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DIABETES MELLITUS.pdf

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia and various symptoms, with two main types: type 1, which is insulin-dependent and typically diagnosed in younger individuals, and type 2, often associated with obesity and insulin resistance. Treatment options include various insulin preparations, oral hypoglycemic agents, and newer medications like GLP-1 receptor agonists and SGLT2 inhibitors. The document details insulin types, mechanisms of action for various drugs, their pharmacokinetics, administration methods, and potential side effects.

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Diabetes or Diabetes Mellitus ❑ Chronic Metabolic Disorder ❑ Vascular Abnormalities Characterized by • Hyperglycemia • Glycosuria • Polydipsia • Polyphagia • Ketoacidosis
Diabetes mellitus Type 1 Diabetes - cells that produce insulin are destroyed - results in insulin dependence - commonly detected before 30 Type 2 Diabetes - blood glucose levels rise due to 1) Lack of insulin production 2) Insufficient insulin action (resistant cells) - commonly detected after 40 - effects > 90% Gestational Diabetes 3-5% of pregnant women develop gestational diabetes
5 Characteristic Type 1 ( 10% ) Type 2 Onset (Age) Usually < 30 Usually > 40 Type of onset Abrupt Gradual Nutritional status Usually thin Usually obese Diet Mandatory with insulin Mandatory with or without drug Hypoglycemic drugs Should not be used Clinically indicated Clinical symptoms Polydipsia, polyphagia, polyurea, Wt loss Often asymptomatic Ketosis Frequent Usually absent Endogenous insulin Absent Present, but relatively ineffective Related lipid abnormalities Hypercholesterolemia frequent, all lipid fractions elevated in ketosis Cholesterol & triglycerides often elevated; carbohydrate- induced hypertriglyceridemia common Insulin therapy Required Required in only 20 - 30% of patients
Liver Muscle Adipose ↓ glucose production ↑ Glucose transport ↑ glucose transport ↑ glycolysis ↑ glycolysis ↑ lipogenesis& lipoprotein lipase activity ↑ TG synthesis ↑ glycogen deposition ↓ intracellular lipolysis ↑ Protein synthesis ↑ protein synthesis
• In the case of type 1 diabetes, insulin levels are grossly deficient. Thus type 1 diabetes is invariably treated with insulin • Type 2 diabetes is frequently associated with obesity. Serum insulin levels are normal or elevated, so this is a disease of insulin resistance. A number of treatment options may be employed.
• 11th January 1922 - pancreatic islet cell extract first administered to 14 year old insulin deficient patient • Bovine and porcine pancreatic extracts • 1980 human insulin available -amino acid modification of porcine insulin - synthesised by introducing DNA for human insulin into bacteria or yeast
❑Liver and Kidney are two organ remove insulin from circulation by hydrolysis of disulfide connection between A & B chains. ❑ Liver remove 60% of insulin. ❑ Kidney remove 35-40% of insulin.
INSULIN RECEPTOR Binding sites Cell membrane Tyrosin kinase Intracellular space
• Human insulin: Humulin® (from E.coli), Novalin® (from yeast) • NPH - neutral protamine Hagedorn (NPH), protamine mixed. • Lente® insulin / Ultralente® insullin- zinc added Regular insulins
• Fatty Acid Acylated insulins • Insulin Lispro (Humalog®) (1996) • Insulin Aspart (NovoLog®) (2000) • Insulin Glargine (Lantus®) (2002) • Insulin Detemir (Levemir®) (Jun.,2005) • Insulin Glulisine (Apidra®) (Jan., 2006) Insulin Analogs
16 ❑ Ultra-short-acting (Rapid acting)-with very fast onset and short duration ❑ Short-acting (Regular)-with rapid onset of action ❑ Intermediate-acting ❑ Long-acting- with slow onset of action TYPES OF INSULIN PREPARATIONS
17 Short-acting (regular) insulins e.g. Humulin R, Novolin R Uses Designed to control postprandial hyperglycemia & to treat emergency diabetic ketoacidosis Physical characteristics Clear solution at neutral pH Chemical structure Hexameric analogue Route & time of administration S.C. 30 – 45 min before meal I.V. in emergency (e.g. diabetic ketoacidosis) Onset of action 30 – 45 min ( S.C ) Peak serum levels 2 – 4 hr Duration of action 6 – 8 hr Usual administration 2 – 3 times/day or more Ultra-Short acting insulins e.g. Lispro, aspart, glulisine Similar to regular insulin but designed to overcome the limitations of regular insulin Clear solution at neutral pH Monomeric analogue S.C. 5 min (no more than 15 min) before meal I.V. in emergency (e.g. diabetic ketoacidosis) 0 – 15 min ( S.C ) 30 – 90 min 3 – 4 hr 2 – 3 times / day or more
• Insulin lispro, the first monomeric insulin analog to be marketed, is produced by recombinant technology wherein two amino acids near the carboxyl terminal of the B chain have been reversed in position: Proline at position B28 has been moved to B29, and lysine at position B29 has been moved to B28 • When injected subcutaneously, the drug quickly dissociates into monomers and is rapidly absorbed with onset of action within 5–15 minutes and peak activity as early as 1 hour. The time to peak action is relatively constant, regardless of the dose
Regular insulins e.g. Humulin R, Novolin R • Short-acting insulin— Regular insulin is a short-acting soluble crystalline zinc insulin that is now made by recombinant DNA techniques to produce a molecule identical to that of human insulin. Its effect appears within 30 minutes, peaks between 2 and 3 hours after subcutaneous injection, and generally lasts 5–8 hours. • The clinical consequence is that when regular insulin is administered at mealtime, the blood glucose rises faster than the insulin with resultant early postprandial hyperglycemia and an increased risk of late postprandial hypoglycemia. Therefore, regular insulin should be injected 30–45 or more minutes before the meal to minimize the mismatching.
20 Intermediate - acting insulins e.g. Isophane (NPH) - neutral protamine Hagedorn, protamine mixed ▪ Subcutaneous injection.(Only) ▪ Onset of action 2 - 5 hr ▪ Peak serum level 5 - 7 hr ▪ Duration of action 4 - 12 hr it is usually mixed with regular, lispro, aspart, or glulisine insulin and given two to four times daily for insulin replacement.
Insulin mixtures • 75/25 70/30 50/50 (NPH / Regular) • Intermediate insulins composed of isophane complexes of protamine with insulin lispro and insulin aspart have been developed: • “NPL” (neutral protamine lispro) - 50%/50% and 75%/25% • “NPA” (neutral protamine aspart) - 70%/30%
22 Lente insulin ▪ Mixture of 30% semilente insulin 70% ultralente insulin ▪ Injected S.C. (only) ▪ Onset of action 1 - 3 hr ▪ Peak serum level 4 - 8 hr ▪ Duration of action 13 - 20 hr
23 Long – acting insulins e.g. Insulin glargine – long-acting insulin analog • Onset of action 1-2 hr • Absorbed less rapidly than NPH & Lente insulins. • Duration of action - 24 hr (Glargine is usually given once daily) Designed to overcome the deficiencies of intermediate acting insulins Advantages over intermediate-acting insulins: ▪ More safe than NPH & Lente insulins due to reduced risk of hypoglycemia(esp.nocturnal hypoglycemia). ▪ Clear solution that does not require resuspension before administration.
• Insulin detemir— This insulin is the most recently developed long-acting insulin analog. • Insulin detemir has a dose-dependent onset of action of 1–2 hours and duration of action of more than 12 hours. • It is given twice daily to obtain a smooth background insulin level.
Insulin degludec Insulin degludec (INN/USAN) is an ultralong-acting basal insulin analogue that was developed by Novo Nordisk under the brand name Tresiba. It is administered via subcutaneous injection once daily to help control the blood sugar level of those with diabetes. It has a duration of action that lasts up to 42 hours (compared to 18 to 26 hours provided by other marketed long-acting insulins such as insulin glargine and insulin detemir), making it a once-daily basal insulin, that is one that provides a base insulin level, as opposed to the fast- and short-acting bolus insulins.
