Presentation on theme: "Management of Diabetes Treat to Target Approach (A1c <7%) by Professor Dr Intekhab Alam Department of Medicine Postgraduate Medical Institute Lady Reading."— Presentation transcript:
1 Management of Diabetes Treat to Target Approach (A1c <7%) by Professor Dr Intekhab Alam Department of Medicine Postgraduate Medical Institute Lady Reading Hospital, Peshawar.This slide module will:Discuss the importance of glycosylated haemoglobin A1c as a marker for blood glucose control in both type 1 and type 2 diabetes managementReview the Diabetes Control and Complications Trial, United Kingdom Prospective Diabetes Study, and other studies to identify the link between good glycaemic control and long-term clinical outcomesDemonstrate the need for aggressive therapy to achieve glycaemic control, thereby reducing the risk of microvascular and macrovascular complications
2 Milestones in Diabetes Treatment 19201940196019802000Insulin glargineNPHinsulinA1cDCCTMetforminInsulin discoveredFirst sulphonylureasUKPDSInsulin pumpLente insulins• It has been more than 80 years since the discovery of insulin, and as this timeline shows, there has been continuing progress. In fact, much of our current understanding of diabetes, its devastating consequences, and its effective management has been attained during the latter part of this timeline. As this presentation will discuss, despite the progress of science, there are still many challenges to be overcomeResearchers at the University of Toronto discovered insulin in 1921The first sulphonylureas appeared during the early 1940sHans Christian Hagedorn’s delayed-action preparation, “neutral protamine Hagedorn,” appeared in 1946; we know it as NPHThe Lente series appeared in 1952Metformin became available (outside the United States) in 1960Portable insulin infusion pumps were introduced during the late 1970sThe Diabetes Control and Complications Trial was published in 1993Rapid-acting insulin analogues became available in 1996The United Kingdom Prospective Diabetes Study was published in 1998Lantus (insulin glargine; the first long-acting insulin analogue) received US Food and Drug Administration approval in 2000Rapid-acting insulinDCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study.1. Tattersall RB. In: Pickup JC, Williams G, eds. Textbook of Diabetes. 3rd ed. Boston, Mass: Blackwell Science; 2003.2. US FDA Center for Drug Evaluation and Research. Available at: Accessed March 18, 2003.3. Lantus Consumer Information. Available at: Accessed March 18, 2003.
3 Dual defect of type 2 diabetes: Treating a moving target InsulinResistanceType 2Diabetesb-cellDysfunctionHyperglycaemiaInsulin Actionb-cell FailureInsulinConcentrationInsulinResistanceDual defect of type 2 diabetes: treating a moving targetThe pathophysiology of type 2 diabetes is complex, and characterised by remorseless progression of the dual metabolic defects of insulin resistance and b-cell dysfunction.Initially, insulin resistance causes the glucose-lowering actions of insulin to be blunted, so that the pancreas secretes more insulin to overcome the deficit. At this stage the subject may develop impaired glucose tolerance, but is not yet diabetic.As insulin resistance progresses, however, the pancreas is no longer able to secrete enough insulin to control glycaemia, and increased hepatic glucose output and reduced glucose disposal by muscle and fat contribute to the chronic fasting and postprandial hyperglycaemia characteristic of type 2 diabetes. Eventually, insulin secretion from the b-cell begins to decline and the severity of the hyperglycaemia increases further.Adapted from DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM. A balanced overview. Diabetes Care 1992;15:EuglycaemiaNormalIGT ± ObesityDiagnosis of type 2 diabetesProgression of type 2 diabetesDeFronzo et al. Diabetes Care 1992;15:318-68
