diabetic agents are targeted for Type 2 DM. None are indicated for Type 1 DM. o At the moment, experiments are being done on -glucosidase inhibitors for the treatment of Type 1 DM, since they don't really address any of the pathophysiologic processes involving insulin. They are just mechanistic, slowing down the breakdown and absorption of carbohydrates in the gut. Classes of Anti-Diabetic Agents A. Standard Drugs (the ones discussed in the lecture) 1. Sulfonylureas (SUs) increase insulin secretion 2. Megletinides increase insulin secretion 3. Biguanides improve insulin sensitivity 4. Alpha-glucosidase inhibitors decreases the amount of sugar that is absorbed in intestines 5. Thiazolidinediones (TZDs) improve insulin sensitivity 6. Incretin-based: DPP4 inhibitors + additional injectables (GLP-1) B. Other Drugs (not yet widely acceptable or available) 1. Bile acid sequestrants 2. Dopamine 2-agonists 3. Amylin mimetics A. Sulfonylureas Insulin secretagogue (along with megletinides) Drug Development: an accidental discovery; derived from chance observations that a sulfonamide derivative (which is an antibiotic for typhoid fever) results in marked lowering of blood glucose nd 2 oral anti-diabetic agent in terms of development (first was Metformin), but 1st oral anti-diabetic agent to be commercially developed Used in patients with relatively recent onset of type 2 DM (<5 years), who have residual insulin production Stimulate release of insulin from the beta cells of the pancreas (independent of glucose stimulation) o Mimics action of glucose in stimulating release of insulin from beta cells Mechanism of Action 1. Mainly act by enhancing insulin release (secretagogue) MOA of glucose: Glucose enters beta cells via GLUT2 receptor in the pancreas Increase ATP Block/Closure of K channel Depolarization Ca influx Vesicles with insulin attach to cell membrane Insulin release

Figure 2. Mechanism of Action of Sulfonylureas Almost same MOA for glucose and SU, but different binding receptor in K channel Glucose-independent o Even during fasting, SU will not be able to detect that there is already low blood glucose. It will still stimulate the pancreatic beta cell to secrete insulin. o Adverse effect: HYPOGLYCEMIA. It should be taken with/before meals since, as mentioned, it will induce insulin secretion even at blood low glucose levels. Not recommended for patients with ischemic heart diseases 2. Reduces hepatic glucose output Model of the SU Receptor

Figure 3. The SU receptor is an ionophore channel. Core inside subunits would open and close depending on presence/absence of glucose Presence of glucose core closes decreased permeability to K If patient is taking SU: SU binds to SUR1 closes channel same effect as glucose Advice patient to take SU before meals so that insulin is released post-prandially, and to avoid hypoglycemia

Millie: Its TRP season again! Lets all go to the practices! Chorale and dance! Its gonna be F-U-N!!! Hello to my future parent! Kailangan mong tapatan si Erik Tongol. :> Hahaha! So excited for Christmas! Pengeng gift. :D Yes, you. Thank you, bait mo talaga! Ginnie: WAHOO!!! ITS THE BEST TIME OF THE YEAAAAR! Roomie, Christmas party tayo ha! :)) Excited na ako magbunutan! HELLO FUTURE KRIS KRINGLE BABY! I will try to spoil you with my limited funds! Haha. Trese Pwede, kelan na Baguio?? Merry Christmas 2016! Love love love!

Figure 1. Mechanism of Action of Sulfonylureas

Bh0bBiE, GiNnhiE, MhiLLiE

UPCM 2016: XVI, Walang Kapantay!

