OHA.pptx

It is all about oral hypoglycemic agents in detail.

1. OHA Dr P K Maharana

2. Introduction According to a report in 2017 by International Diabetes Federation (IDF), 425 million persons suffer from diabetes mellitus out of which more than 90 percent are adults and 352 million had impaired glucose tolerance (IGT) .  In individuals suffering from type II diabetes mellitus (T2DM), hyperglycemia is not the only characteristic; it also involves multiple complications such as kidney failure, blindness, heart attack, stroke, and amputations of the lower limb.  Ample proof suggests that normoglycemia accomplishment will mitigate the risk of complications linked with DM. Diet and exercise are first line treatments along with oral hypoglycaemic drugs to achieve the goal of improving glycaemic control and preventing both microvascular and macrovascular complications. 

3. T2 DM  T1DM is mostly found in the young where as T2DM is an adult-related condition. The risk of T2DM increases with age which is due to the deficiency of insulin secretion which develops with age, and growing insulin resistance caused by a change in body composition. Increase in body weight which leads to obesity is closely associated with diabetes in a condition termed diabesity. This is because increase in body weight leads to increased insulin resistance 

4. Classifications of OHA 1. Biguanides : Phenformin & Metformin 2. Sulphonylureas: 1 st. Generation: Acetohexamide, Chlorpropamide, Tolazamide, Tolbutamide. 2 nd . Generations : ( Glyburide , Glipizide , Glimepiride ) 3. Meglitinides : (R epaglinide ,Nateglinide) . 4. Thiazolidinediones : ( Pioglitazone,Rosiglitazone) . 5. α- Glucosidase inhibitors: ( Acarbose, Miglitol) 6. Incretin agonists 7. DPP-4 inhibitors ( Sitagliptin, Vildagliptin, Saxagliptin,)

5. Biguanides Phenformin :- Taken out of use in 1970s because of Lactic Acidosis. Metformin:- Effective & safe. It has been used in Europe for over thirty years, whereas in the United States it has been available since 1995. Metformin should be prescribed to all people with type 2 diabetes, unless contraindicated . Current recommendations of the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD ) include metformin, diet and exercise as first-line therapy for the treatment of patients with type 2 diabetes , irrespective of the presence of overweight status . In contrast to sulfonylureas, metformin does not directly stimulate insulin secretion ; I ts major effects are To increase insulin action and I nsulin-mediated glucose utilization in peripheral tissues ( such as muscle and liver ), particularly after meals, and to D ecrease hepatic glucose output .

6. Dose Dose: To start with 500mg in evening with dinner, The usual effective dose is 1,500 to 2,000 mg/day per day; the maximum dose of 2,550 mg/day (850 mg TID). A new extended release formulation of metformin was recently introduced to the market ( Glucophage XR), allowing a more convenient once-daily dosing regimen. Combination tablets of metformin and sulfonylureas, thiazolidinediones, or dipeptidyl peptidase (DPP)-4 inhibitors are also available to increase patients’ compliance.

7. Side effects of Metformin Gastrointestinal are most common side effects. 10% of the patients reports GI disturbances with the onset of treatment. (A metallic taste in the mouth, Mild anorexia, Nausea, Abdominal discomfort and, Soft bowel movements or diarrhea)., which disappears stating slowly with low dose. Lactic Acidosis: Lactic acidosis is predominantly due to a lack of lactate's clearance than to an increased production .  When used according to current prescribing recommendations, however, the risk of metformin-induced lactic acidosis is close to zero  .

8. Contraindications Metformin should not be used in patients with elevated serum creatinine levels, (1.4 mg per dL or more in women and 1.5 mg per dL or more in men. In patients undergoing contrast studies, metformin therapy should be withheld for approximately 48 hours following the procedure or until it has been determined that renal function has returned to baseline. Other situations in which metformin therapy should be avoided include cardiogenic or septic shock, congestive heart failure, severe liver disease , pulmonary insufficiency with hypoxemia or severe tissue hypoperfusion.

