Presentation on theme: "Back to Basics: Endocrinology Diabetes, Obesity, Metabolic Syndrome"— Presentation transcript:
1Back to Basics: Endocrinology Diabetes, Obesity, Metabolic Syndrome Dr. Amel Arnaout
2Which of the following statements is true? Type 1 diabetes is not diagnosed after age 50Type 2 diabetes is more strongly inherited than type 1 diabetes.The incidence and prevalence of DM-1 is on the riseGestational diabetes does not increase the risk of developing diabetes in the future.People with type 2 diabetes never get DKA
4Diabetes in Canada: Prevalence of Diagnosed Diabetes by age and sex Prevalence of diagnosed diabetes among individuals aged ≥ 1 year, by age group and sex, 2008/09Overall Prevalence306.4%Females257.2%Males20Total6.8%Prevalence (%)1510Source: Public Health Agency of Canada (July 2011); using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada).5Age group (years)1-1920-2425-2930-3435-3940-4445-4950-5455-5960-6465-6970-7475-7980-84≥85CanadaPrevalence increased with age. The sharpest increase occurred after age 40 years. The highest prevalence was in the year age group.Public Health Agency of Canada. Diabetes in Canada: Facts and figures from a public health perspective. Ottawa, 2011.
5Classification of Diabetes TypeDefinitionType 1 DiabetesDiabetes due to pancreatic beta destruction and prone to ketosisType 2 diabetesDiabetes that ranges from insulin resistance with relative insulin deficiency to a predominant secretory defect with insulin resistanceGestationalDiabetesMellitusGlucose intolerance with onset or first recognition in pregnancyOther typesVariety of uncommon diseases, genetic forms, or diabetes associated with drug use.
6TYPE 2 Diabetes TYPE 1 Diabetes Proportion of diabetes cases PathogenesisEndogenous insulin secretionNeed for insulin therapyAge of onsetBody habitusGenetic componentSymptoms at onsetKetoacidosisLong-term complications present at dx?TYPE 1 Diabetes10%Beta cell destruction(usually autoimmune)Low or absentRequired for survivalOften <30 (but can occur at any age)Usually leanSmallerAcute, severeYesNoTYPE 2 Diabetes90%Insulin resistance, relative insulin deficiencyVariableRequired in <50%, to improve control rather than for survivalOften >40 but even in kidsOften obeseVery largeOften mild, slow onsetRareRetinopathy ~20%, CVD relatively common
8Diabetes mellitus - complications Diabetic RetinopathyLeading cause of blindness in working-age adults1StrokeCardiovascular DiseaseDiabetic NephropathyLeading cause of end-stage renal disease2Type 2 diabetes is indeed a serious disease. The speaker should point out that 80% of deaths are due to cardiovascular disease (CVD). Diabetes is the leading cause of blindness among working adults and the leading cause of end-stage renal disease. Diabetes is also the leading cause of non-traumatic amputations.Diabetic NeuropathyLeading cause of non-traumatic lower extremity amputations51. Fong DS et al. Diabetes Care 2003; 26(Suppl 1):S99-S Molitch ME et al. Diabetes Care 2003; 26 (Suppl 1):S94-S Kannel WB et al. Am J Heart 1990; 120: Gray RP and Yudkin JS. In: Textbook of Diabetes Mayfield JA, et al. Diabetes Care 2003; 26(Suppl 1):S78-S79.
9Diabetes Complications: Macrovascular DM is a major risk factor for cardiac diseaseAcute MI occurs years earlier in those with DMHeart disease accounts for approximately 50% of all deaths among people with diabetes in industrialized countriesREF: Diabetes in Ontario, An ICES Practice Atlas, 2002 pg5.96REF: Diabetes in Ontario, An ICES Practice Atlas, 2002
10Diabetes Complications: Cardiovascula disease Several large epidemiological studies have found a strong relationship betweenglucose level and subsequent coronary events, even at ‘pre-diabetes’ levels (IGT and IFG)glucose levels that are only modestly elevated place patients at risk.REF: Coutiho M. et al Diabetes Care 1999;22:& DECODE Study Group. Arch Intern Med 2001;161:
11Diabetes Complications: Peripheral vascular disease (Macro and microvascular disease) Is the leading cause of non traumatic amputationIncreases the risk of amputation by 20 foldthose living in the north or in low income neighborhoods and those with poor access to physician services are at particular risk for amputation.Page – Diabetes in Ontario, Practice Atlas, 200?It is estimated that 4-10% of people with diabetes will develop a foot ulcer. In other words 80, ,000 Canadians with diabetes will be affected in their lifetime.The numbers get even worse because statistics show that 14-24% of those persons with diabetes and foot ulcers will require amputation (either a partial foot amputation or a leg amputation) because the ulcer won't heal. Quality of life is another big concern because persons suffering from a foot ulcer are often reluctant to go out for fear of offending others with the odour. Routines are interrupted by the need for daily dressing changes, a situation that may mean waiting around for the visiting nurse. It is not surprising that foot ulcers are one of the biggest fears shared by persons with diabetes.REF: Diabetes in Ontario, An ICES Practice Atlas, 2002
