Oral hypoglycemic agents in type 2 diabetes

1. Oral hypoglycemic agents in type 2 diabetes

2. Type 2 diabetes is a disease of progressive β-celldysfunction in presence of insulin resistance, leading to gradual loss of glycemic control. An initial loss of first phase insulin response contributes to elevated postprandial plasma glucose concentrations.

3. Insulin resistance is evident in skeletal muscle, liver, and adipose tissue, the major target tissues of insulin action. Skeletal muscle insulin resistance leads to post-prandial hyperglycemia, while hepatic insulin resistance is a causative factor in the subsequent development of fasting hyperglycemia.

4. Sites of action of the current pharmacological therapies for the treatmentof type 2 diabetes.

5. sulfonylureas • Insulin secretagogues stimulate insulin secretion by interacting with the ATP-sensitive potassium channel on the beta cell . In general, sulfonylureas increase insulin acutely and thus should be taken shortly before a meal; with chronic therapy, though, the insulin release is more sustained.

6. sulfonylureas • At maximum doses, first-generation sulfonylureas are similar in potency to second-generation agents but have a longer half-life, a greater incidence of hypoglycemia, and more frequent drug interactions.

7. sulfonylureas • An advantage to a more rapid onset of action is better coverage of the postprandial glucose rise, but the shorter half-life of such agents requires more than once-a-day dosing

8. sulfonylureas • The most responsive patients are those who exhibit mild-to-moderate fasting hyperglycemia (<200-240 mg/dl; along with adequate residualβ -cell function. These drugs are most effective in individuals with type 2 DM of relatively recent onset (<5 years), who have residual endogenous insulin production.

9. sulfonylureas • The higher the fasting glucose level, the greater the effect will be. In patients with a pre-treatment glucose level of approximately 200 mg/dl, sulfonylureas typically will reduce glucose by 60-70 mg/dl and HbA1C by 1.5-2%.

10. Relationship between baseline HbA1C and reduction in HbA1C from baseline achieved following treatment with oral antihyperglycemic medication.

11. sulfonylureas • Thus, expectations for the overall magnitude of effect from a given agent might be overly optimistic when treating patients whose baseline HbA1c is <7.5-8.0%.

12. sulfonylureas • Approximately 10-20% of patients will exhibit a primary failures. While these patients are typically those who have severe fasting hyperglycemia (>280 mg/dl; and reduced fasting Cpeptide levels, these tests are not specific enough to help decide on the usefulness of a sulfonylurea for an individual patient. In addition, treatment with sulfonylureas results in the eventual loss of therapeutic effectiveness (secondary failure) in the range of 3-10% per year.

13. Adverse effects • Mild hypoglycemic events in 2-4% • severe hypoglycemia 0.2-0.4 cases per 1000 patient-years

14. sulfonylureas • Sulfonylureas reduce both fasting and postprandial glucose and should be initiated at low doses and increased at 1- to 2-week intervals based on SMBG.

15. meglitinides • The mechanism of action of meglitinides also involves the binding to and closure of the KATP channel resulting in membrane depolarization, an influx of calcium, and insulin exocytosis . The kinetics of interaction of nateglinide with the KATP channel are distinct compared to both repaglinide and sulfonylureas, and accounts for its rapid insulinotropic effects.

16. meglitinides • Unlike sulfonylureas, meglitinides stimulate first-phase insulin release in a glucose-sensitive manner, theoretically reducing the risk of hypoglycemic events. The delivery of insulin as an early, transient ‘burst’ at the initiation of a meal affords several major physiological benefits

17. meglitinides • These include rapidly suppressing hepatic glucose production and reducing the stimulus for additional insulin that would be required subsequently to dispose of a larger glucose load. Thus, the rapid onset/short duration stimulation of insulin release by meglitinides should enhance control of prandial hyperglycemia, while reducing the risk for post-absorptive hypoglycemia and limiting exposure to hyperinsulinemia.

18. meglitinides • Repaglinide is approximately 5 times more potent than glyburide in stimulating insulin secretion. Unlike glyburide, repaglinide does not stimulate insulin secretion in vitro in the absence of glucose. Rather, it enhances glucose-stimulated insulin secretion especially at 180mg/dl glucose.