9. Sulphonylureas Sulfonylureas were the mainstay of antidiabetic therapy since the early 1950s . Following the release of the University Group Diabetes Program (UGDP) study, which implicated tolbutamide in increased mortality due to cardiovascular events, the use of the first generation sulfonylureas (acetohexamide, chlorpropamide, tolbutamide and tolazamide) quickly fell out of favour. 

10. 1 St Generation Sulfonylureas They are - Tolbutamide , C hlorpropamide,   Tolazamide , & Acetohexamide.   Because of Hypoglycaemia the 1 st generation of drugs fall out of favour.

11. 2nd generation Sulphonylureas Drugs are : (Gliclazide , Glibenclamide, Glimepiride, gliquidone) . The second generation have a potency that allows them to be given in much lower doses than the first generation.   Sulfonylureas can be used as monotherapy, or in combination with other oral hypoglycemic drugs or insulin .  All sulfonylureas have been associated with weight gain , unless the diabetic diet and exercise program are followed, and thus are not suggested as first choice for obese patients.  Glibenclamide is a long acting drug & gliquidone has a shorter duration of action.

12. Mechanism of Action Stimulating insulin release from the insulin secreting ß-cells of pancreas and may slightly improve insulin resistance in peripheral target tissues (muscle, fat).

13. Mechanism of Action Sulfonylureas are effective only  in patients  with functioning pancreatic β cells . Sulfonylureas act at the pancreatic β-cell membrane by closing ATP-sensitive potassium channels, which leads to an enhanced insulin secretion independent of glucose. The effects of sulfonylureas are initiated by their binding to and blocking an ATP-sensitive K +  channel .   Glimepiride  has been shown to have an additional effect: it increases the sensitivity of peripheral tissues to insulin. Enhancing peripheral insulin  receptor sensitivity  and reducing  glycogenolysis .

14. Pharmacokinetics Sulfonylureas are well absorbed after  oral administration .  Glipizide  absorption is delayed by food . All sulfonylureas are highly bound to  plasma protein  (90% to 99 %).   Plasma protein binding  is least for  chlorpropamide  and greatest for  glyburide . Sulfonylureas are metabolized in the liver and excreted in the urine.

15. Draw Backs ( Sulfonylureas) Hypoglycaemia ( frequent hypoglycaemia), leads to cardiovascular events like arrhythmias, cardiovascular mortality. Weight gain Patients using sulfonylureas and  metformin  in combination are reportedly at greater risk of  cardiovascular mortality  than patients using metformin alone.

16. Dose of Sulfonyl ureas Drugs with longer half-lives ( Glibenclamide and glimepiride) can be given once daily.  They cause greater suppression of overnight hepatic glucose output , thereby lowering fasting blood glucose concentrations more; these benefits, however, may be counterbalanced by an increased risk of hypoglycemia . The usual dose of glyburide is 2.5 to 10 mg twice daily.

17. Dose of Glimepiride Dose: 1-2 mg once a day in an adult. Not more than 8mg in a single day. Swallow the tablets whole, with a drink of water. Do not chew them . With food. Early warning signs of low blood sugar include : feeling hungry trembling or shaking sweating feeling confused having problems concentrating

18. Contraindications Sulfonylureas Hypersensitivity to Sulfa group of drugs. Ketosis Pregnancy Caution in reduced hepatic & renal function.