12Diabetes Complications: Microvascular – Retinopathy Is a leading cause of adult-onset blindnessPrevalence of diabetic retinopathy is ~ 70% in persons with type 1 and 40% with person with type 2 diabetes.NeuropathyREF: Diabetes in Ontario, An ICES Practice Atlas, 2002
13Diabetes Complications: Microvascular - Nephropathy Is the leading cause of ESRDIncreases the risk of developing ESRD by up to 13-foldDiabetes in Ontario, Practice Atlas, 200?) pg 8.166Refs: Meltzer S, et al CMAJ 1998; 159 (8 suppl):S1-S29, &Parchman ML, et al Medical Care 2002; 40(2):
15Walking the dog demonstrates height of physical inactivity
16Diabetes Risk Factors: Modifiable BMI between out strips any of the relative risk factors of physical activity or diet….However, physical activity and diet feed into BMI – it is a complex disease with complex and compounding risk factorsSource: Choi B, Shi F. Diabetologia 2001, 44:
17The Epidemic: Ethnic Groups at High Risk for DM AboriginalLatinoSouth AsianAsianAfrican Descent
18Prevention strategies Primary PreventionPrevent diabetes through reduction of modifiable risk factors in general populationSecondary PreventionScreening those at high-risk for diabetesTertiary PreventionUpon diagnosis of diabetes, prevention of complications morbidity, and mortalitySWB (blue) and Hunt (green)Diabetes BlueprintREF: Diabetes Blueprint
19Primary Prevention Model GoalReducing modifiable risk factors for diabetesTargetGeneral population & high-risk groupsMessagesHealthy lifestyle choicesCurrent Delivery Models of Primary PreventionPopulation HealthPrimary CareCDA, Health CanadaPrevention ProgramsNDSS/ADI/prevention and promotionHealth website educationTelevision Campaign?otherHealth Unit - Wellness Fairweek (schools)
20Primary Prevention Model: Population Health – National CDSHealth CanadaHealth CanadaNational levelNADAREF: Health Canada
21Secondary Prevention Goal Target Messages Early identification of those with dysglycemiaTargetHigh-risk individuals and groupsMessagesDiabetes awarenessCurrent delivery model of secondary prevention relies on primary care
22Secondary Prevention: Is It Effective? Yes….Patients diagnosed with IGT can be prevented from progressing to type 2 diabetes58% reduction with lifestyle changes (DPP, DPS)30% reduction with medication (DPP, Stop NIDDM)Q&A of DPPFor a person with IGT, what is the risk of developing type 2 diabetes? As few as 1 to as many as 10 of every 100 persons with IGT will develop diabetes per year. The risk of getting diabetes rises as people become more overweight and more sedentary, have a stronger family history of diabetes, and belong to a racial or ethnic minority group. In the DPP, about 10 percent of participants in the placebo or standard group developed diabetes per year. The DPP interventions decreased the development of diabetes by 58 percent with intensive lifestyle interventions and by 31 percent with metformin.
23Tertiary Prevention: Is it Effective? Yes…Strong evidence for tertiary prevention particularly for microvascular diseaseDCCT, UKPDSAnd for macrovascular as legacy effect (UKPDS and EDIC follow up studies)How to translate this evidence into practice?…
24Tertiary Prevention Goals Glucose, blood pressure, and lipid control to reduce the development of complicationsComplication screening for early identification and managementPrevention of diabetes once the diagnosis of IGT or IFG has been madeLifestyle changesMedicationsPrevention of complications once the diagnosis of diabetes has been madeGlycemic control to reduce incidence of complicationsComplication screening for early identification
26Why are Obesity and Type 2 DM Increasing in Frequency? More sedentary lifestylesWorldwide changes in urbanization and nutritionAging population due to demographic growth rates (baby boomers) and increased life expectancyKey Teaching Point: Slide is animated to have maximize fun impact of picturesWHO reference:Accessed March 2006.IDF reference:Information from Prevalence section under Facts and Figures tab.Exact website:and accessed March 16, 2006
27Obesity The most common metabolic condition in industrialized nations Statistics Canada: 48% of Canadians between ages yr are overweight (BMI>25), about 25% are obeseAssociated with dyslipidemia, impaired glucose tolerance and insulin resistanceRisk factor for developing metabolic syndrome, type 2 Dm, cardiovascular diseaseHuge economic costs
31Metabolic Syndrome A constellation of risk factors Significantly increased CVD risksSignificantly increased risks for type 2 diabetes
32Definition of Metabolic Syndrome – need central obesity plus 2 others for diagnosis
33Clinical Features of the Metabolic Syndrome Abdominal obesityHyperglycemiaAtherogenic dyslipidemiaHypertensionProinflammatory stateProthrombotic state
34Metabolic SyndromeA common condition associated with increased cardiovascular disease risksTreatment is aimed at lifestyle modification to achieve desirable body weight and reduce abdominal obesityMultiple medical therapy may be required to achieve metabolic targets (lipids, glucose and BP)Lifestyle modification benefits everyone!
