1. Oral hypoglycemic agents in type 2 diabetes

2. Type 2 diabetes is a disease of progressive β-cell dysfunction 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 treatment of 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 (< 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 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 < %.

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 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 mg/dl and in HbA1c by % . 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 to -1.60%) and fasting plasma glucose (-39.1 to mg/dl). The decreases in fasting plasma glucose were observed as early as the second week of therapy; maximal decreases occurred after 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
metformin reduces 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 mg/dl and HbA1c by % . 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 of metformin on fasting plasma glucose when given as add-on therapy to 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 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.

51. α-Glucosidase inhibitors
Therapy should be initiated at a low dose (25 mg of acarbose) with the evening meal and may be increased to a maximal dose over weeks to months (50–100 mg acarbose with each meal).

52. α-Glucosidase inhibitors
If hypoglycemia occurs while a patient is taking an α-glucosidase inhibitor simultaneously with a sulfonylurea, insulin or a meglitinide, the recommended action is oral administration of pure glucose, dextrose or milk.

53. The Incretin Effect
The incretin effect, defined by a significantly greater insulin stimulatory effect evoked after an oral glucose load than that evoked from an intravenous glucose infusion when plasma glucose concentrations are matched, was first described in the 1960’s.

55. Incretin Mimetics
Incretin mimetics are compounds that mimic several of the physiologic effects of GLP-1:
enhancement of glucose-dependent insulin secretion,
suppression of postprandial glucagon secretion,
slowing of gastric emptying,
reduction of food intake and body weight in human studies.
Incretin mimetics have also been shown to promote β-cell proliferation and neogenesis in cell lines and animal models.

56. Furthermore, GLP-1 also has direct effects on the β-cells, as shown in studies done in animal models and cell lines, promoting cell proliferation and neogenesis, while preventing β -cell apoptosis .Additionally, GLP-1 can promote transformation of non insulin-producing pancreatic cells into cells capable of synthesizing and secreting insulin.

57. The characteristic β -cell dysfunction, seen in patients with type 2 diabetes ,most likely develops years before the manifestation of overt hyperglycemia,and it has been suggested that at the time of diagnosis of disease -cell mass and secretory function may have declined by as much as 50%.

58. The pathological loss of β -cell function may be the result of a number of factors including β -cell secretory defects, glucotoxicity due to hyperglycemia, lipotoxicity due to dyslipidemia, and possibly abnormalities in secretion of, or response to, incretin hormones.

59. Patients with type 2 diabetes have a significant reduction of the incretin effect, implying that these patients either have decreased concentration of the incretin hormones, or a resistance to their effects.

60. GLP-1 concentrations are reduced in patients with type 2 diabetes in response to a meal, while GIP concentrations are either normal or increased, suggesting a resistance to the actions of GIP thus making GLP-1 a more logical target for therapeutic intervention.

61. Incretins
"Incretins" amplify glucose-stimulated insulin secretion. Agents that either act as a GLP-1 agonist or enhance endogenous GLP-1 activity have become available and are under development. Exenatide, a synthetic version of a peptide originally found in the saliva of the Gila monster (exendin-4), is an analogue of GLP-1

62. Unlike native GLP-1 which has a half-life of <2 min, differences in the exenatide amino acid sequence render it resistant to the enzyme that degrades GLP-1 (dipeptidyl peptidase IV,). Thus, exenatide has prolonged GLP-1-like action by binding to GLP-1 receptors found in islets, the gastrointestinal tract, and the brain.

63. The A1C reductions with exenatide are modest compared to those with some oral agents. Exenatide is approved only for use as adjunct or combination therapy with metformin or sulfonylureas. Exenatide should not be used in patients taking insulin.

64. The major side effects are nausea, vomiting, and diarrhea; some patients taking insulin secretagogues may require a reduction in those agents to prevent hypoglycemia. Because it slows gastric emptying and may influence the absorption of other drugs, the timing of administration should be coordinated.

65. Patients with type 2 diabetes exhibit reduced levels of active GLP-1 (amino acids 7-36) along with an impaired GLP-1 response to a glucose load, and parenteral administration of GLP-1 has been shown to reduce fasting and post-prandial glycemia in patients with type 2 diabetes.

66. Vildagliptin
A 2nd generation DPP-IV inhibitor, vildagliptin is a selective and orally-effective inhibitor of DPP-4 . Vildagliptin has been found to increase plasma levels of intact (active) GLP-1, to suppress meal-stimulated glucagon, and to improve glucose tolerance during a standardized meal test.

67. sitagliptin
These agents promote insulin secretion in the absence of hypoglycemia or weight gain, and appear to have a preferential effect on postprandial blood glucose. The FDA has approved the first DPP-IV inhibitor, sitagliptin, for use with diet and exercise,metformine and TZD to improve glycemic control in adult individuals with type 2 DM.

68. sitagliptin
Sitagliptin is administered at a dose of 100 mg orally once daily. Reduced doses should be given to patients with moderate (GFR < 30–50 mL/min, 50 mg once daily) or severe (GFR < 30 mL/min, 25 mg once daily) renal insufficiency. Renal function should be assessed prior to initiation of sitagliptin therapy and periodically thereafter.

69. Clinical Efficacy of Pharmacological Therapies to Treat Type 2 Diabetes when Used as Monotherapy

70. assuming a similar degree of glycemic improvement, no clinical advantage to one class of drugs has been demonstrated, and any therapy that improves glycemic control is likely beneficial .

71. Emphasis should be placed on reaching lipid, blood pressure, and glycemic targets rather than the type of therapy needed to reach those goals .