19.  Meglitinides The meglitinides ( repaglinide and nateglinide), are short-acting glucose-lowering drugs. They were designed to achieve more physiologic insulin release and less risk for hypoglycemia.  Mechanism action : S ame as that of Sulphonylureas,  release of insulin from the pancreatic beta cells, this action is mediated through a different binding site on the “sulfonylurea receptor” of the beta cell, and the drug has somewhat different characteristics when compared with the sulfonylureas.  A shorter half life and quicker on set of action ( 15-30 minutes, patients should be instructed to administer a dose immediately before a meal. The meglitinides can be used as monotherapy, or in combination with other oral hypoglycemic drugs like metformin, resulting in superior glycaemic control than with either agent used as monotherapy, a greater decrease in postprandial glucose and a decreased risk of hypoglycemia. Repaglinide had similar efficacy in reducing HbA1C values as metformin, whereas nateglinide was similar or slightly less effective.  DOSE: The recommended starting dose of repaglinide is 0.5 mg before each meal for patients who have not previously taken oral hypoglycemic drugs. Repaglinide can be titrated to a dosage of 4 mg before each meal (maximum dosage of 16 mg per day). Nateglinide can be titrated to a dosage of 120 mg taken immediately before each meal . Hypoglycemia is the most common adverse effect . Nateglinide is hepatically metabolized, with renal excretion of active metabolites . As repaglinide is principally metabolized by the liver, with less than 10 percent renally excreted , it is the drug of choice in patient with impaired renal function .

20. Meglitinides There are no long-term studies of meglitinides assessing cardiovascular outcomes or mortality in patiens treated with his class of drugs . Whether meglitinides are associated with poorer outcomes after a myocardial infarction is not known . However, since its mode of action is similar to sulfonylureas, the same concern exists.

21.  Thiazolidinediones During the last decade a new class of drugs have been available for treatment of type 2 diabetes: the thiazolidinediones (troglitazone, rosiglitazone and pioglitazone). Actually only two thiazolidinediones (rosiglitazone and pioglitazone) are currently marketed.  Mechanism of Action: Thiazolinediones improve glycaemia reducing insulin resistance and preserving pancreatic beta-cell function with different mechanism of action ;( as example, the predominant effect of metformin is to inhibit hepatic glucose production, whereas thiazolidinediones act mainly by improving peripheral uptake and utilization of glucose in muscle and fat, finally decreasing liver glucose production  )

22.  Thiazolidinediones In human adipocytes , rosiglitazone treatment increases expression of genes involved in promoting lipid storage and decreases expression of genes associated with inflammation, such IL-6 . These drugs activate one or more peroxisome proliferator -activated receptors (PPARs), which regulate gene expression in response to ligand binding .   PPAR- α is expressed mostly in liver, heart, skeletal muscle, and vascular walls. It is interesting to note that various thiazolidinediones have differential effects on PPAR- γ and PPAR- α. Troglitazone and rosiglitazone are purely PPAR- γ agonists, while pioglitazone also exerts some PPAR- α effects . PPAR-γ is found predominantly in adipose tissue, pancreatic beta-cells, vascular endothelium, and macrophages; its concentration is also increased in skeletal muscle of obese and diabetic patients [ 26 ]. PPAR-α is expressed mostly in liver, heart, skeletal muscle, and vascular walls. It is interesting to note that various thiazolidinediones have differential effects on PPAR-γ and PPAR-α. Troglitazone and rosiglitazone are purely PPAR-γ agonists, while pioglitazone also exerts some PPAR-α effects. This may account for different effects within this class of drugs. In adipose tissue the insulin-sensitizing effect may be related to the production of adipokines via PPAR-gamma activation   Pioglitazone and rosiglitazone similarly improve blood glucose level; their efficacy is comparable to metformin as monotherapy.  However, thiazolidinediones are not generally indicated over metformin for initial therapy of type 2 diabetes as they are among the most expensive oral agents .

23.  Thiazolidinediones Thiazolidinediones may have antiinflammatory , antithrombotic, and antiatherogenic properties . Although they seem to improve a number of cardiovascular risk factors and their surrogate cardiovascular endpoints ( dyslipidemia , endothelial function, vascular smooth muscle proliferation, markers of inflammation [ 30 ], carotid intima media thickness [ 31 ], vascular reactivity and progression of atherosclerosis on coronary intravascular ultrasound [ 32 , 33 ]), both drugs enhance incidence of heart failure.  However, they might have different effects on ischemic outcomes [ 34 , 35 ]. Some studies and meta-analyses have suggested that rosiglitazone increase the risk of myocardial infarction (MI) [ 36 , 37 ], not confirmed by other studies [ 38 , 39 ], whereas pioglitazone may not have the same cardiovascular risk profile than rosiglitazone: 

24. α- Glucosidase Inhibitors α- Glucosidase inhibitors include acarbose and miglitol. Mechanism of Action: They act on α-glucosidase , an enzyme found in brush border cells of small intestine, cleaving more complex carbohydrates into simple sugars. α-Glucosidase inhibitors  inhibits the breakdown and absorption of carbohydrates (dextrins, maltose, sucrose and starch; no effect on glucose ); impact is on postprandial hyperglycemia and their effect on FPG levels is modest. They have been associated with a reduction in HbA1c & Post Prandial Glucose level.

