Professor Doctor / Nagwa Lachine Department of Internal Medicine, Unit of Diabetes, Lipidology & Metabolism

ORAL ANTIDIABETIC THERAPY & Type2 DM

Type2 diabetes is a progressive disease. In the early stages diet & exercise alone may attain glycemic goals. As diabetes progresses one or more therapeutic agents will be needed. Initially oral monotherapy is used , the second and/or third oral agents are usually added when the dose of the first agent reaches 50-75% of the maximum dose without achieving glycemic goals. As beta- cell exhaustion continues the addition of insulin is often needed. Our essential target is to treat to goal to prevent or at least delay diabetes related complications. Goals of Glycemic Control 1. To relieve symptoms 2. To prevent micro & macrovascular complications. ADA treatment goals for glycemic control Preprandial BG 70-130 mg/dl Postprandial BG <180 mg/dl HbA1c <7% Approximately 10 to 20 % of type2 diabetic patients do to not respond to oral agents & treatment is termed : "primary failure". Secondary failure occurs when a patient responds initially to an oral agent but ceases to respond in the next following years, it is common in the first 3 years. 6 distinct classes of oral antidiabetic agents are actually available : 1. Sulfonylureas (SUs) 2. Biguanides 3. Alpha-glucosidase inhibitors 4. Meglitinides 5. Thiazolidinediones (TZDs) 6. DPP-4 inhibitors or incretin enhancers

1) Sulfonylureas (SUs) :

Decrease HbA1c 1.5% (short acting 4-6 h) (Intermediate acting (long acting 24-60h)

First generation SUs ( less commonly used) 1. Tolbutamide: 500-3000 mg/d ( Rastinon) 2. Acetohexamide 250-1500mg/d (Dymelor) 12-24h) 3. Chlorpropamide: 100-500 mg/d (Pamidine)

Second generation SUs :commonly used ( Intermediate acting) 1. Glibenclamide: 0.5-20 mg/d (Daonil) 2. Gliclazide: 80-240 mg/d (Diamicron) 3. Glipizide: 2.5-40 mg/d (Minidiab).(short acting) Third generation SU :commonly used ( Intermediate acting)

1. Glimepiride: 1-8 mg/d Mechanism of Action of Sulfonylureas Pancreatic effect = main effect : SUs stimulate insulin secretion from beta-cells through binding to SU receptors (SURs) in the plasma membrane of the beta-cells leading to closure of the ATP sensitive K+ (KATP) channels. Sensitize the beta cells to normal insulin releasing stimuli : glucose & amino acids. Extrapancreatic effect (less important) in lowering blood glucose level : SUs improve glucose uptake by peripheral cells .Glimepiride and some of the 2nd generation SUs, stimulate GLUT4 translocation in both normal and insulin resistant cells through dephosphorylation of GLUT4 which prevents its internalization. SUs stimulate the movement of GLUT4 to the cell membrane. Sulfonylurea receptors (SURs): 1. SUR1 (140 Kd) in pancreatic beta-cells for binding of SUs. 2. SURx (65 Kd) in pancreatic beta-cells for binding of glimepiride (3rd generation SU) Side effects: 1. Hypoglycemia. 2. Weight gain. 3. Failure of action either primary or secondary. 4. Skin rashes. 5. Cholestatic jaundice in case of chlorpropamide & acetohexamide 6. Blood dyscrasia & bone marrow depression. Contraindications: Type1 diabetes Diabetic ketoacidosis Pregnant diabetics & gestational Diabetes Type2 Diabetes under stressful conditions : surgery , severe infection , myocardial infarction , corticosteroid therapy or trauma. Diabetics with hepatic & renal impairment Patients with adverse reactions to SUs

2) Biguanides

: Decrease HbA1c 1.5%

Three biguanides were available initially: phenformin, metformin, butformin. Metformin is the only biguanide currently in clinical use.

