The Essentials 5th Annual CE LHIN CME Canadian Diabetes Association 2013 Clinical Practice Guidelines The Essentials 5th Annual CE LHIN CME

Dr. John Sigalas Endocrinologist Rouge Valley Health System Toronto May 15 , 2013

Learning Objectives By the end of this session, participants will be able to: Understand the major changes within the 2013 CDA clinical practice guidelines Understand the rationale behind these changes Apply the recommendations in clinical practice 

Faculty for slide deck development Jonathan Dawrant, BSc, MSc, MD, FRCPC Zoe Lysy, MDCM, FRCPC Geetha Mukerji, MD, FACP, FRCPC Dina Reiss, MD, FACP, FRCPC Steven Sovran, BSc, MD, MA, FRCPC Alice Y.Y. Cheng, MD, FRCPC Peter J. Lin, MD, CCFP Catherine Yu, MD, FRCPC, MHSc

Victor 59 years old Type 2 Diabetes TIA 2005 Stroke 2006 MI 2003 MI 2004 Bypass 2001 PAD 2002 Ischemic Toes Amputation 2004 Neuropathy 2003 CKD 2002 Retinopathy 2004 ACS 2001

Reorganize his history Victor 59 years old Type 2 Diabetes He has EVERY complication of Diabetes That is what we need to avoid TIA 2005 Stroke 2006 PAD 2002 Ischemic Toes Amputation 2004 MI 2003 MI 2004 Bypass 2001 ACS 2001 Macrovascular Neuropathy 2003 CKD 2002 Retinopathy 2004 Microvascular Neuropathy 2002

www.guidelines.diabetes.ca

What is new in making the diagnosis of diabetes?

Fasting = no caloric intake for at least 8 hours Diagnosis of Diabetes 2013 FPG ≥7.0 mmol/L Fasting = no caloric intake for at least 8 hours or A1C ≥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 diabetes 2hPG in a 75-g OGTT ≥11.1 mmol/L Random PG ≥11.1 mmol/L Random= any time of the day, without regard to the interval since the last meal Script: 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 disease 2hPG = 2-hour plasma glucose; FPG = fasting plasma glucose; OGTT = oral glucose tolerance test; PG = plasma glucose

Diagnosis of Prediabetes* 2013 Test Result Prediabetes Category Fasting Plasma Glucose (mmol/L) 6.1 - 6.9 Impaired fasting glucose (IFG) 2-hr Plasma Glucose in a 75-g Oral Glucose Tolerance Test (mmol/L) 7.8 – 11.0 Impaired glucose tolerance (IGT) Glycated Hemoglobin (A1C) (%) 6.0 - 6.4 Prediabetes * Prediabetes = IFG, IGT or A1C 6.0 - 6.4%  high risk of developing T2DM

Individualizing A1C Targets 2013 Consider 7.1-8.5% if: which must be balanced against the risk of hypoglycemia

Diabetes in Canada: Prevalence by Province and Territory Age-standardized† prevalence of diagnosed DM among individuals ≥ 1 year, 2008/09 < 5.0 5.0 < 5.5 5.5 < 6.0 6.0 < 6.5 ≥ 6.5 YT 5.4% NT 5.5% NU 4.4% NL 6.5% BC 5.4% AB 4.9% MB 5.9% Source: Public Health Agency of Canada (September 2011); using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada). PE 5.6% SK 5.4% QC 5.1% ON 6.0% NS 6.1% NB 5.9% † Age-standardized to the 1991 Canadian population. NL, NS and ON had the highest prevalence, while NU, AB and QC had the lowest. Public Health Agency of Canada. Diabetes in Canada: Facts and figures from a public health perspective. Ottawa, 2011. 13

Diabetes in Canada: Prevalence of Diagnosed Diabetes by age and sex Prevalence of diagnosed diabetes among individuals aged ≥ 1 year, by age group and sex, 2008/09 Overall Prevalence 30 6.4% Females 25 7.2% Males 20 Total 6.8% Prevalence (%) 15 10 Source: Public Health Agency of Canada (July 2011); using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada). 5 Age group (years) 1-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 ≥85 Canada Prevalence increased with age. The sharpest increase occurred after age 40 years. The highest prevalence was in the 75-79 year age group. Public Health Agency of Canada. Diabetes in Canada: Facts and figures from a public health perspective. Ottawa, 2011. 14

Patients with DM are more likely to be hospitalized for many conditions Public Health Agency of Canada (August 2011); using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada).