4 Progressive hyperglycaemia in type 2 diabetes 9Diet8InsulinMedian HbA1C (%)Metformin7Progressive hyperglycaemia in type 2 diabetesAll active therapies in the UKPDS reduced HbA1C, compared with placebo. However, the severity of hyperglycaemia increased at a similar rate in all treatment groups during the follow-up period. Current goals for glycaemic management set out by the International Diabetes Federation (Europe) and the American Association of Clinical Endocrinologists (USA) require control of HbA1C to 6.5% or less. The newly-diagnosed patients randomised to receive intensive glycaemic management in the UKPDS would, on average, have achieved this goal for only about 2 years following the initiation of treatment with oral antidiabetic monotherapy.It should be remembered that the UKPDS was essentially an evaluation of oral antidiabetic therapy, and treatment was not intensified until fasting plasma glucose exceeded 15 mmol/L (270 mg/dL). The high levels of HbA1C in the later years of the UKPDS therefore reflect the study design, but nonetheless expose the limitations of oral antidiabetic monotherapy in achieving long-term glycaemic control.UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:HbA1C 6.5%(IDF & AACE goal value)Sulphonylurea6246810Time from randomisation (years)UKPDS Group. Lancet 1998;352:854-65
5 ADA- and AACE/ACE-Recommended Goals for Glycaemic Control: A1c, FPG, and PPG Biochemical Control1Normal1Goal1A1c* (%)<6.0<7.0†FPG (mg/dL) Average preprandial<11090-130‡PPG (mg/dL)<140<180§The goal of diabetes management is to achieve blood glucose levels as close to normal throughout the entire course of a dayTo achieve this goal, the American Diabetes Association recommends a target A1cgoal of <7%. The World Health Association, the International Diabetes Federation, and the American Association of Clinical Endocrinologists/American College of Endocrinology have issued guidelines that recommend the more stringent A1c target of 6.5%The Diabetes Control and Complications Trial, United Kingdom Prospective Diabetes Study, and other studies have shown that to intensively treat to target is to intensively treat diabetes comorbidity. These studies have proven that there is a link between good glycaemic control and long-term clinical outcomes*Referenced to the nondiabetic range using a DCCT assay.1†AACE/ACE recommendation: 6.5%.2‡AACE/ACE recommendation: <110 mg/dL.2§AACE/ACE recommendation: <140 mg/dL.2ADA, American Diabetes Association; AACE/ACE, American Association of Clinical Endocrinologists/American College of Endocrinology; FPG, fasting plasma glucose; PPG, postprandial glucose; DCCT, Diabetes Control and Complications Trial.1. ADA. Diabetes Care. 2003;26(suppl 1):S33-S50.2. AACE/ACE. Endocr Pract. 2002;8(suppl 1):40-82.
6 A1c Reflects Overall Glucose Control A1c is the glycated form of the abundant red blood cell protein1A1c levels provide a 2- to 3-month index of glycaemic control2The target A1c level for patients with diabetes is <7%1Overall blood glucose control is best obtained by monitoring A1c3Circulating serum glucose binds irreversibly to the N-terminal valine within the beta chain of the haemoglobin (Hb) molecule, creating A1cIt is currently accepted that A1c yields the best overall measurement of blood glucose controlA1c levels provide an objective index of glycaemic control for the past 2 to 3 months, based on the turnover of Hb in red blood cellsImportantly, increases in A1c levels reflect both the rise in fasting/preprandial blood glucose levels and postprandial glucose levels; thus, normalisation of A1c levels may require control of both pre- and postprandial glucose levels1. Pickup JC. In: Pickup JC, Williams G, eds. Textbook of Diabetes. 3rd ed. Boston, Mass: Blackwell Science; 2003.2. Clark N. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.3. Cefalu WT. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.
7 Relationship of Mean Plasma Glucose and A1c This slide shows mean plasma glucose (MPG) values at increasing levels of A1c derived from data from the Diabetes Control and Complications TrialUsing fasting plasma glucose alone as a gauge of long-term glycaemia tended to progressively underestimate A1c and 7-point MPG at increasing plasma glucose levelsPostprandial plasma glucose contributes appreciably to A1c, although not all post meal times are equal in their distribution; eg, post lunch levels and MPG show similar relationships to A1c levels, while post breakfast levels markedly overestimate A1cMPG, mean plasma glucose.Adapted from Rohlfing CL et al. Diabetes Care. 2002;25:1. Rohlfing CL, Wiedmeyer H-M, Little RR, England JD, Tennill A, Goldstein DE. Defining the relationship between plasma glucose and HbA1c: analysis of glucose profiles and HbA1cin the Diabetes Control and Complications Trial. Diabetes Care. 2002;25:
8 A1c and Relative Risk of Microvascular Complications: DCCT 20RetinopathyNephropathyNeuropathyMicroalbuminuria1513119Relative Risk75Good glycaemic control is essential to reduce the risk of diabetic complicationsBased on the Diabetes Control and Complications Trial data, the relative risk for microvascular complications such as diabetic retinopathy, nephropathy, neuropathy, and microalbuminuria increases with increasing levels of A1cThe relative risk of complications is set to “1” for an A1c of 6%It is important to note that the risk gradient is continuous, with no glycaemic threshold for developing complications316789101112A1c (%)DCCT, Diabetes Control and Complications Trial.1. Adapted from Skyler JS. Endocrinol Metab Clin North Am. 1996;25:2. DCCT. N Engl J Med. 1993;329:3. DCCT. Diabetes. 1995;44:
9 Type 2 Diabetes Is a Progressive Disease: UKPDS Cross-sectional median valuesConventional Treatment* (n=1138)Intensive Treatment† (n=2729)98Median A1c (%)76United Kingdom Prospective Study was the largest study of newly diagnosed type 2 diabetes patients ever undertaken to examine the outcomes of treatment strategies over timeMore than 4200 patients were eligible for randomisation to receive conventional or intensive treatment for 10 yearsConventional therapy consisted of dietary advice; in patients who developed marked hyperglycaemia, secondary sulphonylurea or insulin therapy was provided, with the additional option of metformin in overweight patientsIntensive therapy consisted of dietary advice, along with sulphonylureas or insulin therapy with once-daily Ultralente insulin or isophane insulin3691215Time From Randomisation (years)*Diet, only.†Insulin or sulphonylurea + diet.UKPDS, United Kingdom Prospective Diabetes Study.Adapted from UKPDS Group. Lancet. 1998;352:
10 Good Glycaemic Control Reduces Incidence of Complications Risk reduction by decrease in A1c (%)Complications DCCT1,2 Ohkubo3 UKPDS4of diabetes mellitus (9% %) (9% 7%) (8% %)Retinopathy -63% -69% -21%Nephropathy -54% -70% -34%Neuropathy -60% – –Macrovascular disease -41%* – -16%*A reduction in risk for organ damage due to diabetes was seen in 3 landmark trials—the Diabetes Control and Complications Trial (DCCT), Ohkubo, and the United Kingdom Prospective Diabetes Study.4 In each, good glycaemic control, reflected by reductions in A1c levels (noted for each study at the head of each column), reduces the long-term incidence of microvascular complicationsAdditionally, there was a strong trend toward reduction of macrovascular complications. The 41% reduction in macrovascular disease in DCCT was impressive, although it did not reach statistical significance due to the low number of events in the studyThus, solid clinical evidence exists to support glycaemic control as a primary goal of therapy for patients with type 1 or 2 diabetes*Not statistically significant.DCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study.1. DCCT Research Group. N Engl J Med. 1993;329:2. DCCT Research Group. Diabetes. 1995;44:3. Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:4. UKPDS Group. Lancet. 1998;352:
11 Correlation of A1c and Complication Risk: UKPDS Type 2 DMRisk reduction in complications pereach 1% reduction in mean A1c4337Risk Reduction (%)212114The United Kingdom Prospective Diabetes Study yielded:A continuous and quantifiable correlation between decreased A1c measurements and a lower likelihood of diabetes-related macrovascular and microvascular complications, including peripheral vascular disease, stroke, and myocardial infarctionOn average, each 1% reduction in A1c is associated with a 37% decrease in the risk of microvascular endpoints and a 21% decrease in the risk of any diabetes-related endpoint or death; even patients with A1c levels only moderately above normal show an increased vulnerability to complicationsThese data demonstrate the value of clinicians’ efforts to bring patients’ A1c levels as near normal as possible. However, even moderate reductions in A1c levels have the potential to prevent deaths from complications related to diabetesMicrovascularAny Endpoint Related to DiabetesDeath Relatedto DiabetesFatal and Nonfatal MIAmputation orDeath From PVDUKPDS, United Kingdom Prospective Diabetes Study; MI, myocardial infarction;PVD, peripheral vascular disease.Stratton IM et al. Br Med J. 2000;321:
12 Preservation of Benefit: EDIC Progression of Retinopathy Type 1 DMConventional Treatment*Intensive Treatment†242220181614Cumulative Incidence (%)1210864The Epidemiology of Diabetes Interventions and Complications trial (EDIC) consisted of patients with type 1 diabetes in the Diabetes Control and Complications Trial (DCCT) who were followed for an additional 4 yearsIntensive therapy consisted of 3 injections of insulin daily or use of an insulin pump, combined with self-monitoring of blood glucose values, diet modification, and exercise. Conventional treatment consisted of 1 or 2 injections of insulin and 1 urine or blood glucose test each dayThose receiving intensive treatment during the DCCT/EDIC showed a lower risk of worsening retinopathy, including macular edema and proliferative retinopathy, and a need for laser therapy (P<.001)20.00.51.01.52.02.53.03.54.0EDIC (year)*1-2 insulin injections and 1 urine/blood glucose test daily.†3 insulin injections/pump treatments daily + SMBG + diet + exercise.EDIC, Epidemiology of Diabetes Interventions and Complications trial; SMBG, self-monitored blood glucose.DCCT/EDIC Research Group. N Engl J Med. 2000;342:
13 Risk of Death Related to A1c Levels 6A1c 7.0%4Relative Risk (%)2The relationship between A1c, diabetes, and mortality was investigated in 4662 men (aged years) in the Norfolk cohort of the European Prospective Investigation of Cancer and NutritionResults of the study showed that the relative risk of death increased through the range of A1c levels evaluated (<5.0%, 5.0%-5.4%, 5.5%-6.9%, 7.0%). It is important to note that between the levels of 5.0% to 5.4% and 5.5% to 6.9% the rise in risk of death is minimal; at A1c levels 7.0%, the risk increases dramaticallyAs can be seen, the higher the A1c level, the greater the relative risk of death from cardiovascular disease (CVD), ischaemic heart disease (IHD), or all causesThe study concluded that the increased risk of death from CVD, IHD, and all causes among men with diabetes could be largely explained by A1c concentrationCardiovascularDiseaseIschaemic HeartDiseaseAll CausesNote: A1c <5.0% was defined as a relative risk of 1.Adapted from Khaw K-T et al. Br Med J. 2001;322:1-6.Norfolk cohort of the European Prospective Investigation of cancer and Nutrition, n-4662
14 A Comprehensive Approach To Treat to Target Type 2 DMConventional TreatmentIntensive Treatment60P=.0075040Primary Composite Endpoint* (%)302010Because hypertension and dyslipidaemia tend to be comorbid with type 2 diabetes, true treatment to target is not a matter of glycaemic control only. A multifactorial intervention is neededThe study from the Steno Diabetes Center in Denmark proves that optimal management in type 2 diabetes includes control of blood pressure (BP) to 130/80 mm Hg and reduction of low-density lipoprotein cholesterolPatients were randomised to either conventional (n=80) or intensive treatment (n=80). Intensive treatment included insulin to control A1c to <6.5%, a diuretic to control BP, and an angiotensin-converting enzyme inhibitor, regardless of BP level. Additional therapies were as follows:Intensive treatment: an angiotensin II receptor blocker to control BP to <130/80 mm Hg, dietary management of serum lipids (cholesterol: <190 mg/dL; fasting triglycerides: <150 mg/dL), and aspirin 150 mg/dayConventional treatment: BP control to <135/85 mm Hg and serum lipid control (cholesterol <250 mg/dL; fasting triglycerides <180 mg/dL), with aspirin therapy reserved for patients with known ischaemiaAt a mean follow-up of 7.8 years, patients receiving intensive treatment were about 50% less likely to have experienced cardiovascular disease, nephropathy, retinopathy, or autonomic neuropathy1224364860728496Follow-up (months)Number at Risk/TreatmentConventionalIntensive807270635950444113807874716663615919*Composite endpoint = cardiovascular death and amputation (with either therapy), and relative risk for organ damage (with intensive therapy).Gaede P et al. N Engl J Med. 2003;348:Steno diabetes center,Denmark. n 160.
15 Insulin Helps Achieve Control Type 2 DM60*47504035Patients Achieving A1c <7% at 6 Years (%)30202010ConventionalGlucose ControlInsulin AloneSU ± InsulinA substudy of the United Kingdom Prospective Diabetes Study evaluated the efficacy of the addition of insulin therapy over 6 years in 826 newly diagnosed patients with type 2 diabetes randomised to either conventional control with diet alone or intensive control (insulin alone or insulin added to maximal sulphonylurea)The aim of conventional control was to achieve the best possible fasting glucose; the aim of intensive control was to achieve and maintain fasting glucose <6.0 mmol/L (<108 mg/dL)Significantly more patients in the combination group were able to achieve an A1c <7.0% than in the insulin-alone group (47% vs 35%, P=.011)Thus, intensive insulin therapy, either alone or added to sulphonylurea, resulted in better control than diet aloneIntensive Glucose Control (FPG < 108 mg%)Median A1c (IQR): % ( ) % ( )† % ( )†‡*P=.011 sulphonylurea insulin vs insulin alone; †P< insulin or sulphonylurea insulin vs conventional glucose control policy; ‡P=.0066 sulphonylurea insulin vs insulin alone.SU, sulphonylurea; IQR, interquartile range.Adapted from Wright A et al. Diabetes Care. 2002;25:
16 Treat to Target A1c A1c is a key marker of diabetes treatment efficacy A1c levels correlate with a patient’s relative risk of death and of microvascular and macrovascular complicationsThe DCCT, UKPDS, and other major trials—as well as major diabetes organizations—support treatment-to-target A1c <7%• A1c level is a key surrogate marker of the relative risk of both death and of microvascular and macrovascular complications in patients with diabetes• The treat-to-target approach (A1c <7%) is supported by the Diabetes Control and Complications Trial, the United Kingdom Prospective Diabetes Study, other major trials, as well as major diabetes organizationsDCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study.
17 Treat to Target A1cAggressive therapy is often necessary to achieve controlTreat to target requires a comprehensive approach: control of blood pressure and control of LDL-c, bolstering a concerted attack on A1c levelsTreat to target reduces risk of complications and its associated costs• Aggressive therapy helps achieve control• Treat to target requires a comprehensive approach: control of blood pressure and low-density lipoprotein cholesterol, and a concerted attack on A1c levelsTreat to target A1c levels reduces the risk of complications, thereby reducing the cost associated with these complicationsEarly diagnosis, along with effective therapeutic agents, may result in more patients reaching and maintaining target A1c goals, thereby maintaining a low-cost state for an extended period of timeLDL-C, low-density lipoprotein cholesterol.