1 of 6

OS 215

LEC 09: ORAL DIABETIC AGENTS

Distribution o SUs in plasma are largely bound to proteins (90-99%) esp. albumin o Clinical implications: in renal & hepatic impairment Renal: delayed excretion, worsens hypoglycemia Hepatic: decreased albumin means more free drug quicker onset of action inc plasma conc hypoglycemia o Plasma protein binding is least for chlorpropamide & greatest for glyburide st o 1 gen SUs: variable half-life & extent of metabolism Acetohexamide: short life but drug is reduced to an active metabolite with a half-life similar to those of tolbutamide & tolazamide (4-7 hrs) Chlorpropamide: long half-life (24-48 hrs) nd o 2 gen SUs: st 100x more potent than 1 gen SUs Half-lives are short (1.5 to 5 hrs) but hypoglycemic effects are evident for 6-12 hrs (thus can offer the advantage of once a day dosing, but timing of meals must strictly be followed) Reason for the discrepancy between the half life & duration of action of these drugs is unclear (biologic half life) Also with modified long acting preparations (24-48 hrs) Metabolism & Excretion o Mostly metabolized in liver (except glipizide mixed) that are cleared in the kidneys o Almost exclusively excreted through renal route o Metabolism of chlorpropamide is incomplete: 20% of the drug is excreted unchanged o Thus, if the Pt has hepatic injury or renal insufficiency, AVOID this drug; SUs should be administered with caution to Pts with either renal or hepatic impairment B. Megletinides Aka glinides Secretagogues but bind at a different area in the SU receptor in the beta cell Advantage over SUs: Ultra-short acting because they are rapidly absorbed from GIT with peak levels in 1 hour thus avoiding hypoglycaemia No meal, no dose: first prandial regulator; this means that the Px only needs to take it when they are going to eat Main use is for people who would like more flexibility in terms of dosing (for athletes, medical students, etc. :P) Administer before eating; onset of action starts during the peak of blood glucose level Specific Drugs 1. Repaglinide (Novonorm/Prandin) Benzoic acid derivative, structurally different from the SUs but with similar MOA Absorbed rapidly from GIT Peak blood levels achieved within 1 hour: allows multiple preprandial use (to control post-prandial hyperglycemia) Metabolism: liver with inactive metabolites Clinical Implications o Use with caution in hepatic insufficiency but can be used in renal insufficiency o Small proportion is metabolized by the kidney (10%), hence increase dose with caution in renal insufficiency 2. Nateglinide (Starlix) Derivative of phenylalanine Metabolized primarily by the liver; caution in hepatic insufficiency 16% of the drug is excreted by the kidney unchanged Dosage adjustment is unnecessary in renal failure (safe for patients with renal problems)
Bobbie: Its TRP season again! Lets all go to the practices! Hi to all altos! You guys rock! Oh oh oh ah ah ah ah ahhhh!! Doo doo doo :P ITS THE BEST TIME OF THE YEAAAAR! Happy Christmas to one and all! P.S. Thank you to all the people who took care of me when I was sick. You know who you guys are, char! :>

Classes of Sulfonylureas (SUs) Table 1. First and second generations SUs First generation Second generation Tolbutamide (1) Glibenclamide (150)- potency Acetohexamide Glipizide (100) Chlorpropamide Gliclazide Glimepiride Longer half-life Shorter half-life Greater incidence of Less hypoglycemic hypoglycemia even in More rapid onset of action supposedly short-acting action Better coverage of More frequent drug postprandial glucose (more interactions potent in glucose lowering) Unpredictable kinetics renal More predictable kinetics; either excretion but some are excreted renal or partial hepatic/fecal unchanged as active metabolites route of excretion but usually or only partially metabolized by inactive metabolites the liver leads to prolonged half-life/action tendency for hypoglycemia *Duration of action & peak levels vary from drug to drug Adverse Effects Generally well tolerated Hypoglycemia: most common side effect o Tolbutamide: least likely to cause hypoglycemia o Glibenclamide: although its cheapest (a peso!? :S), also most notorious; most potent hypoglycemic, thus, not recommended for elderly Pts and those with renal dysfunction; best not to prescribe anymore o Glipizide: less likely since inactive metabolites accumulate in renal failure o Predisposing factors: type of agent (potency), advanced age (because of progressive decline in GFR), impaired renal function, delayed meals, increased physical activities, alcohol intake SU Allergy: skin rashes due to sulfo moiety (just like all other sulfa- drugs); could become SJS o If you know that your px is allergic to other sulfa drugs such as cotramoxizole, DO NOT PRESCRIBE SU Gastrointestinal upset: 3% Bone marrow damage: very rare but severe Steven-Johnsons Syndrome due to sulfo moiety: <1% of Pts (rare) Cardiovascular risks st nd o more for 1 gen and older 2 gen. SUs (like Glibenclamide) o adverse effects on the heart and blood vessels theorized to be caused by binding of sulfonylureas to isoforms of ATP-sensitive K channels in the myocardium and the brain o so, if the patient already has an underlying cardiac problem, avoid these drugs since they can cause blunting of the ischemic preconditioning (IPC) in the heart
IPC is an intrinsic process whereby repeated short episodes of ischaemia protect the myocardium against a subsequent ischaemic insult (Sorry Wiki lang haha!)