 The precise mode of action of metformin remain controversial, most certainly it does not stimulate insulin secretion. Mechanism of Action of Metformin: 1. Increases hepatic glucose production (inhibits gluconeogenesis): directly or through insulin sensitizing effect. 2. Stimulates anaerobic glycosis in muscle. 3. Increases insulin mediated glucose uptake in peripheral tissue: secondary to decreased glucotoxicity or through post-receptor-binding mechanisms. 4. Increase GLUT4 in plasma mb of insulin sensitive cells. 5. Anorexia & decreased intestinal glucose absorption. Dose of Metformin: 500-2500 mg/d * Short acting metformin : 500 mg tablet, duration of action 4-6 h. *Long acting metformin (slow releasing metformin): 850 mg tablet , duration of action 6-12 h. Non Glycemic Benefits of Metformin 1. Promotes weight loss 2. No hypoglycemic episodes 3. Decreases VLDL-TG, TG, LDL-C levels: improve diabetic dyslipidemia. 4. Decreases antifibrinolytic factor PAI-1 5. Amelioration of endothelial function 6. Improves ovulatory function in PSOS 7. Rare 1ry and 2ry failure 8. Cheap Side effects: Gastrointestinal complications : nausea, dyspepsia, anorexia, diarrhea. Lactic acidosis : rare & fatal in 30% of cases , it occur if metformin is given in high doses particularly in patients with impaired kidney functions or CHF. Skin rashes & blood dyscrasia. Impair folic acid & vitamin B12 absorption. Failure of action: rare. Contraindicated in those with impaired renal and hepatic functions, in CHF, acute illness, alcoholism and pregnancy. To be used in obese & non obese non ketotic diabetics .It can be combined with SUs and others oral anti diabetic agents or insulin for achievement of glycemic control.

3) Alpha-glucosidase Inhibitors :
Decrease HbA1c 0.5-0.8% Mechanism of Action

Acarbose, Miglitol, Voglibose

1. Decrease postprandial hyperglycemia and insulin level by delaying the digestion and absorption of disaccharides and more complex CHO, through competitive inhibition of the action of the intestinal brush border alphaglucosidase enzyme. So, the post prandial blood glucose peaks are blunted. 2. Increase release of GLP-1 which stimulates insulin and suppresses glucagon secretion Dose : Acarbose: 25-300 mg/d Miglitol: 25-300 mg/d Advantages of alpha-glucosidase Inhibitors 1. No weight gain 2. No hypoglycemia if used as monotherapy 3. Theoretically it may reduce CV mortality consequent to reduction in post prandial hyperglycemia. Disadvantages 1. GIT distress: abdominal discomfort, flatulence and diarrhea, frequently leading to discontinuation of the drug. 2. Complex dosing schedule (3 times/day). 3. Glucose lowering effect is less than SUs and biguanides. 4. If combined with insulin or SUs hypoglycemia can occur and is only reversed by glucose 5. Expensive

4) Non Sulfonylurea secretagogues , Meglitinides or Prandial glucose regulators

This class is currently presented by: Repaglinide: benzoic acid derivative Nateglinide: phenylalanine derivative Dose : Repaglinide: 1-16 mg/d Nateglinide: 120-360 mg/d

Mechanism of Action of Meglitinides It is similar to that of SUs through interaction with voltage dependent KATP channels on pancreatic beta cells where they bind with high affinity and rapid reversibility to specific sites on the beta cells, distinct from the SU binding sites. Meglitinides are distinguished from SUs by their rapid onset of action and short metabolic half-lives. When given just before meals they result in rapid brief episodic stimulation of insulin secretion with beta-cell rest between doses saving the unnecessary insulin release between meals: Attenuation of post prandial BG excursion Less hypoglycemia during late post prandial phase less pronounced weight gain. The efficacy of repaglinide is similar to that of SUs and metformin, whereas natiglinide appears to be a somewhat less potent

Side Effects and Disadvantages of Meglitinides 1. Hypoglycemia : less than SUs. 2. Weight gain: less than SUs. 3. Nateglinide appear to be a less potent secretagogue. 4. Complex dosing schedule (3 times/day). 5. Expensive.

