Presentation on theme: "Importance of early glycemic control in management of type 2 diabetes"— Presentation transcript:
1 Importance of early glycemic control in management of type 2 diabetes Prof. Khalifa M. AbdallahProfessor of Internal MedicineUnit of Diabetes & Metabolic DiseasesAlexandria Faculty of Medicine
2 Overview The importance of early and sustained glycemic control The rationale for early insulinizationAdvantages of basal insulin therapyTake home message
3 Diabetes Mellitus A Constellation of Complications GastropathyAutonomic NeuropathyRenal DiseasePeripheral NeuropathyRetinopathy/ Macular EdemaHypertensionCardiovascular DiseaseDyslipidemiaPeripheral Vascular DiseaseErectile DysfunctionDiabetesLeading cause of adult blindnessResults in 2- to 4-fold increase in cardiovascular riskNearly double the rates of diagnosed depression1,2,33
4 - A1c & Microvascular Complications 60 – 70 % Reduction of Complications Retinopathy15Nephropathy13119NeuropathyRelative Risk7The relative risk of developing microvascular complications of diabetes (progression of retinopathy, progression to clinical neuropathy, progression to severe nonproliferative or proliferative retinopathy, or progression to microalbuminuria) was directly related to HbA1c level. In this representation of the relationship between the risk of complications and HbA1c, the relative risk of complications is set to 1 at an HbA1c of 6%.ReferenceSkyler J. Diabetic complications. The importance of glucose control. Endocrinol Metab Clin. 1996;25:243–254.5Microalbuminuria316789101112HbA1c (%)Skyler JS. Endocrinol Metab Clin. 1996;25:243–254.
5 Effects of reduction of A1c by 1.9% in intensively treated group Risk Reduction in DCCTEffects of reduction of A1c by 1.9% in intensively treated groupNeuropathyAlbuminuriaRetinopathy76%54%60%39%OnsetProgression20406080albuminuriaRisk ReductionP=0.002P=0.002P=0.002P=0.04P=0.04DCCT Research Group. N Engl J Med. 1993;329:
6 A1c : Myocardial Infarction and Microvascular Complication 80Microvascular disease60Myocardial infarctionIncidence per 1000 patient-years4020Mean HbA1c (%)567891011UKPDS 35. BMJ 2000; 321:
7 UKPDS: Glucose Control Study Summary The intensive glucose control policy maintained a lower HbA1c by a mean of 0.9% over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in risk of:12% for any diabetes related endpoints p=0.02925% for microvascular endpoints p=0.009916% for myocardial infarction p=0.052
8 UKPDS: Glucose Control Study Summary The intensive glucose control policy maintained a lower HbA1c by a mean of 0.9% over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in risk of:12% for any diabetes related endpoints p=0.02925% for microvascular endpoints p=0.009916% for myocardial infarction p=0.052
9 Causes of Death in People With Diabetes 5065%of Diabetic Patients Deathsare from CV CausesDeaths (%)40403020151313101045All otherDiabetesMalignant neoplasmsOther heart diseasePneumonia/influenzaIschemicheart diseaseCerebrovascular diseaseWHO Report World Health Organisation. Geneva 1997
10 Can long-term glycemic control reduce the risk of cardiovascular disease?
11 Summary of ACCORD, ADVANCE and VADT No. of participants10,25111,1401791Participant age ,years626660HbA1C at Baseline, %188.8.131.52Significant Effect on Macrovascular Outcomes?NoSignificant Effect on Microvascular Outcomes?NASignificant for nephropathy, not retinopathyRosiglitazone use, (intensive vs. standard)90% vs. 58%17% vs. 11%85% vs. 78%Duration of follow-up, years3.45.06
12 ACCORD ADVANCE and VADT- No Significant Effect on Macro or Micro Vascular Outcomes No. of participants10,25111,1401791Participant age ,years626660Duration of diabetes at study entry, years10811.5HbA1C at Baseline, %184.108.40.206Participants with prior cardiovascular event, %353240Duration of follow-up, years3.45.06
13 DCCT / EDIC: majority of patients receive intensive therapy and HbA1C levels converge ConventionalConventionalConventionalConventional groupConventional groupConventional group1111encouraged to switchencouraged to switchencouraged to switchto intensiveto intensiveto intensive1010treatmenttreatmenttreatment(%)(%)99cc1188HbAHbADuring DCCT, intensive insulin therapy in people with type 1 diabetes significantly reduced HbA1c relative to those receiving conventional treatment. The intensively-treated group achieved a mean HbA1c of 7.1%, while the conventionally-treated patients had HbA1c of approximately 9.0%. During the EDIC (Epidemiology of Diabetes Intervention and Complications research group) follow-up of the DCCT cohort, all patients were encouraged to adopt intensive insulin therapy. During this time, HbA1c stablised to a similar level (just over 8%) in both treatment groups.7766112233445566778899DCCTDCCT111222333444555666777DCCTDCCTendendEDICEDICEDICYearYearDCCT/EDIC: NEJM, 2005;353, No 25:
14 DCCT / EDIC – incidence of all predefined cardiovascular outcome Patients previously receiving intensive treatment in the DCCT study had a 57% reduced incidence of nonfatal myocardial infarction, stroke or death from cardiovascular diseaseDCCT/EDIC: NEJM, 2005;353, No 25:
15 UKPDS: Post-Trial Changes in HbA1c Mean (95%CI)UKPDS results presentedUKPDS 80. N Eng J Med 2008; 359
16 UKPDS: Legacy Effect of Earlier Glucose Control After median 8.5 years post-trial follow-upAggregate EndpointAny diabetes related endpoint RRR: 12% 9%P:Microvascular disease RRR: 25% 24%P:Myocardial infarction RRR: 16% 15%P:All-cause mortality RRR: 6% 13%P:RRR = Relative Risk Reduction, P = Log RankN Eng J Med 2008
17 Can long-term glycemic control reduce the risk of cardiovascular disease? YesIf early and sustained glycemic control startedbefore atherosclerosis is established
18 At present, The question is not whether to intensively treat people with type 2 diabetes at onset of the disease to prevent long-term complications. The question rather is how to intensively treat patients with type 2 diabetes to consistently keep A1c < 7% all through the course of the disease
19 ADA: Position statement: Need for early treatment “Patients with shorter duration ofType 2 diabetes and withoutestablished atherosclerosis mightreap cardiovascular benefitsfrom intensive glycaemic control”1Skyler JS, et al. J Am Coll Cardiol. 2009;53(3):
20 Glycemic control & A1c Target AACEADA<6.5<7A1c (%)<11080-120Preprandial (mg/dl)<140Postprandial (mg/dl)Bedtime (mg/dl)ADA: American Diabetes AssociationAACE: American Association of Clinical Endocrinologists
21 Two-thirds of Type 2 Patients are not Achieving Glycemic Control R19/p19/C1/P1/L1-4NHANES144.5%35.8%A1c <7%R1/p3/L1-2N=1215N=372AACE surveyOnly about one-third of Americans with type 2 diabetes meet either the ADA or AACE standards for glycemic control.Recent statistics reveal that the majority of patients with diabetes are not achieving adequate glycemic control. The National Health and Nutrition Examination Survey (NHANES) is conducted periodically on a nationwide scale in the United States to gather health and nutritional data. Results from the survey revealed that 44.5% of patients with type 2 diabetes had an A1c level of 7% or lower. NHANES data gathered during are even more disappointing: just over one-third of patients reported having an A1c level of 7% or lower.The NHANES findings are corroborated by data gathered during by the American Association of Clinical Endocrinologists (AACE). In a survey of 157,000 patients with type 2 diabetes across 39 states in the US, two-thirds of respondents were failing to achieve an A1c goal of 6.5% or below.References:Koro CE, Bowlin SJ, Bourgeois N, Fedder DO. Glycemic control from 1988 to 2000 among U.S. adults with type 2 diabetes. Diabetes Care 2004;27:17-20.American Association of Clinical Endocrinologists. “State of Diabetes in America,” Available at: Report.pdf. Accessed January 6, 2006.33%R19/p19/C1/P1/L1-4A1c 6.5%N=157,000 type 2 patients 39 US states includedR1/p3/L1-2NHANES = National Health and Nutrition Examination Survey.1Koro et al. Diabetes Care. 2004;27:17-20; 2 “State of Diabetes in America,” American Association of Clinical Endocrinologists, Available at: DiabetesAmericaReport.pdf. Accessed January 6, 2006.
22 Traditional Type 2 Diabetes Management: A “Treat-to-Fail Approach” Published Conceptual ApproachMean HbA1c of patients1/Del Pratop.1349 Figure 2A2/Campbellp.626 Figure 1OAD +multiple dailyinsulin injectionsDiet and exerciseOADmonotherapyOAD up-titrationOADcombinationOAD +basal insulin1098HbA1c Goal76Duration of DiabetesConventional stepwise treatment approachOAD=oral antihyperglycemic agent.Adapted from Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol. 2000;7(10):625–631. Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.
23 Delays often occur between stepping up from monotherapy to combination therapy Length of time between first monotherapy HbA1c > 8.0% and switch/addition in therapy (months)2520.5 months2014.5 months15Months10Initial improvements in glycemic control seen with conventional antidiabetic agents in monotherapy are usually not maintained long term, and most patients ultimately require combination therapy to achieve good glycemic control.1In practice, there is often a considerable delay between the loss of glycemic control with monotherapy and the introduction of another antidiabetic agent.Analysis of data from the Kaiser Permanente Northwest database(1994–2002)2 found that the average time from when the HbA1c action point of 8% was exceeded and the introduction of an additional or alternative oral antidiabetic agent was:14.5 months for those on metformin monotherapy20.5 months for those on sulfonylurea monotherapy.Earlier introduction of combination therapy could reduce exposure of patients to the risk of diabetes-related complications associated with periods of hyperglycemia.21Turner RC, et al. JAMA 1999; 281:2005– Brown, JB et al. Diabetes Care 2004; 27:1535–1540.5Metformin onlySulfonylurea onlyn = 513n = 3394Brown, JB et al. Diabetes Care 2004; 27:1535–1540.
24 Clinical Inertia: Failure to Advance Therapy When Required Percentage of subjects advancing when A1C >7% < 8%At insulin initiation, the average patient had:1005 years with A1C > 8%10 years with A1C > 7%8066.6%6044.6%% of Subjects35.3%4018.6%20DietSulfonylureaMetforminCombinationBrown JB et al. Diabetes Care 2004;27:
27 Consensus Algorithm Update 2009 Tier 1: Well-validated core therapiesLifestyle + MetforminplusBasal InsulinAt diagnosis:Lifestyle + MetforminLifestyle + MetforminplusIntensive InsulinLifestyle + Metformin plusSulfonylureaaStep 1Step 2Step 3Tier 2: Less well-validated therapiesCheck A1C every 3 months until <7%. Change treatment if A1C is ≥7%Lifestyle + Metformin plusPioglitazoneNo hypoglyceamiaOedema / CHFBone LossLifestyle + Metformin plusPioglitazone plus SulfonylureaLifestyle + Metformin plusGLP-1 agonistNo hypoglyceamiaWeight lossNausea / vomitingLifestyle + Metformin plusBasal InsulinNathan DM et al. Diabetes Care 2009;32:
28 Sulphonylureas failed to maintain glycemic control Glyburide1GlimpirideGlyburideGlibenclamideGliclazideGlyburideHanefeld (n=250)HBA1c % Reduction-1Tan (n=297)Chicago (n=230)-2Periscope (n=181)ADOPT (n=1441)UKPDS (n=1573)1234510Time (years)
29 UKPDS: Islet -cell function and the progressive nature of diabetes Time of diagnosis1008060(% of normal by HOMA)Islet -cell functionPancreatic function= 50% of normal402010987654321123456YearsHOMA = homeostasis model assessmentHolman RR. Diab Res Clin Pract. 1998;40(suppl):S21-S25;UKPDS. Diabetes. 1995;44:
30 Advantages of insulinIt lowers mean blood glucose in a predictable dose-dependent mannerCan be tailored to individual needs on a unit-to-unit basisIt has the longest experience than any other drug (90 years)No contraindications to its use
