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2. better control, better life   dr. ko ko
 

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  • SHARP 75 or 80 Tight control is more important earlier in the disease and has long term benefit
  • This is another example of the diabetes food pyramid. This pyramid recommends: Cereals, whole grains and starch as the staple content of the diet one to two servings of fruit and three to four servings of vegetables two to three servings of milk and meat products per day sugars, fats, oils and fatty foods to be eaten sparingly The number of servings depending on the individual’s caloric requirements. Disadvantages associated with the food pyramid include: Non-specific quantities for portion sizes The absence of healthier alternatives in each group No recommendations for the cooking of foods (ie healthy/unhealthy alternatives, eg fried versus steamed) A lack of differentiation between healthy (monounsaturated) fats and unhealthy ones (butter and ghee) A uniform approach to carbohydrates that fails to distinguish between healthier (whole grains) and refined flours No differentiation between healthier meat/fish options.
  • The plate model is a simple way to planning a balanced diet through appropriate portion sizes. Foods are divided into five basic groups: 1. Starch/cereals; 2. Vegetables; 3. Fruit; 4. Milk; 5. Protein/meat. The plate model recommends: one fourth starch (potato, colocassia, yam, sweet potato, peas, etc) one fourth protein (meat, fish, poultry, pulses, tofu, beans, etc) half of the plate should consist of vegetables (preferably non-starchy, low-carbohydrate vegetables such as cabbage, broccoli, green beans, carrots, mushrooms, tomatoes, cauliflower, spinach, peppers or salad greens) one cup of low-fat milk or yoghurt/curd one piece of fruit. A ‘meal plan’ exercise using the plate model can be carried out in a variety of ways: a paper plate can be used with basic drawings showing the amount of space which should be taken up by each food group (this technique helps to reinforce consistency and prevent large amounts of carbohydrate foods being eaten on any one day) another simple technique is to remind people to carry a ‘Handy Meal Plan’ on their hand: hold up your hand (palm facing forward), point to your four fingers and show that most adults can have about four carbohydrates per meal, a serving of meat/meat substitute the size of the palm (about 110 g) and just a ‘thumb tip’ of fat.
  • 08/13/13 18:42 No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies Speaker Notes No single-agent monotherapy has an MOA that addresses all key pathophysiologies of type 2 diabetes. Alpha-glucosidase inhibitors decrease intestinal absorption of glucose. 1,2 Meglitinides and sulfonylureas stimulate insulin secretion. 3–5 TZDs are insulin sensitizers that also lower hepatic glucose output. 6,7 Metformin, a biguanide, lowers hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity. 8 DPP-4 inhibitors improve insulin synthesis and release and lower hepatic glucose production, both through suppressing glucagon production and release, and by improving insulin synthesis and release. Each class of oral antihyperglycemic agent does not address at least 1 key pathophysiology of type 2 diabetes. Purpose: To examine the key pathophysiologies targeted by each class of oral antihyperglycemic agent. Takeaway: No one class targets all key pathophysiologies of type 2 diabetes. References: 1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004. 3. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007. 4. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 5. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004. 7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005. 8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.
  • ination therapy
  • Overview of anti-hyperglycemic therapy in T2DM (Figure 2.) What follows are variations of this figure to help guide the clinician in choosing agents which may be most appropriate under certain situations: to avoid weight gain, to avoid hypoglycemia, and to minimize costs.
  • Fig. 2B should be considered when the goal is to avoid weight gain. Note that "hidden" agents may obviously still be used when required, but additional care is needed to avoid adverse events. Here, the chances of weight gain when using the hidden agents will be mitigated by more rigorous adherence to dietary recommendations and optimal dosing.
  • Fig. 2C should be considered when the goal is to minimize costs. This reflects prevailing costs in the North America and Europe in early 2012; costs of certain drugs may vary considerably from country to country and as generic formulations become available.  
  • Metformin The clinical efficacy of metformin in patients with type 2 diabetes requires the presence of insulin, but it does not stimulate insulin secretion (hence no risk of hypoglycemia). The predominant glucose-lowering mechanism of action of metformin is to reduce excessive rates of hepatic glucose production. Metformin reduces gluconeogenesis by increasing hepatic sensitivity to insulin and decreasing the hepatic extraction of certain gluconeogenic substrates (e.g. lactate). Hepatic glycogenolysis is also decreased by metformin. Insulin-stimulated glucose uptake in skeletal muscle is enhanced by metformin. This involves an increase in the movement of insulin-sensitive glucose transporter molecules to the cell membrane; an increase in the activity of the enzyme glycogen synthase promotes synthesis of glycogen. Metformin also acts in an insulin-independent manner to suppress oxidation of fatty acids and to reduce triglyceride levels in patients with hypertriglyceridemia. This reduces the energy supply for hepatic gluconeogenesis and has favourable effects on the glucose-fatty acid (Randle) cycle (in which fatty acids are held to compete with glucose as a cellular energy source). Glucose metabolism in the splanchnic bed is increased by metformin through insulin-independent mechanisms. This may contribute to the blood glucose-lowering effect of the drug, and in turn may help to prevent gains in bodyweight. Collectively, the cellular effects of metformin serve to counter insulin resistance and to reduce the putative toxic metabolic effects of hyperglycaemia (glucose toxicity) and fatty acids (lipotoxicity) in type 2diabetes.
  • 1 ADA Consensus Statement ADA recommends sulfonylureas as a first-line therapy for patients with type 2 diabetes 18 Consensus statement was published in 1996 and remains unchanged for 1997
  • In 9 out of 10 cases, you can use them interchangeably. If a standard dose of one SU does not work, then other SUs will also not work Repaglinide and Nateglinide: Act similary but via a different receptor. They have quick action and shorter actions, so work well in post prandial glycemia. if an elderly patient requires avoidance of hypos, then we can use it. Shorter action time means that they will not work so well on fasting glycemia. Need to be given three times a day and are much more expensive than sulfonylureas. So they are not very popular in India.
  • Risk of Hypoglycemia with Different Sulfonylureas Incidence of hypoglycemia with SUs varies with different compounds. 1 Reference 1. Tayek J. SUR receptor activity vs. incidence of hypoglycaemia and cardiovascular mortality with sulphonylurea therapy for diabetics. Diabetes Obes Metab. 2008; 10: 1128–1130.

2. better control, better life   dr. ko ko 2. better control, better life dr. ko ko Presentation Transcript

  • Better control,Better Life Ko Ko Taunggyi MMA 15.2.13 UM 2
  • What new in 2013 BP 140/80 rather than 130/80 Patient centre apporoach
  • Conclusions from recent trials Tight control -early on has long term benefit on CVD -later in the disease has little impact on CVD -later in the disease may CVD risk Severe Hypo may be dangerous BP <120/80 no better than <140/80 Multifactorial management saves lives Early combination Therapy Therapeutic Inertia
  • Do we need better control? YES
  • Are we achieving good control?Are we achieving good control?
  • Are We getting better control? • Why? • Diet and exercise(Life long) • Therapeutic Inertia (Target not achieved) • Not using better drugs,better combination,sup-optimal dose • Poor compliance,Poor monitoring • Not giving drug according to pathogenesis • Secondary drug failure---Need insulin • Stress,Infection,MI, • Steroid No
  • Treatment Strategies for Diabetes:Treatment Strategies for Diabetes: Are Patients Achieving Good Control?Are Patients Achieving Good Control? Controlled Uncontrolle d Hypertension Hyperlipidemia Diabetes 59% 41% Harris MI et al. Diabetes Care. 2000;23:754 BP <140/90 mm Hg LDL-C <130 mg/dL A1C <7.0 59% 41% 58% 42%
  • Need SMBG 3 times per day in Type 1 Type 2—depend on c ontrol,3,5,7 days/week SMBG is associated with a better glycemic control in type 2 diabetes
  • - The pain: the ends of fingers are rich in nervous terminations (sensitivity +++) - Certain professions or certain leisures require a frequent use of the fingers: musicians (guitarists, pianists…), health workforces, plumbers, users of computer, hairdressers… Obstacles with the self-monitoring at the end of the fingers
  • Self-monitoring Blood Glucose (SMBG) American Diabetes Association Recommendations SMBG 3 or more times per day for type 1 diabetes No specific frequency is recommended for type 2 diabetes Standards of medical care in diabetes. Diabetes Care 2008
  • Measures to improve drug-complianceMeasures to improve drug-compliance • Patient’s educationPatient’s education • Promoting patient’s involvement in managementPromoting patient’s involvement in management • Reducing pill load (Reducing pill load (long acting drugs eg.metforminlong acting drugs eg.metformin XR,Gliclazide MR)XR,Gliclazide MR) • Encouraging family involvement in patient’s careEncouraging family involvement in patient’s care
  • DRUGSDRUGS • Correct DrugsCorrect Drugs • Correct DosesCorrect Doses • Correct TimingCorrect Timing • Correct CombinationCorrect Combination • ComplianceCompliance • ?steroid?steroid
  • Correct DrugsCorrect Drugs • InsulinInsulin Type(1)DM/Type 2 DM with Stress/OHA FailureType(1)DM/Type 2 DM with Stress/OHA Failure • TZD/MetforminTZD/Metformin Insulin ResistanceInsulin Resistance • Postprandial HyperglycemiaPostprandial Hyperglycemia Glinites/Acarbose/voglibose/Soluble insulinGlinites/Acarbose/voglibose/Soluble insulin • Insulin DeficiencyInsulin Deficiency SU/GliniteSU/Glinite • Beta cell PreservationBeta cell Preservation TZDTZD
  • Correct Drugs Insulin Resistance Postprandial Hyperglycemic Insulin Deficiency • Glinides • Acarbose • Voglibos • Solube Insulin • Thiazolidine diones • Metformin • Insulin Secretogogues • Sulphonylurea Glinides
  • Correct CombinationCorrect Combination • SU+MFMSU+MFM • SU + AcarboseSU + Acarbose • SU + ThiazolidinedionesSU + Thiazolidinediones • MFM + ThiazolidinedionesMFM + Thiazolidinediones • MFM + AcarboseMFM + Acarbose • SU + MFM + AcarboseSU + MFM + Acarbose • SUSU ++MFM + INSULATARDMFM + INSULATARD
  • 901301802007 Optimal Glycaemic Control  Is important to prevent death ,disability & complications of DM  -FBS - 90-130mg%  -2HPP - <180mg%  -RBS - <200mg%  -Bed time - 110-150mg%  -HbA1c - <7%
  • How Can we get good control of DM?How Can we get good control of DM? ?
  • Diabetes food pyramidDiabetes food pyramid Cereals, wholeCereals, whole grains and starch:grains and starch: 6-11 servings6-11 servings Fruits: 1-Fruits: 1- 2 servings2 servings Vegetables:Vegetables: 3-4 servings3-4 servings Low fat milk and milkLow fat milk and milk products: 2-3 servingsproducts: 2-3 servings Lean meat, fish,Lean meat, fish, poultry, pulses:poultry, pulses: 1-2 servings1-2 servings Fats, oils, sugars, refined foods,Fats, oils, sugars, refined foods, fatty foods: eat sparinglyfatty foods: eat sparingly Exercise for at least 30 minutes every dayExercise for at least 30 minutes every day Therapeutic Lifestyle change Fats, oils, sugars, refined foods,Fats, oils, sugars, refined foods, fatty foods: eat sparinglyfatty foods: eat sparingly Vegetables:Vegetables: 3-4 servings3-4 servings Low fat milk and milkLow fat milk and milk products: 2-3 servingsproducts: 2-3 servings Fats, oils, sugars, refined foods,Fats, oils, sugars, refined foods, fatty foods: eat sparinglyfatty foods: eat sparingly Cereals, wholeCereals, whole grains and starch:grains and starch: 6-11 servings6-11 servings Vegetables:Vegetables: 3-4 servings3-4 servings Low fat milk and milkLow fat milk and milk products: 2-3 servingsproducts: 2-3 servings Fats, oils, sugars, refined foods,Fats, oils, sugars, refined foods, fatty foods: eat sparinglyfatty foods: eat sparingly
  • Plate modelPlate model Vegetable Milk/yoghurt Fruit Vegetable Protein Starch/cereal
  • Physical activityPhysical activity RecommendationsRecommendations • People with diabetes should be advised to performPeople with diabetes should be advised to perform atat least 150 min/weekleast 150 min/week of moderate-intensity aerobicof moderate-intensity aerobic physical activityphysical activity (50 – 70% of maximum heart rate).(50 – 70% of maximum heart rate). (A)(A) • In the absence of contraindications, people with type 2In the absence of contraindications, people with type 2 diabetes should be encouraged to perform resistancediabetes should be encouraged to perform resistance training three times per week. (A)training three times per week. (A) Standard of Medical Care in Diabetes 2010
  • Diabetes And Glycemic Control: A Rational Approach • As low as possible • As early as possible • For as long as possible • As safely as possible • And as rationally as possible Lifestyle + MET + TZD + SU HbA1c < 6%
  • MedicationMedication RouteRoute YearYear Efficacy as monotherapy: %Efficacy as monotherapy: % ↓↓ inin HgbA1cHgbA1c Insulin s.c. 1921 ≥2.5 Sulfonylureas Oral 1946 1.5 -2 Glinides Oral 1997 1.0-1.5 Metformin Oral 1995 1.5-2 α-glucosidase inhibitors OralOral 19951995 0.5-0.80.5-0.8 TZDs OralOral 19991999 0.8-1.00.8-1.0 GLP analogue s.c.s.c. 20052005 0.60.6 DPP-IV Inhibitors OralOral 20062006 0.5-0.80.5-0.8 Amylin analogue s.c.s.c. 20052005 0.60.6 Colesevelam OralOral 20082008 0.50.5 Bromocriptine mesylate OralOral 20092009 0.2-0.40.2-0.4 Type 2 Diabetes Medication ChoicesType 2 Diabetes Medication Choices Experience and PotencyExperience and Potency
  • Mechanisms of Action of Pharmacologic AgentsMechanisms of Action of Pharmacologic Agents for Diabetesfor Diabetes Improving Outcomes in Patients With Type 2 Diabetes Mellitus: Practical Solutions for Clinical Challenges James R. Gavin, III, MD, PhD; Mark W. Stolar, MD; Jeffrey S. Freeman, DO; Craig W. Spellman, DO, PhD JAOA • Vol 110 • No 5suppl6 • May 2010 • 2-14
  • Basic Steps in the Management of Type 2 DiabetesBasic Steps in the Management of Type 2 Diabetes + + diet &exercise Oral monotherapy insulin + Oral combination Oral plus Insulin
  • • Fast onset of action • To stimulate insulin secretion (including first phase) • Decrease fasting and post prandial blood glucose • Preservation of the beta cells • Decrease insulin resistance • Prevent complications • Long duration of action (once daily administration) An Ideal OHA should have…
  • • Control FPG & PPG effectively • Lowest risk of hypoglycemia • Should not produce hyperinsulinemia & weight gain • Less drug interactions An Ideal OHA should have…
  • No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies Alpha-Alpha- GlucosidaseGlucosidase InhibitorsInhibitors1,21,2 MeglitinideMeglitinide ss33 SUsSUs4,54,5 TZDsTZDs6,76,7 MetformiMetformi nn88 DPP-4DPP-4 InhibitorsInhibitors Insulin deficiency Insulin resistance Excess hepatic glucose output MajorPathophysiologies 1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004. 3. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 4. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007. 5. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004. 7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005. 8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.         Intestinal glucose absorption 
  • Early combination approach
  • When you saw a patient with DM • Glucose control?(glucose level) • Monitoring? • Compliance • Comobidities • Drugs • Stress –infection?MI,Pregnancy • Diet,exercise,body weight • Renal ,cardiac,liver • Economic status • Set the Target ----HbA1C,FBS,PPG
  • Glycaemic Indices : Present andGlycaemic Indices : Present and FutureFuture
  • HbA1C 7% in general HbA1C Target <7% General 8% elderly HbA1C Target <7% General 8% elderly