25. α- Glucosidase Inhibitors Complications: Main side effects of α- glucosidase inhibitors are flatulence, abdominal discomfort, bloating and diarrhea, which reduce compliance in treated patients. Similar to metformin, patients should be instructed to take this medication with food, starting with the lowest effective dose and titrated slowly over intervals of two to four week.  Although hypoglycemia is not typically associated with monotherapy with α- glucosidase inhibitors, it can occur in combination with other drugs. It is important, to inform patients that the traditional treatment for hypoglycemia may be blocked during treatment with α- glucosidase inhibitors and only glucose should be consumed in this condition.

26. Contraindications ( α- Glucosidase Inhibitors) Therapy with acarbose has been linked to elevations in serum transaminase levels and the use of this agent is contraindicated in patients with liver cirrhosis . It has been shown to increase proportionally to the degree of renal dysfunction and their use in patients with a serum creatinine level more than 2.0 mg per dL ( 180 μmol per L ) is not recommended. Other contraindications include patients with inflammatory bowel disease or a history of bowel obstruction.

27. Incretins Incretin hormones are : GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory peptide ). These incretins are released within minutes of food intak e , has a shorter half life of two minutes , as degraded by the enzyme DPP-4 quickly after its release. Its level decreases in type2 diabetes . GLP-1 i s a hormone secreted by enteroendocrine L cells of the small intestine . i . It stimulates secretion of insulin by the Beta cells, glucose dependant so dose not produce hypoglycaemia seen with Sulfonylurea. Ii. decreases Glucagon concentration & Iii. delays gastric emptying. GIP is a hormone secreted in the stomach and proximal small intestin e by neuroendocrine K-cells . Its half-life is approximately 7 minutes in healthy individuals and 5 minutes in individuals with type 2 diabetes

28. Advantages 1. No Hypoglycaemia when used as mono therapy. 2. GLP-1 exhibits a short half-life of one to two minutes due to N-terminal degradation by the enzyme DPP4 ( Di peptidyl peptidase IV). 3.GLP-1 might have beneficial effects on myocardial function : improves myocardial contractility, improves glucose uptake in normal and post-ischemic rat hearts, induces an endothelial-dependent reduction in vascular tone of rat lungs.

29. Side effects of Incretin mimetics Hypoglycemia: Hypoglycaemic events are mainly observed when combinations are used: in 20–30% of patients treated in combination with a sulfonylurea and in 13% of patients treated in combination with a thiazolidinedione, hypoglycaemia is not observed with metformin . There have been reports of acute pancreatitis (necrotizing or hemorrhagic) in patients taking exenatide . ( The overall reported rate for pancreatitis in exenatide users is 1 in 3,000 and for the more severe necrotizing or hemorrhagic forms, less than 1 in 10,000, which is similar to the background rate in patients with diabetes mellitus ). 

30. Incretin Mimetics and Incretin Enhancers Drugs Exenatide has a relatively short mean terminal half-life of 2.4 hours. Elimination : The predominant route of elimination is via glomerular filtration with subsequent proteolytic degradation; consequently, Exenatide is not recommended for use in patients with severe renal impairment (GFR<30 mL /minute) or end-stage renal disease. Clinical guidelines suggests that it is indicated as an adjunctive therapy to improve glycaemic control in patients with type 2 diabetes who are already receiving metformin, a sulfonylurea, or both, but continue to have suboptimal glycaemic control. Dose: Exenatide should be initiated at 5 mcg per dose, administered twice daily at any time within the 60-minute period before the morning and evening meals. Exenatide lowers glycosylated hemoglobin (HbA1C) levels by 0.4% to 0.9%, with weight reductions of 0.9 to 3.1 kg. Reductions of systolic blood pressure ( 3.4–3.7 mm Hg) and diastolic blood pressure (0.8–2.3mm Hg) have also been reported.