31 Advantages of insulinInsulin is the only drug that directly reduces lipolysis and free fatty acid concentrations in blood, thus reducing lipotoxicityInsulin improves lipoprotein metabolism, decreases LDL cholesterol and triglycerides, and increases HDL cholesterolInsulin improves endothelial dysfunction
32 thoughts/concerns about starting insulin Common Fears:NeedlesHypoglycemiaWeight gainCommon Beliefs:Insulin is the last optionInsulin causes complicationsInsulin is a personal failureAdverse impact on relationships/lifestyle32
33 What should I tell people with Type 2 diabetes about insulin? ‘Most people with Type 2 diabetes eventually need insulin because their own production of insulin falls off with time and they therefore inevitably become insulin deficient’
34 What should I tell people with Type 2 diabetes about insulin? ‘If you need insulin, it doesn’t mean you failed. Tablets cannot control blood glucose forever, because they don’t stop the problem of your own declining insulin production getting worse’Islet -cell dysfunction worsens over time, regardless of therapy
35 What should I tell the person with Type 2 diabetes who needs insulin, but doesn’t want to take it? ‘Insulin will not make your diabetes worse. In fact, it will help control your glucose, so you’ll have fewer complications and you’ll feel better.’Strict glycaemic control reduces the risks of both microvascular and macrovascular complications
36 Insulin Regimens1. Basal insulin ( NPH or long-acting insulin analogue) + OAD2. Total insulin replacement therapy- Premixed insulins- Basal-bolus
37 24-hour Plasma Glucose Curve: Rationale for Adding Basal Insulin Slide 1-22400Diabetes300Glucose (mg/dL)200Normal1000600100014001800220002000600Time of DayAdapted from Polonsky KS et al. N Engl J Med. 1988;318:
38 24-hour Plasma Glucose Curve: Rationale for Adding Basal Insulin Slide 1-22400300DiabeticGlucose (mg/dL)200100Normal0600100014001800220002000600Time of DayAdapted from Polonsky KS et al. N Engl J Med. 1988;318:
39 Starting With Basal Insulin in DM 2 – Advantages 1 injection with no mixingInsulin pens for increased acceptanceSlow, safe, simple titrationLow dosageEffective improvement in glycemic controlLimited weight gainSlide 6-37INSULIN TACTICSStarting With Basal InsulinAdvantagesPatients who no longer respond adequately to oral agents will benefit from combination therapy that consists of maintaining the use of oral antidiabetic agents together with insulin therapy. The advantages of adding basal insulin to prior treatment with oral agents include the following: (1) only one insulin injection may be required each day, with no need for mixing different types of insulin; (2) the use of insulin pens can enhance patient acceptance of the treatment; (3) titration can be accomplished in a slow, safe, simple fashion; and (4) eventually combination therapy requires a lower total dose of insulin. The result is effective improvement in glycemic control while causing only limited weight gain.
40 Insulin Glargine vs. NPH Insulin Added to Oral Therapy Mean A1C Levels During Study9Insulin glargineNPH insulin8Mean A1C (%)7Target A1C (%)64812162024Time (weeks)Riddle MC et al. Diabetes Care. 2003;26:
41 Less Hypoglycemia with Insulin Glargine vs NPH 350030002500200015001000NPHInsulin glargineHypoglycemia events per 100 patient-yearsT1DMp=0.004 between treatmentsHbA1c20015010050Hypoglycemia events per 100 patient-yearsT2DMp=0.021 between treatmentsHbA1cMullins P et al. Clin Ther 2007;29:1607−19.
42 Insulin Glargine vs. NPH Insulin Added to Oral Therapy Symptomatic Hypoglycemia by Time of DayGlargineNPH insulinBasal insulin1.4**1.2**1.0**0.8*Events per Patient-Year0.60.40.2Similar trends were observed when the overall number of symptomatic hypoglycemic episodes occurring over time were analyzed.Between midnight and 8 am, and breakfast time, there were fewer episodes of symptomatic hypoglycemia in the insulin glargine group compared with the NPH insulin groupAt other times of day, the number of episodes of symptomatic hypoglycemia were similar in both treatment groupsROSENSTOCK AbstractOBJECTIVE: To determine the safety and efficacy of the long-acting analog insulin glargine compared with NPH insulin in patients with type 2 diabetes who were previously treated with insulin alone. RESEARCH DESIGN AND METHODS: A total of 518 subjects with type 2 diabetes who were receiving NPH insulin with or without regular insulin for postprandial control were randomized to receive insulin glargine (HOE 901) once daily (n = 259) or NPH insulin once or twice daily in = 259) for 28 weeks in an open-label, multicenter trial. Doses were adjusted to obtain target fasting glucose <6.7 mmol/l. At study end point, the median total daily insulin dose in both treatment groups was 0.75 IU/kg. RESULTS: The treatment groups showed similar improvements in A1C from baseline to end point on intent-to-treat analysis. The mean change (means +/- SD) in A1C from baseline to end point was similar in the insulin glargine group ( /- 0.1%) and the NPH group ( /- 0.1%) after patients began with an average baseline A1C of approximately 8.5%. The treatments were associated with similar reductions in fasting glucose levels. Overall, mild symptomatic hypoglycemia was similar in insulin glargine subjects (61.4%) and NPH insulin subjects (66.%) However, nocturnal hypoglycemia in the insulin glargine group was reduced by 25% during the treatment period after the dose-titration phase(26.5 vs. 35.5%, P = ). Subjects in the insulin glargine group experienced less weight gain than those in the NPH group (0.4 vs. 1.4 kg, P < ). CONCLUSIONS: In patients with type 2 diabetes, once-daily bedtime insulin glargine is as effective as once- or twice-daily NPH in improving and maintaining glycemic control. In addition, insulin glargine demonstrates a lower risk of nocturnal hypoglycemia and less weight gain compared with NPH insulin.20222424681012141618Time of Day (hour)Hypoglycemia defined as PG 72 mg/dL, by hour*P < 0.05 vs. glargine.Riddle MC et al. Diabetes Care. 2003;26:
44 Insulin Glargine Plus OADs vs Twice-daily Premixed 70/30 Human Insulin Treatment RegimenTarget: FPG 100 mg/dLSubjects (n=364) were randomly assigned to:Insulin glargine once daily + continued OADsOADs*Premixed human insulin 70/30 BIDTime (wk)BaselineEnd Point*Sulfonylurea + metforminOAD=oral antidiabetic drugJanka HU, et al. Diabetes Care. 2005;28:
45 Insulin Glargine Plus OADs vs Twice-daily Premixed Human Insulin Change in A1C from Baseline to Study End Point*P=0.0003Baseline24 weekA1CAt 24 weeks, superior reduction was achieved with insulin glargine plus OADs compared with twice-daily pre-mixed insulin.*Intent-to-treat analysisOAD=oral antidiabetic drugJanka HU, et al. Diabetes Care. 2005;28:Janka H, Plewe G, Kliebe-Frisch C, et al. Starting insulin for type 2 diabetes with insulin glargine added to oral agents vs twice-daily premixed insulin alone. Presented at: American Diabetes Association 64th Scientific Sessions; June 4-8, 2004; Orlando, Fla.
46 LAPTOP: Insulin Glargine Versus 70/30 Premixed Insulin in OHA Failures N=371 insulin-naïve patients Insulin glargine + OADs vs twice-daily human NPH insulin (70/30) Follow-up: 24 weeksTwice-daily premixed insulinInsulin glargine + OADsp=0.0003955.71.3%1.7%48p=0.000937.5%Hypoglycaemia* (events/patient year)HbA1c (%)77.2%2.62615*Confirmed symptomatic hypoglycaemia (blood glucose <60 mg/dl [<3.3 mmol/l])Janka H et al. Diabetes Care 2005;28:254−259.