Weight gain due to increased insulin secretion (improvement in glycemic control), since insulin is a growth factor Pharmacokinetics of SU In general, sulfonylureas increase insulin acutely and thus should be taken shortly before a meal With chronic therapy, insulin release becomes more sustained Absorption o Effectively absorbed from GIT Food & hyperglycemia can reduce the absorption of SUs o Clinical implications: gastroenteropathy in uncontrolled DM, inhibited gastric & intestinal motility retards absorption of many drugs; so kinetics may still be unpredictable even when intake is timed with meals o SUs with short half life may be more effective when given 30 minutes before eating or 2 hours after eating

Bh0bBiE, GiNnhiE, MhiLLiE

UPCM 2016: XVI, Walang Kapantay!

2 of 6

OS 215
Clinical Use

LEC 09: ORAL DIABETIC AGENTS

o CHF o Liver disease o Severe hypoxemia Not recommended for pregnant women Discontinued in patients who are seriously ill, patients who can take nothing orally, and in those receiving radiographic contrast material Side Effects Generally a well-tolerated medication Not associated with the development of hypoglycemia Most severe side-effect: lactic acidosis (very rare though high mortality when it occurs) o Rare: 0.03 per 1,000 patient-years o Mortality can be 50% o By itself, biguanides do not cause renal failure, etc.; however, do not prescribe these If there are any risk factors/disorders (concomitant disease) that may lead to metabolic acidosis Risk factors: renal insufficiency, tissue hypoperfusion (CHF, MI, sepsis, dehydration, surgery, respiratory failure), hepatic failure, alcoholic intoxication; caution in elderly Most common: Gastrointestinal symptoms o Happens in < 5% (maybe, even around 20%) of patients taking metformin o Nausea, vomiting, anorexia, abdominal pain and diarrhea o Minimize by taking with meals & start low (increase gradually) o Metallic taste in 3% o Decreased serum Vitamin B12 by 30% Pharmacokinetics Absorbed mainly from the small intestine Drug is stable (distribution) Does not bind to plasma proteins Excreted unchanged in the urine Use with caution in patients who are prone to metabolic acidosis D. Alpha Glucosidase Inhibitors Dietary carbohydrates (polysaccharides) require enzymatic digestion by -glucosidase into monosaccharides in the GIT in order to be absorbed Inhibiting this enzyme would therefore delay or decrease carbohydrate absorption carbs are flushed! These drugs are taken before a meal st 1 compound: Acarbose is a pseudo-tetrasaccharide (polysaccharide-like) compound isolated from Actinoplanes utanhesis o This property allows it to bind to alpha-glucosidases and inhibit enzymatic action on polysaccharides not absorbed o Delays digestion and absorption of sucrose and complex carbohydrates by inhibiting the action of alpha-glucosidase enzyme at the intestinal brush border 3 agents are available: o Acarbose: 50-100 mg TID o Voglibose: 0.2-0.3 mg TID o Miglitol: 50-100 mg TID not available in the Philippines; therefore kalimutan na Structurally similar to oligosaccharides Reversibly binds with high affinity to -glucosidases, glucoamylase, dextrinase, maltase & sucrase However, the C-N linkage in acarbose cannot be cleaved by the glucosidase enzymes These agents are reversible, competitive inhibitors of oligosaccharide digestion esp. at the upper small intestines

Like other agents, indicated for treatment of Pts with Type 2 DM who do not respond adequately to diet and exercise May be used as mono-therapy or in combination with insulin or metformin in Type 2 DM, and even those with chronic renal insufficiency (because of very short duration of action) Used especially to target consistently elevated post-prandial blood sugar Adverse Effects Only 10-15% are excreted in the kidneys unchanged: inactive metabolites Main side effect is still hypoglycemia o Recent studies indicate that rates of hypoglycemia is minimal if drug is taken as instructed o Can be used in elderly, erratic meals, chronic renal insufficiency C. Biguanides Parent compound guanidine is derived from the plant Galega officinalis Used since medieval times for the treatment of DM in Southern and Eastern Europe 2 derivatives: 1. Phenformin (phenethylbiguanide) (1950s) pulled out in the market because of excess lactic ketoacidosis; also used to treat obesity 2. Metformin (Dimethylbiguanide) o Absorbed mainly from the small intestine o Drug is stable (distribution) o Does not bind to plasma proteins o Excreted unchanged in the urine o Use with caution in Pts prone to lactic acidosis o Most common side effect: GI upset Mechanism of Action Molecular mechanisms NOT well understood Exerts its glucose-lowering actions independent of any effect on insulin secretion Improves insulin sensitivity (mostly hepatic) o Inhibits basal hepatic glucose production o Improves peripheral sensitivity to insulin, that is, insulinmediated glucose uptake, in muscle and adipose tissue o ? Others: up-regulation of insulin receptors, improvements in post receptor events (GLUT 4) Causes anorexia thus inducing modest weight loss; maximum 5kg, ave 2-3 kg Slows the rate of glucose absorption from the intestine, although overall absorption of glucose is not altered Improves lipid profiles by decreasing FFA concentrations & fatty acid oxidation Clinical Use By consensus, most guidelines agree that it is the drug of choice for lean or non-overweight petients Indicated in the treatment of Pts with Type 2 DM who do not respond adequately to a program of dietary modification & exercise BEST for overweight patients; drug of choice as monotherapy for overweight and obese patients o REMEMBER! METFORMIN = BIGuanide for BIG patients o Diet and exercise still more effective than Metformin in achieving weight loss Good for those with a lot of insulin resistance Can be used as mono-therapy or in combination Dose range: 500-3000 mg /day in 2-3 doses Now approved for use in children with Type 2DM (Yey!) o Only agent approved for children with Type 2 DM Contraindications Metformin should not be used in patients with: o Renal insufficiency (GFR < 60 mL/min) o Any form of acidosis

Clinical Use For those who failed on diet and exercise Does not cause hypoglycemia and thus might be best for the elderly Use as monotherapy or in combination Best used for those with post-prandial hyperglycemia

Bh0bBiE, GiNnhiE, MhiLLiE

UPCM 2016: XVI, Walang Kapantay!

3 of 6

OS 215

LEC 09: ORAL DIABETIC AGENTS

Involved in other metabolic pathways like bone regulation and Na regulation o Causes Na retention and water retention edema heart failure Also causes modest reduction in triglycerides and free fatty acids Promote redistribution of fats from a central to a more peripheral location Do not appear to enhance insulin release by the pancreas It has no effects on glucose metabolism in the absence of insulin Clinical Use TZDs are indicated in the treatment of Pts with Type 2 DM who do not respond adequately to diet and exercise May be given both as monotherapy or in combination with other agents o Better to give in combination with metformin to break the cycle of insulin resistance since metformin acts only partly in liver and partly in peripheral tissues Not safe in pregnancy, lactation, and children Adverse Effects Elevations of serum transaminases (>3x) in 2.2% of Pts treated with troglitazone vs 0.6% in placebo-treated Pts However, several cases of troglitazone-induced hepatic failure leading to liver transplantation or death have been reported Idiosyncratic drug reaction causing severe hepatocellular injury In clinical trials, rosiglitazone and pioglitazone have not demonstrated same rates of transaminase elevations TZDs as monotherapy do not cause hypoglycemia More common adverse effects: o plasma volume by 6-8% may lead to edema, worsened CHF, wt gain o Decline in Hb, Hct (dilutional anemia) Also have the potential of causing osteoporosis Increase in occurrence in MI was also observed Increase in occurrence of bladder cancer Why is it still used? Because it complements the effects of Metformin since it acts more on the peripheral tissues Contraindications: given the mentioned adverse effects, please do not prescribe TZDs for patients who have the following: o CHF, other CVS problems o Anemia o Hepatic disease o Osteoporosis o Bladder CA Types of Thiazolidinediones Rosiglitazone (Avandia) & Pioglitazone (Actos) Absorbed within 2 hours after oral intake but maximum clinical effect is not observed for 6-12 weeks Metabolized by the liver and may be administered to Pts with renal insufficiency except in those with edema AVOID in hepatic disease Both are metabolized by cytochrome P450 enzymes in the liver: Rosi- by CYP2C8 and Pio- by CYP3A4 & CYP2C8 Potential for interactions with other drugs that are metabolized via these pathways Control is consistent over the years

Not so potent in decreasing blood glucose but is unique because it reduces postprandial glucose rise even in individuals with type 1 DM Acarbose is the most prescribed drug in China, however, Westerners do not like it because of its side effects, most notably, flatulence. Inumin pagkatapos ng unang subo ng pagkain Contraindications These agents should not be used in individuals with: o Inflammatory bowel disease o Gastroparesis o Serum creatinine of >2 mg/dL Adverse Effects As monotherapy, does not cause hypoglycaemia and does not affect insulin release; it only affects carbohydrate absorption However, hypoglycemia is still possible when administered in combination with other drugs Most common side effects are gastrointestinal symptoms: abdominal pain, diarrhea, and flatulence (due to high CHO) in as much as 30% at the highest doses (parang kumain ka ng kamote) No reports of interference with the absorption of any other medications Poorly absorbed from the gut o No systemic action but still not recommended though for patients with chronic renal disease Reduce intestinal absorption of starch, dextrin and disaccharides by inhibiting the action of intestinal brush border alphaglucosidase E. Thiazolidinediones Fujita and colleagues: synthesized several phenolic compounds with a thiazolidine ring to enhance sensitivity to insulin First agent: Ciglitazone however, never went beyond animal studies due to adverse effects Troglitazone- first compound developed for clinical use (1998); however, pulled out from the market in 1999 because of druginduced hepatitis, which resulted to hepatic failure that requires transplant Have significant effects on carbohydrate and lipid metabolism in those with insulin resistance but not in Pts with insulin deficiency Improves insulin sensitivity in muscle, partly in the liver, and adipose tissues (peripheral action) as opposed to the metformin (action in the liver) o Troglitazone (Rezulin): PULLED OUT due to development of hepatic failure o Rosiglitazone (Avandia): 4-8 mg OD (PULLED OUT recently due to greater tendencies of some patients to heart attacks) o Pioglitazone (Actos); 15-45 mg OD (studies showed that this drug increases the risk for bladder CA) (only remaining drug we
need to memorize, yeah! Baka ma-pull out na rin :p)

Very effective in insulin resistant states: obesity, hypertension, IGT, PCOS Mechanism of Action Act as ligands for the peroxisome proliferator-activated receptor nuclear receptor (PPAR ), a subtype of PPARs that comprise the family of thyroid/steroid hormone receptors that act as nuclear transcription factors PPAR is activated in adipose and skeletal muscles affecting the transcription of various genes that influence multiple steps in lipid and glucose metabolism TZDs bind to the PPAR - a nuclear receptor which is complexed to the retinoid X receptor (RXR) in the nucleus Binding of TZDs causes conformational change in the PPAR -RXR complex which induces the expression of various genes involved in fatty acid and glucose uptake in muscles and adipose tissues Primary mechanism of action for inducing glucose control is through the PPAR , which causes increased expression and translocation of glucose transporters (GLUT 4) (net effect: improve insulin sensitivity)

Bh0bBiE, GiNnhiE, MhiLLiE

UPCM 2016: XVI, Walang Kapantay!