36Fasting = no caloric intake for at least 8 hours Diagnosis of Diabetes2013FPG ≥7.0 mmol/LFasting = no caloric intake for at least 8 hoursorA1C ≥6.5% (in adults)Using a standardized, validated assay, in the absence of factors that affect the accuracy of the A1C and not for suspected type 1 diabetes2hPG in a 75-g OGTT ≥11.1 mmol/LRandom PG ≥11.1 mmol/LRandom= any time of the day, without regard to the interval since the last mealScript:Diabetes can be diagnosed by many different cut-offs. The biggest change from the previous set of guidelines is that HbA1c > 6.5% is part of diagnostic cut-off if a standardized validated assay is used with absence of other factors that affect A1c and not suspecting Dm. So FBG >7, A1c >6.5%, or 2h PG > 11.1 or random PG >11.1 can be used to used to diagnose diabetes.Diagnosis of diabetes is based on thresholds of glycemia that are associated with microvascular disease2hPG = 2-hour plasma glucose; FPG = fasting plasma glucose; OGTT = oral glucose tolerance test; PG = plasma glucose
37Diagnosis of Prediabetes* 2013TestResultPrediabetes CategoryFasting Plasma Glucose(mmol/L)Impaired fasting glucose (IFG)2-hr Plasma Glucose in a 75-g Oral Glucose Tolerance Test (mmol/L)7.8 – 11.0Impaired glucose tolerance (IGT)GlycatedHemoglobin(A1C) (%)Prediabetes* Prediabetes = IFG, IGT or A1C % high risk of developing T2DM
38Definitions of Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT) and Diabetes 8.5Diabetes7.56.9IFGIFG + IGTFasting Glucose (mmol/L)220.127.116.11*5.5NormalGlucoseIGTKey Teaching Point:There is a range of values for the lower limit glucose level for a diagnosis of IFG:World Health Association (WHO) uses 5.6 mmol/L as the threshold for IFG when whole blood is used, 6.1 mmol/L if plasma. American Diabetes Association (ADA) uses 5.6 mmol/L as the threshold for IFG. Canadian Diabetes Association (ADA) uses 6.1 mmol/L as the threshold for IFG. The upper limit is 6.9 mmol/L for the ADA, the CDA, and the WHO.ADA guidelines:American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2006;29:S47.WHO guidelines:World Health Organization. Definition, diagnosis, and classification of diabetes mellitus and its complications: Report of a WHO Consultation. WHO/NCD/NCS/ Available online at Accessed March 2, 2006.CDA guidelines:Canadian Diabetes Association. Clinical practice Guidelines: Screening and Prevention. Can J Diabetes 2003;27(Suppl 2):S18.104.22.1684681012147.811.12-h Post-load Glucose (mmol/L)* 1. ADA Diabetes Care 2006;29(Suppl 1):S47,2. CDA Can J Diabetes 2003;27(Suppl 2):S7,3.WHO NDC/NCS.99.2 accessed Mar from
39Recognize pitfalls of A1C: conditions that can affect value Factors affecting A1CIncreased A1CDecreased A1CVariable Change in A1CErythropoiesisB12/Fe deficiency Decreased erythropoiesisUse of EPO, Fe, or B12ReticulocytosisChronic liver DxAltered hemoglobinFetal hemoglobin Hemoglobinopathies MethemoglobinAltered glycationChronic renal failure(use of EPO decreases A1C)ASA, vitamin C/EHemoglobinopathies↑ erythrocyte pHErythrocyte destructionSplenectomySplenomegalyRheumatoid arthritisHAART meds, RibavirinDapsoneAssaysHyperbilirubinemiaCarbamylated HbETOHChronic opiatesHypertriglyceridemiaScript:While HbA1c is an excellent measure for diagnosis, it is essential to know conditions where the value may not adequate reflect true glycemic control and other measures such as fasting blood sugar or OGTT may be more helpful.Important conditions where the rate of red blood cell turnover is significantly shortened or extended, or the structure of hemoglobin is altered, A1C may not accurately reflect glycemic statusThis includes common conditions such as B12 and Fe deficiency that can falsely increase hbA1c and also increased red cell turn over states and factors that increase erthropoeisis such as use of EPO, Fe, B12 deficiency – which can falsely lower hbA1c.So While HbA1c is convenient for patients understanding the factors that affect the accuracy of it’s ability to diagnose diabetes.TT: point of slide is to teach practionners to recognize common pitfalls and conditions where HbA1c might not be an accurate measure to use for diagnosis.
40Pros and Cons of Diagnostic Tests AdvantagesDisadvantagesFPGEstablished standardFast and easySingle SampleSample not stableDay-to-day variabilityInconvenient to fastGlucose homeostasis in single time point2hPG in 75 g OGTTInconvenient, UnpalatableCostA1CConvenientSingle sampleLow day-to-day variabilityReflects long term [glucose]$$$Affected by medical conditions, aging, ethnicityStandardized, validated assay requiredNot used for age <18, pregnant women or suspected T1DMScript:While all 3 approaches predict microvascular disease and can be used for diagnosis, A1c may be a better predictor of macrovascular disease. The decision of which test to use for diabetes diagnosis is left to clinical judgment. Each diagnostic test has advantages and disadvantagesTT: Slide compares the advantages and disadvantages of the different tests.
42Individualizing A1C Targets 2013Consider % if:which must be balanced against the risk of hypoglycemia
43DCCT n=1441 T1DM Intensive (≥ 3 injections/day or CSII) vs Conventional (1-2 injections per day) N Engl J Med Sep 30;329(14):The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group.[No authors listed]AbstractBACKGROUND:Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications.METHODS:A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.RESULTS:In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia.CONCLUSIONS:Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.
44Reduction in Retinopathy Primary PreventionSecondary Intervention76% RRR(95% CI 62-85%)54% RRR(95% CI 39-66%)N Engl J Med Sep 30;329(14):The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group.[No authors listed]AbstractBACKGROUND:Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications.METHODS:A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.RESULTS:In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia.CONCLUSIONS:Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.RRR = relative risk reduction CI = confidence intervalThe Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:
4557% risk reduction (P=0.02; 95% CI: 12–79%) DCCT/EDIC: Early intensive therapy reduced the risk of nonfatal MI, stroke or death from CVD0.120.100.080.060.040.020.0057% risk reduction (P=0.02; 95% CI: 12–79%)Conventional treatmentMI, stroke or CV deathN Engl J Med Dec 22;353(25):Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group.SourceAbstractBACKGROUND:Intensive diabetes therapy aimed at achieving near normoglycemia reduces the risk of microvascular and neurologic complications of type 1 diabetes. We studied whether the use of intensive therapy as compared with conventional therapy during the Diabetes Control and Complications Trial (DCCT) affected the long-term incidence of cardiovascular disease.METHODS:The DCCT randomly assigned 1441 patients with type 1 diabetes to intensive or conventional therapy, treating them for a mean of 6.5 years between 1983 and Ninety-three percent were subsequently followed until February 1, 2005, during the observational Epidemiology of Diabetes Interventions and Complications study. Cardiovascular disease (defined as nonfatal myocardial infarction, stroke, death from cardiovascular disease, confirmed angina, or the need for coronary-artery revascularization) was assessed with standardized measures and classified by an independent committee.RESULTS:During the mean 17 years of follow-up, 46 cardiovascular disease events occurred in 31 patients who had received intensive treatment in the DCCT, as compared with 98 events in 52 patients who had received conventional treatment. Intensive treatment reduced the risk of any cardiovascular disease event by 42 percent (95 percent confidence interval, 9 to 63 percent; P=0.02) and the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease by 57 percent (95 percent confidence interval, 12 to 79 percent; P=0.02). The decrease in glycosylated hemoglobin values during the DCCT was significantly associated with most of the positive effects of intensive treatment on the risk of cardiovascular disease. Microalbuminuria and albuminuria were associated with a significant increase in the risk of cardiovascular disease, but differences between treatment groups remained significant (P< or =0.05) after adjusting for these factors.CONCLUSIONS:Intensive diabetes therapy has long-term beneficial effects on the risk of cardiovascular disease in patients with type 1 diabetes.Intensive treatmentYears since entryDCCT/EDIC Study Research Group. N Engl J Med 2005;353:2643–2653.45
46UKPDS: N = 3867 T2DM 9 8 7 6 3 6 9 12 15 Conventional 7.9% A1C (%) Lancet Sep 12;352(9131):Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.[No authors listed]Erratum inLancet 1999 Aug 14;354(9178):602.AbstractBACKGROUND:Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial.METHODS:3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy.FINDINGS:Over 10 years, haemoglobin A1c (HbA1c) was 7.0% ( ) in the intensive group compared with 7.9% ( ) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg).INTERPRETATION:Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED)Intensive7.0%763691215UKPDS Study Group. Lancet 1998:352:
47UKPDS: decreased risk of diabetes-related complications associated with a 1% decrease in A1C Observational analysis from UKPDS study dataAny diabetes-relatedendpointDiabetes-relateddeathAll cause mortalityPeripheral vascular disease†Micro-vasculardiseaseMyocardialinfarctionCataract extractionStrokePercentage decrease in relative risk corresponding to a 1% decrease in HbA1C12%14%14%*19%**21%21%****UKPDS 35 was a prospective observational study to determine the relationship between exposure to hyperglycemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes who were participants in the UKPDS.3,642 white, Asian Indian and Afro-Caribbean UKPDS patients who had HbA1c measured 3 months after their diabetes diagnosis and with complete data for potential confounders were included in the sub-analysis of relative risk. Reductions in the risk of microvascular and macrovascular complications that might be achieved by lowering HbA1c by 1% were estimated.The incidence of clinical complications was found to be significantly associated with hyperglycemia. While any reduction in HbA1c is likely to reduce the risk of complications, the lowest risk was observed in those with HbA1c values in the normal range (< 6.0%). A 1% decrease in HbA1c was estimated to correspond with significant reductions in any diabetes-related endpoint, diabetes-related death, all cause mortality, myocardial infarction, stroke, peripheral vascular disease, microvascular disease and cataract extraction.Stratton IM, et al. UKPDS 35. BMJ 2000; 321:405–412.****37%43%†Lower extremity amputation or fatal peripheral vascular disease*P = 0.035; **P <****Adapted from Stratton IM, et al. UKPDS 35. BMJ 2000; 321:405–412.