Guideline Targets Achieved % of patients ABSTRACT Objective: To gain insight into the current management of patients with type 2 diabetes mellitus (T2DM) by Canadian primary care physicians. Methods: 479 primary care physicians from across Canada submitted data on 5123 T2DM patients whom they had seen on a single day on or around World Diabetes Day, November 14th, 2012. Results: Mean A1C was 7.4%, LDL-C 2.1 mmol/L and blood pressure 128/75 mmHg. A1C≤7.0% was met by 50%, LDL-C ≤2.0 mmol/L by 57%, BP <130/80 mmHg by 36% and the composite triple target by 13% of patients. Diet counselling had been offered to 38% of patients. Of the 87% prescribed antihyperglycemic agents, 18% were on 1 non-insulin antihyperglycemic agent (NIAHA) (85% of which was metformin), 15% 2 NIAHAs, 6% ≥3 NIAHAs, 19% insulin only and 42% insulin+≥1 NIAHA(s). Amongst the 81% prescribed lipid-lowering therapy, 88% were on monotherapy (97% of which was a statin). Amongst the 83% prescribed antihypertensive agents, 39%, 34% and 21% and 6% received 1, 2, 3 and >3 drugs, respectively, with 59% prescribed angiotensin-converting enzyme inhibitors and 35% angiotensin II receptor blockers. Conclusion: The DM-SCAN survey highlights the persistent treatment gap associated with the treatment of T2DM and the challenges faced by primary care physicians to gain glycemic control and global vascular protection in these patients. It also reveals a higher use of insulin therapy in primary care practices relative to previous surveys. Practical strategies aimed at more effectively managing T2DM patients are urgently needed. Leiter LA et al. Can J Diabetes 2013; in press 16

Self-Monitoring of Blood Glucose (SMBG) What should we tell patients to do?

Regular SMBG is Required for:

Increased frequency of SMBG may be required: Daily SMBG is not usually required if patient:

Pharmacotherapy in T2DM checklist 2013 CHOOSE initial therapy based on glycemia START with Metformin +/- others INDIVIDUALIZE your therapy choice based on characteristics of the patient and the agent REACH TARGET within 3-6 months of diagnosis

L I F E S T Y 2013 AT DIAGNOSIS OF TYPE 2 DIABETES Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin A1C <8.5% A1C 8.5% Symptomatic hyperglycemia with metabolic decompensation If not at glycemic target (2-3 mos) Start metformin immediately Consider initial combination with another antihyperglycemic agent Initiate insulin +/- metformin Start / Increase metformin If not at glycemic targets Add an agent best suited to the individual: Patient Characteristics Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity Comorbidities (renal, cardiac, hepatic) Preferences & access to treatment Other Agent Characteristics BG lowering efficacy and durability Risk of inducing hypoglycemia Effect on weight Contraindications & side-effects Cost and coverage Other May start Metformin at the time of diagnosis Change to 8.5% as threshold Start metformin immediately as an option Concept of individualizing therapy based on patient and agent characteristics With that in mind, the next figure shows the characteristics of the agents …. 2013 See next page…

Make timely adjustments to attain target A1C within 3-6 months From prior page… L I F E S T Y Concept of RELATIVE A1c lowering – not absolute Concept of RELATIVE cost considerations Change to achieve target within 3-6 months. If not at glycemic target Add another agent from a different class Add/Intensify insulin regimen 2013 Make timely adjustments to attain target A1C within 3-6 months

