Presentation on theme: "Sulphonylurea A Golden Therapy For Diabetes By Eman Rushdy Prof. Internal Medicine Cairo University."— Presentation transcript:
Sulphonylurea A Golden Therapy For Diabetes By Eman Rushdy Prof. Internal Medicine Cairo University
The shoes story Many years ago two salesmen were sent by a British shoe manufacturer to Africa to investigate and report back on market potential. Many years ago two salesmen were sent by a British shoe manufacturer to Africa to investigate and report back on market potential. The first salesman reported back, "There is no potential here - nobody wears shoes." The first salesman reported back, "There is no potential here - nobody wears shoes." The second salesman reported back, "There is massive potential here - nobody wears shoes." The second salesman reported back, "There is massive potential here - nobody wears shoes."
What is your concern about oral hypoglycemic drug ?! B cell exhaution. B cell exhaution. Less effective Less effective Hypoglycemia Hypoglycemia Expensive Expensive
10 µm ~ 10,000 granules Micrograph: Lelio Orci, Geneva The normal beta-cell Presented by Pr Philippe Halban at the 1st Amsterdam Diabetes Meeting, March 30-April 1, 2006 Pancreas consists of 1 million islets of Langerhans Start to develop from week 9-11 gestation
Half-life of ~30 days Half-life of ~30 days Apoptosis is the major mechanism of death Apoptosis is the major mechanism of death normalapoptotic New beta-cells by: *Replication *Neogenesis *Neogenesis
-cell mass (%) ~65% Modified from Butler AE, et al. Diabetes 2003;52:102–10.
Factors for progressive loss of B- cell function & mass Glucotoxicity Lipotoxicity l Apoptosis Insulin Secretion Prentki M et al. Diabetes. 2002;51(suppl 3):s405-s413. Amyloid deposition Inflamatory Cytokines& ROS
B-cell Exhaustion - A physical depletion of B-cell insulin stores secondary to prolonged chronic stimulation with glucose on non-glucose secretagogues. -No defect in insulin synthesis. -The B-cell function fully recovers as it rests. Exhaustion is reversible
Glucotoxicity Non physiological and potentially irreversible B-cell damage caused by chronic exposure to supra-physiological glucose concentration with characteristic decreases in insulin synthesis and secretion caused by decreases insulin gene expression. Glucotoxicity is irreversible
Interplay between B-cell exhaustion & glucotoxicity Excess insulin secretion Prolonged hyperglycemia Insulin depletion from B-cell (Exhaustion) Hyperglycemia More, prolonged hyperglycemia ER Stress ROS Ca ++ Cytokines Irreversible B-cell damage & apoptosis (Glucotoxicity) Treatment
Factors to Consider when Choosing Pharmacological Agent(s) for Diabetes Current A1C Current A1C Duration of diabetes Duration of diabetes Body weight (BMI, abdominal obesity) Body weight (BMI, abdominal obesity) Effectiveness Effectiveness Co-morbidities Co-morbidities Cradiovascular risk Cradiovascular risk Cost of medication Cost of medication Compliance. Compliance.
ADA/EASD: Considerations for the Guidelines 1. Use of information from clinical trials that address the efficacy and safety of different modalities of treatment (Evidence based) 2. Clinical judgment of the panel participants (Recognize that beta cell failure is progressive) 3. Extrapolation of UKPDS data that glucose lowering of drugs (metformin, sulfonylureas, insulin) predicted decrease in complications. 4. Nonglycemic effects of medication, such as effect on CV risk, lipids, hypertension or insulin resistance 5. Safety, side effects, ease of use and expense
AACE/ ACE Criteria Attempts to provide a place and recommendation for all FDA approved drugs Attempts to provide a place and recommendation for all FDA approved drugs Greater emphasis on hypoglycemia avoidance Greater emphasis on hypoglycemia avoidance Recognizes that people may want choices, so allows a wide variety of choices and combinations for individual situations Recognizes that people may want choices, so allows a wide variety of choices and combinations for individual situations
Add basal or intensify insulin Lifestyle intervention and metformin Add sulfonylurea (least expensive) Add basal insulin (most effective) Add TZD Add basal insulin*** Add sulfonylurea If HbA 1c 7%*If HbA 1c 7% Intensive insulin + metformin +/ TZD** Nathan DM et al. Diabetes Care 2006;29(8):1963-72. Nathan DM et al. Diabetologia 2008;51(1):8-11. Intensify insulin*** ADA/EASD Management Algorithm