47 Documented Hypoglycemic Episodes Per Patient-Year Less Hypoglycemia With Glargine Plus OADs vs Twice-daily Premixed 70/30 Human InsulinDocumented Hypoglycemic Episodes Per Patient-YearP<0.0001109.98# of EpisodesPerPatient-Year644.1At 24 weeks, less hypoglycemia was documented with insulin glargine plus oral anti-diabetic drugs versus twice-daily pre-mixed insulin.2Insulin Glargine + OADPremixedAverage dose = 28.2 IU with G + OAD vs 64.5 IU with premixed insulinWeight Gain: 1.4 ± 3.4 kg with G + OAD vs 2.1 ± 4.2 kg with pre mixed insulinJanka HU, et al. Diabetes Care. 2005;28:Janka H, Plewe G, Kliebe-Frisch C, et al. Starting insulin for type 2 diabetes with insulin glargine added to oral agents vs twice-daily premixed insulin alone. Presented at: American Diabetes Association 64th Scientific Sessions; June 4-8, 2004; Orlando, Fla.
48 ConclusionsDue to declining -cell function, insulin therapy will be necessary for most patients with Type 2 diabetesInsulin therapy should be initiated early when glycemic control exceeds the recommended targetsInsulin effectively lowers HbA1c, thereby reducing the risks of both micro- and macrovascular complications
49 Relative Contributions of Fasting and Postprandial Glycemia(%) to The Overall Diurnal Hyperglycemia Over Quintiles of A1CPPGFPG100807070Contribution %6040303020A1c <7%A1c 8%A1c 9%A1c >10%Diabetes Care 2003, 26:
50 Conclusions-cont.Insulin glargine when used as a basal insulin has the following advantages:It effectively lowers fasting and mean blood glucoseEasily initiated and titratedLow risk of hypoglycemia
52 Insulin glargine provides superior long term efficacy vs. NPH. Insulin glargine offers long-term efficacy without the need for intensificationKey pointsInsulin is normally added to oral glucose-lowering drugs in people with type 2 diabetes when glycaemic control becomes suboptimal.Outcomes in people starting insulin therapy with neutral protamine Hagedorn (NPH), detemir, glargine or premixed insulins were evluatedInsulin-naive people with type 2 diabetes (n = 8009), ‡ 35 years old, HbA1c ‡ 6.5% and begun on NPH (n = 1463), detemir (n = 357), glargine (n = 2197) or premix (n = 3992), were identified from a UK database of primary care records (The Health Improvement Network)Unadjusted and multivariate-adjusted analyses were conducted, with persistence of insulin therapy assessed by survival analysis.In the study population (n = 4337), baseline HbA1c was 9.5 ± 1.6%, falling to 8.4 ± 1.5% over 12 months (change )1.1 ± 1.8%, p < 0.001)Compared with NPH, people taking detemir, glargine and premix had an adjusted reduction in HbA1c from baseline, of 0.00% (p = 0.99), 0.19% (p < 0.001) and 0.03% (p = 0.51).Body weight increased by 2.8 kg overall (p < 0.001), and by 2.3, 1.7, 1.9, and 3.3 kg on NPH, detemir, glargine and premix (p < for all groups)Insulin dose at 12 months was 0.70 (overall), 0.64, 0.61, 0.56 and 0.76 U ⁄ kg ⁄ dayAfter 36 months, 57% of people on NPH, 67% on glargine and 83% on premix remained on their initially prescribed insulinIn routine clinical practice, people with type 2 diabetes commenced on NPH experienced a modest disadvantage in glycaemic control after 12 months compared with other insulins.When comparing the insulins, glargine achieved best HbA1c reduction, while premix showed greatest weight gain and the highest dose requirement, but had the best persistence of therapyInsulin glargine provides superior long term efficacy vs. NPH.Gordon J, et al. Int J Clin Pract. 2010;64(12): 5252