Presentation on theme: "Sulphonylurea A Golden Therapy For Diabetes"— Presentation transcript:
1 Sulphonylurea A Golden Therapy For Diabetes ByEman RushdyProf. Internal MedicineCairo University
2 The shoes storyMany 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 second salesman reported back, "There is massive potential here - nobody wears shoes."You will perhaps have heard this very old story illustrating the difference between positive thinking and negative thinking:This simple short story provides one of the best examples of how a single situation may be viewed in two quite different ways - negatively or positively.
3 What is your concern about oral hypoglycemic drug ?! B cell exhaution.Less effectiveHypoglycemiaExpensive
4 The normal beta-cell 10 µm granules Pancreas consists of 1 million islets ofLangerhansStart to develop fromweek 9-11 gestation10 µm~ 10,000granulesPresented by Pr Philippe Halbanat the 1st Amsterdam Diabetes Meeting, March 30-April 1, 2006Micrograph: Lelio Orci, Geneva
5 Apoptosis is the major mechanism of death Half-life of ~30 daysApoptosis is the major mechanism of deathnormalapoptoticNew beta-cells by:*Replication*Neogenesis
6 ~65%-cell mass (%)Modified from Butler AE, et al. Diabetes 2003;52:102–10.
7 Factors for progressive loss of B- cell function & mass GlucotoxicityLipotoxicitylApoptosisInsulin SecretionAmyloid depositionInflamatoryCytokines& ROSPrentki M et al. Diabetes. 2002;51(suppl 3):s405-s413.
8 Exhaustion is reversible 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.Summary: Normal Glucose Homeostasis Involves Pancreatic Islet Cells in Normal SubjectsIn normal subjects, with the ingestion of food, gut hormones are released.1The gut hormones stimulate insulin secretion from pancreatic beta-cells, which helps reduce blood glucose concentration by increasing glucose uptake and reducing glucose production.2Gut hormones also suppress glucagon release from the alpha-cells, thereby causing a reduction in hepatic glucose production.1,2Glucose is taken up by adipose and muscle tissue.3Exhaustion is reversibleReferences:1. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372.2. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–2940.3. Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev. 2002;18:430–441.8
9 GlucotoxicityNon 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.Summary: Normal Glucose Homeostasis Involves Pancreatic Islet Cells in Normal SubjectsIn normal subjects, with the ingestion of food, gut hormones are released.1The gut hormones stimulate insulin secretion from pancreatic beta-cells, which helps reduce blood glucose concentration by increasing glucose uptake and reducing glucose production.2Gut hormones also suppress glucagon release from the alpha-cells, thereby causing a reduction in hepatic glucose production.1,2Glucose is taken up by adipose and muscle tissue.3Glucotoxicity is irreversibleReferences:1. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372.2. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–2940.3. Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev. 2002;18:430–441.9
10 Interplay between B-cell exhaustion & glucotoxicity HyperglycemiaExcess insulin secretionProlonged hyperglycemiaTreatmentInsulin depletion from B-cell (Exhaustion)Summary: Normal Glucose Homeostasis Involves Pancreatic Islet Cells in Normal SubjectsIn normal subjects, with the ingestion of food, gut hormones are released.1The gut hormones stimulate insulin secretion from pancreatic beta-cells, which helps reduce blood glucose concentration by increasing glucose uptake and reducing glucose production.2Gut hormones also suppress glucagon release from the alpha-cells, thereby causing a reduction in hepatic glucose production.1,2Glucose is taken up by adipose and muscle tissue.3More, prolonged hyperglycemiaER StressROSCa++CytokinesIrreversible B-cell damage& apoptosis (Glucotoxicity)References:1. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372.2. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–2940.3. Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev. 2002;18:430–441.10
13 Factors to Consider when Choosing Pharmacological Agent(s) for Diabetes Current A1CDuration of diabetesBody weight (BMI, abdominal obesity)EffectivenessCo-morbiditiesCradiovascular riskCost of medicationCompliance.