19. meglitinides • As a result of more rapid absorption, it produces a generally faster and briefer stimulus to insulin secretion. As a result, it is generally taken with each meal and provides better postprandial control and generally less hypoglycemia and weight gain than glyburide. Repaglinide does seem to have a long residence time on the sulfonylurea receptor and a prolonged effect on fasting glucose, even though its pharmacologic half-life is quite short.

20. meglitinides • The onset of action of netaglinide is similar to that of glyburide but three-fold more rapid than that of repaglinide . When netaglinide is removed from the KATP channel, its effect is reversed twice as quickly as glyburide and five times more quickly than repaglinide. Thus, netaglinide initiates a more rapid release of insulin that is shorter in duration compared to repaglinide ,despite having an in vivo pharmacokinetic profile that is similar.

21. Thiazolidinediones • These drugs bind to the PPAR-δnuclear receptor. The PPAR- δ receptor is found at highest levels in adipocytes but is expressed at lower levels in many other tissues. Agonists of this receptor regulate a large number of genes, promote adipocyte differentiation, reduce hepatic fat accumulation, and appear to reduce insulin resistance indirectly by enhancing fatty acid storage and possibly by increasing adiponectin levels

22. Thiazolidinediones • It does not appear that rosiglitazone and pioglitazone improve insulin sensitivity and glucose disposal by direct effects on either liver or muscle. PPARδ is expressed chiefly in adipose tissue, and its expression in liver and skeletal muscle is low .Thus, it is more likely that the primary effects of these drugs are on adipose tissue, followed by secondary benefits on other target tissues of insulin.

23. Thiazolidinediones • Thiazolidinediones promote a redistribution of fat from central to peripheral locations. Circulating insulin levels decrease with use of the thiazolidinediones, indicating a reduction in insulin resistance.

24. Thiazolidinediones • Each drug as monotherapy, results in a significant reduction in fasting plasma glucose by 60-80 mg/dl and in HbA1c by 1.4-2.6% . In addition, pioglitazone is approved for use in combination with insulin, metformin, or a sulfonylurea, and rosiglitazone is approved for use in combination with metformin or a sulfonylurea.

25. Thiazolidinediones • Unlike other existing anti-diabetic medications that possess a very rapid onset of activity, TZD exhibit a characteristic delay from 4-12 weeks in the onset of their therapeutic benefits.

26. Thiazolidinediones • Patients treated with 15, 30, or 45 mg (once daily) pioglitazone had significant mean decreases in HbA1c (range -1.00 to -1.60%) and fasting plasma glucose (-39.1 to -65.3 mg/dl). The decreases in fasting plasma glucose were observed as early as the second week of therapy; maximal decreases occurred after 10-14 weeks .

27. Due to their mechanism of action, the risk of hypoglycemia with rosiglitazone or pioglitazone monotherapy is low. Mild to moderate hypoglycemia has been reported during combination therapy with sulfonylureas or insulin .

28. Side effets • weight gain (2–3 kg) • small reduction in the hematocrit • mild increase in plasma volume. • Peripheral edema and CHF is more common in individuals also treated with insulin. • rosiglitazone is associated with an increased risk of myocardial infarction. • worsening of diabetic macular edema. • increased risk of fractures has been noted in women taking these agents.

29. contraindications • liver disease • CHF (class III or IV).

30. Thiazolidinediones • Although rosiglitazone and pioglitazone do not appear to induce the liver abnormalities, the FDA recommends measurement of liver function tests prior to initiating therapy with a thiazolidinedione and at regular intervals (every 2 months for the first year and then periodically).

31. Thiazolidinediones • With regard to edema, with appropriate caution almost no one should need to withdraw from therapy as a result of fluid retention. The patients most likely to experience edema are those treated with insulin and those with preexisting edema. Thus, women, overweight patients, and those with diastolic dysfunction or renal insufficiency are at greatest risk

32. Thiazolidinediones • In the previously edematous patient and in patients treated with insulin, it is prudent to initiate therapy with the lowest available dose of glitazone. In 1 to 3 months, if the glycemic response has been inadequate and significant edema has not developed, consider increasing the dose of glitazone further with continued expectant home evaluation for edema.

33. Biguanides • Metformin is representative of this class of agents. It reduces hepatic glucose production through an undefined mechanism and improves peripheral glucose utilization slightly .

34. Metformin • metforminreduces fasting plasma insulin and improve insulin sensitivity. While it is possible that the beneficial effect of metformin on insulin sensitivity is mediated directly, a more likely explanation is that it is secondary to a reduction in hyperglycemia, triglycerides, and free fatty acids.

35. Efficacy • A large number of well-controlled clinical studies have established that metformin monotherapy consistently reduces FBS by 60-70 mg/dl and HbA1c by 1.5-2.0% . Similar to the sulfonylurea treatment, the overall magnitude of response to metformin is directly related to the starting FBS concentration.

36. Metformin • Unlike sulfonylurea treatment, metformin monotherapy is not associated with weight gain and even promotes a modest weight loss.

37. Metformin • The initial starting dose of 500 mg once or twice a day can be increased to 1000 mg bid

38. Metformin • Because of its relatively slow onset of action and gastrointestinal symptoms with higher doses, the dose should be escalated every 2–3 weeks based on SMBG measurements.

39. Effect ofmetformin on fasting plasma glucose when given as add-on therapyto glyburide.

40. Metformin • When added to a sulfonylurea, the effects of both agents are additive, consistent with their different mechanisms of action. Interestingly, in patients that no longer responded to sulfonylurea treatment (secondary failures) and were removed from treatment, addition of metformin had minimal effects . Thus, in these patients, sulfonylurea treatment was still eliciting an effect, emphasizing the need to continue treatment with both agents.

41. Side Effects and Contraindications • The most common are GI disturbances (abdominal discomfort, diarrhea), in 20-30% of patients. These effects are generally transient, and can be minimized or avoided by careful dose titration.

42. The incidence of lactic acidosis is rare and occurs with a frequency of 3 cases per 100,000 patient-years.

43. The risk of lactic acidosis can be minimized when the following are considered: • 1.Withhold in conditions predisposing to renal insufficiency and/or hypoxia • a. CV collapse • b. Acute MI or acute CHF • c. Severe infection • d. Use of iodinated contrast material • e. Major surgical procedures

44. 2. Metformin should not be prescribed for patients with: • a. Renal dysfunction [e.g. Scr >1.5 mg/dl (males), >1.4 mg/dl (females) or abnormal CrCl • b. Liver dysfunction • c. History of alcohol abuse/binge drinking • d. Acute or chronic metabolic acidosis

45. Metformin • Metformin should be discontinued in patients who are seriously ill, in patients who are NPO, and in those receiving radiographic contrast material.

46. α-GLUCOSIDASE INHIBITORS • They bind competitively to the oligosaccharide binding site of the α-Glucosidase enzymes, thereby preventing enzymatic hydrolysis. Acarbose binding affinity for the α-Glucosidase enzymes is: glycoamylase > sucrase > maltase> dextranase . Acarbose has little affinity for isomaltase and no affinity for the β -glucosidase enzymes, such as lactase

47. α-Glucosidase inhibitors • acarbose and miglitol reduce postprandial hyperglycemia by delaying glucose absorption; they do not affect glucose utilization or insulin secretion

48. Efficacy • Clinical trials conducted to date have established that the antihyperglycemic effectiveness of acarbose is less than 50% than that of either sulfonylureas or metformin. When used as monotherapy, acarbose primarily affects post-prandial glucose levels, which is reduced by 40-50 mg/dl after meal

49. Side Effects • The major side effects are GI disturbances. in 25-30% of patients, ( flatulence, diarrhea, bloating, and abdominal discomfort.) • These side effects can often be minimized by careful dose titration, and sometimes diminish with time. • Asymptomatic and reversible; dose dependent hepatotoxicity, serum ALT levels require monitoring for patients receiving high doses (>200 mg three times daily) • Hypoglycemia does not occur as monotherapy.

50. contraindications • inflammatory bowel disease • cirrhosis • elevated plasma creatinine • gastroparesis • Simultaneous treatment with resins and antacids.