  • Effect SU and NSU Metformin TZA AGI Mechanism Increase in insulin secretion Decrease in HGO plus increases muscle sensitivity Decrease in HGO plus increases muscle sensitivity Decrease in glucose absorption Decrease in FPG 60-70 mg% 60-70 mg% 35-40 mg% 20-30 mg% Decrease in HbA 1.5-2.0% 1.5-2.0% 1.0-1.2% 0.7-1.0% TG level No effect Decrease Decrease No effect HDL level No effect Slight increase Increase No effect LDL level No effect Decrease Increase No effect Body weight Increase Decrease Increase No effect Insulin level Increase Decrease Decrease No effect Adverse effects Hypoglycemia GI disturbances Anemia, hepatic GI disturbances
  • Initial Therapy with OHAs Initial Add Add Thin/normal Wt SU Metformin Insulin Obese Metformin SU TZD/Insulin Obese not tolerating MET TZD SU MET contraindicated TZD SU Severe IR Metformin TZD SU Elderly SU Insulin PPHG prominent MEG/AGI PPHG prominent in Sec Failure AGI/Exenatid e
  • Combination Therapy with OHAs • Drug combinations should be based on A. Therapeutic efficacy (“fire power”) B. Complementary mechanisms of action C. Ancillary benefits (CVD risk factors) D. Safety and tolerability E. ? Compliance with multiple dosing regimens
  • Estimated Improvements with Combination Rx Combination AIC% reduction FPG reduction SU + MET 1.7% 65 mg/dl SU + ROS 1.4% 60 mg/dl SU + PIO 1.2% 50 mg/dl SU + ACAR 1.3% 40 mg/dl REP + MET 1.4% 40 mg/dl MET + ROS/PIO 0.7-0.8% 40 mg/dl INS + OHA Open to targets Open to targets De Fronzo, NEJM 1995 Horton, Diabetes Care 1998 Coniff, Diabetes Care 1995 Moses, Diabetes Care 1999 Schneider, Diabetes 1999 Egan, Diabetes 1999 Fonseca, Diabetes 1999
  • Strategies for Antidiabetic Treatment Oral Triple Combination Therapy plus Basal Insulin or plus Oral Monotherapy Oral Dual Combination Therapy Oral Triple Combination Therapy NPG, Glargine, Levemir Metformin + Sulfonylureas + TZDs Metformin + Sulfonylureas+DPP-4- Inhib. Metformin DPP-4 Inhibitors Glinides TZDs Sulfonylureas α-Glucosidase-Inhibitors Metformin + DPP-4-Inhibitors Sulfonylureas + DPP-4-Inhibitors Metformin + Sulfonylureas Sulfonylureas + TZDs Metformin + TZDs Exenatide, Liraglutide
  • Master Decision PathMaster Decision Path Type 2 Diabetes Glycemic ControlType 2 Diabetes Glycemic Control Medical Nutrition TherapyMedical Nutrition Therapy && Activity PlanActivity Plan start monotherapystart monotherapy Medical Nutrition TherapyMedical Nutrition Therapy && Activity PlanActivity Plan start monotherapystart monotherapy Oral combination treatment 2 drugsOral combination treatment 2 drugs If target not reached after maximumIf target not reached after maximum dose for 4 - 8 weeks - - start oral agentdose for 4 - 8 weeks - - start oral agent Oral combination treatment 2 drugsOral combination treatment 2 drugs If target not reached after maximumIf target not reached after maximum dose for 4 - 8 weeks - - start oral agentdose for 4 - 8 weeks - - start oral agent Insulin TherapyInsulin TherapyInsulin TherapyInsulin Therapy Oral Agent(s) + InsulinOral Agent(s) + InsulinOral Agent(s) + InsulinOral Agent(s) + Insulin Oral Combination Rx 3 drugsOral Combination Rx 3 drugs If target not reached after maximumIf target not reached after maximum doses for 4 - 8 weeks -- start insulindoses for 4 - 8 weeks -- start insulin Oral Combination Rx 3 drugsOral Combination Rx 3 drugs If target not reached after maximumIf target not reached after maximum doses for 4 - 8 weeks -- start insulindoses for 4 - 8 weeks -- start insulin FPG < 200FPG < 200 Casual < 250Casual < 250 FPG < 200FPG < 200 Casual < 250Casual < 250 FPG 200-300FPG 200-300 Casual 250-350Casual 250-350 FPG 200-300FPG 200-300 Casual 250-350Casual 250-350 FPG > 350FPG > 350 Casual > 400Casual > 400 FPG > 350FPG > 350 Casual > 400Casual > 400 At Diagnosis (mg/dl) Targets forTargets for Glycemic ControGlycemic Contro HbA1c <7%HbA1c <7% Targets forTargets for Glycemic ControGlycemic Contro HbA1c <7%HbA1c <7% FPG > 300-350FPG > 300-350 Casual > 350-400Casual > 350-400 with severe symptomwith severe symptom FPG > 300-350FPG > 300-350 Casual > 350-400Casual > 350-400 with severe symptomwith severe symptom KK/ESSENTIAL DRUG/3.4.11/tAUNGGHU
  • Practice GuidelinesPractice Guidelines
  • A1C 6.5 – 7.5%** Monotherapy MET + GLP-1 or DPP4 1 TZD 2 Glinide or SU 5 TZD + GLP-1 or DPP4 1 MET + Colesevelam AGI 3 2 - 3 Mos.*** 2 - 3 Mos.*** 2 - 3 Mos.*** Dual Therapy MET + GLP-1 or DPP4 1 + TZD 2 Glinide or SU 4,7 A1C > 9.0% No Symptoms Drug Naive Under Treatment INSULIN ± Other Agent(s) 6 Symptoms INSULIN ± Other Agent(s) 6 INSULIN ± Other Agent(s) 6 Triple Therapy AACE/ACE Algorithm for Glycemic Control Committee Cochairpersons: Helena W. Rodbard, MD, FACP, MACE Paul S. Jellinger, MD, MACE Zachary T. Bloomgarden, MD, FACE Jaime A. Davidson, MD, FACP, MACE Daniel Einhorn, MD, FACP, FACE Alan J. Garber, MD, PhD, FACE James R. Gavin III, MD, PhD George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Edward S. Horton, MD, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, MACE Etie S. Moghissi, MD, FACP, FACE Stanley S. Schwartz, MD, FACE * May not be appropriate for all patients ** For patients with diabetes and A1C < 6.5%, pharmacologic Rx may be considered *** If A1C goal not achieved safely † Preferred initial agent 1 DPP4 if ↑ PPG and ↑ FPG or GLP-1 if ↑↑ PPG 2 TZD if metabolic syndrome and/or nonalcoholic fatty liver disease (NAFLD) 3 AGI if ↑ PPG 4 Glinide if ↑ PPG or SU if ↑ FPG 5 Low-dose secretagogue recommended 6 a) Discontinue insulin secretagogue with multidose insulin b) Can use pramlintide with prandial insulin 7 Decrease secretagogue by 50% when added to GLP-1 or DPP-4 8 If A1C < 8.5%, combination Rx with agents that cause hypoglycemia should be used with caution 9 If A1C > 8.5%, in patients on Dual Therapy, insulin should be considered MET + GLP-1 or DPP4 1 ± SU 7 TZD 2 GLP-1 or DPP4 1 ± TZD 2 A1C 7.6 – 9.0% Dual Therapy 8 2 - 3 Mos.*** 2 - 3 Mos.*** Triple Therapy 9 INSULIN ± Other Agent(s) 6 MET + GLP-1 or DPP4 1 or TZD 2 SU or Glinide 4,5 MET + GLP-1 or DPP4 1 + TZD 2 GLP-1 or DPP4 1 + SU 7 TZD 2 MET † DPP4 1 GLP-1 TZD 2 AGI 3 Available at www.aace.com/pub © AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE
  • Mean Plasma Glucose (mg/dl)Mean Plasma Glucose (mg/dl) A1C %A1C % 135135 66 170170 77 205205 88 240240 99 275275 1010 310310 1111 345345 1212 Correlation between A1c level & mean plasmaCorrelation between A1c level & mean plasma glucose level on multiple testing over 2-3glucose level on multiple testing over 2-3 months (Based on DCCT)months (Based on DCCT) ADA 2010 Guidelines on Diagnosing diabetesADA 2010 Guidelines on Diagnosing diabetes
  • 2. Juliana C. n. Chan; Vasanti Malik: Weiping Jia; et al. JAMA. 2009; 301 (20);2129-2140 (doi:10.1001/jama.2009.726) SU – Sulphonylurea,SU – Sulphonylurea, MET – Metformin,MET – Metformin, TZD - ThiazolidinedioneTZD - Thiazolidinedione HbA1c ≥6.5% after lifestyle interventionHbA1c ≥6.5% after lifestyle intervention MET+ SUMET+ SU HbA1c ≥7.5%HbA1c ≥7.5% MetforminMetformin HbA1c ≥6.5%HbA1c ≥6.5% Insulin + MET + SUInsulin + MET + SU HbA1c ≥7.5%HbA1c ≥7.5% Increase InsulinIncrease Insulin DoseDose (or)(or) Insulin + PioglitazoneInsulin + Pioglitazone SU (DIAMICRON MR)SU (DIAMICRON MR) - Not overweightNot overweight - MET not tolerated orMET not tolerated or is contraindicatedis contraindicated - Rapid therapeutic response- Rapid therapeutic response HbA1c ≥6.5%HbA1c ≥6.5% If MET is contraindicated or notIf MET is contraindicated or not toleratedtolerated SU + DPP4 inhibitor or TZDSU + DPP4 inhibitor or TZD If SU contraindicated orIf SU contraindicated or not toleratednot tolerated MET + DPP4 inhibitorMET + DPP4 inhibitor or TZDor TZD HbA1c ≥7.5%HbA1c ≥7.5% Start InsulinStart Insulin HbA1c ≥7.5%HbA1c ≥7.5% If insulin is unacceptableIf insulin is unacceptable MET + SU + SitagliptinMET + SU + Sitagliptin (or)(or) MET + SU + TZDMET + SU + TZD (or)(or) MET + SU + ExenatideMET + SU + Exenatide HbA1c ≥7.5%HbA1c ≥7.5% NICE guideline forNICE guideline for Type 2 Diabetic Management,Type 2 Diabetic Management, May 09May 09
  • 1st line option in addition to lifestyle measures; start ONE OF METMET SUSU (if intolerate of metformin or if weight loss/ osmotic symptoms) 1st line option in addition to lifestyle measures; start ONE OF METMET SUSU (if intolerate of metformin or if weight loss/ osmotic symptoms) 2nd line options SUSU (Usual approach) SUSU (Usual approach) AlternativeAlternative TZD or DPP-4 InhibitorTZD or DPP-4 Inhibitor AlternativeAlternative TZD or DPP-4 InhibitorTZD or DPP-4 Inhibitor OralOral MET/ SU + TZD (if no HF)MET/ SU + TZD (if no HF) OralOral MET/ SU + TZD (if no HF)MET/ SU + TZD (if no HF) InjectableInjectable MET/ SU + Insulin (before bed)MET/ SU + Insulin (before bed) (or)(or) MET/ SU + GLP -1 agonistsMET/ SU + GLP -1 agonists InjectableInjectable MET/ SU + Insulin (before bed)MET/ SU + Insulin (before bed) (or)(or) MET/ SU + GLP -1 agonistsMET/ SU + GLP -1 agonists Review & if not reaching target move to 2nd line Review & if not reaching target move to 3rd line 3rd line options
  • ADA/EASD Consensus Algorithm for the Initiation and Adjustment of Therapy Diabetes Care 2009; 32:193–203
  • 1. Patient-Centered Approach “...providing care that is respectful of and responsive to individual patient preferences, needs, and values ensuring that patient values guide all clinical decisions.” • Gauge patient’s preferred level of involvement. • Explore, where possible, therapeutic choices. • Utilize decision aids. •Shared decision making – final decisions re: lifestyle choices ultimately lies with the patient. Diabetes Care,Diabetes Care, Diabetologia.Diabetologia. 1919 April 2012 [Epub ahead ofApril 2012 [Epub ahead of ADA-EASD Position Statement: Management of Hyperglycemia in T2DM: A Patient-Centered Approach
  • T2DM Anti-hyperglycemic Therapy: General Recommendations Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
  • Adapted Recommendations: When Goal is to Avoid Hypoglycemia Diabetes Care, Diabetologia. 19 April 201 [Epub ahead of print]
  • Adapted Recommendations: When Goal is to Minimize Costs Diabetes Care, Diabetologia. 19 April 201 [Epub ahead of print]
  • Patient Preference: EfficacyPatient Preference: Efficacy metformin sulfonylurea TZD glinide DPP4 inhibitor α -glucosidase inhibitors
  • Patient Preference: CostPatient Preference: Cost metformin sulfonylurea α- glucosidase inhibitor TZD DPP4 inhibitor
  • Patient Preference: WeightPatient Preference: Weight metformin DPP4 inhibitor α -glucosidase inhibitor TZD sulfonylurea
  • Patient Preference:Patient Preference: Hypoglycemia AvoidanceHypoglycemia Avoidance metformin DPP4 inhibitor TZD α -glucosidase inhibitor sulfonylurea glinide
  • CASE 1 • 56 year male ,newly diagnosed DM, • BMI 35 • RBS 350mg% • BP 150/90 • Creatinine 100 mg% • Total Cholesterol-250mg% • ECG Treatment ?
  • Proplems • DM,obese,hyperglycemia,IHD,increased cholesterol and TG,H/T • Treatment • Metformin 500mg BD • Gliclazide MR 60 mg 1 od • Aspirin 1 od • Atovastatin 10 mg • Metoprolol 25 mg BD • Ramipril 5 mg od • Orlistat 120 mg 3 times • Diet and exercise
  • Why I choose Metformin?
  • Metformin • Obese • Cardiac safe • Reduced mortality • First line drug in every guidelines • Widely available • Cheap-cost effective • Powerful glucose lowering efffect • 80% of Type 2 DM is due to Insulin Resistance • Cannot use in advanced liver, renal and cardiac failure because of lactic acidosis
  • Metformin: Crucial Part ofMetformin: Crucial Part of TherapyTherapy Metformin Effects on Risk Factors Hundal RS, Inzucchi SE. Metformin New Understandings, New Uses. Drugs 2003; 63(18): 1879-1894 Dose – 500 to 3000 mg CI - serum creatinine >1.5 mg%, Advanced Heart Failure SE - Reduce appetite, nausea, vomiting, diarrhoea
  • 12 studies; ≥ 52 weeks; at least 1 CVD event CVD outcomes: - fatal / non-fatal MI or stroke - PVD - other CVD death
  • Effect of Metformin on CVD Events
  • Why I choose Gliclazide (Diamicron MR 60 ) ?
  • Rationale of Use of SU in T2DM “Sulfonylureas are a rational choice to begin pharmacological intervention because almost all patients with NIDDM [type 2 diabetes] are relatively insulin deficient.” ADA Consensus Statement 1996-1997
  • SulfonylureasSulfonylureas • Which ? • When? • Why? 1st line in underwt/normal wt type 2 patients Along with insulin sensitizers: metformin or glitazones Along with insulin to facilitate reduction/frequency of insulin dosing 1st line in underwt/normal wt type 2 patients Along with insulin sensitizers: metformin or glitazones Along with insulin to facilitate reduction/frequency of insulin dosing All have same MOA Require some viable β cell mass to work Do not work in type 1 and after sec failure sets in type 2 Differential effects amongs SUs All have same MOA Require some viable β cell mass to work Do not work in type 1 and after sec failure sets in type 2 Differential effects amongs SUs • Can use in heart failure, renal failure • SE - Weight gain, hypoglycemia • Choice of SU – Newer SU to prevent cardiac side effect, prolong hypoglycemia
  • Sulfonylureas: How to Choose? • Cardiac patients: Glimepiride/GLICLAZIDE • Elderly patients: Glimepiride/GLICLAZIDE • Economy: Glibenclamide • Mild renal insufficiency: Glimepiride • Severe Renal : Gliclazide and glipizide • Require high potency: Glibenclamide • Relatively younger patients: Glibenclamide
  • Glucose control therapy- Rationale
  • Mean HbA1c at final visit Standard: 7.3% Intensive: 6.5% The ADVANCE Study ADVANCE Collaborative Group. NEJM 2008
  • Combined primary outcomes Major macro or microvascular event Follow-up (months) Cumulativeincidence(%) 25 20 15 10 5 0 0 6 12 18 24 30 36 42 48 54 60 66 Standard Intensive Relative risk reduction 10%: 95% CI: 2 to 18% p=0.013 ADVANCE Collaborative Group. NEJM 2008
  • Any prevention of β cell dysfunction and failure (i.e. loss of β cell mass)  Initially correct glucotoxicity, lipotoxicity some SU claims for reduction of ROS  Some literature said : SU can even increase ROS  ↑ apoptosis  Esp in Glipizide,glimepride,glibenclamide  ↓ROS  *Gliclazide
  • Beta-cell apoptosis in islets: gliclazide vs glibenclamide Islets pre-exposed for 5 days to - NG (5.5 mmol/L) - HG (alternating 5.5 & 16.7 mmol/L) Groups differed significantly (p<0.01) by ANOVA: *p<0.05 vs NG; **p<0.005 vs HG and HG + glib after Bonferroni correction S Del Guerra et al. Diabet Metab Res Rev 2007;23:234-8 HG + gliclazide HG + glib NG HG
  • Effect of SU on MI Patients Glipizide ,gliclazide and glimepiride are safer than glibenclamide b/c of more selective effect on pancreatic SU receptor
  • Relative risk of 1st -time MI according to OHA 0 0.5 1 1.5 2 2.5 C Glib Tolb Glicl Glimp C Glib Tolb Glicl Glimp (Johnsen SP, et al. Am J Ther. 2006;13:134-140 OR 2.08 [1.77-2.45] OR 2.32 [1.48-2.64] OR 1.37 [0.84-2.22] OR 1.36 [0.93-1.99]
  • 30-day post MI mortality according to OHA30-day post MI mortality according to OHA 0 0.2 0.4 0.6 0.8 1 1.2 1.4 Controls Glib/Tolb Glic/Glim Controls Glib/Tolb Glic/Glim (Johnsen SP, et al. Am J Ther. 2006;13:134-140 OR 1.29 [1.00-1.67] OR 1.0 [0.53-1.90]
  • Use of Sulfonylureas and mortalityUse of Sulfonylureas and mortality after MI in diabetic patients:after MI in diabetic patients: Danish nationwide population-based studyDanish nationwide population-based study Thisted H,Thisted H, et alet al. EASD 2006. EASD 2006 old SHN new SHN 1.08 0.81 0 0.4 0.8 1.2 old Sus new Sus -25%
  • • Total mortality – Gliclazide - 67% (p<0.01),Total mortality – Gliclazide - 67% (p<0.01), Glimepiride - 40% (p<0.01)Glimepiride - 40% (p<0.01) • CVD mortality – Gliclazide -71% (p<0.001)CVD mortality – Gliclazide -71% (p<0.001)
  • Cardiovascular death 253 289 12% (-4 to 26) All deaths 498 533 7% (-6 to 17) Non-cardiovascular death 245 244 0% (-20 to 16) Number of patients with event Intensive Standard (n=5,571) (n=5,569) Relative risk reduction (95%CI) Favours Intensive Favours Standard Hazard ratio 0.5 1.0 2.0 ADVANCE study - trend to reduction in CV death with gliclazide MR based intensive control regimen ADVANCE Collaborative Group. NEJM 2008
  •  ADVANCE is the only study to show a trend in favor of a reduction in cardiovascular death. Control Group; Turnbull FM, Abraira C, Anderson RJ, et al. Diabetologia. 2009;52(11):2288-2298.
  • 0.5 1.0 2.0 End stage kidney disease Percent of patients with event Intensive Standard (n=5,571) (n=5,569) Relative risk reduction (95% CI) Favours Intensive Favours Standard New microalbuminuria 23.7% 25.7% Total renal events 26.9% 30.0% 9% (2 to 15)‡ 11% (5 to 17)† New macroalbuminuria 2.9% 4.1% 30% (15 to 43)† New / worsening nephropathy 4.1% 5.2% 21% (7 to 34)*** Hazard ratio † P=<0.001 ‡ P=0.02 *** P=0.006 *P=0.09 36% (-8 to 62)*0.4% 0.6% ADVANCE Collaborative Group. NEJM 2008 ADVANCE: Reduction of Renal events Less risk of dialysis, kidney transplantation and most of all death
  • Renal outcomes of the main morbidity-mortality trials in diabetesRenal outcomes of the main morbidity-mortality trials in diabetes 1. UKPDS Group (33). Lancet. 1998;352(9131):837-853. 2. Duckworth W, Abraira C, Moritz T, et al; VADT Investigators. N Engl J Med. 2009;360(2):129-139. 3. Ismail-Beigi F, Craven T, Banerji MA, et al; ACCORD trial group. Lancet. 2010;376(9739):419-430. 4. Zoungas S, Lambers Heerspink HJ, Chalmers J, et al. Diabetologia. 2011;54(suppl 1):S23. 5. The ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, et al. N Engl J Med. 2008;358(24):2560-2572. * new or worsening nephropathy *
  • ADVANCE Collaborative Group. EASD Congress 2010. Stockholm, Sweden. Oral communication 20 mg/l200 mg/l albuminuria Macroalbuminuria Normal range of albuminuria Majority of these patients *versus standard treatment group Microalbuminuria 20% more patients regressed to normal range vs standard treatment (P=0.0002) ADVANCE: New renal results EASD 2010
  •  ADVANCE is currently the only trial demonstrating protection of type 2 diabetic patients from end-stage kidney disease Coca SG, Coca SG, Ismail-Beigi F, Haq N, Krumholz HM, Parikh CR. Arch Intern Med. 2012;172(10):761-769.
  • ACCORD2 ADVANCE3 Intensive Control Standard Control Patientsexperiencingatleastone severehypoglycemicevent(%) 0 5 10 15 20 25 VADT1 2.7% 1.5% 16.2% 5.1% 21.2% 9.9% P<0.001 P<0.001 HR=1.86 (95% CI 1.40-2.40) % HbA1c at study end 7.36.46.9 % change from baseline -0.2-1.7-2.5 8.4 -1.0 7.5 -0.6 6.5 -1.0 Comparison of severe hypoglycemia in morbimortality trials in diabetes 1. VADT Investigators. N Engl J Med. 2009;360:129-139. 2. Bonds DE, et al, BMJ. 2010;340:b4909. 3. ADVANCE Study Group. N Engl J Med. 2008;358(24):2560-2572.
  • • 1066 fasting patients • Comparing incidence of hypos between SUs vs Sitagliptin • Sponsored by MSD Hypoglycemia in Ramadan: Sitagliptin vs SU S. Al Sifri et al. Int J Clin Prac, Nov 2011;65,11: 1132–40
  • Hypoglycemia in Ramadan: Sitagliptin vs SU S. Al Sifri et al. Int J Clin Prac, Nov 2011;65,11: 1132–40
  • 0% 2% 4% 6% 8% 10% Glimepiride Glibenclamide Gliclazide MR (%)ofpatientswith>onesymptomatichypoglycemia Patient fasting Ramadan 2012 comparison Patients’ Safety 9.1% 5.2% 1.8%
  • Hypoglycaemia with different Sulfonylureas *<50 mg/dL. Tayek J. Diabetes Obes Metab. 2008; 10: 0 5 10 15 20 25 30 Gliclazide 0.85 Glipizide 8.70 Glimepiride 0.86 Tolbutamide 3.50 Chlorpropamide 16.00 Glyburide 16.00 Severe hypoglycemia* n/1000 person years RelativeRisk(%) SAFETY
  • Hypoglycemia in SU OHA Risk of hypoglycemia Glinide + Gliclazide ++ Gliclazide MR + Glimepride ++ Glibenclamide +++ All SU can give rise to hypoglycemia
  • HYPOGLYCEMIAHYPOGLYCEMIA Gliclazide MR vs Glimepiride
  • Gliclazide M R n=157 Gliclazide M R n=226 Hypoglycaemia (blood glucose < 3.0 mmol/L) according to Creatinine Clearance (CCl) Glim epiride n=25 Gliclazide M R n=17 0 6 12 18 24 50-80 ml/min 0 6 12 18 24 0 6 12 18 24 Numberofpatients Glim epiride n=182 Glim epiride n=232 CCl > 80ml/minCCl < 50 ml/min 0% 12% 3.2% 12.6 % 4.4% 5.6% (GUIDE-Study: Schernthaner G et al. Eur.J.Clin.Invest. 2004; 34:535-542)
  • 50 year Male DM 12 years on Metformin 500mg 2 TDS gliclazide MR 60 2 od Pioglitazone 45 mg od HbA1C 8%,FBG-200,2hpp 350mg% Next Treatment? CASE 2
  • Uncontrolled DM  Check Diet  Check Steroid  Check Compliance  Check Infection and Stress 3 drugs ,maximum dose for 3 months Drug Failure,Beta cell failure Need INSULIN 3 drugs ,maximum dose for 3 months Drug Failure,Beta cell failure Need INSULIN
  • Insulin Regimen for Type 2 Diabetes Mellitus Guidelines for initiating insulin 0.15 units /kg /body wt /day C h a r t G u i d e l i n e s f o r S t a r t i n g I n s u l i n T h e r a p y ( A s ia P a c if ic T y p e 2 D ia b e t e s P o lic y g r o u p ) M o r n i n g 2 / 3 P r e - M i x - 3 0 / 7 0 E v e n i n g 1 / 3 P r e - M i x - 3 0 / 7 0 P r e - m i x e d i n s u l i n 3 0 / 7 0 > 3 0 - 4 0 i u - - s t o p p i n g O A D T e s t F P G / A d j u s t 3 - 4 d a y s O A D + 1 0 i u N P H i n s u l i n ( B e d t i m e )
  • TWO basic INSULINTWO basic INSULIN REGIMENSREGIMENS SupplementarySupplementarySupplementarySupplementary SubstitutionSubstitutionSubstitutionSubstitution (OHD +Bed time insulin) ( No OHD +Only insulin) Premixed/split mixedPremixed/split mixedPremixed/split mixedPremixed/split mixed Basal bolus insulinBasal bolus insulinBasal bolus insulinBasal bolus insulin
  • Insulin Regimen for Type 2 Diabetes Mellitus Guidelines for Starting insulin therapy (Asia Pacific Type 2 Diabetes Policy group) In normal person = 0.5 units /kg /BW /Day Pre-mixed insulin 30/70Pre-mixed insulin 30/70 Morning 2/3 Pre-Mix 30/70 Morning 2/3 Pre-Mix 30/70 SubstitutionSubstitution Evening 1/3 Pre-Mix 30/70 Evening 1/3 Pre-Mix 30/70
  • 60 0 20 40 Insulin PREMIX 30/70 PREMIX 30/70 6 AM 6 PM12 AM 12 PM Insulin Regimen for Type 2 Diabetes Mellitus PREMIXPREMIX
  • Basal Bolus Regimen (Substitution)Basal Bolus Regimen (Substitution) 106 • Mimics physiological insulin profile: starting dose - 40% daily dose as basal insulin (Intermediate-acting insulin- Insulatard or Humulin N) - 60% as short acting insulin (Actrapid or Humulin R) divided into 20% at breakfast 20% at lunch 20% at dinner • Insulin dose adjusted if needed • Requires highly motivated patients with constant monitoring
  • • Cardiac •Lipid Management •Smoking cessation •Vaccines •Transfer and discharge Blood sugar control •Patient education •Nutrition counseling •Medication •Physical activity •Foot care •Retinopathy
  • Take Home Messages:Take Home Messages: Place of Sulfonylureas in T2DMPlace of Sulfonylureas in T2DM • Are effective • Proven in OUTCOME trials → ↓ Complications • ADVANCE (Gliclazide MR) – weight gain NOT a given – hypoglycaemia can be minimised – effective irrespective of age, BMI or duration of DM – ↓ renal failure / worsening of nephropathy • Not ALL Sulfonylureas are the same
  • CASE B • 65 male with DM 10 years,IHD,Hypertension ,,Stroke • HbAIC Target? • A. 7% • B.8% • C.6.5%
  • CASE c • 45 female DM 3 year Thin ,RBS 230 ,creatinine 140,pedal oedema + • Start with • A.Metformin • B.Metformin with Gliclazide MR • C.Gliclazide MR • D.Pioglitazone
  • CASE c • 48 female DM 6 year ,RBS 350 , • Start with • A.Metformin • B.Gliclazide MR • C.Metformin +Gliclazide MR
  • f RBS is >500mg% Poorly controlled DM DKA HHS(HONK) Admisssion is needed in patient with stressful conditions such as Infection Stroke Myocardial infact. If there is no stressful condition Can be managed as OPD patient
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