31. Mechanism of Action of GLP-1 Agonists. Increasing insulin production Decreasing glucagon release Slowing the rate at which food leaves the stomach Feeling less hungry (having a sense of fullness) so that you feel satisfied with less food

32. GLP-1 Agonists Dulaglutide ( Trulicity ) Exenatide (Byetta) Extended-release exenatide (Bydureon) Liraglutide (Victoza) Lixisenatide ( Adlyxin ) Semaglutide ( Ozempic , Rybelsus ) Tirzepatide ( Mounjaro ) All of these drugs are given as injections except Semaglutide ( Rybelsus ), which is an oral formulation.

33. Mechanism of Action DPP-4 is a ubiquitous enzyme that acts on incretin hormones, and degrades these hormones immediately. DPP-4 inhibitors : By inhibiting the enzyme DPP-4 increase the levels of incretin hormones,GLP-1 and GIP, which in turn increase beta-cell insulin secretion in the pancreas, thereby reducing postprandial and fasting hyperglycemia. Incretin hormones are : GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory peptide ). These incretins are released within minutes of food intak e. GLP-1 i s a hormone secreted by enteroendocrine L cells of the small intestine . i . It stimulates secretion of insulin by the Beta cells, decreases Glucagon concentration & delays gastric emptying. ii. It has a half-life of fewer than 2 minutes. GIP is a hormone secreted in the stomach and proximal small intestin e by neuroendocrine K-cells . i .  Its half-life is approximately 7 minutes in healthy individuals and 5 minutes in individuals with type 2 diabetes

34. DPP-4 inhibitors  Sitagliptin , Vildaglipti n and Saxagliptin are DPP-IV inhibitors. Are approved as initial pharmacologic therapy for the treatment of type 2 diabetes; As a second agent in those who do not respond to a single agent, such as a sulfonylurea, metformin or a thiazolidinedione; As a third agent when dual therapy with metformin and a sulfonylurea does not provide adequate glycemic control. Dose: The usual dose of Sitagliptin is 100 mg once daily , with reduction to 50 mg for moderate to severe renal insufficiency (GFR <30 to 50 mL /min) and 25 mg for severe renal insufficiency (<30 mL /min). Dose of Saxagliptin is 2.5 or 5 mg once daily , with the 2.5 mg dose recommended for patients with moderate to severe chronic kidney disease (GFR ≤ 50 mL /min) and for patients taking strong cytochrome P450 3A4/5 inhibitors (e.g., ketoconazole ).

35. DPP4 Mechanism of Action : DPP-4 inhibitors mimic the therapeutic effects of incretin mimetics  Stimulation of insulin secretion,  Inhibition of glucagon secretion,  P reservation of β-cell mass and inhibition of apoptosis. These drugs display quite similar efficacy in lowering HbA1C (≤1% reduction) compared with other antihyperglycemic agents , but they are weight neutral and have a low potential for hypoglycaemia when used as monotherapy . 

36. DPP4 inhibitors side effects One safety concern involves the potential of DPP-4 inhibitors to interfere with immune functions : indicates an increased risk for infection (nasopharyngitis and urinary tract infection) and headache. Other adverse effects occurring with more frequency in sitagliptin —treated include, back pain, osteoarthritis, and extremities pain . DPP-4 inhibitors have minimal to no interactions with other drugs because of their pharmacokinetic properties, the exception being saxagliptin. Saxagliptin is metabolized to its active form by CYP3A4/5; hence the levels of the drug and its active metabolite might be modified when administered along with drugs affecting CYP3A4/5 isoforms such as ketoconazole , diltiazem (inhibitors of CYP3A4/5), or rifampicin (inducer of CYP3A4/5). Dose adjustments of saxagliptin may be necessary for such instance