18 Pitfalls In HbA1C Estimation False high HbA1C:Hb F, Acetylated Hb, Cabamoylated Hb.False low HbA1C:Hb S or C, Hemolytic anemias, Hemmorhage.Reliability in diagnosing Diabetes:sensitivity 85%specificity 91%.Fructosamine levels:nonenzymatic glycosylation of serum proteins esp Albumin1.5-2,4 mmol/l with 5gm/dl of Albumin.
19 The ABC of Diabetes Management Effective management of diabetes requiresA – Control of A1cB – Control of Blood pressureC – Control of CholesterolThe effective management of diabetes requires control ofA - A1cB –Blood pressureC –Cholesterol
20 ADA Glycemic Targets Normal Goal Action Level HbA1c (%) <6 <7 >8Fasting and preprandial blood glucose (mg/dL) < to >140The ADA recommendations for glycemic targets is as followsNormalGoalAction LevelHbA1c (%)< 6<7> 8Fasting and prandial blood glucose (mg/dl)< 11080 to 120> 140American Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus. Diabetes Care 1999;22(Suppl):S32-S41.
21 ADA Blood Pressure Targets Goal (mm Hg)Usual patient <130/85Isolated systolic hypertension If ≥180 < If 160 to 179 Reduce by 20The ADA recommendations for blood pressure targets is as followsGoal (mm Hg)Usual patient< 130/ 85Isolated systolic hypertensionIf 180If 160 to 179<160Reduce by 20American Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus. Diabetes Care 1999;22(Suppl):S32-S41.
22 ADA LDL-Cholesterol Targets (mg/dl) Medical Nutrition Therapy Drug Therapy Begin Rx Goal Begin Rx GoalWith CV disease >100 ≤ > ≤100No CV disease > ≤ > ≤100The ADA recommendations for LDL – cholesterol targets is as followsMedical Nutrition therapyBegin Rx GoalDrug therapyBegin Rx GoalWith CV disease>100 mg/dl 100 mg/dl>100 mg/dl 100 mg/dlNo CV disease>100 mg/dl 100 mg/dl>130 mg/dl 100 mg/dlAmerican Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus. Diabetes Care 1999;22(Suppl):S32-S41 & S56-S59.
23 European Diabetes Policy Group Desktop Guide ‘Providing a greater emphasis on arterial risk factor management rather than just good blood glucose control’The European Diabetes Policy Group Desktop Guide recommends“Providing a greater emphasis on arterial risk factor management rather than just good blood glucose control”European Diabetes Policy Group (1998–1999)
24 European Diabetes Policy Group Desktop Guide At each assessmentSet individual targets for blood glucose, blood lipid and blood pressureTargets should incorporate an assessment of risk and the patient’s needsSet realistic objectives within a time periodEvaluate individual targets at least yearly in the light of past successes and if clinical circumstances changeThe European Diabetes Policy Group Desktop Guide also recommends that at each assessmentSet individual targets for blood glucose, blood lipid and blood pressureTargets should incorporate an assessment of risk and the patient’s needsSet realistic objectives within a time periodEvaluate individual targets at least yearly in the light of past successes and if clinical circumstances changeEuropean Diabetes Policy Group (1998–1999)
25 Assessment Measure HbA1c every 2-6 months blood lipid profile (total, LDL- and HDL-cholesterol, and triglycerides) every 2-6 months if previously above assessment levels otherwise annuallyblood pressure at each consultation unless known to be below assessment levelsOne should measureHbA1c every 2-6 monthsblood lipid profile (total, LDL- and HDL-cholesterol, and triglycerides) every 2-6 months if previously above assessment levels otherwise annuallyblood pressure at each consultation unless known to be below assessment levelsEuropean Diabetes Policy Group (1998–1999)
26 European Diabetes Policy Group advice ‘Failure to attempt to reach agreed targets is inadequate care’The European Diabetes Policy Group advises that‘Failure to attempt to each agreed targets is inadequate care’European Diabetes Policy Group (1998–1999)