4 of 6

OS 215

LEC 09: ORAL DIABETIC AGENTS

F. Summary of Actions of Oral ADAS Two Major Incretins Table 9. Comparison of GIP and GLP-1 GLP-1 GIP Secreted by L-cells in the distal Secreted by K-cells in the gut (ileum and colon) proximal gut (duodenum) Stimulates glucose-dependent Stimulates glucoseinsulin release dependent insulin release Suppresses hepatic glucose output by inhibiting glucagon secretion in a glucosedependent manner Enhances beta-cell Enhances beta-cell proliferation and survival in proliferation and survival animal models and isolated in islet cell lines human islets Not pharmacologically useful due to rapid degradation. The solution is to find analogs. Actions of GLP-1 o Stimulates Glycogenesis in liver and muscle Pancreatic secretion of insulin and somatostatin Lipogenesis in adipose o Inhibits Pancreatic secretion of glycogen Gastric acid secretion and emptying Food and water intake o Causes weight loss (greater than metformin but still not very great) and appetite suppression o Agents in this class do not cause hypoglycemia because of the glucose-dependent nature of incretin-stimulated insulin secretion (unless taken with an agent that can cause hypoglycemia i.e. sulfonylureas) o Rapidly metabolized due to very short bioavailability o GLP-1 as a drug: very expensive (8K and also uncomfortable as an injectable)

Figure 4. Target Organs of Oral Diabetic Agents Table 2. Effect of Oral Anti-diabetic Agents on A1c and FBG
(Reference only! No need to memorize.)

*Most potent: SUs and Biguanides Combination Therapy Never combine drugs of the same class/MOA except for sensitizers. Sensitizers can be combined to other drugs. Try to combine drugs that have different/complementary MOA to improve treatment Table 8. Improvements in Glycemic Control Using Combination Therapy

G. Incretin-based Therapy The Incretin Concept Based on the concept that intrajejunal infusion of glucose causes a higher insulin response than intravenous infusion Suggests humoral substance released by the jejunum acts in concert with glucose to stimulate pancreatic insulin release Incretins- gut hormones released in response to ingestion of a meal Regulate glucose homeostasis through effects on islet cells Eating and passage of food in our gut ambient sugar levels increase increase in GLP-1 and GIP stimulate glucosedependent insulin release and inhibits glucagon secretion (GLP1) increases peripheral glucose uptake and decreases hepatic glucose output Causes post-prandial peak insulin release Incretin effect diminished in Type 2 DM It is better if the route of drug administration is oral instead of IV since the GIT is stimulated to release insulin if the oral route is taken

Figure 5. Biologic Effects of Incretin GLP-1 Strategies for Increasing Incretin Action Provide more GLP-1 Limit its metabolism and excretion so as to have more active hormones: enzyme inhibition GLP-1 agonists: Liraglutide and Exenatide o GLP-1 analogues from exendin-4 - Initially derived from saliva of the Gila monster (rawr!) which only eats 4 times a year and when not eating is able to turn its pancreas off; now its available through recombinant DNA technology; except its expensive (8k/month) Exenatide Unlike native GLP-1, exenatide has changes in its amino acid sequence that makes it resistant to breakdown by the enzyme that causes degradation of native GLP-1, dipeptidyl peptidase IV or DPP-IV Binds to GLP-1 receptors in the islets, GIT, & brain Injected 2x a day but once a week preparation is being developed

Bh0bBiE, GiNnhiE, MhiLLiE

UPCM 2016: XVI, Walang Kapantay!