Patient Characteristics Agent Characteristics AT DIAGNOSIS OF TYPE 2 DIABETES L I F E S T Y Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin A1C < 8.5% A1C  8.5% Symptomatic hyperglycemia with metabolic decompensation If not at glycemic target (2-3 mos) Start metformin immediately Consider initial combination with another antihyperglycemic agent Initiate insulin +/- metformin Start / Increase metformin If not at glycemic targets Add an agent best suited to the individual: Patient Characteristics Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity Comorbidities (renal, cardiac, hepatic) Preferences & access to treatment Other Agent Characteristics BG lowering efficacy and durability Risk of inducing hypoglycemia Effect on weight Contraindications & side-effects Cost and coverage Other May start Metformin at the time of diagnosis Change to 8.5% as threshold Start metformin immediately as an option Concept of individualizing therapy based on patient and agent characteristics With that in mind, the next figure shows the characteristics of the agents …. 2013 See next page…

2013

Antihyperglycemic agents and Renal Function Not recommended / contraindicated Safe Caution and/or dose reduction Repaglinide Metformin 30 60 Saxagliptin Linagliptin Glyburide 50 Thiazolidinediones GFR (mL/min): < 15 15-29 30-59 60-89 ≥ 90 CKD Stage: 5 4 3 2 1 Gliclazide/Glimepiride 15 Liraglutide Exenatide Acarbose 25 Sitagliptin 2.5 mg 50 mg 25 mg Adapted from: Product Monographs as of March 1, 2013; CDA Guidelines 2008; and Yale JF. J Am Soc Nephrol 2005; 16:S7-S10.

What are the options for Insulin?

Insulin Type (trade name) Types of Insulin Insulin Type (trade name) Onset Peak Duration Bolus (prandial) Insulins Rapid-acting insulin analogues (clear): Insulin aspart (NovoRapid®) Insulin glulisine (Apidra™) Insulin lispro (Humalog®) 10 - 15 min 1 - 1.5 h 1 - 2 h 3 - 5 h 3.5 - 4.75 h Short-acting insulins (clear): Insulin regular (Humulin®-R) Insulin regular (Novolin®geToronto) 30 min 2 - 3 h 6.5 h Basal Insulins Intermediate-acting insulins (cloudy): Insulin NPH (Humulin®-N) Insulin NPH (Novolin®ge NPH) 1 - 3 h 5 - 8 h Up to 18 h Long-acting basal insulin analogues (clear) Insulin detemir (Levemir®) Insulin glargine (Lantus®) 90 min Not applicable Up to 24 h (glargine 24 h, detemir 16 - 24 h)

Insulin Type (trade name) Types of Insulin (continued) Insulin Type (trade name) Time action profile Premixed Insulins Premixed regular insulin – NPH (cloudy): 30% insulin regular/ 70% insulin NPH (Humulin® 30/70) (Novolin®ge 30/70) 40% insulin regular/ 60% insulin NPH (Novolin®ge 40/60) 50% insulin regular/ 50% insulin NPH (Novolin®ge 50/50) A single vial or cartridge contains a fixed ratio of insulin (% of rapid-acting or short-acting insulin to % of intermediate-acting insulin) Premixed insulin analogues (cloudy): 30% Insulin aspart/70% insulin aspart protamine crystals (NovoMix® 30) 25% insulin lispro / 75% insulin lispro protamine (Humalog® Mix25®) 50% insulin lispro / 50% insulin lispro protamine (Humalog® Mix50®)

Analogue Basal: Lantus, Levemir Serum Insulin Level Time Analogue Bolus: Apidra, Humalog, NovoRapid Human Basal: Humulin-N, Novolin ge NPH Analogue Basal: Lantus, Levemir Human Bolus: Humulin-R, Novolin ge Toronto

Serum Insulin Level Time Human Premixed: Humulin 30/70, Novolin ge 30/70 Analogue Premixed: Humalog Mix25, NovoMix 30

What about Hypoglycemia?

Definition of Hypoglycemia Development of neurogenic or neuroglycopenic symptoms Low blood glucose (<4 mmol/L if on insulin or secretagogue) Response to carbohydrate load Neurogenic (autonomic) Neuroglycopenic Trembling Difficulty Concentrating Palpitations Confusion Sweating Weakness Anxiety Drowsiness Hunger Vision Changes Nausea Difficulty Speaking Dizziness The CDA defines hypoglycemia as the development of autonomic (trembling, palpitations, sweating, anxiety, hunger, nausea, tingling) or neuroglycopenic (difficulty concentrating, confusion, weakness, drowsiness, vision changes, difficulty speaking, headache, dizziness) symptoms, a low plasma glucose, and symptoms responding to the administration of a carbohydrate. In mild to moderate hypoglycemia, blood glucose is <4 mmol/L, autonomic and/or neuroglycopenic symptoms are present, but the patient is able to self-treat. However, patients who maintain a higher blood glucose level may experience hypoglycemia at levels >4.0 mmol/L. Severe hypoglycemia indicates the patient is unable to treat the reaction without outside assistance. He/she may or may not be conscious. 32

Steps to Address Hypoglycemia Recognize autonomic or neuroglycopenic symptoms Confirm if possible (blood glucose <4.0 mmol/L) Treat with “fast sugar” (simple carbohydrate) (15 g) to relieve symptoms Retest in 15 minutes to ensure the BG >4.0 mmol/L and retreat (see above) if needed Eat usual snack or meal due at that time of day or a snack with 15 g carbohydrate plus protein Teaching patients to recognize and treat hypoglycemia can be done in 3 steps 1) It is important to teach patients to recognize the common autonomic and neuroglycopenic symptoms associated with hypoglycemia including: Trembling, Palpitations, Sweating, Anxiety, Hunger, Nausea, Tingling which are common autonomic symptoms and Difficulty concentrating, Confusion, Weakness, Vision change, and Headache are common neuroglycopenic symptoms.

Macrovascular Disease Vascular Protection: Who and When?

Vascular Protection Checklist 2013 A • A1C – optimal glycemic control (usually ≤7%) B • BP – optimal blood pressure control (<130/80) C • Cholesterol – LDL ≤2.0 mmol/L if decided to treat D • Drugs to protect the heart A – ACEi or ARB │ S – Statin │ A – ASA if indicated E • Exercise – regular physical activity, healthy diet, achieve and maintain healthy body weight S • Smoking cessation

Who Should Receive Statins? 2013 ≥40 yrs old or Macrovascular disease or Microvascular disease or DM >15 yrs duration and age >30 years or Warrants therapy based on the 2012 Canadian Cardiovascular Society lipid guidelines Among women with childbearing potential, statins should only be used in the presence of proper preconception counseling & reliable contraception. Stop statins prior to conception.

Who Should Receive ACEi or ARB Therapy? 2013 Who Should Receive ACEi or ARB Therapy? ≥55 years of age or Macrovascular disease or Microvascular disease At doses that have shown vascular protection (ramipril 10 mg daily, perindopril 8 mg daily, telmisartan 80 mg daily) 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 pregnancy

No. of events/No. in group ASA Control/placebo RR (95% CI) RR (95% CI) Major CV events ASA for 1⁰ Prevention in Diabetes Meta analysis of 6 studies (n = 10,117) JPAD POPADAD WHS PPP ETDRS Total 68/1262 105/638 58/514 20/519 350/1856 601/4789 86/1277 108/638 62/513 22/512 379/1855 657/4795 0.80 (0.59-1.09) 0.97 (0.76-1.24) 0.90 (0.63-1.29) 0.90 (0.50-1.62) 0.90 (0.78-1.04) 0.90 (0.81-1.00) Myocardial infarction JPAD POPADAD WHS PPP ETDRS PHS Total 28/1262 90/638 36/514 5/519 241/1856 11/275 395/5064 14/1277 82/638 24/513 10/512 283/1855 26/258 439/5053 0.87 (0.40-1.87) 1.10 (0.83-1.45) 1.48 (0.88-2.49) 0.49 (0.17-1.43) 0.82 (0.69-0.98) 0.40 (0.20-0.79) 0.86 (0.61-1.21) No overall benefit for: Major CV events MI Stroke CV mortality All-cause mortality Stroke JPAD POPADAD WHS PPP ETDRS Total 12/1262 37/638 15/514 9/519 92/1856 181/4789 32/1277 50/638 31/513 10/512 78/1855 201/4795 0.89 (0.54-1.46) 0.74 (0.49-1.12) 0.46 (0.25-0.85) 0.89 (0.36-2.17) 1.17 (0.87-1.58) 0.83 (0.60-1.14) Death from CV causes This meta-analysis examined whether ASA is beneficial for patients with diabetes who have no clinical evidence of CVD. Of 6 eligible studies included in the meta-analysis of over 10,000 participants, there is no statistically significant reduction in the risk of Major CV events, MI, stroke, CV mortality or all-cause mortality when ASA was compared with placebo for primary prevention among patients with diabetes. Of 157 studies in the literature searches, six were eligible (10,117 participants). When ASA was compared with placebo, there was no statistically significant reduction in the risk of major CV events (five studies, 9,584 participants; RR 0.90; 95% CI 0.81-1.00), CV mortality (four studies, 8,557 participants; RR 0.94; 95% CI 0.72-1.23), or all-cause mortality (four studies, 8,557 participants; RR 0.93; 95% CI 0.82-1.05). Significant heterogeneity was found in the analyses for MI (I2 = 62.2%; p = 0.02) and stroke (I2 = 52.5%; p = 0.08). ASA significantly reduced the risk of MI in men (RR 0.57; 95% CI 0.34-0.94) but not in women (RR 1.08; 95% CI 0.71-1.65; p for interaction = 0.056). Evidence relating to harms was inconsistent. These authors concluded that a clear benefit of ASA in the primary prevention of major CV events in people with diabetes remains unproved, that sex may be an important effect modifier, and that toxicity is to be explored further. The analysis shows ASA has benefit for men in prevention of MI but not for stroke prevention, but no benefit in women for either MI or stroke prevention Reference: De Berardis G, Sacco M, Strippoli GF, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ 2009; 339:b4531. JPAD POPADAD PPP ETDRS Total 1/1262 43/638 10/519 244/1856 298/4275 10/1277 35/638 8/512 275/1855 328/4282 0.10 (0.01-0.79) 1.23 (0.80-1.89) 1.23 (0.49-3.10) 0.87 (0.73-1.04) 0.94 (0.72-1.23) JPAD = Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes POPADAD = Prevention of Progression of Arterial Disease and Diabetes PPP = Primary Prevention Project ETDRS = Early Treatment Diabetic Retinopathy Study PHS = Physicians’ Health Study WHS = Women’s Health Study De Beradis G, et al. BMJ 2009; 339:b4531. All-cause mortality JPAD POPADAD PPP ETDRS Total 34/1262 94/638 25/519 340/1856 493/4275 38/1277 101/638 20/512 366/1855 525/4282 0.90 (0.57-1.14) 0.93 (0.72-1.21) 1.23 (0.69-2.19) 0.91 (0.78-1.06) 0.93 (0.82-1.05) 2 0.03 0.125 0.5 1 8 Favors ASA Favors control/placebo

Summary of Pharmacotherapy for Hypertension in Patients with Diabetes Threshold equal or over 130/80 mmHg and Target below 130/80 mmHg Combination of 2 first line drugs may be considered as initial therapy if the blood pressure is >20 mmHg systolic or >10 mmHg diastolic above target With Nephropathy, CVD or CV risk factors ACE Inhibitor or ARB Diabetes Without the above 1. ACE Inhibitor or ARB or 2. Thiazide diuretic or DHP-CCB > 2-drug combinations 1. Persons with diabetes mellitus should be treated to attain systolic blood pressure of lower than130 mmHg (Grade C) and diastolic blood pressure of less than 80 mmHg (Grade A). (These target blood pressure levels are the same as the blood pressure treatment thresholds.) Combination therapy using two first-line agents may also be considered as initial treatment of hypertension (Grade B) if the SBP is 20 mmHg above the target or if DBP is 10 mmHg above the target. However caution should be exercised in patients in whom a substantial fall in blood pressure is more likely or poorly tolerated (e.g. elderly patients, patients with autonomic neuropathy). 2. For persons with cardiovascular or kidney disease, including microalbuminuria or with cardiovascular risk factors in addition to diabetes and hypertension, an ACE inhibitor or an ARB is recommended as initial therapy (Grade A). 3. For persons with diabetes and hypertension not included in the above recommendation, appropriate choices include (in alphabetical order): ACE inhibitors (Grade A), angiotensin receptor blockers (Grade B), dihydropyridine CCBs (Grade A) and thiazide/thiazide-like diuretics (Grade A). 4. If target blood pressures are not achieved with standard-dose monotherapy, additional antihypertensive therapy should be used. For persons in whom combination therapy with an ACE inhibitor is being considered, a dihydropyridine CCB is preferable to hydrochlorothiazide (Grade A). Monitor serum potassium and creatinine carefully in patients with CKD prescribed an ACEI or ARB Combinations of an ACEI with an ARB are specifically not recommended in the absence of proteinuria More than 3 drugs may be needed to reach target values If Creatinine over 150 µmol/L or creatinine clearance below 30 ml/min ( 0.5 ml/sec), a loop diuretic should be substituted for a thiazide diuretic if control of volume is desired 40

Vascular Protection Checklist 2013 A • A1C – optimal glycemic control (usually ≤7%) B • BP – optimal blood pressure control (<130/80) C • Cholesterol – LDL ≤2.0 mmol/L if decided to treat D • Drugs to protect the heart A – ACEi or ARB │ S – Statin │ A – ASA if indicated E • Exercise – regular physical activity, healthy diet, achieve and maintain healthy body weight S • Smoking cessation

What if we did all the right things What if we did all the right things? How much could we protect our patients?

STENO-2: Intensive Group Achieved Targets Patients in the intensive arm significantly achieved targets for glycemia (A1c<6.5%), cholesterol < 175 mg/dL, SBP < 130 and DBP < 80 compared to the conventional arm in the study. Gaede et al. NEJM. 2003: 348;383-393

Intensive Group had Improved CV Outcomes 60 P = 0.007 50 53 % RRR Any CV event NNT = 5 Conventional therapy 40 Intensive therapy 30 20 Intensive Therapy Resulted in Improved Combined CV OutcomesSignificantly fewer primary endpoints (a composite of CV death, non-fatal stroke or MI, revascularization, or amputation) occurred in the Intensive treatment group. 10 12 24 36 48 60 72 84 96 Months of Follow-up RRR= relative risk reduction Gaede et al. NEJM. 2003: 348;383-393

STENO 2 Extended Follow-up: Effect of a multi- factorial vascular protective strategy on total mortality 60 50 40 30 20 10 Total mortality (%) 3 Years of follow-up 1 2 4 5 6 7 8 9 11 12 13 Conventional therapy Intensive therapy END OF TRIAL HR = 0.54 (0.32-0.88) p = 0.015 Effect of a multifactorial intervention on mortality in type 2 diabetes. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Steno Diabetes Center, Copenhagen, Denmark. PMID: 18256393 [PubMed - indexed for MEDLINE] Intensified multifactorial intervention—with tight glucose regulation and the use of renin-angiotensin system blockers, ASA, and lipid-lowering agents—has been shown to reduce the risk of nonfatal CVD among patients with type 2 diabetes and microalbuminuria. The STENO 2 trial evaluated whether this approach would have an effect on the rates of death from any cause and from CV causes. In the STENO 2 Study, 160 patients with type 2 diabetes and persistent microalbuminuria were randomly assigned to receive either intensive therapy or conventional therapy; the mean treatment period was 7.8 years. Patients were subsequently followed observationally for a mean of 5.5 years, until December 2006. The primary endpoint at 13.3 years of follow-up was the time to death from any cause. Twenty-four patients in the intensive-therapy group died, as compared with 40 in the conventional-therapy group (HR 0.54; 95% CI 0.32 to 0.89; p = 0.02). Intensive therapy was associated with a lower risk of death from CV causes (HR 0.43; 95% CI 0.19 to 0.94; p = 0.04) and of CV events (HR 0.41; 95% CI 0.25 to 0.67; p < 0.001). One patient in the intensive-therapy group had progression to end-stage renal disease, as compared with six patients in the conventional-therapy group (p = 0.04). Fewer patients in the intensive-therapy group required retinal photocoagulation (RR 0.45; 95% CI 0.23 to 0.86; p = 0.02). Few major side effects were reported. In at-risk patients with type 2 diabetes, intensive intervention with multiple drug combinations and behavior modification had sustained beneficial effects with respect to vascular complications and on rates of death from any cause and from CV causes. Gaede et al. N Engl J Med. 2008; 358(6):580-91.

STENO 2 – Microvascular Disease Gaede et al. NEJM. 2003: 348;383-393

What about Microvascular Disease? Nephropathy Retinopathy Neuropathy

Chronic Kidney Disease (CKD) Checklist 2013 Chronic Kidney Disease (CKD) Checklist SCREEN regularly with random urine albumin creatinine ratio (ACR) and serum creatinine for estimated glomerular filtration rate (eGFR) DIAGNOSE with repeat confirmed ACR ≥ 2.0 mg/mmol and/or eGFR < 60 mL/min DELAY onset and/or progression with glycemic and blood pressure control and ACE inhibitor or angiotensin receptor blocker (ARB) PREVENT complications with “sick day management” counselling and referral when appropriate Use same check marks as Geetha

Counsel all Patients About Sick Day Medication List 2013

Retinopathy Checklist 2013 SCREEN regularly DELAY onset and progression with glycemic and blood pressure control ± fibrate TREAT established disease with laser photocoagulation, intra-ocular injection of medications or vitreoretinal surgery Use same check marks as Geetha

Delaying Retinopathy Glycemic control: target A1C ≤7% Blood pressure control: target BP <130/80 Lipid-lowering therapy: fibrates have been shown to decrease progression and may be considered 2013

PREVENT with blood glucose control Neuropathy Checklist 2013 PREVENT with blood glucose control SCREEN with monofilament or tuning fork TREAT pain symptoms with anticonvulsants or antidepressants Use Geetha’s check marks

Recommendation 4 2013 The following agents may be used alone or in combination for relief of painful peripheral neuropathy: Anticonvulsants (pregabalin [Grade A, Level 1], gabapentin‡, valproate‡) [Grade B, Level 2] Antidepressants (amitriptyline‡, duloxetine, venlafaxine‡) [Grade B, Level 2] Opioid analgesics (tapentadol ER, oxycodone ER, tramadol) [Grade B, Level 2] Topical nitrate spray [Grade B, Level 2] ‡This drug is not currently approved by Health Canada for the management of neuropathic pain associated with diabetic peripheral neuropathy.

Why diagnose and treat GDM? Macrosomia Shoulder dystocia and nerve injury Neonatal hypoglycemia Preterm delivery Hyperbilirubinemia Caesarian section Offspring obesity (?) Offspring diabetes (?)

Need a PRECONCEPTION checklist for women with pre-existing diabetes 2013 Need a PRECONCEPTION checklist for women with pre-existing diabetes 1. Attain a preconception A1C of ≤ 7.0% (if safe) 2. Assess for and manage any complications 3. Switch to insulin if on oral agents 4. Folic Acid 5 mg/d: 3 mo pre-conception to 12 weeks post-conception 5. Discontinue potential embryopathic meds: Ace-inhibitors/ARB (prior to or upon detection of pregnancy) Statin therapy Script:

2013 GDM diagnosis: Two approaches

Recommendation 8-9: Management in Pregnancy for pre-gestational diabetes Women with pregestational diabetes may use aspart or lispro in pregnancy instead of regular insulin to improve glycemic control and reduce hypoglycemia [Grade C level 2 for aspart , Grade C, Level 3 for lispro]. Detemir [Grade C, Level 2] or glargine [Grade C, Level 3 ] may be used in women with pregestational diabetes as an alternative to NPH. 2013 2013

What about insulin analogues and oral agents among patients with GDM? May use rapid-acting analog insulin for postprandial glucose control – no difference in perinatal outcomes May use glyburide or metformin for women who are non-adherent to or who refuse insulin Likely safe BUT it is OFF- Label  no long-term data, need discussion with patient

“Neither evidence nor clinical judgment alone is sufficient “Neither evidence nor clinical judgment alone is sufficient. Evidence without judgment can be applied by a technician. Judgment without evidence can be applied by a friend. But the integration of evidence and judgment is what the healthcare provider does in order to dispense the best clinical care.” (Hertzel Gerstein, 2012)

CDA Clinical Practice Guidelines www.guidelines.diabetes.ca – for professionals 1-800-BANTING (226-8464) www.diabetes.ca – for patients