48Legacy 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:N Engl J Med Oct 9;359(15): doi: /NEJMoa Epub 2008 Sep 10.10-year follow-up of intensive glucose control in type 2 diabetes.Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA.SourceDiabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom.AbstractBACKGROUND:During the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes mellitus who received intensive glucose therapy had a lower risk of microvascular complications than did those receiving conventional dietary therapy. We conducted post-trial monitoring to determine whether this improved glucose control persisted and whether such therapy had a long-term effect on macrovascular outcomes.METHODS:Of 5102 patients with newly diagnosed type 2 diabetes, 4209 were randomly assigned to receive either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control. In post-trial monitoring, 3277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires. We examined seven prespecified aggregate clinical outcomes from the UKPDS on an intention-to-treat basis, according to previous randomization categories.RESULTS:Between-group differences in glycated hemoglobin levels were lost after the first year. In the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P=0.04) and microvascular disease (24%, P=0.001), and risk reductions for myocardial infarction (15%, P=0.01) and death from any cause (13%, P=0.007) emerged over time, as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P=0.01), myocardial infarction (33%, P=0.005), and death from any cause (27%, P=0.002).CONCLUSIONS:Despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of post-trial follow-up. A continued benefit after metformin therapy was evident among overweight patients. (UKPDS 80; Current Controlled Trials number, ISRCTN )Holman R, et al. N Engl J Med 2008;359.
49Therapeutic strategies for the management of type 2 diabetes.
50L I F E S T Y 2013 AT DIAGNOSIS OF TYPE 2 DIABETES Start lifestyle intervention (nutrition therapy and physical activity) +/- MetforminA1C <8.5%A1C 8.5%Symptomatic hyperglycemia with metabolic decompensationIf not at glycemic target (2-3 mos)Start metformin immediatelyConsider initial combination with another antihyperglycemic agentInitiate insulin +/-metforminStart / Increase metforminIf not at glycemic targetsAdd an agent best suited to the individual:Patient CharacteristicsDegree of hyperglycemiaRisk of hypoglycemiaOverweight or obesityComorbidities (renal, cardiac, hepatic)Preferences & access to treatmentOtherAgent CharacteristicsBG lowering efficacy and durabilityRisk of inducing hypoglycemiaEffect on weightContraindications & side-effectsCost and coverageOtherMay start Metformin at the time of diagnosisChange to 8.5% as thresholdStart metformin immediately as an optionConcept of individualizing therapy based on patient and agent characteristicsWith that in mind, the next figure shows the characteristics of the agents ….2013See next page…
52Major Classes of Medications 1. Drugs that sensitize the body to insulin and/or control hepatic glucose production2. Drugs that stimulate the pancreas to make more insulin3. Drugs that slow theabsorption of starchesThiazolidinedionesBiguanidesSulfonylureasMeglitinidesAlpha-glucosidase inhibitorsThere are five major classes of oral diabetes medications: thiazolidinediones, biguanides, sulfonylureas, meglitinides, and alpha-glucosidase inhibitors. These five classes of medication operate in essentially three different ways.Thiazolidinediones and biguanides decrease glucose production in the liver and increase insulin sensitivity in peripheral body tissues.Sulfonylureas and meglitinides stimulate the pancreatic beta cells to make more insulin.Finally, alpha-glucosidase inhibitors slow the absorption of starches in the gut, reducing the amount of glucose that enters the bloodstream.
53New Class of Medications IncretinsDerived from gut hormone GLP-1Glucagon like peptide 1There are five major classes of oral diabetes medications: thiazolidinediones, biguanides, sulfonylureas, meglitinides, and alpha-glucosidase inhibitors. These five classes of medication operate in essentially three different ways.Thiazolidinediones and biguanides decrease glucose production in the liver and increase insulin sensitivity in peripheral body tissues.Sulfonylureas and meglitinides stimulate the pancreatic beta cells to make more insulin.Finally, alpha-glucosidase inhibitors slow the absorption of starches in the gut, reducing the amount of glucose that enters the bloodstream.
54GLP-1 Effects in Humans: Understanding Glucoregulatory Role of Incretins Speaker’s NotesGLP-1 exerts two simultaneous effects on beta cells.It enhances beta-cell response by stimulating glucose-dependent insulin secretion in response to the ingestion of food.At the same time, it decreases the beta-cell workload by inhibiting gastric emptying and reducing glucagon secretion from the alpha cells of the pancreas.The reduced glucagon levels in the portal circulation result in decreased stimulation of gluconeogenesis and glycogenolysis in the liver, leading in turn to decreased hepatic glucose output.The central action of GLP-1 promotes satiety, reduces appetite, and decreases weight, and this again decreases the demands placed on the beta cells.Adapted from Flint A, et al. J Chin Invest. 1998;101: ; Larsson H, et al. Acta Physiol Scand. 1997;160: ; Nauck MA, et al. Diabetologia. 1996;39: ; Drucker DJ. Diabetes. 1998;47:
55ThiazolidinedionesThiazolidinediones decrease insulin resistance by making muscle and adipose cells more sensitive to insulin. They also suppress hepatic glucose production.EfficacyDecrease fasting plasma glucose ~ mmol/LReduce A1C ~ %6 weeks for maximum effectOther EffectsWeight gain, edemaHypoglycemia (if taken with insulin or agents that stimulate insulin release)Contraindicated in patients with abnormal liver function or CHFImproves HDL cholesterol and plasma triglycerides; usually LDL neutralMedications in this Class: pioglitazone (Actos), rosiglitazone (Avandia),Thiazolidinediones (TZDs) enhance insulin sensitivity in muscle and adipose tissue by binding to cell receptors,which leads to an increase in glucose transporter expression. TZDs encourage beta cells to respond more efficiently by lowering the amount of glucose and free fatty acids in the bloodstream, both of which are known to be detrimental to insulin secretion. Finally, these drugs reduce glucose production in the liver.Clinical trials indicate that pioglitazone and rosiglitazone are slightly more effective at reducing A1C ( % reduction) than troglitazone (1.1% reduction).Some of the beneficial side effects of thiazolidinediones include an increase in HDL cholesterol and reduction of triglyceride concentrations. This class of drugs has also been shown to lower blood pressure and decrease vascular inflammation in vitro. There are clinical studies underway to further examine the cardiovascular benefit to TZDs.Some adverse effects of TZDs include weight gain, a potential increase in LDL cholesterol levels, and a possible increase in alanine aminotransferase levels (ALT). Because of the risk of weight gain, edema, and increased LDL cholesterol, thiazolidinediones are contraindicated in patients with advanced forms of congestive heart failure. Due to reported cases of liver failure and liver toxicity caused by the increase in ALT levels, TZDs are contraindicated in patients with abnormal liver function.TZDs are the most expensive of the oral antidiabetic agents.
56BiguanidesBiguanides decrease hepatic glucose production and increase insulin-mediated peripheral glucose uptake.EfficacyDecrease fasting plasma glucose mmol/LReduce A1C %Other EffectsDiarrhea and abdominal discomfortRisk of Lactic acidosis in those at risk (renal failure, CHF)Cause small decrease in LDL cholesterol level and triglyceridesNo specific effect on blood pressureNo weight gain, with possible modest weight lossContraindicated in patients with impaired renal function (eGFR<33 ml/min)Medications in this Class: metformin (Glucophage), metformin hydrochloride extended release (Glumetza)The mechanism of action of metformin is not entirely understood, but it's predominant effect is to suppress hepatic glucose production and to enhance insulin sensitivity in peripheral tissues (primarily muscle). It is unclear if insulin sensitivity occurs by metformin binding to cell receptors,which leads to an increase in glucose transporter expression, or whether insulin sensitivity is simply a secondary effect of the suppressed glucose production.Metformin's ability to lower A1C and decrease fasting plasma glucose is similar to that of sulfonylurea drugs. However, the UKPDS showed that those who received metformin had less hypoglycemia and weight gain than those who received sulfonylureas.Metformin must be avoided in patients with renal impairments, as those patients are at higher risk of experiencing lactic acidosis. However, metformin is an effective monotherapy and may be an ideal drug for overweight patients since it does not cause weight gain and has been seen to cause modest amounts of weight loss when first administered. Diarrhea and abdominal discomfort can be alleviated by changes in diet and slow increases in metformin dosage.
57Sulfonylureas Sulfonylureas increase endogenous insulin secretion EfficacyDecrease fasting plasma glucose mmol/LReduce A1C by %Other EffectsHypoglycemiaWeight gainNo specific effect on plasma lipids or blood pressureGenerally the least expensive class of medicationMedications in this Class:glyburide (DiaBeta), glimepiride (Amaryl), gliclizide (Diamicron)Sulfonylureas (SUs) increase insulin secretion by binding to receptors on the surface of pancreatic beta cells, triggering a series of reactions which leads to insulin secretion.Because SUs cause circulating insulin levels to increase, there is a risk of hypoglycemia. There is also some concern that increased insulin levels are associated with cardiovascular disease, however the UKPDS did not show a relationship between increased mortality and SU administration. Finally, there is concern that SUs will exhaust beta cell function by increasing insulin secretion. However, the decline in beta cell function is more likely caused by the disease itself, and not the use of SUs.First generation sulfonylureas are just as efficacious as the second generation drugs, however the second generation may be more potent and safer than first. When diet and exercise fail, SUs are an effective monotherapy.
58MeglitinidesMeglitinides stimulate insulin secretion (rapidly and for a short duration) in the presence of glucose.EfficacyDecreases peak postprandial glucoseDecreases plasma glucose mmol/LReduce A1C %Other EffectsHypoglycemia (although may be less than with sulfonylureas if patient has a variable eating schedule)Weight gainNo significant effect on plasma lipid levelsSafe at higher levels of serum Cr than sulfonylureasMedications in this Class: repaglinide (Gluconorm), nateglinide (Starlix)The mechanism of action of repaglinide is similar to that of the sulfonylurea drugs: binding to beta cell receptors to stimulate insulin secretion. The major difference between the two drug classes is that meglitinides are shorter-acting, and are most effective when taken after meals in the presence of glucose.Adverse effects include weight gain and hypoglycemia. An additional drawback to this drug is the dosing schedule since it must be taken with meals.
59Alpha-glucosidase Inhibitors Alpha-glucosidase inhibitors block the enzymes that digest starches in the small intestineEfficacyDecrease peak postprandial glucose mmol/LDecrease fasting plasma glucose mmol/LDecrease A1C %Other EffectsFlatulence or abdominal discomfortNo specific effect on lipids or blood pressureNo weight gainContraindicated in patients with inflammatory bowel disease or cirrhosisMedications in this Class: acarbose (Glucobay)Alpha-glucosidase inhibitors (AGIs) work by blocking the enzyme in the small intestine that breaks down complex carbohydrates, alpha-glucosidase. By blocking this enzyme these drugs prevent starches from being absorbed into the bloodstream and in doing so lower blood glucose levels. AGIs are the only drug class used to treat type 2 diabetes that does not specifically target the pathology of the disease.Because AGIs work in the digestive tract, they are more effective at lowering postprandial glucose levels than fasting plasma glucose levels. On average, AGIs are less effective at lowering A1c levels than biguanides or sulfonylureas.What makes this class of drug attractive to patients and physicians is it's disassociation with weight gain and hypoglycemia. However, it is known to cause abdominal discomfort and diarrhea. AGIs are also rarely used as monotherapy because of their low efficacy.
65Normal Pancreatic Function Basal: Beta cells secrete small amounts of insulinthroughout the day.Bolus: At mealtime, insulin is rapidly released in response to food.Bolus InsulinBasal InsulinEnsure audience understands normal basal insulin secretionDiscussion pointsThe ideal insulin regimen should strive to match normal insulin secretion patterns.This includes;A basal component that covers basal glucose levels throughout the day.Bolus components that cover glucose excursions due to meals.MealMealMealExpected insulin changes during the day for individuals with a healthy pancreas.*Insulin effect images are theoretical representations and are not derived from clinical trial data.
66Action Profiles of Bolus & Basal Insulins lispro/aspart 4–6 hoursBOLUS INSULINSBASAL INSULINSregular 6-10 hoursNPH 12–20 hoursdetemir ~ 6-23 hours (dose dependant)Plasma Insulin levelsglargine ~ hoursEDUCATIONAL TIP: Please note this slide is animated. Analogue insulins mimic normal physiology better than regular based insulins.Also, note that detemir’s duration of action can vary depending on the dose given (curve shown above is for 0.4 units/kg). Insulin detemir is a long-acting basal human insulin analog with a relatively flat action profile. The mean duration of action of insulin detemir ranged from 5.7 hours at the lowest dose (0.1 units/kg.) to 23.2 hours at the highest dose (1.6 units/kg) (sampling period 24 hours). Plank J, et al. “A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir.” Diabetes Care, 2005 May;28(5):HoursNote: action curves are approximations for illustrative purposes. Actual patient response will vary.Mayfield, JA.. et al, Amer. Fam. Phys.; Aug. 2004, 70(3): 491Plank, J. et.al. Diabetes Care, May 2005; 28(5):
67BID NPH and Regular Insulin Therapy - Compared to Normal Physiology Basal needs: NPHBolus needs: RegularEDUCATIONAL TIP: Please note this slide is animated to discuss normal physiology of insulin action first, then basal, then mealtimeDiscussion pointsThe ideal insulin regimen should strive to match normal insulin secretion patterns.The combination of two injections of intermediate acting NPH insulin (to cover the basal requirements) mixed with short acting Regular insulin (to cover the bolus requirements) may be the best regimen a patient will accept. However, it does not mimic normal insulin physiology.MealMealMealExpected insulin changes during the dayfor individuals with a healthy pancreas.*Insulin effect images are theoretical representations and are not derived from clinical trial dataMayfield, JA. et al., Amer. Fam. Phys.; Aug. 2004, 70(3):
68Multiple Daily Injections (MDI) – Strive to Mimic Normal Physiology MDI insulin therapy addresses:Basal needs: Glargine, DetemirBolus needs: Lispro, AspartEDUCATIONAL TIP: Please note this slide is animated to discuss normal physiology of insulin action first, then basal then mealtime.Discussion points"Insulin aspart or insulin lispro, in combination with adequate basal insulin, is preferred to regular insulin to achieve postprandial glycemic targets and improve A1C while minimizing the occurrence of hypoglycemia" (CDA Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Canadian Journal of Diabetes Dec, 2003;27(Suppl 2)The ideal insulin regimen should strive to match normal insulin secretion patterns.The combination of a long acting insulin to cover the basal dose with rapid acting insulin to cover the bolus doses may be the best regimen by which to mimic the normal secretion of insulin.MealMealMealExpected insulin changes during the dayfor individuals with a healthy pancreas.*Insulin effect images are theoretical representations and are not derived from clinical trial data.
69Insulin Regimens Type 2Usually – a single bedtime injection of basal insulin added to OAD.Occasionally - twice daily injections of basal insulin with OAD.Twice daily injection of “pre-mixed” insulinIntensive insulin – basal/bolus (THE ONLY RECOMMENDED OPTION FOR DM TYPE 1)40% basal/20% mealtime with each meal
70Case 1 Breakfast Lunch Dinner Bedtime 9.5 7.5 7.1 7.0 55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5%On metformin, glyburide,Breakfast Lunch Dinner BedtimeIs this patient well controlled?Does this patient require insulin?EDUCATIONAL TIP: To gain group comfort with making and expressing decisions, reinforce that there are no wrong answers. Split group evenly into 2-4 groups. Give each a flipchart paper sectioned for each of 4 cases. Each group has 5 minutes to answer the above 5 questions and then present back recording answer in first section.If a group(s) say that this patient does NOT require insulin, address their reasons, be prepared to address the situation and offer guidance. Encourage the participants who said the patient DOES require insulin to play a role in those discussions. After the discussion, explain the cause of the high fasting blood glucose (gluconeogenesis from the liver).NOTE: Use of a TZD with insulin is not an approved indication and would be off label for use in Canada.