ADA/EASD Consensus Algorithm for Management of Diabetes Diabetes Care. 2009, 32:193-203 At diagnosis: Lifestyle + Metformin Lifestyle+Metformin + Pioglitazone (No hypoglycemia, edema, CHF, bone loss) Lifestyle+Metformin + Sulfonylurea Lifestyle+Metformin + Intensive insulin Lifestyle+Metformin + Basal Insulin Lifestyle+Metformin + GLP1 (No hypoglycemia, wt loss, Nausea/vomiting) Lifestyle+Metformin + Pioglitazone + Sulfonylurea Lifestyle+Metformin + Basal Insulin Tier 2: less well-validated therapies Tier 1: Well-validated core therapies Step 1 Step 2 Step 3 Amylin agonists, Glinides DPP-4 inhibitors may be appropriate in selected patients *Useful when hypoglycemia is to be avoided
18 Life style modification AACE consensus Algorithm (2009)
Alexander, G. C. et al. Arch Intern Med 2008;168:2088-2094. Trends in Use of Different Therapeutic Drug Classes to Treat Diabetes, 1994-2007 SU Big
Leading Diabetes Medications by Treatment Class Alexander, G. C. et al. Arch Intern Med 2008;168:2088-2094. SU SU+Met
Sulfonylureas - Drug Profile Advantages Potent glucose lowering effect Favorable adverse effect profile Disadvantages *Hypoglycemia, less with Glimipride *Weight gain, less with Glimipride Concomitant use with other drugs Can be used as monotherapy and with all classes including insulin
Sulfonylureas Divided into First, Second, and Third Generation Divided into First, Second, and Third Generation –First Generation: rarely used today –Second Generation: glipizide, Gliclazide –Third Generation: glimepiride The duration of action depends on the affinity to SUR and which part of it, the rate of metabolism, activity of metabolites and rate of excretion The duration of action depends on the affinity to SUR and which part of it, the rate of metabolism, activity of metabolites and rate of excretion
K+K+ K+K+ 140 kDa 140 kDa 65 kDa 65 kDa - cell membrane K+K+ K+K+ K ATP channel Modes of action: Most Sulphonylureas Glimepiride Sulphonylurea Receptor The duration of action depends on the affinity to SUR, rate of metabolism, activity of metabolites and rate of excretion So What ?? Glimepiride
Pharmakokinetics of sulphonylurea: *Glimepiride has a lower affinity to the -cell membrane than others membrane than others *The metabolites of glibenclamide are active while those of glimipride and gliclazide are inactive.
Glimepiride Controls Glycemia with Less Insulin Secretion Mean ratio between increased level of insulin and reduced glycemia 5 10 15 0 1 2 3 20 0 Glimepiride Glibenclamid e Glipizide Gliclazide 0.00 0.05 0.10 0.15 0.20 n=16 n=13 n=14 n=16 Ratio Muller G, et al. Diabetes Res Clin Pract 1995; 28 (Suppl): S115-37 Sulfonylureas tested in fasted male beagle dogs to determine ratios of mean plasma insulin release/ blood glucose decrease
*Defined as requiring IV glucose or glucagon Significantly lower incidence of severe hypoglycemic events with Significantly lower incidence of severe hypoglycemic events with Glimepiride vs glibenclamide (0.86 vs 5.6/1000 person-years) Holstein A et al. Diabetes Met Res Rev 2001; 17:467-73 0.86 5.6 Glibenclamide Glimepiride # Episodes/1000 person-years 0 2 4 6 Prospective, population- based, 4-year study to compare frequency of severe hypoglycemia in patients with T2DM treated with Amaryl ® (estimated n=1768) versus glibenclamide (estimated n=1721) Hypoglycemia vs Glibenclamide 6.5x less risk of hypo
Less weight gain: Weight gain is seen with all agents, glimepride has been reported to be the most weight-neutral sulphonylurea Weight gain is seen with all agents, glimepride has been reported to be the most weight-neutral sulphonylurea
Müller G, Wied S. Diabetes. 1993;42: 1852-1867 Insulin Resistance The extrapancreatic effect of Glimipride The extrapancreatic effect of Glimipride – Translocation of GLUT4 transporters from low-density microsomes to plasma membrane of insulin-resistant fat and muscle cells
Tsunekawa et al, Plasma Adiponectin Plays an Important Role in Improving Insulin Resistance With Glimepiride in Elderly Type 2 Diabetic Subjects Diabetes Care 26:285–289, 2003 Glimepiride Increases Plasma Adiponectin Hyperinsulinemic-euglycemic clamp study elderly T2 diabetic patients 12 weeks treatment + 54%
NormalIGTType 2 INSULIN RESISTANCE FPG / PPG HbA 1C INSULIN SECRETION Glimepiride Dual Mechanism for Dual Problem Graphic interpretation based on: Type 2 Diabetes BASICS. Minneapolis, MN: International Diabetes Center; 2000 Muller G, et al. Diabetes Res Clin Pract 1995; 28 (Suppl): S115-37; Massi-Benedetti M. Clin Ther 2003; 25(3): 799-816
Expected HbA1c reduction according to intervention Intervention Expected in HbA 1c (%) Lifestyle interventions 1to2% Metformin1to2% Sulfonylureas1to2% Insulin1.5to3.5% Glinides1to 1.5% 1 Thiazolidinediones0.5to1.4% -Glucosidase inhibitors -Glucosidase inhibitors0.5to0.8% GLP-1 agonist 0.5to1.0% Pramlintide0.5to1.0% DPP-IV inhibitors 0.5to0.8% 1. Repaglinide is more effective than nateglinide Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.
Glimepiride Efficacy Proven in Monotherapy Schade DS et al. J Clin Pharmacol 1998;38:636-51 Δ in median HbA 1c (%) 6.7% 9.1% HbA 1c <7.2% was achieved in 69% of Glimepiride patients and 32% of placebo patients HbA 1c <7.2% was achieved in 69% of Glimepiride patients and 32% of placebo patients 7.9% -1% 8.9% Baseline HbA 1c -4 -3 -2 0 HbA 1c at Endpoint -2.4% # Glimepiride decreased FPG by 46 mg/dL more and 2-hour PPG by 86 mg/dL more than placebo (p<0.001) Glimepiride decreased FPG by 46 mg/dL more and 2-hour PPG by 86 mg/dL more than placebo (p<0.001) n=117n=118n=108n=101 Δ in glucose concentration (mg/dL) FPGPPG -59* -117* -13 -31 -140 -120 -100 -80 -60 -40 -20 0 GlimepiridePlacebo *p<0.001 vs placebo
Suitable for Combination Therapy Efficacy of Glimepiride + Metformin Efficacy of Glimepiride + Gliptins Efficacy of Glimepiride + Insulins
Glimepiride + Metformin Combination Reduces Insulin Resistance More than Metformin Monotherapy Bermúdez-Pirela VJ, et al. Am J Therapeutics 2007; 14: 194-202 -52.4 -65.3* -46.9 -70 -60 -50 -40 -30 -20 -10 0 Metformin + diet & exercise (n=29) Metformin + Glimepiride + diet & exercise (n=21) Diet & exercise (n=9) Δ in HOMA IR (%) Percent change in homeostasis model assessment for insulin resistance (HOMA IR ) at week 10 *p<0.01 vs metformin and vs diet and exercise alone 7.811.76.4 Baseline HOMA IR values
Efficacy: Glimepiride + Gliptin Combination 1 Hermansen K, et al. Diabetes Obes Metab 2007; 9: 733-745 –The EU s Committee for Medicinal Products for Humans (CHMP) recently recommended that sitagliptin be approved for use in combination with a sulfonylurea and for triple therapy in combination with metformin + sulfonylurea 2 2 European Medicines Agency, 15 Nov 2007: Available at http://emea.europa.eu/pdfs/human/opinion/Januvia_53120907en.pdf in HbA 1c (%) -0.9 -0.8 -0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0 -0.57* -0.89* Glimepiride + sitagliptin Glimepiride + metformin + sitagliptin *p<0.001 vs placebo Baseline HbA 1c 8.4%8.3%
Efficacy: Glimepiride + Insulin Combination Reduced insulin requirement and faster glycemic control Reduced insulin requirement and faster glycemic control Riddle et al. Diabetes Care 1998;21:1052-1057 * p<0.001; p<0.05 vs Glimepiride Placebo + Insulin (n=62) Glimepiride + Insulin (n=70) Units/day Weeks 0 25 50 75 100 04812162024 * * * * * * 78 U/day 49 U/day -38% Mean insulin dosage required to restore glycemic control Weeks Mean FPG (mg/dL) 100 150 200 250 300 04812162024 * * Evolution of mean FPG over time
Additionnal Benefits for the Patient Beyond Blood Glucose Control
Mode of action: Different SURs in different tissues Pancreatic beta-cellSUR1/Kir6.2 Pancreatic beta-cellSUR1/Kir6.2 Cardiac and skeletal muscle SUR2A/Kir6.2 Cardiac and skeletal muscle SUR2A/Kir6.2 Vascular smooth muscleSUR2B/Kir6.1 Vascular smooth muscleSUR2B/Kir6.1 Non-vascular smooth muscle SUR2B/Kir6.2 Non-vascular smooth muscle SUR2B/Kir6.2 BrainSUR1-2B/Kir6.2 BrainSUR1-2B/Kir6.2 Proks P et al., Diabetes 2002; 51: S368-S376.
Glimepiride accompanied by a better CV risk marker Glimepride Efficient in reducing CV risk markers Lp(a), PAI-I and Hcy Lp (a) = lipoprotein (a) ; PAI-I = plasminogen activator inhibitor – I ; Hcy = homocysteine Lp (a) PAI - I Hcy 12 months
Glimepiride Beneficial Effects on HDL-C and Adiponectin Motoyama K, et al. Diabetes 2006; 55 (Suppl. 1): 468 [conference abstract] Baseline3 months 0 5 10 15 Time Plasma adiponectin ( g/dL) 7.5 8.3* Baseline3 months 0 10 20 30 40 50 60 70 Time HDLcholesterol (mg/dL) 50 53* *P < 0.05 vs baseline AdiponectinHDL-C
Ischemic preconditioning is a powerful, endogenous mechanism by which the heart protects itself from lethal ischemic insult Ischemic preconditioning is a powerful, endogenous mechanism by which the heart protects itself from lethal ischemic insult Brady et al. J Am Coll Cardiol 1998;31(5):950. NO ISCHEMIC PRECONDITIONING Prolonged occlusion of a major coronary artery leads to myocardial infarction ISCHEMIC PRECONDITIONING Repeated and brief occlusion of the same vessel preconditions the myocardium such that subsequent prolonged occlusion leads to a smaller infarct SULFONYLUREAS Sulfonylureas other than Glimepiride abolish ischemic preconditoning, resulting in large infarction size
% change in mean ST shift Baseline After drug administration Mean ST segment depression during balloon occlusion according to treatment Klepzig et al. Eur Heart J 1999;20:439-446 Glimepiride does not block the beneficial cardioprotective effect of ischemic preconditioning Glimepiride does not block the beneficial cardioprotective effect of ischemic preconditioning 50 100 Placebo (n=15) Glimepiride (n=15) Glibenclamide (n=15) p = 0.01 p = NS p = 0.049 0
More efficacy ( more reduction in HbA1c) More efficacy ( more reduction in HbA1c) Have an established long-term benefit with regard to decreased risk of micro and macro cardiovascular diabetes-related complications (UKPDS), Have an established long-term benefit with regard to decreased risk of micro and macro cardiovascular diabetes-related complications (UKPDS), You can lower risk of hypoglycemia in the case of second-generation sulfonylureas, such as glimepiride. You can lower risk of hypoglycemia in the case of second-generation sulfonylureas, such as glimepiride. Necessitate almost no precautions for use in patients with i mpaired renal function Necessitate almost no precautions for use in patients with i mpaired renal function Have no detrimental effect on ischemic preconditioning, Have no detrimental effect on ischemic preconditioning, Have a favorable cost/efficacy/safety ratio. Have a favorable cost/efficacy/safety ratio. Sulfonylureas 1 Nathan et al. Diabetes Care 2009;32:193-203. 2 Briscoe et al. Expert Opin Drug Metab 2010;6:225-235.
Advantages of Glimepiride Single daily dosing Single daily dosing Comparable hypoglycaemic side effect profile to other SU Comparable hypoglycaemic side effect profile to other SU Safer in the presence of cardiac disease Safer in the presence of cardiac disease Peripheral action conserves endogenous insulin Peripheral action conserves endogenous insulin Safer to use in the physically active Safer to use in the physically active
Review Annals of Internal Medicine Systematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus Shari Bolen, MD, MPH; Leonard Feldman, MD; Jason Vassy, MD, MPH; Lisa Wilson, BS, ScM; Hsin-Chieh Yeh, PhD; Spyridon Marinopoulos, MD, MBA; Crystal Wiley, MD, MPH; Elizabeth Selvin, PhD; Renee Wilson, MS; Eric B. Bass, MD, MPH; and Frederick L. Brancati, MD, MHS Conclusions: Compared with newer, more expensive agents older agents (second-generation sulfonylureas and metformin) have similar or superior effects on glycemic control, lipids, and other intermediate end points. Large, long-term comparative studies are needed to determine the comparative effects of oral diabetes agents on hard clinical end points. Ann Intern Med. 2007;147:386-399