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Dr.SEENAJ CHANDRAN,MD,Dip.DIABSr.PHYSICIAN & DIABETOLOGISTKIMS,COCHIN 29/06/2013,CHERAI RESORTS,PARUR A DISCUSSION ON Metformin + Glimepiride + Voglibose COMBINATION THERAPY IN TYPE 2 DM
Calculated dietPlanned physical activityOral drugsInsulin injectionsOthersTreatment choices for Diabetes
Rationale for combination therapyFactors influencing glucose metabolism are:Rate of GI absorbtion of carbohydrateInsulin secretary rateGlucose balance across liverPeripheral (Muscle) glucose uptake and utilization
Matching Pharmacology To Pathophysiology
Currently available classes of Antidiabetic Agents
Site & Mode Of Action Of Oral Anti-hyperglycemic Medications
Evolution of understandingTreatment of diabetesInsulin to multiple drugsFrom purist approach to integrative strategyFrom monotherapy to combinationFrom one drug at a time to multiple drugs
Glycemic control: current situationThe current situation of glycemic control is far from ideal.The largest observational study suggests an avg HbA1c of 9.5% patients across the globe (against >7%)And inability to achieve desired glycemic control is due in part toPoor compliancePoor AdherencePoor Persistence with the suggested therapyAll These require multidrug therapyBecause….
Appropriate triple fixed dose combinations:Need is to improve glycemic control by using appropriate fixed dose combinations:MetforminAGIsSulfonylurea
Goals for glycemic controlRecent Guidelines Aimed at Improving Glycemic Control for Individuals with Type 2 diabetes
To achieve a normal or near normal HbA1c, both FPG and PPG levels must be normal or near normal.Thus both FPG and PPG must be targets for therapyNevertheless, might there be situations in which it is preferable to treat one or the other first ???Targets for glycemic control
Post-meal hyperglycaemia begins prior to type 2 diabetesThe development of type 2 DM is characterized by a progressive decline in insulin action & deterioration of β-cell function & hence insulin secretion.Prior to clinical diabetes, these metabolic abnormalities are first evident as elevations in post-meal plasma glucose, due to the loss of first phase insulin secretion, decreased insulin sensitivity in peripheral tissues and consequent decreased suppression of hepatic glucose output after meals due to insulin deficiency
Natural history of type 2 diabetes Post-meal hyperglycaemia begins prior to type 2 diabetes
Is PPG important?Why PPG is important?
Correlation of FPG & PPG to A1CA strong correlation exists between HbA1C levels and FPG and PPG concentrationsThe contribution of FPG to A1C is greater at higher A1C levels, While PPG contributes more to A1C when A1C levels are closer to goal In patients with an A1C below 7.3%, 70% of the A1C is attributed to PPG.
As Patients Get Closer to A1C Goal, the Need to Successfully Manage PPG Significantly IncreasesAdapted from Monnier L, Lapinski H, Collette C. Contributions of fasting and postprandial plasnma glucose increments to the overall diurnal hyper glycemia of Type 2 diabetic patients: variations with increasing levels of HBA(1c).Diabetes Care. 2003;26:881-885.
Relative Changes in FPG and 2-h PG as HbA1c IncreasesVan Haeften T et al Metabolism 2000
PPG Levels – better indicatorPPG levels contribute to a large portion of the HbA1C value, and there are differences in the degree to which PPG affects the HbA1C value for specific meals.A number of studies suggest that PPG may be a better indicator of glycemic control than fasting/premeal blood glucose levels
Postmeal hyperglycaemia is common in diabetesIn a cross-sectional study of 443 individuals with type 2 diabetes, 71% of those studied had a mean two hour postmeal plasma glucose of >14 mmol/l (252mg/dl). A study looking at daily plasma glucose profiles from 3,284 people with type 2 diabetes compiled over a one-week period, demonstrated PPG value > 8.9 mmol (160 mg/dl) was recorded at least once in 84% of those studied.Postprandial hyperglycemia is manifest in about 60% of newly diagnosed patients with type 2 diabetes1. Guideline for Management of Postmeal Glucose. IDF, 2007 ; 2. Ezenwaka et al. Clinical Nutrition (2004) 23, 631–640
Many patients have high PPG at FPG ≤126mg/dl% of patients PPG >200mg/dlFPGSouth Med J. 2001;94(8)
Down loaded from IDF home page: www.idf.org.IDF Guideline for Management of Postmeal Glucose has been revised and announced at IDF Annual Congress at Dubai in Dec-’112007 2011Page 24
PPG : Better predictor of CVD and all-cause mortality DECODE & DECODA analysisThe Diabetes Epidemiology Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) and the Diabetes Epidemiology Collaborative Analysis of Diagnostic Criteria in Asia (DECODA) studies,Analyzed baseline & 2-hr postmeal glucose data from prospective cohort studies including a large number of men & women of European and Asian origin, Analysis found 2-hr plasma glucose to be a better predictor of cardiovascular disease and all-cause mortality than fasting plasma glucose.
Relative risk for death increases with 2-hour blood glucose irrespective of the FPG level <6.1 6.1–6.9 ³7.0³11.17.8–11.0<7.8Fasting plasma glucose (mmol/l)2-hour plasma glucose(mmol/l)2.52.01.51.00.50.0Hazard ratioAdjusted for age, center, sexDECODE Study Group. Lancet 1999;354:617–621
Impact of Postprandial Hyperglycemia on Microvascular RiskStudies also documented association between A1C & the development of microvascular complicationsStudies suggests that FPG & 2-hour PPG have similar abilities to predict nephropathy & retinopathy.For example, in one study of 5023 Indians, increases in the risk of retinopathy and nephropathy with elevated FPG and 2-hour PPG were similar, suggesting that elevated FPG does not increase the risk of microvascular complications to a greater extent than PPG.Southern Medical Journal • Volume 102, Number 1, January 2009
Summary2011 Guideline for Management of Postmeal Glucose
2011 Guideline for Management of Postmeal Glucose
Effect on Endothelial Dysfunction.
Effect on CIMT
Risk of Retinopathy
Risk of Cancer
Effect on Cognitive Function
Effect of AGI on CVD in Patients with IGT (STOP-NIDDM)( Chiasson J - L et al JAMA July 2003 ) AGI
AGI also reduce progression of CIMTVoglibose has been shown to reduce the progression of CIMT
Evidence StatementThere is currently a lack of direct RCT evidence that correcting postmeal hyperglycaemia improves clinical outcomes [Level 1-]1Despite the overall negative result (of HEART2D study2), a recent post hoc analysis suggested that older T2DM AMI survivors may have a lower risk for a subsequent CV event with insulin targeting PPG versus fasting/premeal glycaemia31. IDF Postmeal Glucose Management Guideline 2011; Available at http://www.idf.org/guidelines/postmeal-glucose; 2. Diabetes Care 2009;32:381-386 . 3. Diabetes Care 34:1511–1513, 2011
Pharmacological Agents to treat PPGMeglitinidesAlpha-Glucosidase Inhibitors: Acarbose, VoglibosePrandial InsulinGLP-1 analoguesDPP-IV inhibitorsPramlintideAlpha-Glucosidase Inhibitors are the commonly used drugs specifically to treat PPG
Alpha-glucosidase inhibitors (AGIs)The alpha-glucosidase inhibitors are effective in lowering PPG because they delay carbohydrate absorption The alpha-glucosidase inhibitors have the added advantage of being weight neutral; J of Family Practice, May 2010 · Vol. 59, No. 05 Suppl: S9-S14
Where can AGIs be used to target PPGAt diagnosis when PPG is highPatients uncontrolled on monotherapy with high PPGPatients uncontrolled on monotherapy with high PPGStart with AGI – alternative to MetforminAdd AGI if PPG is high on monotherapyAdd AGI if PPG is high on dual therapyHowever, gastrointestinal side effects often limit patient acceptance…..
Alpha-Glucosidase InhibitorsMonotherapy or in combination with SU, metformin, TZD or insulinMaintenance 50-100 mg TID OF ACARBOSE0.2 /0.3 OF VOGLIBOSEExamples: Acarbose, Miglitol, Voglibose
Alpha-Glucosidase Inhibitors – Mechanism of ActionAct locally in small intestine to delay digestion and absorption of complex carbohydratesCompetitively inhibit pancreatic alpha-amylaseSlow conversion of complex carbohydrates into oligosaccharides Inhibit glucoamylase, maltase, isomaltase and sucraseReduce breakdown of oligosaccharides, trisaccharides, disaccharides to monosaccharidesRetards movement of sugars into systemic circulation, reduces postprandial blood glucose
FPG<150 mg/dl PPG>200 mg/dlDiet and exerciseAcarboseMetforminTZDT2DMDiet and ExerciseMonotherapyInsulin RegimenInsulin + Insulin sensitizersInsulin resistanceMetforminTZDInsulin deficiencySURepaglinide/voglibose/acarboseNateglinideCombination of Oral Agents Insulin Secretagogue + Insulin sensitzer2 insulin sensitizers + or – Insulin secretagogueBed time insulin + Oral AgentsMarked Symptoms FPG>270 mg/dl
Voglibose has better GI side effect profile
Aghgjhjhj1. IDF T2DM Treatment Algorhithm 2011; Available at http://www.idf.org Role of α-Glucosidase Inhibitors is emphasized
Voglibose is used commonly in combinationsVoglibose + MetforminVoglibose + SU combination (Adjunct)
Combined use of Voglibose & SU is effective
Combined use of Voglibose & SU is effective
Also is available in triple combinationMetformin + Glimepiride + Voglibose
Combination therapy in T2 DMAdvantagesCombination therapy offers several advantages. ConvenienceEase of administrationEase of remembranceEfficacy:Synergistic effectComplementary mechanism of actionTolerability:Better results are achieved at lower doses with fewer side effects. Improve compliance & control.PsychologicalReduce pill burden
Why Voglibose??Voglibose is an α-glucosidase inhibitorDelays the absorption of carbohydrates in the intestineIt is 20 – 30 times more potent than acarbose in inhibiting disaccharides in intestine (animal study)Voglibose has significantly lesser GI side effects as compared to acarboseUnlike acarbose, Voglibose is selective inhibitor of the α-glucosidase without effect on maltase.
Voglibose triple: Dosage recommendationVoglibose triple dose : with major meals or as directed by physician
Voglibose triple : Dosage recommendationSuggested to be administered with major mealsDosage must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended daily dose of 2000 mg metformin/8mg of Glimepiride/0.9mg of voglibose
Voglibose triple : Mechanism of actionActs on wider glucose metabolismNeed is to improve glycemic control by using appropriate fixed dose combinations:MetforminVogliboseSulfonylurea
Mechanism of action:Acts on wider glucose metabolismMetforminActs to reduce hepatic glucose outputSecondary action: improves muscle & adipose tissue sensitivityGlimepirideActs on SUR receptors of beta cells to increase insulin secretionVoglibose α-glucosidase inhibitorActs in intestine to inhibit α-glucosidase, delays carbohydrate absorption
Voglibose: May avoid secondary failure of SUsVoglibose has been shown to improve insulin sensitivityThis may reduce the requirement of insulin secretion from the beta cells – reduce overwork of beta cellsThis mechanism helps when used with SUsWith SUs there may be secondary failure because of most probably exhaustion of beta cellsTherefore it is assumed that concomitant use of voglibose and sulfonylureas, may avoid this secondary failureDiabetes care, Vol 21, No-2, Feb 1998
Voglibose triple: Suitable Patient Populationis suitable for following patients:Patients who need triple drug at diagnosis with high HbA1c & high PPGPatients uncontrolled on dual drug with high PPGPatients requiring triple drug therapy not suitable for pioglitazonePatients at risk of bladder cancerPatients with edema/signs of CCF
Voglibose triple : BenefitsThe suggested benefits to the patients are:The FDC improves the complianceWider action on glucose metabolism helps for effective glycemic control Complimentary action Better control of PPG with safetyImproves efficacyNo impairement of ischemic preconditioning
Voglibose triple : Added Benefits of VogliboseBetter control of post prandial hypoglycemiaLowers daily glycemic excursionsInhibits overwork of beta cellsReduced cardiovascular riskReduces CIMT progressionLesser chances of hypoglycemiaDiabetes care, Vol 21, No-2, Feb 1998
Voglibose triple : ContraindicationsHypersensitivity to glimepiride, metformin hydrochloride, voglibose or any other sulphonylureas or sulphonamides or to any ingredients of the formulation. Diabetic ketoacidosis, diabetic pre-coma. Renal failure or renal dysfunction (e.g., serum creatinine levels ≥ 1.5mg/dL in males and> 1.4mg/dL in females). Acute or chronic disease which may cause tissue hypoxia such as: cardiac or respiratory failure, recent myocardial infarction, shock Hepatic insufficiency, acute alcohol intoxication, alcoholism Cardiac failure or history of cardiac failure (NYHA stages I to IV) Inflammatory bowel disease, Intestinal obstruction, colonic ulceration, chronic intestinal diseases.Pregnancy and lactation.
Voglibose triple : PrecautionsMetformin:Lactic acidosisRenal function: should not be given if Sr Cr >1.5mg/dLAdministration of iodinated contrast agent : should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.Glimepiride:Treatment with glimepiride may lead to hypoglycaemia. Treatment with glimepiride requires regular monitoring of glucose levels in blood & urine. Regular hepatic & haematological monitoring (especially leucocytes and thrombocytes) are required during treatment with glimepiride.To minimize the risk of hypoglycemia, the recommended starting dose of glimepiride is 1 mg daily for all patients with type 2 diabetes and renal impairment.
PrecautionsVogliboseAdminister with care in patients with history of laprotomy or ileus, chronic intestinal disease, disturbance in digestion or absorption. Severe hernia or stenosis or ulceration or large intestinal gas etc, serious hepatic & renal dysfunction. Monitor blood glucose levels at regular intervals
Voglibose triple : Drug Interactions Metformin:Alcohol: Avoid consumption of alcohol and alcohol-containing medications.Glucocorticoids (systemic and local routes), beta-2-agonists, and diuretics
Voglibose triple : Drug Interactions Glimepiride:Potentiation of the blood-glucose-lowering effect and, thus, in some instances hypoglycaemia may occur when one of the following drugs is taken, for example:phenylbutazone, azapropazon, oxyphenbutazone, sulphinpyrazone, insulin and oral antidiabetic products, Weakening of the blood-glucose-lowering effect : oestrogens and progestagens, thiazide diuretics, thyroid stimulating agents, H2 antagonists, beta blockers, clonidine and reserpine may lead to either potentiation or weakening of the blood glucose lowering effect. Voglibose: Hypoglycemia may occur with co-administration of voglibose with other insulin preparation.
Voglibose triple : Adverse effectsMetformin:Nausea, vomiting, diarrhoea, abdominal pain, loss of appetite and metallic taste. Rarely mild erythema and lactic acidosis reported.Glimepiride:Generally well tolerated. Rash and urticaria. Rarely hypoglycaemic reactions, nausea, vomiting, diarrhoea, pressure or a feeling of fullness in the stomach, abdominal pain, elevation of liver enzymes, Voglibose: The G.I adverse effects like diarrhea, loose stools, abdominal pain, constipation, anorexia, nausea, vomiting
Voglibose triple : SummaryWider action of glucose metabolismReduce daily glycemic excursionsLesser chances of hypoglycemiaMay avoid secondary failure of SUsReduced cardiovascular riskTriple drug combination for comprehensive glycemic control
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