71Case 1 - Bedtime Insulin Breakfast Lunch Dinner Bedtime 55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5%On metformin, glyburide,Breakfast Lunch Dinner BedtimeNPH, Glargine orDetemir - 10 unitsStart with 10 units1, or use units/kg and titrate2Ex. 84 kg X 0.1 = 8 units OR 84 kg X 0.2 = 17 unitsContinue metformin, glyburide. Continuing TZD would be off-label in CanadaEducational Tip: Please note that use of a TZD with insulin is not an approved indication and would be off label for use in Canada. Bedtime insulin targets the high fasting blood sugar appropriately.1 Riddle et.al., Diabetes Care, 2003, 26(11):2 CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S135
72Hypoglycemia – Recognition Hypoglycemia = development of symptoms or a plasma glucose <4.0 mmol/L.Symptoms of hypoglycemiaAutonomicNeuroglycopenicTremblingPalpitationsSweatingAnxietyHungerNauseaTinglingDifficulty concentratingVision changesDifficulty speakingHeadacheDizzinessConfusionWeaknessDrowsinessTirednessSeverity of hypoglycemiaMild: Autonomic symptoms are present. The individual is able to self-treat.Moderate: Autonomic and neuroglycopenic symptoms are present. The individual is able to self-treat.Severe: Individual requires assistance of another person. Unconsciousness may occur. Plasma glucose is typically <2.8 mmol/L.CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S43
79LEC: Acute and Chronic Complications of Diabetes (revised)
80Consequences of DKA Hyperglycemia acidosis osmotic diuresis dehydrationloss of K, Na, HCO3 in urinehyperosmolar stateincrease free water into blood hyponatremia, cerebral dehydration decreased level of consciousnessacidosiscompensatory respiratory alkalosisK shifts (hyperkalemia)
81Laboratory Calculations for diagnosis and treatment Serum osmolality2(Na + K) + glucose +BUNserum Nafor each 3-4 mmol/l increase in glucose, Na should decrease by 1anion gapNa -(Cl+HCO3)compensation for metabolic acidosisIf suspect other causes for acidosis; meausre serum lactate and salicylate
82Treatment GOAL: replace volume loss (with normal saline) stop ketone production (with insulin)replace K loss (K initially high but falls rapidly with treatment)lower serum glucose*Need to correct INSULIN DEFICIENCY*Look for precipitating cause and treat
83bicarbonate generally avoided potassium FluidNS 1L per hour first 2 hours, then 1L over 4 hrsNS until glucose < 15then D5/NS or D5 depending if still replacing volumeinsulinintravenous50 units regular in 500 normal saline (0.1U/ml)Bolus 0.1 unit per kg body weight (IM/IV)Infusion 0.1 unit/kg/hourGlucoscans q1h, adjust IV rate and IV D5* Do not stop insulin infusion until acidosis/ AG correctedbicarbonate generally avoidedpotassiumstart when K , 20 mmol/L (hold insulin if K is <3.3 and give 40 meq/h
84Hyperosmolar non-ketotic state Severe hyperglycemia generally in DM type 2dehydrationserum hyperosmolalitylack of significant ketosis (still some circulating insulin)* takes less insulin to prevent ketosis than to stop hyperglycemia
86LEC: Acute and Chronic Complications of Diabetes (revised)
87Treatment of HONK Correct increased serum osmolality Blood glucose will fall in response to fluid repletionIf Na>155 mmol/L, start 0.45% NS as initial fluidInsulin infusion only if persistent hyperglycemia after fluid replete
89Who Should Receive Statins? 2013≥40 yrs old orMacrovascular disease orMicrovascular disease orDM >15 yrs duration and age >30 years orWarrants therapy based on the 2012 Canadian Cardiovascular Society lipidAmong women with childbearing potential, statins should only be used in the presence of proper preconception counseling & reliable contraception. Stop statins prior to conception.
90Who Should Receive ACEi or ARB Therapy? 2013≥55 years of age orMacrovascular disease orMicrovascular diseaseAt doses that have shown vascular protection [perindopril 8 mg daily (EUROPA), ramipril 10 mg daily (HOPE), telmisartan 80 mg daily (ONTARGET)]ACE inhiibitor or ARB therapy should be offered to people with diabetes age ≥55 years, or in the presence of macrovasular disease or microvascular disease. This recommendation is regardless of blood pressure. It is important that the ACEi or ARB be titrated to the doses that have been shown to provide vascular protection since low dose ACE-inhibitor or ARB may not result in any benefit (DIABHYCAR study). These vascular protection benefits have been shown to be present irrespective of baseline blood pressure. Since it is not proven that low dose ACEi or ARB confers the same vascular protection, it is recommended that the ACEi or ARB dose be increased to the vascular protective doses (peripdopril 8mg, ramipril 10 mg, telmisartan 80 mg daily). Given that not all ACEi or ARB have conducted “vascular protection” type of studies and of those that have, not all have been positive, it is justified to titrate to doses shown to have vascular protection.Among women with childbearing potential, ACEi or ARB should only be used in the presence of proper preconception counseling & reliable contraception. Stop ACEi or ARB either prior to conception or immediately upon detection of pregnancyEUROPA Investigators, Lancet 2003;362(9386):HOPE study investigators. Lancet. 2000;355:ONTARGET study investigators. NEJM. 2008:358: