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

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

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  • 1. MODERN MODALITIES FOR MANAGEMENT OF DIABETES Dr. Mahir Khalil Jallo Associate Professor of Medicine Consultant Diabetes & Endocrinology Gulf Medical University Doctor MEET 2013 Mahir Jallo
  • 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. 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. Macrovascular Microvascular Stroke Heart disease and hypertension Ulcers and amputation Diabetic eye disease (retinopathy and cataracts) Renal disease (Kidney) Neuropathy Foot problems Peripheral vascular disease Diabetes Complications
  • 5. Diabetes = CVD Up to 80% of adults with diabetes will die of cardiovascular disease. Adapted from Barrett-Connor 2001.
  • 6. Macrovascular Microvascular Stroke Heart disease and hypertension Ulcers and amputation Diabetic eye disease (retinopathy and cataracts) Renal disease (Kidney) Neuropathy Foot problems Peripheral vascular disease Diabetes Complications
  • 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. PORTION SIZE: 1950S TO 2000
  • 9. Millions of years < 30 years
  • 10. A GROWING DIVIDE Evidence Behaviour How can we facilitate translating science to better outcomes?
  • 11. POLYPHARMACY A reality in modern diabetes management
  • 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. TYPE 2 DIABETES High blood glucose 1. Defective beta cell function • Diminished phase 1 insulin release • Delayed phase 2 insulin release 2. Overproduction of glucagon Impaired GI motility 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. 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 DeFronzo RA. Diabetes. 2009;58:773-795 18
  • 18. TYPE 2 DIABETES MEDICATIONS 19 1960 1995 2000 2005 2010 Insulin 1922 SUs 1957 Metformin AGIs 1995 Glinides TZDs 1997 Exenatide Pramlintide 2005 Sitagliptin 2006 Liraglutide 2010 Patlak M. Breakthroughs in Bioscience 2002. Philippe J. Int J Clin Pract 2009;63:321-332 Saxagliptin 2009
  • 19. NONINSULIN AGENTS AVAILABLE FOR THE TREATMENT OF TYPE 2 DIABETES (2012) Class Primary Mechanism of Action Agent Available as -Glucosidase inhibitors  Delay carbohydrate absorption from intenstine Acarbose Precose or generic Miglitol Glyset Amylin analog  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 DPP-4 inhibitors  Increase glucose-dependent insulin secretion  Decrease glucagon secretion Linagliptin Trajenta Saxagliptin Onglyza Sitagliptin Vildagliptin Januvia Galvus Dopamine-2 agonist  Activates dopaminergic receptors Bromocriptine Cycloset 20Inzucchi SE, et al. Diabetes Care, 19 April 2012 [Epub ahead of print]
  • 20. NONINSULIN AGENTS AVAILABLE FOR THE TREATMENT OF TYPE 2 DIABETES (2012) Class Primary Mechanism of Action Agent Available as Glinides  Increase insulin secretion Nateglinide Starlix or generic Repaglinide Prandin GLP-1 receptor agonists  Increase glucose-dependent insulin secretion  Decrease glucagon secretion  Slow gastric emptying  Increase satiety Exenatide Byetta Exenatide XR Bydureon Liraglutide Victoza SGLT2 inhibitors  Increase urinary excretion of glucose Canagliflozin Invokana Sulfonylureas  Increase insulin secretion Glimepiride Amaryl or generic Glipizide Glucotrol or generic Glyburide Diaeta, Glynase, Micronase, or generic Thiazolidinediones  Increase glucose uptake in muscle and fat  Decrease HGP Pioglitazone Actos Rosiglitazone* Avandia *Use restricted due to increased risk of myocardial infarction (MI) 21Inzucchi SE, et al. Diabetes Care, 19 April 2012 [Epub ahead of print]
  • 21. INSULINS AVAILABLE FOR THE TREATMENT OF TYPE 2 DIABETES (2012) Class Primary Mechanism of Action Agent Available as Insulin  Increase glucose uptake  Decrease HGP Basal Detemir Levemir Glargine Lantus Neutral protamine Hagedorn (NPH) Generic Prandial Aspart NovoLog Glulisine Apidra Lispro Humalog Regular human Humulin Premixed Biphasic aspart NovoLog Mix Biphasic lispro Humalog Mix 22Inzucchi SE, et al. Diabetes Care, 19 April 2012 [Epub ahead of print]
  • 22. COMBINATION AGENTS AVAILABLE FOR THE TREATMENT OF TYPE 2 DIABETES (2012) Class Added Agent Available as Metformin + DPP-4 inhibitor Linagliptin Jentadueto Saxagliptin Kombiglyze XR Sitagliptin Janumet Metformin + glinide Repaglinide Prandimet Metformin + sulfonylurea Glipizide Metaglip and generic Glyburide Glucovance and generic Metformin + thiazolidinedione Pioglitazone ACTOplus Met Rosiglitazone* Avandamet Thiazolidinedione + sulfonylurea Pioglitazone Duetact Rosiglitazone* Avandaryl *Use restricted due to increased risk of myocardial infarction (MI) 23
  • 23. TREATMENT ORAL OPTIONS FOR TYPE 2 DIABETES  Sulfonylureas  1st generation e.g. chlorpropamide, tolbutamide  2nd generation e.g. glyburide, gliclazide, glipizide, gliquidone  3rd generation e.g. glimepiride  Modified release  Glinides/meglitinides  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 – 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. DPP-4 INHIBITORS & COMBINATIONS DRUGS IN THE CLASS Active Ingredient Brand Strengths FDA Approval Date Patent Expiration Date Sitagliptin 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 Linagliptin Trajenta (Lilly/BI) 5mg 5/2/2011 - Vildagliptin Galvus (Novartis) 50mg EUROPE September 2007 - Vildagliptin/ Metformin Galvusmet (Novartis) 50mg/850mg 50mg/1000mg -
  • 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. 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. 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. 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. ROLE OF INCRETINS IN GLUCOSE HOMEOSTASIS 35 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. Ingestion of food Beta cells Alpha cells Release of gut hormones : Incretins Pancreas2,3 Glucose-dependent  Insulin from beta cells (GLP-1 and GIP) Glucose uptake by muscles Glucose production by liver Blood glucose Glucose dependent  Glucagon from alpha cells (GLP-1) Active GLP-1 & GIP DPP-4 enzyme Inactive GIP Inactive GLP-1
  • 36. 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) DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS
  • 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. SGLT-2 INHIBITORS 43 Drugs 2010;70(4):377-385
  • 39. 44 • 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. GLP1 Exenatide BYETTA®
  • 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 45 ThrGlu Gly PheThr Ser Asp Val Ser SerAlaHis Tyr Leu Glu Gly Gln Ala Ala Arg GlyPhe Ile TrpAla Leu Val Arg GlyGluLys Glu Albumin Liraglutide, NN2211 (NovoNordisk)‫‏‬ C-16 fatty acid (noncovalent binding to albumin)
  • 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 46 Better efficacy and tolerability than BYETTA Improves Patient compliance and outcomes
  • 43. INCRETIN MIMETICS AND DPP-4 INHIBITORS: MAJOR DIFFERENCES 48 Properties/effect Incretin mimetics DPP-4 inhibitors Restitution of insulin secretion Yes (exenatide) Yes Hypoglycaemia No No Maintained counter-regulation by glucagon in hypoglycaemia Yes Not tested Inhibition of gastric emptying Yes Marginal Effects on satiety Reduces food intake None Effect on body weight Weight loss Weight neutral Side effects Nausea None observed Administration Subcutaneous Oral Dosage Twice daily Once daily
  • 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. PIPELINE CLASSES AND AGENTS (2013) Class Phase of Development Agents Description Dual peroxisome proliferator activated receptor - (PPAR-) agonist Phase 3 Aleglitazar Improve insulin sensitivity in the periphery as well as lipid profiles Approved agents may reduce both cardiovascular risks and potential for diabetes complications Short-acting GLP-1 receptor agonist Lixisenatide 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 Ultra-long-acting basal insulin (half-life ~25 hours) with low within-subject variability and potential for reduced incidence of hypoglycemia DegludecPlus Premixed insulin containing degludec plus aspart, providing both fasting and postprandial glucose control Salicylates Phase 3 Salsalate Generically available anti-inflammatory medication currently approved for treatment of arthritis; inhibits activity of NF-B, an inflammatory factor 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 11-Hydroxysteroid dehydrogenase type 1 (11HSD-1) inhibitors Phase 2 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 51 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; Tahrani AA, et al. Lancet. 2012;379:1465-1467.
  • 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 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 53 Testing positively affects glycemia in T2DM when the results are used to: • Modify behavior • Modify pharmacologic treatment SMBG, self-monitoring of blood glucose. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
  • 50. CSII IN TYPE 2 DIABETES: PATIENT CANDIDATES  Absolutely insulin- deficient  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 55CSII, continuous subcutaneous insulin infusion. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
  • 51. SURGICAL INTERVENTION IN TYPE 2 DIABETES 56 Schauer PR, et al. N Engl J Med. 2012;366:1567-1576. MonthsMonths 3.5 2.5 1.5 0.5 0.0 1.0 2.0 3.0 Baseline 3 6 9 12 Averageno.diabetes medications P<0.001 P<0.001 -2 -6 -10 -12 -8 -4 0 Baseline 3 6 9 12 BMI(kg/m2) P<0.001 P<0.001 20 -40 -100 -140 -160 -120 -60 -20 -80 0 Baseline 3 6 9 12 FPG(mg/dL) P=0.02 P<0.001 0.0 1.0 2.0 3.0 3.5 2.5 1.5 0.5 Baseline 3 6 9 12 A1C(%) P<0.001 P<0.001 Intensive medical therapy Sleeve gastrectomy Roux-en-Y gastric bypass
  • 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 58 Ann Pharmacother 2010;44:1231-1239
  • 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%) 59 Lancet 2010;375:2244-2253
  • 55. AACE COMPREHENSIVE CARE PLAN 60 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
  • 56. Mahir Jallo