14 ADA/EASD: Considerations for the Guidelines Use of information from clinical trials that address the efficacy and safety of different modalities of treatment (Evidence based)Clinical judgment of the panel participants (Recognize that beta cell failure is progressive)Extrapolation of UKPDS data that glucose lowering of drugs (metformin, sulfonylureas, insulin) predicted decrease in complications.Nonglycemic effects of medication, such as effect on CV risk, lipids, hypertension or insulin resistanceSafety, side effects, ease of use and expense
15 AACE/ ACE CriteriaAttempts to provide a place and recommendation for all FDA approved drugsGreater emphasis on hypoglycemia avoidanceRecognizes that people may want choices, so allows a wide variety of choices and combinations for individual situations
16 ADA/EASD Management Algorithm Lifestyle intervention and metforminIf HbA1c ≥7%*Add basal insulin (most effective)Add sulfonylurea (least expensive)Add TZDIf HbA1c ≥7%Intensify insulin***Add basal insulin***Add sulfonylureaAdd TZDKey PointThe ADA/EASD recommends lifestyle modifications and metformin as the first step in treatment for patients with newly diagnosed diabetes.References:Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithmfor the initiation and adjustment of therapy. Diabetes Care 2006;29(8):Nathan DM et al. Management of hyperglycaemia in type 2 diabetes mellitus: a consensusalgorithm for the initiation and adjustment of therapy : Update regarding thethiazolidinediones. Diabetologia 2008;51(1):8-11.If HbA1c ≥7%Add basal or intensify insulinIntensive insulin + metformin +/− TZD**Nathan DM et al. Diabetes Care 2006;29(8):Nathan DM et al. Diabetologia 2008;51(1):8-11.16
17 ADA/EASD Consensus Algorithm for Management of Diabetes Diabetes Care Tier 1: Well-validated core therapiesAt diagnosis:Lifestyle+MetforminLifestyle+Metformin+Basal InsulinLifestyle+Metformin+Intensive insulinLifestyle+Metformin+SulfonylureaStep 1Step 2Step 3Tier 2: less well-validatedtherapiesLifestyle+Metformin+PioglitazoneSulfonylureaLifestyle+Metformin+Pioglitazone(No hypoglycemia, edema,CHF, bone loss)*Useful when hypoglycemia is to be avoidedLifestyle+Metformin+GLP1(No hypoglycemia, wt loss,Nausea/vomiting)Lifestyle+Metformin+Basal InsulinAmylin agonists, GlinidesDPP-4 inhibitors may be appropriate in selected patients
24 Sulfonylureas - Drug Profile AdvantagesPotent glucose lowering effectFavorable adverse effect profileDisadvantages*Hypoglycemia, less with Glimipride*Weight gain, less with GlimiprideConcomitant use with other drugsCan be used as monotherapy and with all classes including insulin
25 Sulfonylureas Divided into First, Second, and Third Generation First Generation: rarely used todaySecond Generation: glipizide, GliclazideThird Generation: glimepirideThe duration of action depends on the affinity to SUR and which part of it , the rate of metabolism, activity of metabolites and rate of excretionAction:Directly stimulate Beta cells (secretagogue)Increase tissue sensitivity to insulinDivided into First, Second, and Third GenerationFirst Generation: (Orinase, Diabinase): rarely used todaySecond Generation: glyburide (Diabeta), glipizide (Glucatrol)Third Generation: glimepiride (Amaryl)More potent, smaller doses neededhour action- take once or twice per dayShorter half life, shorter duration than first generationLess risk of hypoglycemia than first generationSide effects: (all)GI upset, skin rashes,photosensitivityAlcohol sensitivity (especially Diabenase)Prolonged hypoglycemia (drug action hours)
26 Modes of action: Glimepiride Most Sulphonylureas Glimepiride K+140kDa65 - cell membraneKATP channelMost SulphonylureasGlimepirideSulphonylureaReceptorThe duration of action depends on the affinity to SUR, rate of metabolism, activity of metabolites and rate of excretionSo What ??
