Disclosure of Potential Conflict of Interest

Disclosure of Potential Conflict of Interest
Dr. First Name Last Name ROAR DM Speaker Financial Disclosure: Grants/Research Support Speaker Bureau/Honoraria Consulting Fees: Other:

Accreditation Statement
This program meets the accreditation criteria of The College of Family Physicians of Canada and has been accredited for up to 7 Mainpro-C credits.

This program was planned by the Canadian Heart Research Centre, a not-for-profit academic organization, and a national Planning Committee to achieve scientific integrity, objectivity, and balance. Eli Lilly Canada and Boehringer-Ingelheim have provided funding for this program but have not been involved in the needs assessment, objectives, agenda, content, or evaluation.

Learning Objectives: At the completion of this program, participants will be able to:
Identify currently available treatments for type 2 diabetes, their pharmacological target among multiple risk factors contributing to hyperglycemia, and their treatment indications Design an effective treatment plan for type 2 diabetes, combining lifestyle modification and available pharmacological options Describe the renal and cardiovascular complications of diabetes and the factors linking them Explore the effects of kidney function on the selection of diabetes medications in terms of efficacy and side effects to identify the appropriate choice for each patient Employ guidelines, improve office systems for the comprehensive treatment of type 2 diabetes, and adapt educational resources and patient education materials to improve the care of patients with type 2 diabetes

Diabetes in Canada: A Challenge for the Busy Primary Care Practitioner
Module 1 Diabetes in Canada: A Challenge for the Busy Primary Care Practitioner

The Prevalence of Diabetes in Canada is Increasing
The prevalence of diabetes in Canada is expected to increase by ~6% per year By 2012, ~2.8 million Canadians will have diagnosed diabetes This will represent a 25% increase in prevalence from 2007 Source: Public Health Agency of Canada. Report from the National Diabetes Surveillance: Diabetes in Canada, Available at: Accessed February 19, 2010. Public Health Agency of Canada Available at:

Family Physicians Provide 92% of Diabetes Care
74% family physician care alone Reference Jaakkimainen L, Shah BR, Kopp A. Sources of Physician Care for People With Diabetes. In: Hux JE, Booth GL, Slaughter PM, Laupacis A (eds). Diabetes in Ontario: An ICES Practice Atlas. 2003;9:181–9,191. 1% specialist alone 92% 18% family physician and specialist care 7% no diabetes care (orphans) Jaakkimainen L, ICES

Glycemic Management in Two Canadian Cohorts with T2DM
Treatment, % of patients DICE1 ( ) N = 2473 DRIVE2 ( ) N = 3002 Oral agents only 73.0 76.0 Monotherapy 36.0 48.5 Dual therapy 30.0 36.5 3+ agents 8.0 15.0 (Using metformin) 61.0 72.0 Insulin 12.0 Insulin monotherapy 6.0 5.0 Insulin with oral agents 10.0 No antihyperglycemic agents 9.0 1Harris S, et al. Diabetes Res Clin Prac. 2005;70(1):90-97. 2Braga M, et al. Can J Cardiol. 2010;26(6):

What do you believe is/are the most challenging guideline goal(s) to achieve in your practice?
A1C at target LDL-C < 2.0 mmol/L BP < 130/80 All of the above

What strategies do you think improve clinical diabetes care the most in family practice?
Use of flow sheets Financial incentives (i.e., billing) Delegation of DM care clinical follow-up Use of ‘‘mini-clinics’’ Establishing a diabetes registry from your practice

How do incretins fit into our practice?
Module 2 Therapeutic Options: How do incretins fit into our practice?

With regard to GLP-1 Which of the following statements is TRUE ?
GLP-1 increases insulin secretion in a glucose- dependent fashion GLP-1 decreases glucagon secretion in a glucose- dependent fashion GLP-1 increases insulin secretion and decreases glucagon secretion in a glucose-dependent fashion Correct Answer is 3