37. Adverse effects Gliptins are associated with a low incidence of adverse events, including hypoglycemia, and have weight-neutral effects. However, the risk of hypoglycemia increases when used in conjunction with sulfonylureas. The most common side effects noticed with the DPP-4 inhibitors sitagliptin and saxagliptin are upper respiratory tract infection, nasopharyngitis, headache, urinary tract infection, arthralgia. Reports of acute pancreatitis , including fatal and non-fatal hemorrhagic or necrotizing variants, have correlations with the use of sitagliptin, vildagliptin, and saxagliptin in post marketing data. DPP-4 inhibitors ( alogliptin , sitagliptin, saxagliptin, linagliptin ) did not show an increased risk of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke when compared to placebo in patients with type 2 diabetes,  although saxagliptin had an association with an increased rate of hospitalization for heart failure.

38. Contraindications DPP4 inhibitors Contraindications to gliptins include : 1. Type 1 diabetes and diabetic ketoacidosis.  2. Sitagliptin is contraindicated in individuals who are sensitive to the drug or its components. 3.Caution is necessary when using gliptins in patients with a history of pancreatitis ; it would be reasonable to discontinue these drugs if pancreatitis is suspected.

39. Combination Therapy When mono therapy fails . A two drug combination : sulfonylurea plus metformin , a sulfonylurea plus an alpha-glucosidase inhibitor , a sulfonylurea plus a thiazolidinedione , metformin plus repaglinide , biguanide plus alpha-glucosidase inhibitor , and metformin plus a thiazolidinedione . A three drugs combinations : (sulfonylurea, metformin, thiazolidinedione or sulfonylurea, metformin, alpha-glucosidase inhibitor).

40. SGLT-2 Inhibitors There are four SGLT-2 inhibitors approved for use in people with type 2 diabetes in the United States: Canagliflozin ( Invokana ) Dapagliflozin ( Farxiga ) Empagliflozin ( Jardiance ) Ertugliflozin ( Steglatro ) This group of medications works by acting on the kidneys, so there is an increased elimination of blood sugar into the urine. At the same time, the drugs help to reduce blood pressure and promote weight loss. SGLT-2 inhibitors are sometimes recommended for people with type 2 diabetes who have high A1C levels. SLGT-2 inhibitors have been shown in studies to lessen the progression of kidney disease by 45% and to reduce the risk of hospitalization due to heart failure (by 31%).

41. 1. Metformin should be started at the time type 2 diabetes is diagnosed unless there are contraindications. 2. Metformin is effective and safe, is inexpensive, and may reduce risk of cardiovascular events and death. 3. The principal side effects of metformin are gastrointestinal intolerance due to bloating, abdominal discomfort, and diarrhea; these can be mitigated by gradual dose titration. 4.A recent randomized trial confirmed previous observations that metformin use is associated with vitamin B12 deficiency and worsening of symptoms of neuropathy 

42. The drug is cleared by renal filtration, and very high circulating levels (e.g., as a result of overdose or acute renal failure) have been associated with lactic acidosis. However, the occurrence of this complication is now known to be very rare, and metformin may be safely used in patients with reduced estimated glomerular filtration rates ( eGFR );

43. Insulin in Type-2 DM Insulin has the advantage of being effective where other agents are not and should be considered as part of any combination regimen when hyperglycemia is severe, especially if catabolic features (weight loss, hypertriglyceridemia, ketosis) are present. It is common practice to initiate insulin therapy for patients who present with blood glucose levels ≥300 mg/ dL (16.7 mmol /L) or A1C >10% (86 mmol /mol).

44. Combination Therapy If the A1C target is not achieved after approximately 3 months, metformin can be combined with any one of the preferred six treatment options. 1. sulfonylurea, 2. thiazolidinedione, 3. DPP-4 inhibitor, 4. SGLT2 inhibitor, 5. GLP-1 RA, or 6. Basal insulin; The choice of which agent to add is based on drug-specific effects and patient factors

45. For patients with established ASCVD or indicators of high ASCVD risk (such as patients ≥55 years of age with coronary, carotid, or lower-extremity artery stenosis >50% or left ventricular hypertrophy), established kidney disease, or heart failure, an SGLT-2 inhibitor or GLP-1 RA with demonstrated CVD benefit is recommended as part of the glucose-lowering regimen independent of A1C and in consideration of patient-specific factors). For patients without established ASCVD , indicators of high ASCVD risk, HF, or CKD, the choice of a second agent to add to metformin is not yet guided by empiric evidence. Rather, drug choice is based on avoidance of side effects, particularly hypoglycemia and weight gain, cost, and patient preferences . 

46. Similar considerations are applied in patients who require a third agent to achieve glycemic goals; there is very little trial-based evidence to guide this choice. In all cases, treatment regimens need to be continuously reviewed for efficacy, side effects, and patient burden. Common reasons for this include ineffectiveness, intolerable side effects, expense, or a change in glycemic goals.

47. Although most patients prefer oral medications to drugs that need to be injected, the eventual need for the greater potency of injectable medications is common, particularly in people with a longer duration of diabetes. The addition of basal insulin, either human NPH or one of the long-acting insulin analogs, to oral agent regimens is a well-established approach that is effective for many patients.

48. Trial results support injectable GLP-1 RAs as the preferred option for patients requiring the potency of an injectable therapy for glucose control. However, high costs and tolerability issues are important barriers to the use of GLP-1 RAs.

49. Post Prandial Many individuals with type 2 diabetes require doses of insulin before meals, in addition to basal insulin, to reach glycemic targets. A dose of 4 units or 10% of the amount of basal insulin at the largest meal or the meal with the greatest postprandial excursion is a safe estimate for initiating therapy.  The prandial insulin regimen can then be intensified based on patient needs. ( People with type 2 diabetes are generally more insulin resistant than those with type 1 diabetes, require higher daily doses (∼1 unit/kg), and have lower rates of hypoglycemia). Titration can be based on home glucose monitoring or A1C.  When initiating combination injectable therapy, metformin therapy should be maintained while sulfonylureas and DPP-4 inhibitors are typically discontinued.

50. use of a thiazolidinedione or an SGLT2 inhibitor In patients with suboptimal blood glucose control, especially those requiring large insulin doses, adjunctive use of a thiazolidinedione or an SGLT2 inhibitor may help to improve control and reduce the amount of insulin needed.

51. DPP-4i  (Dipeptidyl peptidase 4 inhibitor); GLP-1 RA,  ( glucagon-like peptide 1 receptor agonist); SGLT2i  (sodium–glucose cotransporter 2 inhibitor); SLP TZD  (Thiazolidinedione.) SU  ( Sulfonylurea)

52. Conclusion The first line of treatment are lifestyle modifications and metformin. If metformin alone cannot achieve a good glycemic control or it is not tolerated or is contraindicated, a second drug selected among the sulfonylureas, thiazolinediones, incretin mimetics and incretin enhancer drugs must be used. What is particularly relevant, anyway, is to avoid therapeutic inertia, thus therapy should be modified as soon as possible to keep glycemic control HbA1c at about 7%.  In this second step, various factors such risk of hypoglycemia, comorbidities, age of patients, presence of diabetic complications and cost of treatment must be properly considered to individualize treatment.

53. Metformin Activation of Adenosine monophosphate kinase . Inhibition of Gluconeogenesis . Improves Beta cell functions. Increase Insulin sensitivity

54. Thiazolidinedions Activation of PPPAR- Y Increase glucose transporter Expression ( GLUT 1 & GLUT 4) Decrease Gluconeogenesis Increase differentiation of Preadipocytes in to adipocytes .

55. DPP-4 inhibitors that have FDA approval include sitagliptin, saxagliptin, linagliptin , and alogliptin . Vildagliptin has approval from the European Medicines Agency (EMA), but not by the FDA.