5 of 6

OS 215

LEC 09: ORAL DIABETIC AGENTS

Advantages o Orally administered o Weight neutral to slight weight loss o Can be combined with metformin for greater benefit o More expensive than other oral agents Sitagliptin (not discussed) o DPP-4 inhibitor developed for the treatment of patients with Type 2 DM o Approved by the FDA on October 17 2006; approved in 12countries o Provides potent and highly selective inhibition of the DPP-4 enzyme o Fully reversible and competitive inhibitor o Pharmacokinetics support once daily dosing No effect on food on pharmacokinetics Well absorbed orally Primarily renal excretion No drug-drug interaction H. Effectiveness of Diabetes Therapy Aside from showing the effectiveness of diabetes therapy, the figure below also shows the glycemic management of Type 2 DM

Liraglutide Almost same action as exenatide Injected once a day Increased risk of thyroid C-cell tumors in rodents thus is contraindicated in patients with medullary CA of the thyroid and multiple endocrine neoplasia (MEN) Taspoglutide o GLP-1 agonists slow gastric emptying, thus they may increase absorption of other drugs o Advantages: cause weight loss o Disadvantages: adverse GI reactions (nauses and vomiting), cost, injectable Inhibitors of Dipeptidyl Peptidase 4 (DPP-4) o Serine protease of the prolyl oligopeptidase enzyme family that exists in two forms: Membrane-bound (widely expressed) Soluble o Modulates the biological activity of several peptide hormones, chemokines, and neuropeptides o In vitro and In vivo DPP-4 inhibition increases levels of biologically active incretins GLP-1 and GIP

Figure 6. DPP-4 inhibitors inhibit the enzyme that breaks down the intestinal incretins GIP and GLP-1 Available Preparations o Sitagliptin tested among patients with renal problems o Vildagliptin o Saxagliptin o Linagliptin- tested among pts with hepatic problems; also renal o Alogliptin Figure 7. Effectiveness of Diabetes Therapy. Values of Starting HbA1c indicate the appropriate level at which the interventions should be applied. The values written alongside the mode of management indicate the absolute decrease in the HbA1c. END

APPENDIX. SUMMARY OF ORAL DIABETIC AGENTS

Drug Sulfonylureas =ides Target Organ Pancreas Action Stimulate pancreatic -cells to release insulin into the bloodstream Advantages Inexpensive Disadvantages Hypoglycemia, weight gain Contraindications Renal/liver disease Examples Chlorpropamide Glipizide Glimepiride Gliclazide Glibenclamide Repaglinide Nateglinide

Meglitinides = glinides

Pancreas

Also an insulin secretagogue (but short acting)

Biguanides = metformin

Liver

Decrease the amount of glucose made by the liver Increases insulin sensitivity of mm & adipose Improves insulin sensitivity by stimulating PPARreceptors;

Thiazolidinediones (TZD) = glitazone

Muscle and fat tissues Muscle and fat tissues

Short onset of action, lower postprandial glucose Weight neutral, Do not cause hypoglycemia, inexpensive Lower insulin requirements

Hypoglycemia

Renal/liver disease

Diarrhea, nausea, lactic acidosis

Alpha-Glucosidase Inhibitors (AGI) = ose

GIT intestines

Block -glucosidase enzymes that break down complex CHO into a more absorbable form (simple sugars)

Reduce postprandial glycemia

Peripheral edema, CHF, weight gain, fractures, macular edema; rosiglitazone may increase cardiovascular risk GI flatulence, liver function tests

Serum creatinine>1.5 mg/dL (men) >1.4 mg/dL (women), CHF, radiographic contrast studies, seriously ill patients, acidosis CHF, liver disease

Metformin

Rosiglitazone Pioglitazone

Renal/liver disease

Acarbose Voglibose

Bh0bBiE, GiNnhiE, MhiLLiE

UPCM 2016: XVI, Walang Kapantay!

6 of 6