Incretins Regulate Glucose Homeostasis Through Effects on Islet Cell Function
Ingestion of food Glucose dependent Insulin from beta cells (GLP-1 and GIP) Insulin increases peripheral glucose uptake Pancreas Release of incretin gut hormones Beta cells Blood glucose control Alpha cells Active GLP-1 and GIP Animated Slide The presence of nutrients in the gastrointestinal tract rapidly stimulates the release of incretins: GLP-1 from L cells located primarily in the distal gut (ileum and colon), and GIP from K cells in the proximal gut (duodenum).1,2 Collectively, these incretins exert several beneficial actions, including stimulating the insulin response in pancreatic beta cells and reducing glucagon production from pancreatic alpha cells when glucose levels are elevated.3,4 Increased insulin levels improve glucose uptake by peripheral tissues; the combination of increased insulin and decreased glucagon reduces hepatic glucose output.5 Increased insulin and decreased glucagon reduce hepatic glucose output GI tract Glucagon from alpha cells (GLP-1) Glucose dependent Adapted from Brubaker PL, Drucker DJ. Endocrinology. 2004;145:2653–2659; Zander M, et al. Lancet. 2002;359:824–830; Ahrén B, Curr Diab Rep. 2003;3:365–372; Buse JB, et al. In Williams Textbook of Endocrinology. 2003;(10th ed. Philadelphia, Saunders):1427–1483.

Incretin Effect in T2DM A clinical study showed that the incretin effect was diminished in patients with T2DM (n=14) compared with metabolically healthy control subjects (n=8). As shown on the graphs, glucose profiles were closely mimicked at similar levels after oral versus intravenous glucose administration. This matching of intravenous glucose loads to oral glucose loads after ingestion was achieved in both control subjects and patients with diabetes. ß-cell secretory responses, reflected by increases in plasma levels of immunoreactive (IR) insulin, are shown on the bottom graphs in the slide. These graphs show that plasma IR insulin peaks were delayed and diminished in patients with T2DM. Although insulin levels were greater after oral glucose ingestion versus intravenous administration in both groups, the incretin effects were markedly less pronounced in diabetic patients. Nauck MA, et al. Diabetologia.1986;29:46–52.

GLP-1 actions are glucose dependent in patients with T2DM – Lower Hypoglycemia Risk
Nauck MA, et al. Diabetologia.1993;36:741–744.

Summary of Incretin Actions on Different Target Tissues: GLP-1
Heart Brain Neuroprotection Appetite Gastric Emptying Cardioprotection Cardiac Output Stomach Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3(3): _ Liver (indirect effect) GI Tract Insulin Secretion β-Cell Neogenesis* β-Cell Apoptosis* Glucagon Secretion * preclinical data Glucose Production + Muscle (indirect effect) Glucose Uptake Adapted from Drucker DJ. Cell Metab. 2006;3:

Strategies to Exploit the Beneficial Actions of Incretins
GLP-1 mimetic/GLP-1R agonists Stable peptide preparations with actions similar to the natural incretin hormones Exenatide Liraglutide Incretin enhancers (DPP-4 inhibitors) Inhibit the normal degradation of incretin hormones and thereby increase their plasma concentrations and biological actions Linagliptin Saxagliptin Sitagliptin Strategies to Exploit the Beneficial Actions of Incretins

Which of the following statements about incretins is/are CORRECT?
Both DPP-4 inhibitors and GLP-1R agonists raise GLP-1 levels into the pharmacological range The use of both DPP-4 inhibitors and GLP-1R agonists is typically associated with weight loss The use of GLP-1R agonists is typically associated with weight loss The use of DPP-4 inhibitors is typically associated with nausea 1 and 3 Correct Answer is 3

Effects of GLP-1: Dose-response relationship
Vomiting Diarrhea Nausea Abdominal pain  Appetite  Food intake = Weight loss GLP-1 levels achieved with GLP-1-receptor agonists Increasing plasma GLP-1 concentrations Animated Slide Effects of GLP-1: Dose-response relationship There is a clear dose–response relationship between plasma concentrations of GLP-1 (or GLP-1-receptor agonists) and physiological effects observed. When levels of GLP-1 are increased by a moderate amount, as can be achieved by either GLP-1 analogs or dipeptidyl peptidase 4 (DPP-4) inhibitors, effects on the pancreas include increased insulin secretion and decreased glucagon secretion. However, higher plasma concentrations of GLP-1 are needed to achieve a reduction in gastric emptying and reduced appetite and food intake. These effects are not observed with DPP-4 inhibitors, as only a limited increase in plasma GLP-1 concentration can be achieved with these agents; thus, weight loss is not a characteristic of DPP-4 inhibitors. In contrast, GLP-1 analogs are able to attain plasma concentrations sufficient to induce decreased appetite, food intake and subsequent weight loss. At even higher plasma concentrations of GLP-1, side effects may be observed including nausea, diarrhea, and vomiting.  Gastric emptying Pharmacological effects Physiological effects  Insulin secretion  Glucagon secretion = improved glycemic control GLP-1 levels achieved with DPP-4 inhibitors GLP-1 effects Holst JJ, et al. Trends Mol Med. 2008;14:161–168.