Dosage Forms & Strengths injectable solution (prefilled pen, FlexTouch) • 100 units/mL • 200 units/mL Type 1 Diabetes Mellitus Long-acting basal insulin indicated to improve glycemic control in patients with diabetes mellitus Initial dose For insulin-naïve patients Start ~1/3 to 1/2 of the total daily insulin dose; use remaining of total daily insulin dose on short-acting insulin and divided between each daily meal Usual initial dose range: 0.2-0.4 units/kg
Type 2 Diabetes Mellitus Long-acting basal insulin indicated to improve glycemic control in adults with type 2 diabetes mellitus Initial dose • For insulin-naïve patients • Start 10 units SC qDay
Adverse Effects >10% • Nasopharyngitis (12.9- 23.9%) • Severe hypoglycemic episode (0.3-12.3%) • Upper respiratory tract infection (8.4-11.9%) • Headache (8.8-11.8%) 1-10% • Diarrhea (6.3%) • Sinusitis (5.1%) • Gastroenteritis (5.1%) • Injection site reactions (3.8%) • Peripheral edema (0.9-3%) <1% • Lipodystrophy
Methods of Adminisration A. Standard Delivery - The standard mode of insulin therapy is subcutaneous injection using conventional disposable needles and syringes. B. Portable Pen Injectors -These contain cartridges of insulin and replaceable needles. C. Continuous Subcutaneous Insulin Infusion Devices (CSII, Insulin Pumps) -Continuous subcutaneous insulin infusion devices are external open-loop pumps for insulin delivery
• Hypoglycemia • Immunopathology of Insulin Therapy • Lipodystrophy at Injection Sites • Increased Cancer Risk
❑ Sulfonylurea drugs ❑ Meglitinide analogues ❑ Biguanides ❑ α -glucosidase inhibitors. ❑ Thiazolidinediones. ❑ Dipeptidyl peptidase-4 inhibitors e.g. Sitagliptin, vildagliptin ❑ GLP1 receptor agonists ❑ SGLT2 inhibitors
A closer look at CV effects of 21st century T2D agents 33 Adapted from 1. Kirby. Br J Diabetes Vasc Dis 2012;12:315–20. 2. Lantus® SPC. FDA 2015. 1950 1960 1970 1980 1990 2000 2010 2012 2013 Lente class of insulins produced SUs first used Metformin introduced in the UK Recombinant human insulin produced 2nd generation SUs available Three new classes introduced: -glucosidase inhibitors, meglitinides and TZDs Glimepiride: 3rd generation SU DPP4 inhibitors GLP1 receptor agonists SGLT2 inhibitors Insulin degludec  Older T2D agents Newer T2D agents → Insulin glargine available2
Insulin secretagogues ❑ Sulfonylurea drugs ❑ Meglitinide analogues ❑ GLP1 receptor agonists ❑ Dipeptidyl peptidase-4 inhibitors Insulin sensitizers ❑ Biguanides ❑ Thiazolidinediones or glitazones Drugs inhibiting hydrolysis of complex saccharides : ❑ α-glycosidase inhibitors Drugs inhibiting reabsorption of glucose in the kidney ❑ SGLT2 inhibitors
SULFONYLUREAS : First generation Second generation Tolbutamide Glipizide Tolazamide Glyburide Acetohexamide (Glibenclamide) Chlorpropamide Glimepiride (Amaryl)
36 MECHANISM OF ACTION OF SULPHONYLUREAS 1) Release of insulin from β-cells 2) Reduction of serum glucagon concentration 3) Potentiation of insulin action on target tissues
Pharmacokinetics of sulfonylureas: • Orally, well absorbed. • Reach peak concentration after 2-4 hr. • All are highly bound to plasma proteins. • Duration of action is variable. • Second generation has longer duration than first generation. • Metabolized in liver • excreted in urine • Cross placenta, stimulate fetal B cells to release insulin → hypoglycemia at birth.
39 Glipizide Short- acting Glibenclamide (Glyburide) Long-acting Glimepiride Long-acting Absorption Well Well Well Metabolism Yes Yes Yes Metabolites Inactive Inactive Inactive Half-life 3 – 4 hrs Less than 3 hrs 5 - 9 hrs Duration of action 10 – 16 hrs 12 – 24 hrs 12 – 24 hrs Excretion Urine Urine Urine SECOND GENERATION SULPHONYLUREA COMPOUNDS
• Type II diabetes: monotherapy or in combination with other antidiabetic drugs. Uses of sulfonylureas
41 SIDE EFFECTS OF SULPHONYLUREAS 1) Nausea, vomiting, abdominal pain, diarrhea 2) Hypoglycaemia 3) Dilutional hyponatraemia & water intoxication (Chlorpropamide) 4) Disulfiram-like reaction with alcohol (Chlorpropamide) 5) Weight gain
42 SIDE EFFECTS OF SULPHONYLUREAS (contd.) 6) Blood dyscrasias (not common; less than 1% of patients) - Agranulocytosis - Haemolytic anaemia - Thrombocytopenia 7) Cholestatic obstructive jaundice (uncommon) 8) Dermatitis (Mild) 9) Muscle weakness, headache, vertigo (not common) 10) Increased cardio-vascular mortality with longterm use ??
43 CONTRAINDICATIONS OF SULPHONYLUREAS 1) Type 1 DM ( insulin dependent) 2) Parenchymal disease of the liver or kidney 3) Pregnancy, lactation 4) Major stress
44 DRUGS THAT AUGMENT THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS WARFARIN SULFONAMIDES SALICYLATES PHENYLBUTAZONE PROPRANOLOL ALCOHOL CHLORAMPHENICOL FLUCONAZOLE
45 DRUGS THAT ANTAGONIZE THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS DIURETICS (THIAZIDE, FUROSEMIDE) DIAZOXIDE CORTICOSTEROIDS ORAL CONTRACEPTIVES PHENYTOIN, PHENOBARB., RIFAMPIN ALCOHOL ( chronic pts )
MEGLITINIDE ANALOGUES Repaglinide (Prandin) Nateglinide (Starlix)
Mechanism of Action Stimulate insulin release from functioning B cells by modulating K efflux via blocking ATP-sensitive K channels resulting in depolarization and calcium influx.
48 MEGLITINIDES PHARMACOKINETICS Taken orally Rapidly absorbed ( Peak approx. 1hr ) Metabolized by liver t1/2 = 1 hr Duration of action 4-5 hr
49 MEGLITINIDES CLINICAL USE Approved as monotherapy and in combination with metformin in type 2 diabetes Taken before each meal, 3 times / day Does not offer any advantage over sulfonylureas; Advantage: Pts. allergic to sulfur or sulfonylurea SIDE EFFECTS: Hypoglycemia Wt gain ( less than SUs ) Caution in pts with renal & hepatic impairement.
