Modern Modalities for Management of Diabetes Dr Mahir Jallo Gulf Medical University 2013 signed


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Modern Modalities for Management of Diabetes : An Overview for All Diabetic care Providers

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Modern Modalities for Management of Diabetes Dr Mahir Jallo Gulf Medical University 2013 signed

  1. 1. Dr. Mahir Khalil Jallo Associate Professor of Medicine Consultant Diabetes & Endocrinology Gulf Medical University Doctor MEET 2013 MODERN MODALITIES FOR MANAGEMENT OF DIABETES Mahir Jallo
  2. 2. WHAT IS DIABETES? Type 1 diabetes (5-10%)  Body’s own immune system attacks the cells in the pancreas that produce insulin Type 2 diabetes (90 - 95%)  The pancreas does not produce enough insulin and/or the bodies’ tissues do not respond properly to the actions of insulin  Caused by both genetic and environmental factors Gestational diabetes  Diabetes with first onset or recognition during pregnancy  Puts women at higher risk for type 2 DM later in life
  3. 3. WHAT DIABETES IS NOT Diabetes is NOT “a touch of sugar”  It is a serious chronic disease that can lead to complications.  Heart attack  Stroke  Blindness  Amputation  Kidney disease  Sexual dysfunction  Nerve damage 
  4. 4. Diabetes Complications Macrovascular Stroke Microvascular Diabetic eye disease (retinopathy and cataracts) Heart disease and hypertension Renal disease (Kidney) Peripheral vascular disease Neuropathy Ulcers and amputation Foot problems
  5. 5. Diabetes = CVD Up to 80% of adults with diabetes will die of cardiovascular disease. Adapted from Barrett-Connor 2001.
  6. 6. Diabetes Complications Macrovascular Stroke Heart disease and hypertension Microvascular Diabetic eye disease (retinopathy and cataracts) Renal disease (Kidney) Peripheral vascular disease Neuropathy Ulcers and amputation Foot problems
  7. 7. WHY THE EPIDEMIC?  Physical Inactivity  60% to 85% of adults are not active enough to maintain their health  Diet  Calorie dense; high fat Aging population  Urbanization   Shift from an agricultural to an urban lifestyle means a decrease in physical activity
  8. 8. PORTION SIZE: 1950S TO 2000
  9. 9. Millions of years < 30 years
  10. 10. A GROWING DIVIDE Evidence Behaviour How can we facilitate translating science to better outcomes?
  11. 11. POLYPHARMACY A reality in modern diabetes management
  12. 12. DIABETES MEDICATIONS In order to reach A1C, BP and lipid targets, people with diabetes typically require many medications:  To lower blood glucose: 1-3 pills and/or insulin  To lower cholesterol: 1 or 2 pills  To lower blood pressure: 2 or 3 pills  For general vascular protection: aspirin Adherence to complex drug regimens can be a challenge for patients
  16. 16. TYPE 2 DIABETES High blood glucose Impaired GI motility 1. Defective beta cell function • • Diminished phase 1 insulin release Delayed phase 2 insulin release 2. Overproduction of glucagon 1. Tissues less sensitive to insulin 2. Liver produces excess glucose Image Obtained From: Diabetes 101: Overview of Drug Therapy by Jennifer Danielson, RPh, CDE Type 2 Video from
  17. 17. PATHOPHYSIOLOGY OF T2DM Organ System Defect Major Role Pancreatic beta cells Decreased insulin secretion Muscle Inefficient glucose uptake Liver Increased endogenous glucose secretion Contributing Role Adipose tissue Increased FFA production Digestive tract Decreased incretin effect Pancreatic alpha cells Increased glucagon secretion Kidney Increased glucose reabsorption Nervous system Neurotransmitter dysfunction 18 DeFronzo RA. Diabetes. 2009;58:773-795
  18. 18. TYPE 2 DIABETES MEDICATIONS Insulin 1922 SUs 1957 1960 Metformin AGIs 1995 1995 Sitagliptin Saxagliptin 2006 2009 2000 Glinides TZDs 1997 2005 2010 Exenatide Pramlintide 2005 Liraglutide 2010 Philippe J. Int J Clin Pract 2009;63:321-332 Patlak M. Breakthroughs in Bioscience 2002. 19
  19. 19. NONINSULIN AGENTS AVAILABLE FOR THE TREATMENT OF TYPE 2 DIABETES (2012) Class Primary Mechanism of Action -Glucosidase inhibitors  Delay carbohydrate absorption from intenstine Agent Acarbose Available as Precose or generic Miglitol Glyset    Decrease glucagon secretion Slow gastric emptying Increase satiety Pramlintide Symlin Biguanide   Decrease HGP Increase glucose uptake in muscle Metformin Glucophage or generic Bile acid sequestrant   Decrease HGP? Increase incretin levels? Colesevelam WelChol  Increase glucose-dependent insulin secretion Decrease glucagon secretion Linagliptin Saxagliptin Trajenta Onglyza Sitagliptin Vildagliptin Januvia Galvus Bromocriptine Cycloset Amylin analog DPP-4 inhibitors  Dopamine-2 agonist  Activates dopaminergic receptors 20 Inzucchi SE, et al. Diabetes Care, 19 April 2012 [Epub ahead of print]
  20. 20. NONINSULIN AGENTS AVAILABLE FOR THE TREATMENT OF TYPE 2 DIABETES (2012) Class Primary Mechanism of Action Glinides  Increase insulin secretion  Increase glucose-dependent insulin secretion Decrease glucagon secretion Slow gastric emptying Increase satiety Increase urinary excretion of glucose SGLT2 inhibitors Sulfonylureas       Thiazolidinediones  Increase insulin secretion Increase glucose uptake in muscle and fat Decrease HGP Available as Starlix or generic Prandin Exenatide Byetta Exenatide XR Bydureon Liraglutide Victoza Canagliflozin Invokana Glimepiride Glipizide Amaryl or generic Glucotrol or generic Glyburide GLP-1 receptor agonists Agent Nateglinide Repaglinide Diaeta, Glynase, Micronase, or generic Pioglitazone Actos Rosiglitazone* Avandia *Use restricted due to increased risk of myocardial infarction (MI) 21 Inzucchi SE, et al. Diabetes Care, 19 April 2012 [Epub ahead of print]
  21. 21. INSULINS AVAILABLE FOR THE TREATMENT OF TYPE 2 DIABETES (2012) Class Primary Mechanism of Action Insulin   Basal Prandial Premixed Agent Available as Detemir Glargine Levemir Lantus Neutral protamine Hagedorn (NPH) Generic Aspart Glulisine Lispro Regular human Biphasic aspart Biphasic lispro NovoLog Apidra Humalog Humulin NovoLog Mix Humalog Mix Increase glucose uptake Decrease HGP 22 Inzucchi SE, et al. Diabetes Care, 19 April 2012 [Epub ahead of print]
  22. 22. COMBINATION AGENTS AVAILABLE FOR THE TREATMENT OF TYPE 2 DIABETES (2012) Class Metformin + sulfonylurea Metformin + thiazolidinedione Thiazolidinedione + sulfonylurea Jentadueto Saxagliptin Kombiglyze XR Sitagliptin Metformin + glinide Available as Linagliptin Metformin + DPP-4 inhibitor Added Agent Janumet Repaglinide Prandimet Glipizide Metaglip and generic Glyburide Glucovance and generic Pioglitazone ACTOplus Met Rosiglitazone* Avandamet Pioglitazone Duetact Rosiglitazone* Avandaryl *Use restricted due to increased risk of myocardial infarction (MI) 23
  23. 23. TREATMENT ORAL OPTIONS FOR TYPE 2 DIABETES  Sulfonylureas       Non-sulfonylureic e.g. repaglinide Amino acid derivatives e.g. nateglinide Biguanides    e.g. Metformin. Metformin XR Thiazolidinediones  e.g. Pioglitazone -glucosidase inhibitors  e.g. Acarbose DPP4 Inhibitors – – – – Glinides/meglitinides   1st generation e.g. chlorpropamide, tolbutamide 2nd generation e.g. glyburide, gliclazide, glipizide, gliquidone 3rd generation e.g. glimepiride Modified release   Sitagliptin. Vildagliptin. Saxagliptin. Linagliptin. Fixed-dose oral antidiabetic drug combinations  e.g. Glyburide/Metformin, Glimepride/Metformin, Pioglitazone/Metformin Sitagliptin/Metformin, Sitagliptin/Simvastatin Vildagliptin/Metformin, Saxagliptin/Metformin XR
  24. 24. DPP-4 INHIBITORS & COMBINATIONS DRUGS IN THE CLASS Strengths FDA Approval Date Patent Expiration Date Januvia (Merck) 25mg, 50mg, 100mg 10/16/2006 04/24/2017 Sitagliptin/ Metformin Janumet (Merck) 50mg/500mg, 50mg/1000mg 03/30/2007 04/24/2017 Saxagliptin Onglyza (BMS) 2.5mg, 5mg 07/31/2009 02/16/2021 Saxagliptin/ Metformin XR Kombiglyze XR (BMS) 2.5mg/1000mg 5mg/500mg 5mg/1000mg 11/05/2010 02/16/2021 5mg 5/2/2011 - 50mg EUROPE September 2007 - Active Ingredient Brand Sitagliptin Linagliptin Vildagliptin Vildagliptin/ Metformin Trajenta (Lilly/BI) Galvus (Novartis) Galvusmet (Novartis) 50mg/850mg 50mg/1000mg -
  26. 26. FIRST PRINCIPLES OF THE AACE/ACE ALGORITHM Avoidance of hypoglycemia is a priority  Avoidance of weight gain is a priority  All medication options need to be considered  Acquisition cost is not the total cost of a drug  Therapy selection must be stratified by A1C  Post-prandial glucose is an important target  Rodbard HW, et al. Endocr Pract. 2009;15:540-559
  27. 27. SECONDARY PRINCIPLES OF THE AACE/ACE ALGORITHM Ease of use improves adherence  Minimal side effects improves adherence  Improved -cell performance over a longer period of time is possible  Multiple combinations are required  Rodbard HW, et al. Endocr Pract. 2009;15:540-559
  28. 28. NINE TO KNOW THE MINIMUM THAT MUST BE KNOWN ABOUT DRUGS!          Brand & Generic Name Mechanism of action Therapeutic effect Relevant pharmacokinetics and pharmacodynamics Dosing by route Adverse reactions and contraindications Monitoring parameters Drug-drug and drug food interactions Comparisons between agents w/in the same class of drugs
  29. 29. DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS INDICATIONS Diabetes Mellitus Type II MOA Inhibits the breakdown of GLP-1 by DPP-4 therefore increasing GLP-1 levels resulting in increased glucose-dependent insulin release and decreased level of circulating glucagon and hepatic glucose production
  30. 30. ROLE OF INCRETINS IN GLUCOSE HOMEOSTASIS Ingestion of food Pancreas2,3 Glucose-dependent  Insulin from beta cells (GLP-1 and GIP) Release of gut hormones : Incretins Glucose uptake by muscles Blood glucose Beta cells Alpha cells Active GLP-1 & GIP DPP-4 enzyme Glucose dependent  Glucagon from alpha cells (GLP-1) Glucose production by liver Inactive Inactive GLP-1 GIP DPP-4 = dipeptidyl-peptidase 4 Sources :1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913. 2. Ahrén B. Curr Diab Rep. 2003;2:365–372. 3. Drucker DJ. Diabetes Care. 2003;26:2929–2940. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441. 35
  36. 36. DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS SPECIAL POPULATION CONSIDERATIONS: Renal Impairment: avoid combo drugs w/ metformin  For Sitagliptin:  CrCl 30-50 mL/min : 50 mg daily  CrCl < 30 mL/min: 25 mg daily  End Stage Renal Disease Requiring dialysis: 25 mg daily  Geriatric: caution due to age related renal function decreases Cautions/Severe Adverse Reactions  Acute pancreatitis  Rash (Stevens-Johnson syndrome) 
  37. 37. SODIUM GLUCOSE CO-TRANSPORTER 2 INHIBITORS  Canagliflozin    Invokana not only helped patients improve blood sugar control, but also lose weight and control their BP. Losing weight help people control their diabetes. In one 26-week study, those on Invokana lost about 6 to 8 pounds.  Dapagliflozin 42
  38. 38. SGLT-2 INHIBITORS Drugs 2010;70(4):377-385 43
  39. 39. GLP1 Exenatide BYETTA® • Approved by FDA in April 2005 • Indication and usage : Type 2 Diabetes : Combination therapy with metformin and/or a sulfonylurea and/or thiazolidinedione when the single agent does not provide adequate glycemic control. • Important limitations of use : BYETTA® should not be used in patients with T1D or for the treatment of diabetic ketoacidosis. 44
  40. 40. LIRAGLUTIDE VICTOZA     An extended half-life (~12 hours)‫ ‏‬long-acting analog of GLP1 Single daily injection 0.6 -1.8 ↓ Weight and ↓ HbA1c Nausea is the most common adverse effect Liraglutide, NN2211 (NovoNordisk)‫‏‬ His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Arg Gly Arg Gly Glu Albumin C-16 fatty acid (noncovalent binding to albumin) 45
  41. 41. EXENATIDE LAR BYDUREON  First once-weekly injection for type 2 diabetes 52 doses a year vs. 730  Based on Alkermes’ proprietary technology for long-acting medications Better efficacy and tolerability than BYETTA Improves Patient compliance and outcomes 46
  43. 43. INCRETIN MIMETICS AND DPP-4 INHIBITORS: MAJOR DIFFERENCES Properties/effect Restitution of insulin secretion Incretin mimetics DPP-4 inhibitors Yes (exenatide) Yes Hypoglycaemia No No Maintained counter-regulation by glucagon in hypoglycaemia Yes Not tested Inhibition of gastric emptying Yes Marginal Reduces food intake None Weight loss Weight neutral Nausea None observed Subcutaneous Oral Twice daily Once daily Effects on satiety Effect on body weight Side effects Administration Dosage 48
  45. 45. INVESTIGATIONAL GLP-1 AGONISTS  Albiglutide (GlaxoSmithKline)  Recruitment  complete in 8 Phase III studies Lixisenatide (Sanofi-Aventis)  Phase III results presented at EASD 2010  Decreased A1C significantly vs placebo  Additional Phase III results expected Q2 2011  Taspoglutide (Roche)  Returned rights to Ipsen after hypersensitivity, GI reactions led to halt of Phase III trials in 9/2010 50
  46. 46. PIPELINE CLASSES AND AGENTS (2013) Class Phase of Development Dual peroxisome proliferator activated receptor - (PPAR-) agonist Phase 3 Short-acting GLP-1 receptor agonist Agents Description Lixisenatide Improve insulin sensitivity in the periphery as well as lipid profiles Approved agents may reduce both cardiovascular risks and potential for diabetes complications Human-derived molecule with effects similar to exenatide Long-acting GLP-1 receptor agonists Phase 3 Albiglutide Taspoglutide Effects probably similar to currently available GLP-1 receptor agonists Longer duration of action will permit longer intervals between injections Insulin Phase 3 Degludec Aleglitazar DegludecPlus Ultra-long-acting basal insulin (half-life ~25 hours) with low within-subject variability and potential for reduced incidence of hypoglycemia Premixed insulin containing degludec plus aspart, providing both fasting and postprandial glucose control Generically available anti-inflammatory medication currently approved for treatment of arthritis; inhibits activity of NF-B, an inflammatory factor Salicylates Phase 3 Salsalate Sodium-dependent glucose cotransporter 2 (SGLT-2) inhibitors Phase 3 Dapagliflozin Empagliflozin Tofogliflozin Act in the kidney Reduce hyperglycemia by inhibiting glucose reabsorption into the bloodstream from the renal filtrate, increasing urinary excretion of glucose INCB13739 RG4929 Inhibit 11HSD-1 mediated conversion of low-activity cortisone to cortisol, which is primarily produced in the liver and adipose tissue May lessen stress-induced obesity, improve insulin sensitivity, enhance insulin-secretory responsiveness, and improve glucose tolerance in patients with metabolic syndrome and/or type 2 diabetes 11-Hydroxysteroid dehydrogenase type 1 (11HSD-1) inhibitors Phase 2 Bakris GL, et al. Kidney Int. 2009;75:1272-1277; Calado J, et al. Kidney Int Suppl. 2011:S7-S13; Garber AJ. Expert Opin Investig Drugs. 2012;21:45-57; Goldfine AB, et al. Ann Intern Med. 2010;152:346-357; King A. J Fam Pract. 2012;61:S28-S31; Tahrani AA, et al. Lancet. 2011;378:182-197; 51 Tahrani AA, et al. Lancet. 2012;379:1465-1467.
  48. 48. SMBG IN TYPE 2 DIABETES: AACE/ACE RECOMMENDATIONS    Noninsulin Users Introduce at diagnosis Personalize frequency of testing Use SMBG results to inform decisions about whether to target FPG or PPG for any individual patient Testing positively affects glycemia in T2DM when the results are used to: • Modify behavior • Modify pharmacologic treatment  Insulin Users All patients using insulin should test glucose    ≥2 times daily Before any injection of insulin More frequent SMBG (after meals or in the middle of the night) may be required   Frequent hypoglycemia Not at A1C target SMBG, self-monitoring of blood glucose. 53 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
  50. 50. CSII IN TYPE 2 DIABETES: PATIENT CANDIDATES     Absolutely insulindeficient Take 4 or more insulin injections a day Assess blood glucose levels 4 or more times daily Motivated to achieve tighter glucose control     Mastery of carbohydrate counting, insulin correction, and adjustment formulas Ability to troubleshoot problems related to pump operation and plasma glucose levels Stable life situation Frequent contact with members of their healthcare team, in particular their pump-supervising physician CSII, continuous subcutaneous insulin infusion. 55 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
  51. 51. SURGICAL INTERVENTION IN TYPE 2 DIABETES 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Baseline P<0.001 P<0.001 3 6 9 12  FPG (mg/dL) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Baseline Sleeve gastrectomy Roux-en-Y gastric bypass 20 0 -20 -40 -60 -80 -100 -120 -140 -160 Baseline P=0.02 P<0.001 3 6 9 12 0 P<0.001 P<0.001 3 6 Months 9 12  BMI (kg/m2) Average no. diabetes medications  A1C (%) Intensive medical therapy -2 -4 -6 P<0.001 -8 -10 -12 Baseline P<0.001 3 6 9 12 Months 56 Schauer PR, et al. N Engl J Med. 2012;366:1567-1576.
  53. 53.  Afrezza® (MannKind)  Excipient: fumaryl diketopiperazine (FKDP)  FKDP self-assembles into microspheres 2 - 5 µm diameter  Insulin microencapsulated within microspheres  Freeze dried to form powder for inhalation  Rapid acting mealtime insulin (tmax = 15 min)  Bioavailability = 37% of SQ regular insulin Ann Pharmacother 2010;44:1231-1239 58
  54. 54. TECHNOSPHERE® INHALED INSULIN Randomized, open-label, 52 week trial  Prandial inhaled insulin + basal insulin glargine OR  Twice daily premixed biaspart insulin (Novolog Mix 70/30)  A1C: -0.68% vs -0.76% (noninferior)  Hypoglycemia: 48% vs 69%  Cough (33%), URI (12%)  Lancet 2010;375:2244-2253 59
  55. 55. AACE COMPREHENSIVE CARE PLAN 60 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
  56. 56. Mahir Jallo