27 Pharmakokinetics of sulphonylurea: *Glimepiride has a lower affinity to the -cellmembrane than others*The metabolites of glibenclamide are active while those of glimipride and gliclazide are inactive.
28 Glimepiride Controls Glycemia with Less Insulin Secretion Mean ratio between increased level of insulin and reduced glycemiaSulfonylureas tested in fasted male beagle dogs to determine ratios of mean plasma insulin release/ blood glucose decrease3Ratio210.20n=160.15n=130.105n=14100.05n=16150.0020GlibenclamideGlipizideGliclazideGlimepirideMuller G, et al. Diabetes Res Clin Pract 1995; 28 (Suppl): S115-37
29 Hypoglycemia vs Glibenclamide Significantly lower incidence of severe hypoglycemic events withGlimepiride vs glibenclamide (0.86 vs 5.6/1000 person-years)6Prospective, 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)6.5x less risk of hypo45.6# Episodes/1000 person-yearsThe reasons for the differences noted in hypoglycemia rate in this study are probably multifactorial. One factor is thought to be related to the differences in receptor binding between the two medications. Glimepiride has a considerably lower binding affinity to the -cell receptor and a higher exchange rate, associating with its receptor (65 kDa protein on the pancreatic sulfonylurea receptor in the cell membrane) 2 to 3 times faster than glyburide (which binds to 140 kDa protein) and dissociating about 8 to 9 times faster than glibenclamide. Additionally, glibenclamide accumulates after long-term use. Taken together, these factors can lead to a high risk of severe hypoglycemia.Furthermore, for the same blood-glucose lowering effect, glimepiride stimulates the secretion of smaller amounts of insulin than glibenclamide, both when fasting and postprandially. This ability to suppress endogenous insulin production between meals (and during exercise) is clearly different from glibenclamide and presumably lessens the risk of hypoglycemia.Holstein et al. Diabetologia 2000;43:A40.20.86GlibenclamideGlimepiride*Defined as requiring IV glucose or glucagonHolstein A et al. Diabetes Met Res Rev 2001; 17:467-73
30 Less weight gain:Weight gain is seen with all agents, glimepride has been reported to be the most weight-neutral sulphonylurea
31 Müller G, Wied S. Diabetes. 1993;42: 1852-1867 Insulin ResistanceThe extrapancreatic effect of Glimipride↑ Translocation of GLUT4 transporters from low-density microsomes to plasma membraneof insulin-resistant fat and muscle cellsIn extrapancreatic tissues, sulfonylureas promote the synthesis of glucose transporters (Jacobs, Hayes, & Lockwood, 1989), improving insulin sensitivity by potentiating glucose transport in adipose tissue and glycogen synthesis in skeletal muscle (Groop, 1992).Müller G, Wied S. Diabetes. 1993;42:1
32 Glimepiride Increases Plasma Adiponectin Hyperinsulinemic-euglycemic clamp study elderly T2 diabetic patients 12 weeks treatment+ 54%Rimonabant (Acomplia) 20 mg from Sanofi also has amazing results in 1,041 obese American patients in adiponectin increase of 1 year (+41%)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
33 Glimepiride Dual Mechanism for Dual Problem INSULINRESISTANCEFPG / PPG HbA1CINSULINSECRETIONNormalIGTType 2Graphic interpretation based on: Type 2 Diabetes BASICS. Minneapolis, MN: International Diabetes Center; 2000Muller G, et al. Diabetes Res Clin Pract 1995; 28 (Suppl): S115-37; Massi-Benedetti M. Clin Ther 2003; 25(3):