50 BIGUANIDES MECHANISM OF ACTION 1. Increase peripheral glucose utilization 2. Inhibits gluconeogenesis 3. Impaired absorption of glucose from the gut Does not stimulate insulin release. Metformin
51 BIGUANIDES PHARMACOKINETICS Given orally Not bind to plasma proteins Not metabolized Excreted unchanged in urine t 1/2 2 hr
• Obese patients with type II diabetes • Monotherapy or in combination. Advantages: • No risk of hyperinsulinemia or hypoglycemia or weight gain (anorexia). Uses of metformin
53 BIGUANIDES (Contd.) SIDE EFFECTS 1. Metallic taste in the mouth 2. Gastrointestinal (anorexia, nausea, vomiting, diarrhea, abdominal discomfort) 3. Vitamin B 12 deficiency (prolonged use) 4. Lactic acidosis ( rare – 01/ 30,000-exclusive in renal & hepatic failure)
54 1. Hepatic impairment 2. Renal impairment 3. Alcoholism 4. Heart failure BIGUANIDES CONTRAINDICATIONS
55 Glucovance® (Glyburide & Metformine HCl) Sulfonylurea & Biguanide Combo drugs
Hypoglycemics, Metformins PRODUCT LIST AND FDA-APPROVED INDICATIONS
Hypoglycemics, Metformins
Thiazolidinediones (Glitazones)-Tzds • Insulin Sensitizers • Activation of Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ). • Do not promote Insulin secretion from β-cells • Two agents are : Pioglitazone Rosiglitazone
Mechanism of Action
60 MECHANISM OF ACTION - Increase target tissue sensitivity to insulin by: reducing hepatic glucose output & increase glucose uptake & oxidation in muscles & adipose tissues. They do not cause hypoglycemia (similar to metformin and acarbose ) . THIAZOLIDINEDIONE DERIVATIVES
61 PHARMACOKINETICS - 99% absorbed - Metabolized by liver - 99% of drug binds to plasma proteins - Half-life 3 – 4 h - Eliminated via the urine 64% and feces 23% THIAZOLIDINEDIONE DERIVATIVES
62 INDICATIONS Type II diabetes alone or in combination with metformin or sulfonylurea or insulin in patients resistant to insulin treatment. Pioglitazone may be taken once daily; the usual starting dose is 15–30 mg/d, and the maximum is 45 mg/d. THIAZOLIDINEDIONE DERIVATIVES
63 ADVERSE EFFECTS - Mild to moderate edema - Increase the risk of heart failure - Wt gain - Headache - Myalgia - Hepatotoxicity ? (liver function tests for 1st year of therapy). THIAZOLIDINEDIONE DERIVATIVES
α-Glucosidase Inhibitors • Competitive inhibitor of Intestinal α- Glucosidase . • Delays carbohydrate absorption • Reducing postprandial increase in blood glucose • Agents are : - Acarbose - Miglitol
Acarbose Acarbos e Acarbose Mechanism of Action
Acarbose • Given orally, poorly absorbed. • Metabolized by intestinal bacteria. • Excreted in stool and urine. Kinetics of -glucosidase inhibitors
67 INDICATIONS Patients with Type II inadequately controlled by diet with or without other agents( SU, Metformin) Can be combined with insulin may be helpful in obese Type II patients (similar to metformin) α-GLUCOSIDASE INHIBITORS
68 SIDE EFFECTS Flatulence Loose stool or diarrhea Abdominal pain Alone does not cause hypoglycemia α-GLUCOSIDASE INHIBITORS
CONTRAINDICATIONS • patients with inflammatory bowel disease or any intestinal condition that could be worsened by gas and distention • patients with renal impairment • acarbose has been associated with reversible hepatic enzyme elevation and should be used with caution in the presence of hepatic disease.
Incretin mimetics • Incretins are GI hormones secreted in response to food, carried through circulation to the beta cells to stimulate insulin secretion & decrease glucagon secretion.
Incretins • Two main Incretin hormones: – GLP-1 (glucagon-like peptide-1) – GIP (gastric inhibitory peptide or glucose- dependent insulinotropic peptide) Both are inactivated by dipeptidyl peptidase-4 (DPP-4).
Incretin mimetics - Exenatide - Liraglutide • is glucagon-like peptide-1 (GLP-1) agonist. • Therapy of patients with type 2 diabetes. who are not controlled with oral medicine.
GLP1 has various potential effects on the CV system: Data derived from non-clinical and mechanistic proof-of-concept studies 73 1. Jax. Clin Res Cardiol 2009;98:75–9. 2. Grieve. Br J Pharmacol 2009;157:1340–51 (modified). 3. Robinson et al. BMJ Open 2013;3:pii e001986. ↑ Insulin sensitivity (direct or indirect?) ↑ Insulin secretion ↓ Glucagon secretion ↑ Insulin biosynthesis ↑ β-cell proliferation ↓ β -cell apoptosis ↓ Appetite ↑ Neuroprotection ↓ Glucose output Brain Pancreas Liver Muscle and adipose tissue ↑ Endothelial function ↑ Nitric oxide production ↑ ↓ Myocardial contractility (data conflict) ↑ Systolic function in myocardial infarction ↑ Systolic function in cardiomyopathy ↓ Infarct size ↑ Ischaemic pre-conditioning ↑ Post-ischaemic recovery ↑ Myocardial glucose uptake Heart Incretin hormone1,2 Clinical trial data show that GLP1 receptor agonists are associated with small increases in heart rate and modest reductions in body weight and blood pressure3
GLP 1 Mimetic - Exenatide Effects: • Stimulates post-prandial insulin secretion (Stimulation of GLP-1 secretion from intestine which in turn stimulate insulin secretion from β cells). • Slows gastric emptying • Reduces appetite Administered: • Subcutaneous injection • Twice daily
Exenatide • Less hypoglycemic compared to insulin • BIG benefit of weight loss • Only licensed to lower blood sugars, not as weight loss agent • S.E: Nausea (about 44% of users), vomiting and diarrhea • Pancreatitis (liraglutide)
Dipeptidyl peptidase-4 (DPP- 4 ) inhibitors • e.g. Sitagliptin, Vildagliptin • Orally • Given once daily • half life 8-14 h • Dose is reduced in pts with renal impairment
Mechanism of action of sitagliptin Inhibit DPP-4 enzyme and leads to an increase in incretin hormones level. This results in an increase in insulin secretion & decrease in glucagon secretion.
Mechanism of action
DPP4 inhibitors: Mechanism of action Adapted from Drucker. Expert Opin Invest Drugs 2003;12:87–100 and Ahrén Curr Diab Rep. 2003;3:365–372. Food intake Glucose-dependent insulin secretion Increases glucose utilisation by muscle and adipose tissue Decreases hepatic glucose release improving overall glucose control Glucose-dependent glucagon suppression β-cells α-cells DPP4 Active GLP1 (7-36) Inactive GLP1 (9-36) amide 2 amino acids cleaved from amino terminus Pancreas DPP4 inhibitors Intestine 79
Selected mechanistic trials indicate potential CV effects of the DPP4 inhibitor class 80 1. Ye et al. Am J Physiol Heart Circ Physiol 2010;298:H1454–65. 2. Hocher et al. Int J Cardiol 2013;167:87–93. 3. van Poppel et al. Diabetes Care 2011;34:2072–77. 4. Kröller-Schön et al. Cardiovasc Res 2012;96:140–9. 5. Ta et al. J Cardiovasc Pharmacol 2011;58:157–66. 6. Sauvé et al. Diabetes 2010;59:1063–73. 7. Read et al. Circ Cardiovasc Imaging 2010;3:195–201. 8. Matikainen et al. Diabetologia 2006;49:2049–57. Endothelial function3 Atherosclerotic plaque volume5 Left ventricular function6,7 Myocardial infarct size1,2 Triglycerides8 Inflammation and oxidative stress4
Clinical uses Type 2 DM as an adjunct to diet & exercise as a monotherapy or in combination with other antidiabetic drugs. Adverse effects -Nausea, diarrhea - Headaches -Nasopharyngitis, upper respiratory infections -Hypoglycemia -Allergic and hypersensitivity reactions
Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors • SGLT2 inhibitors, also called gliflozins, are a class of medications that alter essential physiology of the nephron; unlike SGLT1 inhibitors that modulate sodium/glucose channels in the intestinal mucosa. • The foremost metabolic effect appears to show that this pharmaceutical class inhibits reabsorption of glucose in the kidney and therefore lower blood sugar. • They act by inhibiting sodium-glucose transport protein 2 (SGLT2). SGLT2 inhibitors are used in the treatment of type II diabetes mellitus (T2DM)
Urinary glucose excretion via SGLT2 inhibition1 83 1. Bakris et al. Kidney Int 2009;75;1272–7. SGLT2 SGLT2 inhibitor SGLT1 SGLT2 inhibitors reduce glucose reabsorption in the proximal tubule, leading to urinary glucose excretion* and osmotic diuresis Filtered glucose load > 180 g/day
SGLT2 Inhibitors • The SGLT2 inhibitors are efficacious agents in reducing HbA1c, postprandial glucose, and fasting plasma glucose, as well as reducing systolic blood pressure and weight • Medicines in the SGLT2 inhibitor class include canagliflozin, dapagliflozin, and empagliflozin.
Pharmacological properties of available SGLT2 inhibitors 85 *For the 300 mg dose. Data from http://www.ema.europa.eu/ (Jardiance SPC, Forxiga SPC , Invokana PI, Invokana SPC, all accessed June 2015); 1. Sha et al. Diab Obes Metab 2015;17:188–97. Empagliflozin Dapagliflozin Canagliflozin Therapeutic dose (mg/day) Starting dose 10–25 10 5–10 10 100–300 100 Administration QD With or without food QD With or without food QD Before first meal Peak plasma concentration (hours post-dose) 1.5 Within 2 1–2 Absorption (mean oral bioavailability) ≥ 60% ~ 78% ~ 65% Metabolism  Primarily glucuronidation - no active metabolite → Elimination (half-life, hours) Hepatic:renal 43:57 [12.4] Hepatic:renal 22:78 [12.9] Hepatic:renal 67:33 [13.1]* Selectivity over SGLT1 1:5000 > 1:1400 > 1:1601 Glucose excretion with higher dose (g/day) 78 ~ 70 119 Link to SGLT2 clinical data
86 Hypoglycemics, SGLT2 Reaching across Arizona to provide comprehensive quality health care for those in need Drug Manufacturer Indications canagliflozin (Invokana®) Janssen ▪ Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM) ▪ To reduce the risk of major adverse cardiovascular events (MACE) in adults with T2DM and established cardiovascular disease (CVD) ▪ To reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults T2DM and diabetic nephropathy with albuminuria > 300 mg/day canagliflozin/ metformin (Invokamet®) Janssen ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM when treatment with both canagliflozin and metformin is appropriate ▪ To reduce the risk of MACE in adults with T2DM and established CVD* canagliflozin/ metformin (Invokamet® XR) Janssen ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM when treatment with both canagliflozin and metformin is appropriate ▪ To reduce the risk of MACE in adults with T2DM and established CVD* dapagliflozin (Farxiga®) AstraZeneca ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM ▪ To reduce the risk of hospitalization for heart failure in adults with T2DM and established CVD or multiple cardiovascular (CV) risk factors
87 Hypoglycemics, SGLT2 Reaching across Arizona to provide comprehensive quality health care for those in need dapagliflozin/ metformin ER (Xigduo® XR) AstraZeneca ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM when treatment with both dapagliflozin and metformin is appropriate ▪ Dapagliflozin is indicated to reduce the risk of hospitalization for heart failure in adults with T2DM and established CVD or multiple CV risk factors. empagliflozin (Jardiance®) Boehringer Ingelheim ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM ▪ To reduce the risk of cardiovascular death in adults with T2DM and established CVD empagliflozin/ metformin (Synjardy®) Boehringer Ingelheim ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM when treatment with both empagliflozin and metformin is appropriate ▪ To reduce the risk of cardiovascular death in adults with T2DM and established CVD* empagliflozin/ metformin ER (Synjardy® XR) Boehringer Ingelheim ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM when both empagliflozin and metformin is appropriate ▪ To reduce the risk of cardiovascular death in adults with T2DM and established CVD* ertugliflozin (Steglatro™) Merck, Sharp & Dohme ▪ Adjunct to diet and exercise to improve glycemic control in adults T2DM ertugliflozin/ metformin (Segluromet™) Merck, Sharp & Dohme ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM who are not adequately controlled on a regimen containing ertugliflozin or metformin, or in patients who are already treated with both ertugliflozin and metformin
88 Potential Adverse Effect Practical Considerations Adverse drug-drug Interaction Pharmacokinetic drug-drug interactions are minimal Canagliflozin is a P-glycoprotein substrate (modest inhibition); co-administration with digoxin may increase plasma levels of digoxin; monitor digoxin levels and for signs and symptoms of toxicity when both are used together Genital and urinary infections Mycotic infections more common among females and in uncircumcised males Reinforce importance of adequate hygiene Counsel patients to urgently report genital/perineal tenderness, redness, or swelling No significant increase in risk of urinary tract infections Hypoglycemia Uncommon; risk increased with concomitant use of sulfonylureas and insulin
89 Potential Adverse Effect Practical Considerations Diabetic ketoacidosis Avoid pre-emptive substantial reductions in insulin dose Hold dose if acutely ill with limited oral intake, and 3 days before major surgery Use caution with low carbohydrate diets to minimize excessive ketosis Discourage excessive alcohol intake Counsel patients regarding potential symptoms of diabetic ketoacidosis (fruity odor on breath, thirst, polyuria, nausea, vomiting, abdominal pain, confusion, and fever) Renal injury Baseline and periodic monitoring of renal function is recommended, especially if used in chronic kidney disease Cases of acute kidney injury are rare, except in concert with volume depletion
90 Potential Adverse Effect Practical Considerations Volume depletion Increased risk with concomitant diuretic use; consider diuretic dose adjustment Educate patient about potential for orthostatic hypotension and necessity to monitor daily weights and blood pressure, particularly in the first week of therapy Lower limb amputations Predominantly toe and metatarsal More apparent with canagliflozin Increased risk among those with previous amputations or in patients with peripheral artery disease Remind patients to perform regular foot exams and to see a podiatrist annually
Hypoglycemics, SGLT2 • Per the AACE/ACE guidelines, agents for monotherapy are recommended in the following order (highest to lowest recommendation): 1.metformin, 2.GLP-1 receptor agonists, 3.SGLT2 inhibitors, 4.DPP-4 inhibitors, 5.TZDs, 6.Alpha-glucosidase inhibitors, and sulfonylureas/secretagogue glinides • AACE/ACE recognizes that empagliflozin and canagliflozin are associated with significantly reduced cardiac mortality, hospitalization for heart failure, as well as secondary renal endpoints • Additionally, dapagliflozin demonstrated reduced all-cause mortality and the composite of CV death and HF hospitalization; however, it did not significantly lower the combined risk of CV death and nonfatal MI and stroke • The American College of Physicians’ (ACP) revised 2017 guidelines for T2DM recommend metformin as first-line therapy, and a sulfonylurea, TZD, SGLT-2 inhibitor, or a DPP-4 inhibitor as preferred second-line treatments
Hypoglycemics, SGLT2 • Per the 2019 American Diabetes Association (ADA) Standards of Medical Care in Diabetes, metformin is recommended as initial therapy for the treatment of T2DM, along with lifestyle interventions at the time of diagnosis, unless metformin is contraindicated
Hypoglycemics, SGLT2 • If metformin fails to produce the target HbA1c after 3 months of therapy, a thiazolidinedione (TZD), sulfonylurea (SU), dipeptidyl peptidase-4 (DPP-4) inhibitor, SGLT2 inhibitor, glucagon-like peptide-1 (GLP-1) receptor agonist, or basal insulin should be added in patients without atherosclerotic cardiovascular disease (ASCVD) or chronic kidney disease (CKD) • In patients with ASCVD or CKD, the addition of an agent with known cardiovascular (CV) or renal benefit (select GLP-1 agonist or select SLGT2 inhibitor) is preferred • The selection of medications should be patient-centric and prescribers should consider potential issues such as HbA1c target, impact on weight and hypoglycemia, side effects, the frequency and mode of administration, patient adherence, patient preference, and cost • Thiazolidinediones and sulfonylureas are generally considered less safe than glucagon- like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter type 2 (SGLT2) inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, or alpha-glucosidase inhibitors
Hypoglycemics, SGLT2 • If there is a compelling need to minimize weight gain or promote weight loss, a GLP-1 agonist or SGLT2 inhibitor are recommended • In patients with atherosclerotic cardiovascular disease (ASCVD), the addition of empagliflozin (Class A recommendation), liraglutide (Class A recommendation), or canagliflozin (Class C recommendation) is preferred • In patients with heart failure (HF) or chronic kidney disease (CKD), empagliflozin, canagliflozin, or dapagliflozin is preferred • The American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) 2019 diabetes management algorithm and 2015 clinical practice guidelines for developing a diabetes care plan include the use of SGLT2 inhibitors as an alternative to metformin for monotherapy and as an appropriate add-on to metformin in dual therapy and triple therapy
Insulin Th in DM type II. • Insufficient glycaemic control despite of maximal doses of PAD in combination • Decompensation during intercurrent diseases (infections, trauma, stress) • Perioperative period • Pregnancy and lactation • Vital organs failure (stroke, IM) • Allergy • Contraindications and adverse effects • Significant hyperglycaemia at admission
DIABETES MELLITUS.pdf

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DIABETES MELLITUS.pdf

  • 2.
    Diabetes or DiabetesMellitus ❑ Chronic Metabolic Disorder ❑ Vascular Abnormalities Characterized by • Hyperglycemia • Glycosuria • Polydipsia • Polyphagia • Ketoacidosis
  • 4.
    Diabetes mellitus Type 1Diabetes - cells that produce insulin are destroyed - results in insulin dependence - commonly detected before 30 Type 2 Diabetes - blood glucose levels rise due to 1) Lack of insulin production 2) Insufficient insulin action (resistant cells) - commonly detected after 40 - effects > 90% Gestational Diabetes 3-5% of pregnant women develop gestational diabetes
  • 5.
    5 Characteristic Type 1( 10% ) Type 2 Onset (Age) Usually < 30 Usually > 40 Type of onset Abrupt Gradual Nutritional status Usually thin Usually obese Diet Mandatory with insulin Mandatory with or without drug Hypoglycemic drugs Should not be used Clinically indicated Clinical symptoms Polydipsia, polyphagia, polyurea, Wt loss Often asymptomatic Ketosis Frequent Usually absent Endogenous insulin Absent Present, but relatively ineffective Related lipid abnormalities Hypercholesterolemia frequent, all lipid fractions elevated in ketosis Cholesterol & triglycerides often elevated; carbohydrate- induced hypertriglyceridemia common Insulin therapy Required Required in only 20 - 30% of patients
  • 8.
    Liver Muscle Adipose ↓glucose production ↑ Glucose transport ↑ glucose transport ↑ glycolysis ↑ glycolysis ↑ lipogenesis& lipoprotein lipase activity ↑ TG synthesis ↑ glycogen deposition ↓ intracellular lipolysis ↑ Protein synthesis ↑ protein synthesis
  • 9.
    • In thecase of type 1 diabetes, insulin levels are grossly deficient. Thus type 1 diabetes is invariably treated with insulin • Type 2 diabetes is frequently associated with obesity. Serum insulin levels are normal or elevated, so this is a disease of insulin resistance. A number of treatment options may be employed.
  • 10.
    • 11th January1922 - pancreatic islet cell extract first administered to 14 year old insulin deficient patient • Bovine and porcine pancreatic extracts • 1980 human insulin available -amino acid modification of porcine insulin - synthesised by introducing DNA for human insulin into bacteria or yeast
  • 12.
    ❑Liver and Kidneyare two organ remove insulin from circulation by hydrolysis of disulfide connection between A & B chains. ❑ Liver remove 60% of insulin. ❑ Kidney remove 35-40% of insulin.
  • 13.
  • 14.
    • Human insulin:Humulin® (from E.coli), Novalin® (from yeast) • NPH - neutral protamine Hagedorn (NPH), protamine mixed. • Lente® insulin / Ultralente® insullin- zinc added Regular insulins
  • 15.
    • Fatty AcidAcylated insulins • Insulin Lispro (Humalog®) (1996) • Insulin Aspart (NovoLog®) (2000) • Insulin Glargine (Lantus®) (2002) • Insulin Detemir (Levemir®) (Jun.,2005) • Insulin Glulisine (Apidra®) (Jan., 2006) Insulin Analogs
  • 16.
    16 ❑ Ultra-short-acting (Rapidacting)-with very fast onset and short duration ❑ Short-acting (Regular)-with rapid onset of action ❑ Intermediate-acting ❑ Long-acting- with slow onset of action TYPES OF INSULIN PREPARATIONS
  • 17.
    17 Short-acting (regular) insulins e.g.Humulin R, Novolin R Uses Designed to control postprandial hyperglycemia & to treat emergency diabetic ketoacidosis Physical characteristics Clear solution at neutral pH Chemical structure Hexameric analogue Route & time of administration S.C. 30 – 45 min before meal I.V. in emergency (e.g. diabetic ketoacidosis) Onset of action 30 – 45 min ( S.C ) Peak serum levels 2 – 4 hr Duration of action 6 – 8 hr Usual administration 2 – 3 times/day or more Ultra-Short acting insulins e.g. Lispro, aspart, glulisine Similar to regular insulin but designed to overcome the limitations of regular insulin Clear solution at neutral pH Monomeric analogue S.C. 5 min (no more than 15 min) before meal I.V. in emergency (e.g. diabetic ketoacidosis) 0 – 15 min ( S.C ) 30 – 90 min 3 – 4 hr 2 – 3 times / day or more
  • 18.
    • Insulin lispro,the first monomeric insulin analog to be marketed, is produced by recombinant technology wherein two amino acids near the carboxyl terminal of the B chain have been reversed in position: Proline at position B28 has been moved to B29, and lysine at position B29 has been moved to B28 • When injected subcutaneously, the drug quickly dissociates into monomers and is rapidly absorbed with onset of action within 5–15 minutes and peak activity as early as 1 hour. The time to peak action is relatively constant, regardless of the dose
  • 19.
    Regular insulins e.g. HumulinR, Novolin R • Short-acting insulin— Regular insulin is a short-acting soluble crystalline zinc insulin that is now made by recombinant DNA techniques to produce a molecule identical to that of human insulin. Its effect appears within 30 minutes, peaks between 2 and 3 hours after subcutaneous injection, and generally lasts 5–8 hours. • The clinical consequence is that when regular insulin is administered at mealtime, the blood glucose rises faster than the insulin with resultant early postprandial hyperglycemia and an increased risk of late postprandial hypoglycemia. Therefore, regular insulin should be injected 30–45 or more minutes before the meal to minimize the mismatching.
  • 20.
    20 Intermediate - actinginsulins e.g. Isophane (NPH) - neutral protamine Hagedorn, protamine mixed ▪ Subcutaneous injection.(Only) ▪ Onset of action 2 - 5 hr ▪ Peak serum level 5 - 7 hr ▪ Duration of action 4 - 12 hr it is usually mixed with regular, lispro, aspart, or glulisine insulin and given two to four times daily for insulin replacement.
  • 21.
    Insulin mixtures • 75/2570/30 50/50 (NPH / Regular) • Intermediate insulins composed of isophane complexes of protamine with insulin lispro and insulin aspart have been developed: • “NPL” (neutral protamine lispro) - 50%/50% and 75%/25% • “NPA” (neutral protamine aspart) - 70%/30%
  • 22.
    22 Lente insulin ▪ Mixtureof 30% semilente insulin 70% ultralente insulin ▪ Injected S.C. (only) ▪ Onset of action 1 - 3 hr ▪ Peak serum level 4 - 8 hr ▪ Duration of action 13 - 20 hr
  • 23.
    23 Long – actinginsulins e.g. Insulin glargine – long-acting insulin analog • Onset of action 1-2 hr • Absorbed less rapidly than NPH & Lente insulins. • Duration of action - 24 hr (Glargine is usually given once daily) Designed to overcome the deficiencies of intermediate acting insulins Advantages over intermediate-acting insulins: ▪ More safe than NPH & Lente insulins due to reduced risk of hypoglycemia(esp.nocturnal hypoglycemia). ▪ Clear solution that does not require resuspension before administration.
  • 24.
    • Insulin detemir—This insulin is the most recently developed long-acting insulin analog. • Insulin detemir has a dose-dependent onset of action of 1–2 hours and duration of action of more than 12 hours. • It is given twice daily to obtain a smooth background insulin level.
  • 25.
    Insulin degludec Insulin degludec(INN/USAN) is an ultralong-acting basal insulin analogue that was developed by Novo Nordisk under the brand name Tresiba. It is administered via subcutaneous injection once daily to help control the blood sugar level of those with diabetes. It has a duration of action that lasts up to 42 hours (compared to 18 to 26 hours provided by other marketed long-acting insulins such as insulin glargine and insulin detemir), making it a once-daily basal insulin, that is one that provides a base insulin level, as opposed to the fast- and short-acting bolus insulins.
  • 26.
    Dosage Forms &Strengths injectable solution (prefilled pen, FlexTouch) • 100 units/mL • 200 units/mL Type 1 Diabetes Mellitus Long-acting basal insulin indicated to improve glycemic control in patients with diabetes mellitus Initial dose For insulin-naïve patients Start ~1/3 to 1/2 of the total daily insulin dose; use remaining of total daily insulin dose on short-acting insulin and divided between each daily meal Usual initial dose range: 0.2-0.4 units/kg
  • 27.
    Type 2 DiabetesMellitus Long-acting basal insulin indicated to improve glycemic control in adults with type 2 diabetes mellitus Initial dose • For insulin-naïve patients • Start 10 units SC qDay
  • 28.
    Adverse Effects >10% • Nasopharyngitis(12.9- 23.9%) • Severe hypoglycemic episode (0.3-12.3%) • Upper respiratory tract infection (8.4-11.9%) • Headache (8.8-11.8%) 1-10% • Diarrhea (6.3%) • Sinusitis (5.1%) • Gastroenteritis (5.1%) • Injection site reactions (3.8%) • Peripheral edema (0.9-3%) <1% • Lipodystrophy
  • 29.
    Methods of Adminisration A.Standard Delivery - The standard mode of insulin therapy is subcutaneous injection using conventional disposable needles and syringes. B. Portable Pen Injectors -These contain cartridges of insulin and replaceable needles. C. Continuous Subcutaneous Insulin Infusion Devices (CSII, Insulin Pumps) -Continuous subcutaneous insulin infusion devices are external open-loop pumps for insulin delivery
  • 30.
    • Hypoglycemia • Immunopathologyof Insulin Therapy • Lipodystrophy at Injection Sites • Increased Cancer Risk
  • 32.
    ❑ Sulfonylurea drugs ❑Meglitinide analogues ❑ Biguanides ❑ α -glucosidase inhibitors. ❑ Thiazolidinediones. ❑ Dipeptidyl peptidase-4 inhibitors e.g. Sitagliptin, vildagliptin ❑ GLP1 receptor agonists ❑ SGLT2 inhibitors
  • 33.
    A closer lookat CV effects of 21st century T2D agents 33 Adapted from 1. Kirby. Br J Diabetes Vasc Dis 2012;12:315–20. 2. Lantus® SPC. FDA 2015. 1950 1960 1970 1980 1990 2000 2010 2012 2013 Lente class of insulins produced SUs first used Metformin introduced in the UK Recombinant human insulin produced 2nd generation SUs available Three new classes introduced: -glucosidase inhibitors, meglitinides and TZDs Glimepiride: 3rd generation SU DPP4 inhibitors GLP1 receptor agonists SGLT2 inhibitors Insulin degludec  Older T2D agents Newer T2D agents → Insulin glargine available2
  • 34.
    Insulin secretagogues ❑ Sulfonylureadrugs ❑ Meglitinide analogues ❑ GLP1 receptor agonists ❑ Dipeptidyl peptidase-4 inhibitors Insulin sensitizers ❑ Biguanides ❑ Thiazolidinediones or glitazones Drugs inhibiting hydrolysis of complex saccharides : ❑ α-glycosidase inhibitors Drugs inhibiting reabsorption of glucose in the kidney ❑ SGLT2 inhibitors
  • 35.
    SULFONYLUREAS : First generationSecond generation Tolbutamide Glipizide Tolazamide Glyburide Acetohexamide (Glibenclamide) Chlorpropamide Glimepiride (Amaryl)
  • 36.
    36 MECHANISM OF ACTIONOF SULPHONYLUREAS 1) Release of insulin from β-cells 2) Reduction of serum glucagon concentration 3) Potentiation of insulin action on target tissues
  • 38.
    Pharmacokinetics of sulfonylureas: •Orally, well absorbed. • Reach peak concentration after 2-4 hr. • All are highly bound to plasma proteins. • Duration of action is variable. • Second generation has longer duration than first generation. • Metabolized in liver • excreted in urine • Cross placenta, stimulate fetal B cells to release insulin → hypoglycemia at birth.
  • 39.
    39 Glipizide Short- acting Glibenclamide (Glyburide) Long-acting Glimepiride Long-acting Absorption Well WellWell Metabolism Yes Yes Yes Metabolites Inactive Inactive Inactive Half-life 3 – 4 hrs Less than 3 hrs 5 - 9 hrs Duration of action 10 – 16 hrs 12 – 24 hrs 12 – 24 hrs Excretion Urine Urine Urine SECOND GENERATION SULPHONYLUREA COMPOUNDS
  • 40.
    • Type IIdiabetes: monotherapy or in combination with other antidiabetic drugs. Uses of sulfonylureas
  • 41.
    41 SIDE EFFECTS OFSULPHONYLUREAS 1) Nausea, vomiting, abdominal pain, diarrhea 2) Hypoglycaemia 3) Dilutional hyponatraemia & water intoxication (Chlorpropamide) 4) Disulfiram-like reaction with alcohol (Chlorpropamide) 5) Weight gain
  • 42.
    42 SIDE EFFECTS OFSULPHONYLUREAS (contd.) 6) Blood dyscrasias (not common; less than 1% of patients) - Agranulocytosis - Haemolytic anaemia - Thrombocytopenia 7) Cholestatic obstructive jaundice (uncommon) 8) Dermatitis (Mild) 9) Muscle weakness, headache, vertigo (not common) 10) Increased cardio-vascular mortality with longterm use ??
  • 43.
    43 CONTRAINDICATIONS OF SULPHONYLUREAS 1) Type1 DM ( insulin dependent) 2) Parenchymal disease of the liver or kidney 3) Pregnancy, lactation 4) Major stress
  • 44.
    44 DRUGS THAT AUGMENTTHE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS WARFARIN SULFONAMIDES SALICYLATES PHENYLBUTAZONE PROPRANOLOL ALCOHOL CHLORAMPHENICOL FLUCONAZOLE
  • 45.
    45 DRUGS THAT ANTAGONIZETHE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS DIURETICS (THIAZIDE, FUROSEMIDE) DIAZOXIDE CORTICOSTEROIDS ORAL CONTRACEPTIVES PHENYTOIN, PHENOBARB., RIFAMPIN ALCOHOL ( chronic pts )
  • 46.
  • 47.
    Mechanism of Action Stimulateinsulin release from functioning B cells by modulating K efflux via blocking ATP-sensitive K channels resulting in depolarization and calcium influx.
  • 48.
    48 MEGLITINIDES PHARMACOKINETICS Taken orally Rapidly absorbed( Peak approx. 1hr ) Metabolized by liver t1/2 = 1 hr Duration of action 4-5 hr
  • 49.
    49 MEGLITINIDES CLINICAL USE Approved asmonotherapy and in combination with metformin in type 2 diabetes Taken before each meal, 3 times / day Does not offer any advantage over sulfonylureas; Advantage: Pts. allergic to sulfur or sulfonylurea SIDE EFFECTS: Hypoglycemia Wt gain ( less than SUs ) Caution in pts with renal & hepatic impairement.
  • 50.
    50 BIGUANIDES MECHANISM OF ACTION 1.Increase peripheral glucose utilization 2. Inhibits gluconeogenesis 3. Impaired absorption of glucose from the gut Does not stimulate insulin release. Metformin
  • 51.
    51 BIGUANIDES PHARMACOKINETICS Given orally Not bindto plasma proteins Not metabolized Excreted unchanged in urine t 1/2 2 hr
  • 52.
    • Obese patientswith type II diabetes • Monotherapy or in combination. Advantages: • No risk of hyperinsulinemia or hypoglycemia or weight gain (anorexia). Uses of metformin
  • 53.
    53 BIGUANIDES (Contd.) SIDE EFFECTS 1.Metallic taste in the mouth 2. Gastrointestinal (anorexia, nausea, vomiting, diarrhea, abdominal discomfort) 3. Vitamin B 12 deficiency (prolonged use) 4. Lactic acidosis ( rare – 01/ 30,000-exclusive in renal & hepatic failure)
  • 54.
    54 1. Hepatic impairment 2.Renal impairment 3. Alcoholism 4. Heart failure BIGUANIDES CONTRAINDICATIONS
  • 55.
    55 Glucovance® (Glyburide &Metformine HCl) Sulfonylurea & Biguanide Combo drugs
  • 56.
    Hypoglycemics, Metformins PRODUCT LISTAND FDA-APPROVED INDICATIONS
  • 57.
  • 58.
    Thiazolidinediones (Glitazones)-Tzds • InsulinSensitizers • Activation of Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ). • Do not promote Insulin secretion from β-cells • Two agents are : Pioglitazone Rosiglitazone
  • 59.
  • 60.
    60 MECHANISM OF ACTION -Increase target tissue sensitivity to insulin by: reducing hepatic glucose output & increase glucose uptake & oxidation in muscles & adipose tissues. They do not cause hypoglycemia (similar to metformin and acarbose ) . THIAZOLIDINEDIONE DERIVATIVES
  • 61.
    61 PHARMACOKINETICS - 99% absorbed -Metabolized by liver - 99% of drug binds to plasma proteins - Half-life 3 – 4 h - Eliminated via the urine 64% and feces 23% THIAZOLIDINEDIONE DERIVATIVES
  • 62.
    62 INDICATIONS Type II diabetesalone or in combination with metformin or sulfonylurea or insulin in patients resistant to insulin treatment. Pioglitazone may be taken once daily; the usual starting dose is 15–30 mg/d, and the maximum is 45 mg/d. THIAZOLIDINEDIONE DERIVATIVES
  • 63.
    63 ADVERSE EFFECTS - Mildto moderate edema - Increase the risk of heart failure - Wt gain - Headache - Myalgia - Hepatotoxicity ? (liver function tests for 1st year of therapy). THIAZOLIDINEDIONE DERIVATIVES
  • 64.
    α-Glucosidase Inhibitors • Competitiveinhibitor of Intestinal α- Glucosidase . • Delays carbohydrate absorption • Reducing postprandial increase in blood glucose • Agents are : - Acarbose - Miglitol
  • 65.
  • 66.
    Acarbose • Given orally,poorly absorbed. • Metabolized by intestinal bacteria. • Excreted in stool and urine. Kinetics of -glucosidase inhibitors
  • 67.
    67 INDICATIONS Patients with TypeII inadequately controlled by diet with or without other agents( SU, Metformin) Can be combined with insulin may be helpful in obese Type II patients (similar to metformin) α-GLUCOSIDASE INHIBITORS
  • 68.
    68 SIDE EFFECTS Flatulence Loose stoolor diarrhea Abdominal pain Alone does not cause hypoglycemia α-GLUCOSIDASE INHIBITORS
  • 69.
    CONTRAINDICATIONS • patients withinflammatory bowel disease or any intestinal condition that could be worsened by gas and distention • patients with renal impairment • acarbose has been associated with reversible hepatic enzyme elevation and should be used with caution in the presence of hepatic disease.
  • 70.
    Incretin mimetics • Incretinsare GI hormones secreted in response to food, carried through circulation to the beta cells to stimulate insulin secretion & decrease glucagon secretion.
  • 71.
    Incretins • Two mainIncretin hormones: – GLP-1 (glucagon-like peptide-1) – GIP (gastric inhibitory peptide or glucose- dependent insulinotropic peptide) Both are inactivated by dipeptidyl peptidase-4 (DPP-4).
  • 72.
    Incretin mimetics - Exenatide -Liraglutide • is glucagon-like peptide-1 (GLP-1) agonist. • Therapy of patients with type 2 diabetes. who are not controlled with oral medicine.
  • 73.
    GLP1 has variouspotential effects on the CV system: Data derived from non-clinical and mechanistic proof-of-concept studies 73 1. Jax. Clin Res Cardiol 2009;98:75–9. 2. Grieve. Br J Pharmacol 2009;157:1340–51 (modified). 3. Robinson et al. BMJ Open 2013;3:pii e001986. ↑ Insulin sensitivity (direct or indirect?) ↑ Insulin secretion ↓ Glucagon secretion ↑ Insulin biosynthesis ↑ β-cell proliferation ↓ β -cell apoptosis ↓ Appetite ↑ Neuroprotection ↓ Glucose output Brain Pancreas Liver Muscle and adipose tissue ↑ Endothelial function ↑ Nitric oxide production ↑ ↓ Myocardial contractility (data conflict) ↑ Systolic function in myocardial infarction ↑ Systolic function in cardiomyopathy ↓ Infarct size ↑ Ischaemic pre-conditioning ↑ Post-ischaemic recovery ↑ Myocardial glucose uptake Heart Incretin hormone1,2 Clinical trial data show that GLP1 receptor agonists are associated with small increases in heart rate and modest reductions in body weight and blood pressure3
  • 74.
    GLP 1 Mimetic- Exenatide Effects: • Stimulates post-prandial insulin secretion (Stimulation of GLP-1 secretion from intestine which in turn stimulate insulin secretion from β cells). • Slows gastric emptying • Reduces appetite Administered: • Subcutaneous injection • Twice daily
  • 75.
    Exenatide • Less hypoglycemiccompared to insulin • BIG benefit of weight loss • Only licensed to lower blood sugars, not as weight loss agent • S.E: Nausea (about 44% of users), vomiting and diarrhea • Pancreatitis (liraglutide)
  • 76.
    Dipeptidyl peptidase-4 (DPP-4 ) inhibitors • e.g. Sitagliptin, Vildagliptin • Orally • Given once daily • half life 8-14 h • Dose is reduced in pts with renal impairment
  • 77.
    Mechanism of actionof sitagliptin Inhibit DPP-4 enzyme and leads to an increase in incretin hormones level. This results in an increase in insulin secretion & decrease in glucagon secretion.
  • 78.
  • 79.
    DPP4 inhibitors: Mechanismof action Adapted from Drucker. Expert Opin Invest Drugs 2003;12:87–100 and Ahrén Curr Diab Rep. 2003;3:365–372. Food intake Glucose-dependent insulin secretion Increases glucose utilisation by muscle and adipose tissue Decreases hepatic glucose release improving overall glucose control Glucose-dependent glucagon suppression β-cells α-cells DPP4 Active GLP1 (7-36) Inactive GLP1 (9-36) amide 2 amino acids cleaved from amino terminus Pancreas DPP4 inhibitors Intestine 79
  • 80.
    Selected mechanistic trialsindicate potential CV effects of the DPP4 inhibitor class 80 1. Ye et al. Am J Physiol Heart Circ Physiol 2010;298:H1454–65. 2. Hocher et al. Int J Cardiol 2013;167:87–93. 3. van Poppel et al. Diabetes Care 2011;34:2072–77. 4. Kröller-Schön et al. Cardiovasc Res 2012;96:140–9. 5. Ta et al. J Cardiovasc Pharmacol 2011;58:157–66. 6. Sauvé et al. Diabetes 2010;59:1063–73. 7. Read et al. Circ Cardiovasc Imaging 2010;3:195–201. 8. Matikainen et al. Diabetologia 2006;49:2049–57. Endothelial function3 Atherosclerotic plaque volume5 Left ventricular function6,7 Myocardial infarct size1,2 Triglycerides8 Inflammation and oxidative stress4
  • 81.
    Clinical uses Type 2DM as an adjunct to diet & exercise as a monotherapy or in combination with other antidiabetic drugs. Adverse effects -Nausea, diarrhea - Headaches -Nasopharyngitis, upper respiratory infections -Hypoglycemia -Allergic and hypersensitivity reactions
  • 82.
    Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors •SGLT2 inhibitors, also called gliflozins, are a class of medications that alter essential physiology of the nephron; unlike SGLT1 inhibitors that modulate sodium/glucose channels in the intestinal mucosa. • The foremost metabolic effect appears to show that this pharmaceutical class inhibits reabsorption of glucose in the kidney and therefore lower blood sugar. • They act by inhibiting sodium-glucose transport protein 2 (SGLT2). SGLT2 inhibitors are used in the treatment of type II diabetes mellitus (T2DM)
  • 83.
    Urinary glucose excretionvia SGLT2 inhibition1 83 1. Bakris et al. Kidney Int 2009;75;1272–7. SGLT2 SGLT2 inhibitor SGLT1 SGLT2 inhibitors reduce glucose reabsorption in the proximal tubule, leading to urinary glucose excretion* and osmotic diuresis Filtered glucose load > 180 g/day
  • 84.
    SGLT2 Inhibitors • TheSGLT2 inhibitors are efficacious agents in reducing HbA1c, postprandial glucose, and fasting plasma glucose, as well as reducing systolic blood pressure and weight • Medicines in the SGLT2 inhibitor class include canagliflozin, dapagliflozin, and empagliflozin.
  • 85.
    Pharmacological properties of available SGLT2inhibitors 85 *For the 300 mg dose. Data from http://www.ema.europa.eu/ (Jardiance SPC, Forxiga SPC , Invokana PI, Invokana SPC, all accessed June 2015); 1. Sha et al. Diab Obes Metab 2015;17:188–97. Empagliflozin Dapagliflozin Canagliflozin Therapeutic dose (mg/day) Starting dose 10–25 10 5–10 10 100–300 100 Administration QD With or without food QD With or without food QD Before first meal Peak plasma concentration (hours post-dose) 1.5 Within 2 1–2 Absorption (mean oral bioavailability) ≥ 60% ~ 78% ~ 65% Metabolism  Primarily glucuronidation - no active metabolite → Elimination (half-life, hours) Hepatic:renal 43:57 [12.4] Hepatic:renal 22:78 [12.9] Hepatic:renal 67:33 [13.1]* Selectivity over SGLT1 1:5000 > 1:1400 > 1:1601 Glucose excretion with higher dose (g/day) 78 ~ 70 119 Link to SGLT2 clinical data
  • 86.
    86 Hypoglycemics, SGLT2 Reaching acrossArizona to provide comprehensive quality health care for those in need Drug Manufacturer Indications canagliflozin (Invokana®) Janssen ▪ Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM) ▪ To reduce the risk of major adverse cardiovascular events (MACE) in adults with T2DM and established cardiovascular disease (CVD) ▪ To reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults T2DM and diabetic nephropathy with albuminuria > 300 mg/day canagliflozin/ metformin (Invokamet®) Janssen ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM when treatment with both canagliflozin and metformin is appropriate ▪ To reduce the risk of MACE in adults with T2DM and established CVD* canagliflozin/ metformin (Invokamet® XR) Janssen ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM when treatment with both canagliflozin and metformin is appropriate ▪ To reduce the risk of MACE in adults with T2DM and established CVD* dapagliflozin (Farxiga®) AstraZeneca ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM ▪ To reduce the risk of hospitalization for heart failure in adults with T2DM and established CVD or multiple cardiovascular (CV) risk factors
  • 87.
    87 Hypoglycemics, SGLT2 Reaching acrossArizona to provide comprehensive quality health care for those in need dapagliflozin/ metformin ER (Xigduo® XR) AstraZeneca ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM when treatment with both dapagliflozin and metformin is appropriate ▪ Dapagliflozin is indicated to reduce the risk of hospitalization for heart failure in adults with T2DM and established CVD or multiple CV risk factors. empagliflozin (Jardiance®) Boehringer Ingelheim ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM ▪ To reduce the risk of cardiovascular death in adults with T2DM and established CVD empagliflozin/ metformin (Synjardy®) Boehringer Ingelheim ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM when treatment with both empagliflozin and metformin is appropriate ▪ To reduce the risk of cardiovascular death in adults with T2DM and established CVD* empagliflozin/ metformin ER (Synjardy® XR) Boehringer Ingelheim ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM when both empagliflozin and metformin is appropriate ▪ To reduce the risk of cardiovascular death in adults with T2DM and established CVD* ertugliflozin (Steglatro™) Merck, Sharp & Dohme ▪ Adjunct to diet and exercise to improve glycemic control in adults T2DM ertugliflozin/ metformin (Segluromet™) Merck, Sharp & Dohme ▪ Adjunct to diet and exercise to improve glycemic control in adults with T2DM who are not adequately controlled on a regimen containing ertugliflozin or metformin, or in patients who are already treated with both ertugliflozin and metformin
  • 88.
    88 Potential Adverse EffectPractical Considerations Adverse drug-drug Interaction Pharmacokinetic drug-drug interactions are minimal Canagliflozin is a P-glycoprotein substrate (modest inhibition); co-administration with digoxin may increase plasma levels of digoxin; monitor digoxin levels and for signs and symptoms of toxicity when both are used together Genital and urinary infections Mycotic infections more common among females and in uncircumcised males Reinforce importance of adequate hygiene Counsel patients to urgently report genital/perineal tenderness, redness, or swelling No significant increase in risk of urinary tract infections Hypoglycemia Uncommon; risk increased with concomitant use of sulfonylureas and insulin
  • 89.
    89 Potential Adverse EffectPractical Considerations Diabetic ketoacidosis Avoid pre-emptive substantial reductions in insulin dose Hold dose if acutely ill with limited oral intake, and 3 days before major surgery Use caution with low carbohydrate diets to minimize excessive ketosis Discourage excessive alcohol intake Counsel patients regarding potential symptoms of diabetic ketoacidosis (fruity odor on breath, thirst, polyuria, nausea, vomiting, abdominal pain, confusion, and fever) Renal injury Baseline and periodic monitoring of renal function is recommended, especially if used in chronic kidney disease Cases of acute kidney injury are rare, except in concert with volume depletion
  • 90.
    90 Potential Adverse EffectPractical Considerations Volume depletion Increased risk with concomitant diuretic use; consider diuretic dose adjustment Educate patient about potential for orthostatic hypotension and necessity to monitor daily weights and blood pressure, particularly in the first week of therapy Lower limb amputations Predominantly toe and metatarsal More apparent with canagliflozin Increased risk among those with previous amputations or in patients with peripheral artery disease Remind patients to perform regular foot exams and to see a podiatrist annually
  • 91.
    Hypoglycemics, SGLT2 • Perthe AACE/ACE guidelines, agents for monotherapy are recommended in the following order (highest to lowest recommendation): 1.metformin, 2.GLP-1 receptor agonists, 3.SGLT2 inhibitors, 4.DPP-4 inhibitors, 5.TZDs, 6.Alpha-glucosidase inhibitors, and sulfonylureas/secretagogue glinides • AACE/ACE recognizes that empagliflozin and canagliflozin are associated with significantly reduced cardiac mortality, hospitalization for heart failure, as well as secondary renal endpoints • Additionally, dapagliflozin demonstrated reduced all-cause mortality and the composite of CV death and HF hospitalization; however, it did not significantly lower the combined risk of CV death and nonfatal MI and stroke • The American College of Physicians’ (ACP) revised 2017 guidelines for T2DM recommend metformin as first-line therapy, and a sulfonylurea, TZD, SGLT-2 inhibitor, or a DPP-4 inhibitor as preferred second-line treatments
  • 92.
    Hypoglycemics, SGLT2 • Perthe 2019 American Diabetes Association (ADA) Standards of Medical Care in Diabetes, metformin is recommended as initial therapy for the treatment of T2DM, along with lifestyle interventions at the time of diagnosis, unless metformin is contraindicated
  • 93.
    Hypoglycemics, SGLT2 • Ifmetformin fails to produce the target HbA1c after 3 months of therapy, a thiazolidinedione (TZD), sulfonylurea (SU), dipeptidyl peptidase-4 (DPP-4) inhibitor, SGLT2 inhibitor, glucagon-like peptide-1 (GLP-1) receptor agonist, or basal insulin should be added in patients without atherosclerotic cardiovascular disease (ASCVD) or chronic kidney disease (CKD) • In patients with ASCVD or CKD, the addition of an agent with known cardiovascular (CV) or renal benefit (select GLP-1 agonist or select SLGT2 inhibitor) is preferred • The selection of medications should be patient-centric and prescribers should consider potential issues such as HbA1c target, impact on weight and hypoglycemia, side effects, the frequency and mode of administration, patient adherence, patient preference, and cost • Thiazolidinediones and sulfonylureas are generally considered less safe than glucagon- like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter type 2 (SGLT2) inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, or alpha-glucosidase inhibitors
  • 94.
    Hypoglycemics, SGLT2 • Ifthere is a compelling need to minimize weight gain or promote weight loss, a GLP-1 agonist or SGLT2 inhibitor are recommended • In patients with atherosclerotic cardiovascular disease (ASCVD), the addition of empagliflozin (Class A recommendation), liraglutide (Class A recommendation), or canagliflozin (Class C recommendation) is preferred • In patients with heart failure (HF) or chronic kidney disease (CKD), empagliflozin, canagliflozin, or dapagliflozin is preferred • The American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) 2019 diabetes management algorithm and 2015 clinical practice guidelines for developing a diabetes care plan include the use of SGLT2 inhibitors as an alternative to metformin for monotherapy and as an appropriate add-on to metformin in dual therapy and triple therapy
  • 95.
    Insulin Th inDM type II. • Insufficient glycaemic control despite of maximal doses of PAD in combination • Decompensation during intercurrent diseases (infections, trauma, stress) • Perioperative period • Pregnancy and lactation • Vital organs failure (stroke, IM) • Allergy • Contraindications and adverse effects • Significant hyperglycaemia at admission