5) Thiazolidinediones (TZDs) , Insulin Sensitizers or PPAR gamma agonists : decrease HbA1c 0.5-1.4%
This class of drugs was introduced in 1997. Troglitazone, the 1st TZD, was removed in March 2000 because of severe idiosyncratic hepatocellular injury. This class is currently presented by: rosiglitazone and pioglitazone since 1999. Mechanism of action: They decrease insulin resistance or improve insulin sensitivity at the level of the peripheral tissues : the muscles , adipose tissues & liver through stimulation of a nuclear receptor" peroxisome proliferator activated receptor gamma" (PPAR gamma) TZDs are ligands with agonistic activity for nuclear receptors: peroxisome proliferator activated receptors gamma (PPARg) found in insulin sensitive tissue. PPAR gamma binds to retinoid X receptor to form a heterodimer that enhances production of proteins essential in cell response to insulin : glucose transport & utilization & lipid metabolism. Activation of PPAR gamma adipocytes by TZDs leads to : 1. Increase differentiation of small adipocytes which are more sensitive to insulin. TZDs may also enhance apoptosis of large adipocytes. 2. Decrease adipose tissue expression and release of mediators of Insulin Resistance: FFAs, TNFa. 3. Increase adipose tissue secretion of adiponectin: which is antiatherogenic, anti-inflammatory and improves insulin sensitivity. 4. redistribution of adipose tissue from central to subcutaneous depot. Protective effect of TZDs on beta cells: 1. TZDs improve beta cell function by decreasing hyperglycemia and FFAs preventing their deleterious effect on beta cells. 2. TZDs directly reduce insulin resistance: improving the response of tissue to endogenous insulin; less pressure is exerted on the pancreas to release high levels of insulin which preserves beta cells function . 3. TZDs prolong beta cell survival (in animals studies) Effect of TZDs on diabetic dyslipidemia:

1. decrease FFAs and TG levels significantly 2. increase HDL-C level 3. Pioglitazone is without effect on LDL-C, rosiglitazone increase LDL-C due to a shift from small dense to large LDL particles which are less atherogenic 4. increase resistance of LDL-C to oxidation. Cardiovascular Protective Effects of TZDs Provide efficient glycemic control Directly decrease insulin resistance decrease endogenous insulin level decrease FFA level and correct diabetic dyslipidemia decrease systolic & diastolic blood pressure. decrease microalbuminuria Improve endothelial function decrease carotid IMT(Intima media thickeness) marker of atherosclerosis decrease the antifibrinolytic plasminogen activator inhibitor-1 (PAI-1) level decrease vascular SMC(smooth muscle cell) proliferation (in vitro) Doses : Pioglitazone: 15-45 mg/d Rosiglitazone: 4-8 mg/d

Other Advantages 1. No hypoglycemia 2. Convenient once daily dosing Side Effects and Disadvantages of TZDs 1. Hepatotoxicity unique to troglitazone ( the first PPAR gamma agonist which was removed from the market because of its hepatotoxicity ) not a class effect 2. Weight gain 3. Oedema 4. Anemia 5. Slow onset of action 6. Frequent liver function test monitoring 7. Contraindicated in CHF and liver disease 8. Expensive

6)DPP-4 Inhibitors or Incretin enhancers:decrease HbA1c 0.5-1%.

Sitagliptin , Vildagliptin , Saxagliptin. GLP-1 (glucagon-like peptide-1); and GIP (glucose-dependent insulinotropic polypeptide) are the major incretin gut hormones released in response to food ingestion . GLP-1 and GIP enhance insulin secretion from cells in a glucose -dependent manner . GLP-1 suppresses glucagons release from -cells in a glucose-

dependent manner.Incretins account for up to 60% of the postprandial insulin response GLP-1 : Is released from L cells in ileum and colon, stimulates insulin response from cells in a glucose-dependent manner , inhibits gastric emptying, reduces food intake and body weight, inhibits glucagon secretion from cells in a glucosedependent manner,appear to have effect on -cell turnover in preclinical models . GIP : Is released from K cells in duodenum, stimulates insulin response from cells in a glucose-dependent manner, has minimal effects on gastric emptying, has no significant effects on satiety or body weight, does not appear to inhibit glucagon secretion from cells , appear to have effect on -cell turnover in preclinical models. The incretin effect is diminished in T2DM: In those without diabetes , the plasma insulin response to an oral glucose load was far greater than the plasma insulin response to an IV glucose load (incretin effect), that is : the pancreatic cells secreted much more insulin when the glucose load was administered through the GI tract. In patients with T2 DM , the same effect was observed but was diminished in magnitude . GLP-1 Levels are decreased in type 2 Diabetes. GLP-1 action remained intact in patients with type 2 Diabetes. In contrast GIP level remained intact in type 2 diabetes while its action was impaired in type2 diabetes. Beta cell function as determined by : HOMA-B , Post-prandial insulin, C-peptide responses, Pro-insulin/insulin ratio , improved in type2 diabetic patients by DPP4 inhibitors (drugs which increase GLP-1). In vitro studies: GLP-1 improves the viability and function of freshly isolated human islets, also the number of apoptotic cells was significantly lower in GLP-1treated islets versus control islets. These results help to provide evidence that GLP-1 preserves morphology and function and inhibits apoptosis of islet cells. Degradation: GLP-1 & GIP are degraded very rapidly by dipeptidyl peptidase enzyme (DPP-4 enzyme), an enzyme that is localized vastly in the endothelium and can be also measured in the circulation. The two fragments resulting from DPP-4 activity on each of GLP-1 & GIP are both biologically inactive GLP-1 exerts its insulinotropic effects by binding to receptors on -cells. 1. One approach to improving GLP-1 activity is through the administration of incretin mimetics. These compounds are molecular analogues of GLP-1 which have the ability to activate -cell receptors but which are structurally different enough to reduce or prevent degradation by DPP-4. 2. A second approach involves the use of incretin enhancers; these prolong the bioactivity of GLP-1 by inhibiting the action of DPP-4 Hence, the two possible solutions to utilize GLP-1 action therapeutically: 1- Long-acting DPP-4-resistant GLP-1 analogues / incretin mimetics 2- DPP-4 inhibitors / incretin enhancers GLP-1 analogues with longer half-life: exenatide, liraglutide, are Injectables Incretin mimetics

Block DPP-4, the enzyme that degrades GLP-1 by DPP4 inhibitors: sitagliptin, vildagliptin & saxagliptin are orally administered incretin enhancers Mechanism of Action of DPP-4 Inhibitors Incretin hormones GLP-1 and GIP are released by the intestine throughout the day; their levels increase in response to a meal. The incretin effect is diminished in type2 diabetes. The concentrations of the active intact hormones are increased by Dipeptidyl peptidase enzyme inhibitors ( DPP-4 inhibitors) thereby increasing and prolonging the actions of these hormones which increase insulin secretion & decrease glucagon secretion in a glucose dependent manner. Dose of sitagliptin :100mg/d, vildagliptin:50mgBid, saxagliptin: 5mg/d Algorithm for monotherapy & combination therapy Lifestyle modification is a cornerstone in management of type2 diabetic patients Before Jully 2006 the following was followed: in obese diabetics begin with Metformin . In non obese diabetics begin with SUs or meglitinides. If glycemic targets are not achieved combination therapy should be considered, add : 1. SU or meglitinide 2. Insulin sensitizer To the obese diabetics 3. a-glucosidase inhibitor & 1. 2. 3. Metformin Insulin sensitizer a-glucosidase inhibitor

To the non obese diabetics

Lifestyle intervention HbA1c>7%

Overweight Begin with metformin Renal impairment Contraindication or intolerance to metformin Begin with sulfonylurea Not Overweight

HbA1c>7%
Metformin + Sulfonylurea Metformin + Thiazolidinedione Sulfonylurea + Metformin Sulfonylurea + Thiazolidinedione

HbA1c>7%
Metformin + Sulfonylurea + Thiazolidinedione

HbA1c>7.5%
Metformin + Sulfonylurea + Once-daily basal insulin Metformin + Twice-daily premix insulin Multiple daily insulin

In Jully 2006 the American diabetes association (ADA) &

the Europeen association for the study of diabetes(EASD) settled the following algorithm

Diagnosis Diagnosis

Lifestyle Intervention + Metform Lifestyle Intervention + Metform

No No
Add basal insullin## Add basal insullin --Most effective Most effective
No No

A1C>7%
Add Sulfonylurea Add Sulfonylurea --Least expensive Least expensive

Yes Yes ``

A1C>7%

In 2008 updating of the ADA EASD consensus has been done

Yes Yes **

No No

A1C>7%

Yes* Yes*

Intensify Insulin## Intensify Insulin

No No

Well validated core therapie

A1C>7%
Yes* Yes*

AddGlitazone++ AddGlitazone

Add basal Insulin Add basal Insulin

Intensive insulin + Intensive insulin + At diagnosis Metformin Glitazone Metformin Glitazone

No No LSM +MET A1 + Basal or intens insulin Add basal

Add basal or intens

LSM + MET

ADA & EASD August iss Aug ust

LSM + MET +