34 Expected HbA1c reduction according to intervention Expected ↓ in HbA1c (%)Lifestyle interventions1to2%MetforminSulfonylureasInsulin1.53.5%Glinides1.5%1Thiazolidinediones0.51.4%-Glucosidase inhibitors0.8%GLP-1 agonist1.0%PramlintideDPP-IV inhibitors1. Repaglinide is more effective than nateglinideAdapted from Nathan DM, et al. Diabetes Care 2009;32:34
37 Glimepiride Efficacy Proven in Monotherapy Glimepiride decreased FPG by 46 mg/dL more and 2-hour PPG by 86 mg/dL more than placebo (p<0.001)HbA1c<7.2% was achieved in 69% of Glimepiride patients and 32% of placebo patientsBaseline HbA1cFPGPPG9.1%8.9%n=117n=118n=108n=101-1%-1-20-13-2.4%#-40-31Δ in median HbA1c (%)-27.9%Δ in glucose concentration (mg/dL)-60-59*-3-80-46.7%-100HbA1c at Endpoint-120-117**p<0.001 vs placebo-140GlimepiridePlaceboSchade DS et al. J Clin Pharmacol 1998;38:636-51
38 Suitable for Combination Therapy Efficacy of Glimepiride + MetforminEfficacy of Glimepiride + GliptinsEfficacy of Glimepiride + Insulins
39 Baseline HOMAIR values Glimepiride + Metformin Combination Reduces Insulin Resistance More than Metformin MonotherapyPercent change in homeostasis model assessment for insulin resistance (HOMAIR) at week 107.811.76.4Baseline HOMAIR values-10Metformin+ diet & exercise(n=29)-20Δ in HOMAIR (%)-30Metformin + Glimepiride+ diet & exercise(n=21)-40-46.9Diet & exercise(n=9)-52.4-50-60-65.3*-70*p<0.01 vs metformin and vs diet and exercise aloneBermúdez-Pirela VJ, et al. Am J Therapeutics 2007; 14:
40 Efficacy: Glimepiride + Gliptin Combination Baseline HbA1c8.4%8.3%-0.1-0.2Glimepiride + sitagliptin-0.3-0.4Glimepiride + metformin + sitagliptin∆ in HbA1c (%)-0.57*-0.5-0.6-0.7-0.89*-0.8-0.9-11Hermansen K, et al. Diabetes Obes Metab 2007; 9:*p<0.001 vs placeboThe 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 + sulfonylurea22European Medicines Agency, 15 Nov 2007: Available at
41 Efficacy: Glimepiride + Insulin Combination Reduced insulin requirement and faster glycemic controlMean insulin dosage required to restore glycemic controlEvolution of mean FPG over time1001001502002503004812162024*78 U/day**75****-38%50Units/dayMean FPG (mg/dL)†49 U/day254812162024WeeksWeeksPlacebo + Insulin (n=62)Glimepiride + Insulin (n=70)* p<0.001; † p<0.05 vs GlimepirideRiddle et al. Diabetes Care 1998;21:
43 Additionnal Benefits for the Patient Beyond Blood Glucose Control
44 Mode of action: Different SURs in different tissues Pancreatic beta-cell SUR1/Kir6.2Cardiac and skeletal muscle SUR2A/Kir6.2Vascular smooth muscle SUR2B/Kir6.1Non-vascular smooth muscle SUR2B/Kir6.2Brain SUR1-2B/Kir6.2KATP channels have been identified in many tissue types, including myocardial cells.In most tissues, Kir6.2 serves as the pore-forming subunit, but it associates with different SUR subunits; for example, it associates with SUR1 in the pancreas and brain; SUR2A in heart and skeletal muscle; and SUR2B in brain and smooth muscle. In vascular smooth muscle, the KATP channel is composed of Kir6.1 in association with SUR2B.Amaryl® is highly selective for pancreatic channels over cardiac potassium channels, and therefore has a neutral CV profileProks P et al., Diabetes 2002; 51: S368-S376.
45 Glimepiride accompanied by a better CV risk marker Glimepride Efficient in reducing CV risk markersLp(a), PAI-I and Hcy12 monthsLp (a)PAI - IHcyLp(a) is in mg/dL, PAI-I in ng/mL and Hcy in µmol/L : when present in high plasma concentration, these extraglycemic measures of risk factors. Lp(a) potentiates thrombosis. PAI-I has been suggested to be a major determinant in the plasmin formation in the circulatory system. The amino acid Hcy is an atherothrombotic.Signification des differences en termes de statistiques :P<0,05 vs baseline for all except p<0,01 vs baseline for glim for Lp(a) and Hcy and p<0,05 vs repaglinide for HcyGlimepiride accompanied by a better CV risk markerLp (a) = lipoprotein (a) ; PAI-I = plasminogen activator inhibitor – I ; Hcy = homocysteine45
46 Glimepiride Beneficial Effects on HDL-C and Adiponectin Baseline3 months51015TimePlasma adiponectin (g/dL)7.58.3*Baseline3 months10203040506070TimeHDLcholesterol (mg/dL)53*Uncontrolled study in Japan enrolling 40 patients with T2D. Plasma adiponectin and HDL cholesterol levels were measured at baseline and after 3 months of treatment with Glimepiride 1mg/day.Plasma adiponectin and HDL cholesterol levels at baseline and after 3 months of treatmentGlimepiride significantly increases plasma adiponectin and HDL cholesterol levels*P < 0.05 vs baselineMotoyama K, et al. Diabetes 2006; 55 (Suppl. 1): 468 [conference abstract]
47 NO ISCHEMIC PRECONDITIONING ISCHEMIC PRECONDITIONING Ischemic preconditioning is a powerful, endogenous mechanism by which the heart protects itself from lethal ischemic insultIP occurs when cardiac KATP channels open automatically during brief episodes of mild myocardial ischemiaDrugs that inhibit cardiac KATP channel opening (e.g. glibenclamide) may be harmful to the ischemic myocardium by blunting the KATP channel-dependent component of the ischemic preconditioning responseNO ISCHEMIC PRECONDITIONINGProlonged occlusion of a major coronary artery leads to myocardial infarctionISCHEMIC PRECONDITIONINGRepeated and brief occlusion of the same vessel preconditions the myocardium such that subsequent prolonged occlusion leads to a smaller infarctSULFONYLUREASSulfonylureas other than Glimepiride abolish ischemic preconditoning, resulting in large infarction sizeBrady et al. J Am Coll Cardiol 1998;31(5):950.
48 % change in mean ST shift Glimepiride does not block the beneficial cardioprotective effect of ischemic preconditioningp = 0.049p = 0.01p = NS100% change in mean ST shift50Glimepiride May Offer Cardiovascular Advantages Compared With Other Sulfonylurea DrugsThe onset of ischemia causes the opening of the cardiovascular ATP-sensitive potassium (KATP) channels, a mechanism that plays a role in protecting the myocardium; this process is called ischemic preconditioning. It has been suggested that classical sulfonylureas such as glibenclamide have adverse effects on the cardiovascular system , mainly because they abolish the cardioprotective responses of the KATP channel opening, presumably by inhibiting mitochondrial KATP channel opening in cardiac myocytes.Unlike glibenclamide, data from animal and human studies show glimepiride does not block the beneficial effects of mitochondrial KATP channel opening in cardiac tissue.This may have implications for the treatment of T2DM patients who are typically at increased cardiovascular complications vs. non-diabetic subjects.Placebo(n=15)Glimepiride(n=15)Glibenclamide(n=15)BaselineAfter drug administrationMean ST segment depression during balloon occlusion according to treatmentKlepzig et al. Eur Heart J 1999;20:
50 Sulfonylureas 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),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 impaired renal functionHave no detrimental effect on ischemic preconditioning,Have a favorable cost/efficacy/safety ratio.In contrast to DDP IV inhibitors, sulfonylureas1Nathan et al. Diabetes Care 2009;32:2Briscoe et al. Expert Opin Drug Metab 2010;6:50
51 Advantages of Glimepiride Single daily dosingComparable hypoglycaemic side effect profile to other SUSafer in the presence of cardiac diseasePeripheral action conserves endogenous insulinSafer to use in the physically active
52 ReviewAnnals of Internal MedicineSystematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes MellitusShari 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, MHSConclusions: 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: