Diabetes treatment

Controlling blood sugar (glucose) levels is the major goal of diabetes treatment, in order to prevent complications of the disease.
Type 1 diabetes is managed with insulin as well as dietary changes and exercise.
Type 2 diabetes may be managed with non-insulin medications, insulin, weight reduction, or dietary changes.
Medications for type 2 diabetes are designed to

increase insulin output by the pancreas,
decrease the amount of glucose released from the liver,
increase the sensitivity (response) of cells to insulin,
decrease the absorption of carbohydrates from the intestine, and
slow emptying of the stomach, thereby delaying nutrient digestion and absorption in the small intestine.

1. Dr. Chavan P.R. Pharm D Diabetes treatment

2. TREATMENT General approach Maintain normal glycemia Reduces the risk of microvascular disease complications Management of traditional cardiovascular risk factors (I.E., Smoking cessation, treatment of dyslipidemia , intensive blood pressure control, antiplatelet therapy) Regular monitoring for complications; Dietary and exercise modifications; Appropriate self-monitoring of blood glucose (SMBG); and Appropriate assessment of laboratory parameters.

3. NONPHARMACOLOGIC THERAPY • Medical nutrition therapy for individuals with type 1 dm, Maintain a healthy body weight. Balanced meals -moderate in carbohydrates and low in saturated fat, Type 2 dm - caloric restriction for weight loss.

4. Aerobic exercise can improve insulin resistance and glycemic control and may reduce cardiovascular risk factors, contribute to weight loss or maintenance, and improve well-being. Exercise should be started slowly in previously sedentary patients . Older patients and those with atherosclerotic disease should have a cardiovascular evaluation prior to beginning a substantial exercise program.

5. PHARMACOLOGIC THERAPY Currently 6 classes of drugs Sulfonylureas - Glibenclamide , Glipizide Biguanides - metformin Meglitinide analogs - Repaglinide , Nateglinide Thaizolidinediones - Pioglitazone Α lpha glucosidase inhibitors - Acarbose Dipeptidyl Peptidase-IV Inhibitors - Sitagliptin , Vildagliptin

6. Insulin Anabolic and anti-catabolic hormone Plays major role in Carbohydrate, Protein and Fat metabolism Cleaved from Pro-insulin  insulin

7. Characteristics Categorization on the basis of source, strength, onset, duration of action, analogs etc . Analogs- amino acids in insulin modified to impart particular physico -chemical and pharmacokinetic advantages U-500 and U-100 common insulins available in USA U-500 for larger doses and vice a versa

8. Sources Beef or pork sources Beef insulin- differs by 3 AA Pork insulin- differs by 1 AA Now a days- recombinant DNA technology insulins are used When injected sc it is in hexameric form….gets dissociated into monomers

9. Types Rapid acting (15-30 min) e.g. Aspart , lispro Intermediate acting (2-4 hrs) e.g. Lente Long acting (4-10 hrs) e.g. Glargine Short-acting insulins (30–60 minutes ) e.g.Humulin R (regular), Novolin R (regular)

10. Pharmakokinetics Depending factors-onset, peak, duration of action Absorption depends on- source of insulin, concentration, additives (Zinc, protamine ), blood flow to the area, injection site.

11. Common sites of injection Abdominal fat Posterior upper arm, Lateral thigh area Superior buttocks area

12. Degradation In liver, muscle, kidneys Liver 20-50% Kidneys 15-20% Inhaled insulin Efficacy Glycemic control

13. Adverse effects Hypoglycemia & weight gain are major adverse effects Patient education plays an important role in hypoglycemia. Symptoms of hypoglycemia-tachycardia, sweating Initial symptoms are often neuro-glycopenic i.E. Confusion, agitation, LOC and/or progression to coma Driving, certain sports Treatment- glucagon/glucose IV Takes 10-15 min to raise blood glucose levels

14. Dosing & administration Type 1- 0.5-0.6 units/kg Honeymoon phase- 0.1-0.4 units/kg Type 2 higher doses may be required depending upon IR

15. Storage Unopened insulin is recommended to be refrigerated (36-46ºF) Because of Financial constraints pts may attempt the use after expiration How to identify? Clumping, ppt , discoloration

16. standards Never freeze. (Frozen insulin should be thrown away.) Never use insulin beyond the expiration date stamped on the vial, pen, or cartridge that is supplied from the drug manufacturer. Never expose insulin to direct heat or light. Inspect insulin prior to each use. Any insulin that has clumps or solid white particles should not be used. Insulin that is supposed to be clear should not have any cloudy appearance.

17. Check storage guidelines specific to the insulin formulation. This is usually in the product package insert. Unopened, not-in-use insulin should be stored in a refrigerator at a temperature of 36-46º f. Opened, in-use insulin should be stored at room temperature below 86º f. If receiving insulin through the mail, always confirm that the insulin is going to be stored under proper requirements. When storing pre-filled insulin syringes, store them with the needle pointing up.

18. Insulin and Other Injectable Preparations Regular insulin – slow onset of action subcutaneously, requiring injection 30 minutes prior to meals to achieve optimal postprandial glucose control and to prevent delayed postmeal hypoglycemia.

19. Lispro , aspart , and glulisine insulins are analogs that are more rapidly absorbed, peak faster, and have shorter durations of action than regular insulin. more convenient dosing within 10 minutes of meals, produces better efficacy in lowering postprandial blood glucose than regular insulin in type 1 DM, and minimizes delayed postmeal hypoglycemia.

20. Neutral protamine hagedorn (NPH) is intermediate-acting. Variability in absorption, inconsistent preparation by the patient, and inherent pharmacokinetic differences may contribute to a labile glucose response , nocturnal hypoglycemia , and fasting hyperglycemia . Glargine and detemir are long-acting “ peakless ” human insulin analogs that result in less nocturnal hypoglycemia than NPH insulin when given at bedtime.

21. In type 1 DM, the average daily insulin requirement is 0.5 to 0.6 units/kg. Requirements may fall to 0.1 to 0.4 units/kg in the honeymoon phase. Higher doses (0.5 to 1 unit/kg) are warranted during acute illness or ketosis.

22. In type 2 DM, a dosage range - 0.7 to 2.5 units/kg. Hypoglycemia and weight gain are the most common adverse effects of insulin. Treatment of hypoglycemia is as follows: ✓ Glucose (10 to 15 g) given orally is the recommended treatment in conscious patients . ✓ Dextrose IV may be required in individuals who have lost consciousness . ✓ Glucagon , 1 g intramuscular, is the treatment of choice in unconscious patients when IV access cannot be established.

23. Exenatide is a synthetic analog of exendin-4, a 39-amino acid peptide isolated from the saliva of the Gila monster that enhances glucose dependent insulin secretion and reduces hepatic glucose production . It also decreases appetite and slows gastric emptying , which may reduce caloric intake and cause weight loss. It significantly decreases postprandial glucose excursions but has only a modest effect on FPG values. Exenatide should be used as adjunctive therapy in patients who have not achieved adequate glycemic control despite treatment with metformin , a sulfonylurea, and/or a thiazolidinedione .

24. The average A1C reduction is approximately 0.9% . The most common adverse effects are nausea, vomiting, and diarrhea. The initial dose is 5 mcg subcutaneously twice daily, titrated to 10 mcg twice daily in 1 month if needed and as tolerated. It should be injected 0 to 60 minutes before the morning and evening meals.

25. Pramlintide is a synthetic analog of amylin , a neurohormone cosecreted from β -cells with insulin. Pramlintide suppresses inappropriately high postprandial glucagon secretion , reduces food intake (which can cause weight loss), and slows gastric emptying . The average A1C reduction is approximately 0.6% , but optimization of concurrent insulin therapy may result in further A1C decreases.

26. Adverse effects - nausea, vomiting, and anorexia. It does not cause hypoglycemia when used alone, but it is indicated only in patients receiving insulin, so hypoglycemia can occur. If a prandial insulin dose is used, it should be reduced by 30% to 50% when pramlintide is started to minimize severe hypoglycemic reactions.

27. In type 2 DM, the starting dose is 60 mcg subcutaneously prior to major meals; the dose is titrated up to 120 mcg per dose as tolerated and as warranted based on postprandial plasma glucose levels. In type 1 DM, dosing starts at 15 mc g prior to each meal, titrated up to a maximum of 60 mcg prior to each meal if tolerated and warranted.

28. Sulphonylureas (MOA) Increase insulin secretion Bind to a receptor SUR Ca channel opening and influx of Ca ions Depolarization Exocytosis Decrease in hepatic glucose production

29. Classification First generation- Tolbutamide , Cholpropamide Second generation - Glibenclamide ( Glyburide ), Glipizide Gliclazide Glimepiride

30. P’kinetics Metabolized in liver by CYP450 2C9 enzyme Excreted through urine Dosage can be titrated every 1 to 2 weeks Dose reduction in elderly with renal /hepatic impairement Efficacy Equipotent doses of SU are equally effective A1C will fall by 1.5% to 2% with FPG reductions of 60 to 70 mg/ dL (3.3 to 3.9 mmol /L).

31. Adverse effects Hypoglycemia Weight gain Skin rash Hemolytic anemia GI disturbances cholestasis Patients At risk of hypoglycemia skip meals, exercise vigorously, loss of weight renal insufficiency or advanced liver disease

32. Hyponatremia Na levels <129 mEq /L Risk factors- Age (>60 yrs) Female gender Concomitant use of thiazide diuretics chlorpropamide , tolbutamide .

33. Short acting insulin secretogogues Acts in analogous way to SU Bind to SUR & other distinct receptors Closure of ATP dependant K channels Depolarization Insulin release Repaglinide - benzoic acid derivative Nateglinide - phenylalanine acetic acid derivative

34. I nsulin release is glucose dependent and diminishes at low blood glucose concentrations. Hypoglycemic risk appears to be less with meglitinides than with sulfonylureas . The average reduction in A1C is about 0.8% to 1%. They should be administered before each meal (up to 30 minutes prior). If a meal is skipped, the medication should also be skipped.

35. Repaglinide ( Prandin ) is initiated at 0.5 to 2 mg with a maximum dose of 4 mg per meal (up to four meals per day or 16 mg/day). Nateglinide ( Starlix ) dosing is 120 mg three times daily before each meal. The dose may be lowered to 60 mg per meal in patients who are near goal A1C when therapy is initiated.

36. P’kinetics Rapidly absorbed (0.5-1 hr) Short half life (1-1.5 hrs) Both metabolized in liver Adverse effects Hypoglycemia Less as compared to SU Weight gain

37. Biguanides Metformin E nhances insulin sensitivity of both hepatic and peripheral (muscle) tissues ↓ A1C - 1.5% to 2 % ↓ FPG by 60 to 80 mg/ dL ↓ Plasma TG & LDL- 8% to 15% ↑HDL upto 2% No hypoglycemia lonely

38. ADRS Abdominal discomfort, Stomach upset, Diarrhea, Anorexia, and a metallic taste Lactic acidosis, Congestive heart failure, or conditions predisposing to hypoxemia or inherent lactic acidosis

39. Dose Metformin immediate-release 500 mg twice daily with the largest meals and increased by 500 mg weekly until glycemic goals or 2,000 mg/day is achieved. Metformin 850 mg can be dosed once daily and then increased every 1 to 2 weeks to a maximum of 850 mg three times daily (2,550 mg/day). Metformin extended-release ( Glucophage XR) can be initiated with 500 mg with the evening meal and increased by 500 mg weekly to a maximum dose of 2,000 mg/day. Administration two to three times a day may help minimize GI side effects and improve glycemic control. The 750-mg tablets can be titrated weekly to the maximum dose of 2,250 mg/day.

40. Thiazolidinediones Agonists for the receptors- PPAR-gamma Peroxisome proliferator activated receptor gamma Located in fat & vascular tissues Less concentration in muscles Enhance transcription of several insulin responsive genes Tend to reverse IR Suppression of hepatic gluconeogenesis Activation of genes regulating FA metabolism and lipogenesis

41. P’kinetics ½ life periods Pioglitazone-3-7 hrs Rosiglitazone - 3-4 hrs

42. Outcomes 6 months therapy, A1C - 1.5% FPG levels by about 60 to 70 mg/ dL Glycemic lowering effect- 3 to 4 months of therapy Pioglitazone - decrease TG- 10-20%, NO LDL Rosiglitazone - 5-15% LDL rise

43. dilutional anemia – no t/t Pioglitazone ( Actos ) is started at 15 mg once daily. The maximum dose is 45 mg/day. Rosiglitazone ( Avandia ) is initiated with 2 to 4 mg once daily. The maximum dose is 8 mg/day. A dose of 4 mg twice daily can reduce A1C by 0.2% to 0.3% more than a dose of 8 mg taken once daily.

44. ADRS Hepatotoxicity Low Hb levels (2-4%) Edema (4-5%) Weight gain MI

45. Α lpha glucosidase inhibitors Final enzymes in the digestion of CH Slows down & decrease digestion and absorption of polysaccharides and sucrose Competitive inhibit- maltase, isomaltase , sucrase , glucoamylase in small intestine Delay in breakdown sucrose and complex CH PPBS not increased

46. EFFICACY 40-50 mg/ dL reduction in PPBS HbA1c levels reduction 0.3-1%

47. ADR GI disturbances Bloating (swelling due to fluid/gas) Diarrhoea Flatulance (accumulation of gases ) Degradation of undigested CH by microflora results in prodution of gases (CO2 & methane ) Hypoglycemia Increased AST & ALT levels

48. Dipeptidyl Peptidase-iv Inhibitors prolong the half-life of an endogenously produced glucagon-like peptide-1. reduce the inappropriately elevated glucagon post prandially and stimulate glucose dependent insulin secretion A1C - 0.7% to 1% at a dose of 100 mg/day. Mild hypoglycemia

49. Sitagliptin ( Januvia ) is usually dosed at 100 mg orally once daily. In patients with renal impairment, the daily dose should be reduced to 50 mg ( creatinine clearance 30–50 mL /min) or 25 mg ( creatinine clearance <30 mL /min). Vildagliptin was not approved in the United States at the time of this writing (June 2008). The usual dose is expected to be similar to Sitagliptin .

50. Complications Retinopathy Neuropathy Nephropathy

51. Retinopathy Examination by an ophthalmologist at least every 6 to 12 months. Early background retinopathy may reverse with improved glycemic control. More advanced disease will not regress with improved control and may actually worsen with short-term improvements in glycemia . Laser photocoagulation has markedly improved sight preservation in diabetic patients.

52. Neuropathy Type 2 DM Paresthesias , numbness, or pain Feet symptomatic and empiric low-dose tricyclic antidepressants , anticonvulsants (e.g., gabapentin , pregabalin , carbamazepine ), duloxetine , venlafaxine , topical capsaicin , and various analgesics , including tramadol and nonsteroidal antiinflammatory drugs.

53. Gastroparesis Discontinuation of medications that slow gastric motility Metoclopramide or erythromycin Orthostatic hypotension may require mineralocorticoids or adrenergic agonists.

54. Diabetic diarrhea –nocturnal -10-14 days t/t Doxycycline or metronidazole Octreotide Erectile dysfunction- sildenafil , vardenafil , tadalafil

55. Nephropathy Also called as Diabetic Kidney Disease Glomeruli get damaged Leaking of proteins in urine Proteinurea Common in T1DM but more people are there of T2DM Detection through urine tests Treatment- ACE inhibitors

56. Nephropathy Glucose and blood pressure control Angiotensin-converting enzyme inhibitors and angiotensin receptor Diuretics are frequently necessary due to volume-expanded states and are recommended second-line therapy.

57. Peripheral Vascular Disease and Foot Ulcers Claudication and nonhealing foot ulcers Smoking cessation, correction of dyslipidemia , and antiplatelet therapy Pentoxifylline ( Trental ) or cilostazol ( Pletal ) Revascularization is successful in selected patients. Local debridement and appropriate footwear and foot care are important in the early treatment of foot lesions. Topical treatments may be beneficial in more advanced lesions.

58. Coronary Heart Disease T reatment of dyslipidemia and hypertension, smoking cessation, antiplatelet therapy The National Cholesterol Education Program Adult Treatment Panel III guidelines

59. Niacin or a fibrate - if triglycerides are 201 to 499 mg/ dL The American Diabetes Association and the National Kidney Foundation- blood pressure of <130/80 mm Hg Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers b blockers, diuretics, calcium channel blockers

60. Thank you