Which of the following statements with regard to the DPP-4 inhibitors is/are CORRECT?
They all lower A1c to a similar degree The use of all of them can be associated with nausea They all have similar routes of excretion They all have similar indications in Canada Correct Answer is 1

Pharmacological Features of the DDP-4 Inhibitors
Alogliptin 25 mg QD Linagliptin 5 mg QD Saxagliptin 5 mg QD Sitagliptin 100 mg QD Vildagliptin 50 mg BID Relevant organ for metabolism1 None None Liver None Liver Metabolism Active metabolites No No Yes No No Main route of excretion Kidney Bile & gut Kidney Kidney Kidney Excretion Share of renal excretion2 % 5% 75% 87% 85% Dose adjustment and/or limitations in RI3 Yes No Yes Yes Yes Dosing and monitoring Drug-related monitoring Kidney function No Kidney function Kidney function Kidney and liver function 1 If metabolized to a relevant degree 2 Including metabolites and unchanged drug; excretion after single-dose administration of C14-labelled drug 3 As recommended in countries where respective DPP-4 inhibitor is available Respective US prescribing information or EUSmPc: Scheen, et al. DOM. 2010;2: ; Deacon, et al. DOM. 2011;13:7-18; Vincent, et al. Drug Metab Dispos. 2007;35: ; He, et al. Drug Metab Dispos. 2009;37: ; Christopher, et al. Clin Ther. 2008;30:

Efficacy of DPP-4 Inhibitors in Monotherapy Trials
Placebo-corrected, adjusted mean change from baseline HbA1c Linagliptin1* 5 mg QD 8.1% Linagliptin1 5 mg QD 8.0% Saxagliptin2 5 mg QD ≥7% to ≤10% Saxagliptin2 5 mg QD 8.0% Sitagliptin3* 100 mg QD 8.0% Sitagliptin3 100 mg QD 8.0% Vildagliptin4 50 mg BID 8.6% Vildagliptin4 50 mg BID 8.4% Dosage Baseline HbA1c -0.4% -0.5% -0.6% -0.6% -0.6% When assessed in trials with comparable baselines HbA1c, linagliptin monotherapy achieves equivalent blood sugar lowering compared with other DPP-4 inhibitors.1 Placebo correction provides clarity about the degree of real clinical benefit seen with linagliptin * 18 weeks treatment duration, 24 weeks otherwise Sources: 1-4. Respective US Prescribing information 5. EU Summary of product characteristics. -0.7% -0.7% -0.8% n = 147 272 69 103 193 229 90 79 p-value† <0.0001 <0.0001 =0.0059 <0.0001 <0.0001 <0.0001 <0.05 <0.05 * 18 weeks’ treatment duration, 24 weeks otherwise † Between-group difference versus placebo 1– 3. US PI for linagliptin, saxagliptin, sitagliptin 4. EU SmPC for vildagliptin

Efficacy of DPP-4 Inhibitors in Add-on to Metformin Trials
Placebo-corrected, adjusted mean change from baseline HbA1c Dosage 8.0 8.4 8.1 Linagliptin2 Linagliptin1* Saxagliptin3 Sitagliptin4 Vildagliptin5 5 mg QD 100 mg QD 50 mg BID -0.8% -0.7% -1.1% -0.6% 513 n = 209 453 186 143 <0.0001 < <0.05 Baseline HbA1c (%) p-value When assessed in trials with comparable baselines HbA1c, linagliptin as add-on to metformin achieves equivalent blood sugar lowering compared with other DPP-4 inhibitors. Placebo correction provides clarity about the degree of real clinical benefit seen with linagliptin Lina -0.8% from study .62, data on file. Lina -0.6% from US PI Saxa -0.8% from US PI Sita -0.7% from US PI Vilda -1.1% from EU SmPC * 12 weeks treatment duration, 24 weeks otherwise Sources: 1. Linagliptin data on file 2-4. Respective US Prescribing information 5. EU Summary of product characteristics. * 12 weeks’ treatment duration, 24 weeks otherwise Sources: 1. Linagliptin data on file 2–4. US PI for linagliptin, saxagliptin, sitagliptin 5. EU SmPC for vildagliptin

Rate of patients achieving HbA1c target of <7%
Linagliptin Brings Patients to Target (Hba1c <7%) with Significantly Less Hypoglycemia and Relative Weight Loss Compared to Glimepiride Linagliptin Glimepiride 7.5 Adjusted2 means for body weight change from baseline ± SE Kg - FAS (OC) 2.0 1.5 1.0 0.5 -0.5 -1.0 -1.5 -2.0 p<0.0001 28 104 weeks 52 78 12 -2.9 +1.4 Incidence of hypoglycemia Percentage of patients - Treated set1 Rate of patients achieving HbA1c target of <7% Percentage of patients at week 104 completers cohort3 1 Treated set: linagliptin n=776, glimepiride n=775 2 Model includes baseline HbA1c, baseline weight, no. prior OADs, treatment, week repeated within patients and week by treatment interaction 3 Completers cohort: linagliptin n=233, glimepiride n=271 Gallwitz B, et al. ADA Late Breaker 39-LB.

Linagliptin: Safety and Tolerability
Organ-specific adverse event (AE) rate for AE previously associated with the DPP-4 inhibitor class1 Linagliptin 2,523 3.3% 5.9% 1.7% 1.0% 0.1% 2.2% 2.9% 0.0% Placebo 1,049 4.9% 5.1% 1.0% 1.2% 0.1% 2.7% 3.1% n Headache Upper respiratory tract infection Pancreatitis: Pancreatitis was reported more often in patients randomized to linagliptin (1 per 538 person years versus zero in 433 person years for comparator)* Nasopharyngitis Cough Hepatic enzyme increase DPP-4 inhibitors as a class are well tolerated Linagliptin exhibits an adverse event profile that is similar to placebo. Importantly, there is no evidence that linagliptin is associated with and increased incidence of pancreatitis Scherntharner G., von Eynatten M., Emser A., Woerle H-J. Safety and Tolerability of Linagliptin: A Pooled Analysis of Data from 3572 Patients with Type 2 Diabetes. American Diabetes Association, 71st Scientific Sessions, San Diego, CA, June 24-28, 2011; 2327-PO * Linagliptin US prescribing information Serum creatinine increase Urinary tract infection Blood and lymphatic system disorders Hypersensitivity 1. Organ-specific adverse events taken from label of currently marketed DPP-4 inhibitor in the US; * Linagliptin US PI Schernthaner G, et al. ADA Abstract 2327-PO. Pooled data from 8 studies.

Which of the following statements with regard to the GLP-1R Agonists is CORRECT?
They lower body weight to a similar degree in all patients The use of all of them may be associated with allergic reactions They reduce A1C to a similar degree in all patients The nausea is typically transient Correct Answer is 4

Exenatide: A1C Lowering in Major Trials
NI: Non-Inferior Buse JB, et al. Diabetes Care. 2004;27: ; DeFronzo RA, et al. Diabetes Care. 2005;28: ; Kendall DM, et al. Diabetes Care. 2005;28: ; Zinman B, et al. Ann Intern Med 2007;146: ; Moretto TJ, et al. Clin Ther. 2008; 30: ; Heine R, et al. Ann Intern Med 2005;143:

Results of 30-week exenatide studies
Exenatide Large Phase 3 Clinical Studies – Combined (ITT): Adverse Events Results of 30-week exenatide studies Adverse event Placebo BID (n = 483) Exenatide BID 5 mcg and 10 mcg (n = 963) Nausea 18% 44% Vomiting 4% 13% Diarrhea 6% Feeling jittery 9% Dizziness Headache Dyspepsia 3% Large Phase 3 Clinical Studies – Combined (ITT) Other Adverse Events DISCUSSION POINTS: In addition to hypoglycemia seen in the presence of an SFU, the adverse events (AEs) shown here were reported more frequently in the BYETTA treatment groups than in the placebo groups and had an overall incidence greater than 5%. AEs were mostly gastrointestinal in nature Nausea, the most common AE, was mostly mild to moderate in intensity Incidence of severe nausea low (placebo 1%, BYETTA 4%) Few “dropouts” due to nausea (placebo < 1%, BYETTA 3%) Vomiting and diarrhea were reported much less frequently than nausea SLIDE BACKGROUND: Combined Phase 3 Studies: three 30-week, placebo-controlled, double-blind studies Subjects with type 2 diabetes treated with met, SFU, or metformin + SFU Randomized to placebo (n = 483), 5 mcg BID (n = 480), or 10 mcg BID (n = 483) References: FDA. US prescribing information. Available at: Accessed September 29, 2008. FDA. Information for Healthcare Professionals Exenatide. Available at: Accessed September 29, 2008. If pancreatitis is suspected, exenatide should be discontinued. FDA. Available at: Accessed September 29, FDA. Available at: Accessed September 29, 2008.

Liraglutide: A1C Lowering in Major Trials
Estimated means are obtained from an analysis of covariance (ANCOVA) with treatment, country, and previous treatment as fixed effects and baseline value as a covariate; estimated mean ± 1.96 x SE. Marre, et al. Diabetic Medicine. 2009; Nauck MA, et al. Diabetes Care. 2009;32:84-90; Pratley, et al. Lancet. 2010; Garber A, et al. Lancet. 2009; Zinman B, et al. Diabetes Care. 2009; Russell-Jones, et al. Diabetologia. 2009; Buse J, et al. Lancet

Weight Loss with GLP1s is Variable
A quarter of patients lose an average of 7.7 kg with liraglutide 0–Q1: mean weight change for the 25% of subjects who had the largest weight loss Q1–Q2: mean weight change for the 25–50% weight loss quartile Q2–Q3: mean weight change for the 50–75% weight loss quartile Q3–Q4: mean weight change for the 75–100% weight loss quartile, that is, the 25% who had the smallest weight loss Nauck, et al. Diabetes Care. 2009;32;84–90 (LEAD-2).

Total patients in analysis
CV Meta-analyses of Individual Incretin Agents No increased risk of CV events was observed in patients randomly treated with DPP-4 inhibitors or GLP-1R agonists Total patients in analysis CV composite endpoint Comments FDA Upper Bound 95% Criterion for Approvability Exenatide1 0.7 0.38 1.31 MedDRA terms for stroke, MI, cardiac mortality, ACS, revascularization Post hoc/ No formal adjudication 3,945 5,239 6,638 4,607 10,246 CV death, MI, stroke, hospitalization due to angina pectoris Prespecified/ Independent adjudication Linagliptin2 0.15 0.34 0.74 Post hoc/ No formal adjudication MedDRA terms for MACE Liraglutide3 0.32 0.63 1.24 Saxagliptin4 MI, stroke, CV death Post hoc/ Independent adjudication Cardiovascular risk reduction with any antidiabetic drug 0.23 0.43 0.80 Sitagliptin5 MedDRA terms for MACE Post hoc/ No formal adjudication 0.41 0.68 1.12 0.125 0.25 0.5 1 2 4 8 Incretin agent better Comparator better Risk ratio for major CV events1-5 Ratner R, et al. Cardiovascular Diabetology. 2011;10:22. Johansen O-E, et al. ADA Late breaker 30-LB. Accessed Sept. 23, 2011. Frederich R, et al. Postgrad Med. 2010;122(3):16–27. Williams-Herman D, et al. BMC Endocr Disord. 2010;10:7.

Incretin-based Therapies: Pancreatitis
Patients with type 2 diabetes have a 2.8-fold higher risk than the general population (4.2 vs. 1.5 cases per 1000 pt-yrs) Exenatide: Isolated cases in clinical development program (8 cases = 1.8 per 1,000 pt-yrs) Incidence consistent with expected rate in type 2 diabetes and similar to placebo (2.6 per 1,000 pt-yrs) 971 post-marketing cases reported to FDA AERS Linagliptin: Isolated cases reported during clinical development (8 cases = 1.9 per 1,000 pt-yrs) Incidence consistent with expected rate in type 2 diabetes patients Liraglutide: Isolated cases reported in clinical development program (7 cases = 2.2 cases per 1,000 pt-yrs) Saxagliptin: Isolated cases reported during clinical development (6 cases = 0.2%) Consistent with expected rate in type 2 diabetes and similar to comparators (2 cases = 0.6%) Sitagliptin: Isolated cases reported in controlled clinical trials (4 cases = 0.8 per 1,000 pt-yrs) Consistent with expected rate in type 2 diabetes and similar to comparators (1 per 1,000 pt-yrs) 131 post-marketing cases reported to FDA AERS Noel R, et al. Diabetes Care. 2009;32(5): ; Victoza, Product Monograph. Novo Nordisk Canada Inc., 2010; Anderson S, et al. Ann Pharmacother. 2010;44; Engel S, et al. Int J Clin Pract.2010; FDA. September 25, PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm htm. Saxagliptin FDA Briefing Document March 2009; Elashoff M, et al. Gastroenterology. 2011;doi: /j.gastro ; Linagliptin Procuct Monograph Canada 2011.

Which of the Following Differences Between DPP-4 inhibitors and GLP-1R agonists is CORRECT?
They both decrease gastric emptying They both increase satiety They both reduce glucagon secretion They both can be given orally or subcutaneously Correct Answer is 3

GLP-1R Agonists vs. DPP- 4 Inhibitors
Administration Injection Orally available GLP-1 concentrations Pharmacological Physiological Mechanisms of action Activation of portal glucose sensor GLP-1 No GLP-1 + GIP Yes Insulin secretion +++ + Glucagon secretion ++ Gastric emptying Inhibited +/- Weight loss Expansion of beta-cell mass In preclinical studies Nausea and vomiting Potential immunogenicity GLP-1R Agonists vs. DPP-4 Inhibitors The overlapping and distinct properties of GLP-1R agonists vs. DPP-4 inhibitors for the treatment of type 2 diabetes are contrasted in this table. These agents exhibit similar actions on the islet beta cell. GLP-1 also inhibits glucagon secretion. GLP-1 and GIP have contrasting actions on weight loss and gastric emptying.1-4 The side-effect profile is also different, with GLP-1R agonists exhibiting a much greater tendency to produce gastrointestinal side effects.3

GLP-1 agonists DPP- 4 inhibitors
Patient Targets for Incretin-Based Therapy GLP-1 agonists Obese type 2 diabetes patients Patients failing to maintain goals with oral agents Add-on to other agents, including insulin* Advantages weight loss easy dosing new mechanism with possible beta cell sparing DPP- 4 inhibitors Dysfunctional needle phobia Add-on to other oral agents, including insulin* Advantages oral availability excellent tolerance weight neutral new mechanism with possible beta cell sparing The combination of an incretin agent with insulin is not approved in Canada * The combination of an incretin agent with insulin is not approved in Canada

Add-on to sulfonylureas Add-on to metformin and sulfonylureas
Approved Canadian Indications for Incretin-Based Therapies Monotherapy (Met intol. or contraind.) Add-on to metformin (dual Tx) Add-on to sulfonylureas Add-on to metformin and sulfonylureas (triple Tx) DPP-4 inhibitors Linagliptina  Saxagliptinb Sitagliptinc GLP-1 receptor agonists Exenatided Liraglutidee Facilitator’s Notes New slide This slide displays the approved Canadian indications for the various incretin-based therapies. Reference: Health Canada. Drug Products. Available at: Accessed: February 1, 2011. a: Based on Canadian linagliptin product monograph of July 26,2011. b: Based on Canadian saxagliptin product monograph of Sept 14,2009. c: Based on Canadian sitagliptin product monograph of Oct 25,2010. d: Based on Canadian exenatide product monograph of Jan 11,2011. e: Based on Canadian liraglutide product monograph of May 21,2010.

Antihyperglycemic Medications and Renal Function
CKD Stages (GFR) 1 (> 90) 2 Mild (60-89) 3 Moderate (30-59) 4 Severe (15-29) 5 ESKD* (<15) 25 15 5 mg OD DPP-4 Inhibitors 50 30 15 5 mg OD 2.5 mg OD 50 30 100 mg OD 50 mg OD 25 mg OD 50 30 GLP-1R Agonists 50 60 30 Sulfonylurea 50 30 30 100 75 50 25 GFR (ml/min) CKD = Chronic Kidney Disease GFR = Glomerular Filtration Rate * ESKD – End Stage Kidney Disease Based on Canadian product monographs as of September 10, 2012 Adapted from product monographs, CDA Guidelines, 2008 and Yale JF, J Am Soc Nephrol. 2005;16:S7-S10.

Summary The incretin agents, are efficacious in monotherapy and in combination with other antihyperglycemic agents with the lack of hypoglycemia and beneficial/neutral effects on body weight providing potential advantages relative to other classes of antihyperglycemic agents The incretin agents may have other important pancreatic and non-pancreatic benefits (e.g., beta cell preservation, CV risk reduction), but these must be proven in long-term studies Chronic kidney disease is common in diabetes and is one of a number of factors that must be considered in the selection of an appropriate antihyperglycemic agent

How the Kidney Affects Diabetes Control and its Complications
Module 3 How the Kidney Affects Diabetes Control and its Complications

Contributing factors to hypoglycemia in CKD patients include:
Loss of renal cortical gluconeogenesis Malnutrition Decreased insulin clearance Failure to adjust dose of antihyperglycemic medication All of the above Correct Answer is 5

Risk For Hypoglycemia in Veterans Classified by Presence or Absence of Chronic Kidney Disease (CKD) And Diabetes Incident Rate Ratios Risk for hypoglycemia of varying severity and expressed as an adjusted incidence rate ratio in veterans classified by presence or absence of chronic kidney disease (CKD) and diabetes. Reference group are veterans without CKD or diabetes. Rates adjusted for race, gender, age, Charlson comorbidity index, cancer, diabetes, and cardiovascular disease (all rate ratios P < ). This was a retrospective cohort analysis of 243,222 patients who had 2,040,206 glucose measurements and were cared for at the Veterans Health Administration. CKD was defined as an estimated GFR of <60 ml/min per 1.73 m2. Hypoglycemia was set at <70 mg/dl. Mortality was measured 1 day after glucose measurement. Results: The incidence of hypoglycemia was higher in patients with CKD versus without CKD. Among patients with diabetes, the rate was versus 5.33 per 100 patient-months and among patients without diabetes was 3.46 versus 2.23 per 100 patient-months, for CKD versus no CKD, respectively. The odds of 1-d mortality were increased at all levels of hypoglycemia but attenuated in CKD versus no CKD. Adjusted odds ratios for 1-d mortality that were associated with glucose values of <50, 50 to 59, and 60 to 69 mg/dl, respectively, versus glucose of ≥70 mg/dl were 6.09, 4.10, and 1.85 for inpatient records from patients with CKD; 9.95, 3.79, and 2.54 for inpatients records from patients without CKD; 6.84, 3.28, and 3.98 for outpatient records from patients with CKD; and 13.28, 7.36, and 4.34 for outpatient records from patients without CKD All p-values <0.0001, (95% CI) Moen MF, et al. CJASN. 2009;4:

Hypoglycemia often caused by drugs in CKD patients
Etiology Of Hypoglycemic Events in ESRD* Patients Hospitalized Due to Hypoglycemia Several factors may account for hypoglycemia in ESRD patients; As stated above, in diabetic patients, the role of renal glucose production is more substantial, and its cessation may probably lead hypoglycemia. Sulfonylureas and insulin levels may rise as a result of diminished degradation by the kidney. While acidosis suppresses hepatic glucose production via glycogenolysis [[9]], it enhances renal gluconeogenesis, thereby predisposing to hypoglycemia as renal function deteriorates. Hyperkalemia has also been associated with hyperinsulinemia and hypoglycemia [[1]]. Drugs, primarily beta-blockers, but also class Ia anti arrhythmic drugs and warfarin, are often used in ESRD, and have been associated with hypoglycemic effects, especially in ESRD patients. Malnutrition in ESRD may lead to energy expenditure imbalance, as is reduced elimination of several drugs, such as salycilates and sulfonamides that may predispose to hypoglycemia. Counterregulatory hormonal reaction to hypoglycemia may be diminished in ESRD patients because of autonomic neuropathy and malnutrition. Therefore it is not surprising to find that ESRD is the second most common cause of hypoglycemia in hospitalized patients after hypoglycemic agents Hypoglycemia often caused by drugs in CKD patients ESRD: End Stage Renal Disease Yosef S, et al. Renal Failure. 2000;22(2):

Possible Mechanisms of Hypoglycemia in CKD
Most advanced CKD patients with hypoglycemia have some degree of cachexia/malnutrition/anorexia Chronic malnutrition decreases hepatic glycogen content and may also contribute to hypoglycemia in CKD Decreased gluconeogenesis: Substrate limitation hepatic and renal Reduced renal cortical mass Decreased renal clearance of insulin and AHA in diabetes Use of either a contraindicated drug (most often an anti-diabetic agent) or one requiring dose adjustment increased 6-year mortality by 40% in the elderly Nephrol Dial Transplant (2011) 26 (9): Nephrol Dial Transplant (2011) 26: 1888–1894

According to their product monographs, which of the following antihyperglycemic agents are contraindicated or require dose adjustment when eGFR is <50? Metformin Saxagliptin Exenatide Glyburide All of the above Correct Answer is 5

Antihyperglycemic Medications and Renal Function
CKD Stages (GFR) 1 (> 90) 2 Mild (60-89) 3 Moderate (30-59) 4 Severe (15-29) 5 ESKD* (<15) HEMO 25 15 5 mg OD DPP-4 Inhibitors 50 30 15 5 mg OD 2.5 mg OD 50 30 100 mg OD 50 mg OD 25 mg OD 50 30 GLP-1R Agonists 50 60 30 Sulfonylurea 50 30 30 100 75 50 25 GFR (ml/min) CKD = Chronic Kidney Disease GFR = Glomerular Filtration Rate * ESKD – End Stage Kidney Disease Based on Canadian product monographs as of September 10, 2012 Adapted from product monographs, CDA Guidelines, 2008 and Yale JF, J Am Soc Nephrol. 2005;16:S7-S10.

Intensive glucose control has been shown to delay the progression of CKD in the setting of diabetes
True False Correct Answer is 1 (True)

Cumulative Incidence of an Impaired Glomerular Filtration Rate According to Treatment Group
This effect was only evident after 10 years of follow-up, emphasizing the long-term renal benefits of this intervention and the need to follow patients for this long period of time for clinical trials evaluating impaired GFR." "Impaired GFR can be prevented in type 1 diabetes, and hyperglycemia likely plays an initiating role in this GFR loss. Diabetes therapy applied early in the disease course has long-lasting renal benefits.” Investigators determined that 29 diabetic patients would have to be treated intensively for 6.5 years to prevent one case of impaired GFR. de Boer and colleagues acknowledged that, "the beneficial effects of intensive diabetes therapy on the risk of an impaired GFR were fully attenuated by statistical adjustment for the glycated hemoglobin level (P=0.44) or albumin excretion rate (P=0.73 to P=0.30)." "Together these results suggest that hyperglycemia contributes to the pathogenesis of both albuminuria and an impaired GFR in patients with type 1 diabetes and that the biologic pathways through which intensive diabetes therapy prevents of the GFR are reflected by a reduction in albuminuria," de Boer and co-authors wrote in their discussion of the results. The DCCT/EDIC Research Group. N Engl J Med. 2011;DOI: /NEJMoa

THRESHOLD equal to or over 130/80 mmHg and TARGET below 130/80 mmHg
CHEP 2012: Treatment of Hypertension in association with Diabetic Nephropathy THRESHOLD equal to or over 130/80 mmHg and TARGET below 130/80 mmHg ACE Inhibitor or ARB Addition of one or more of long-acting CCB or thiazide diuretic DIABETES With Nephropathy IF ACEI and ARB are contraindicated or not tolerated, SUBSTITUTE • Long-acting CCB or • Thiazide diuretic 3 - 4 drugs combination may be needed 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). 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 Monitor serum potassium and creatinine carefully in patients with CKD prescribed an ACEI or ARB

Chronic Kidney Disease in Diabetes
The DCCT/EDIC Research Group. N Engl J Med. 2011;DOI: /NEJMoa

Module 4 Optimal Glucose Management: How to choose the right agent for the right patient

2008 CDA Guidelines The 2008 Canadian Diabetes Association (CDA) clinical practice guidelines indicate that lifestyle is the foundation of management for type 2 diabetes. From a pharmacologic perspective, metformin is the usual first choice, particularly when the A1C is < 9%. If A1C is ≥ 9%, metformin should be initiated with a second agent. In a patient with metabolic decompensation, insulin should be initiated along with metformin. Reference: CDA Clinical Practice Guidelines Expert Committee. CDA 2008 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2008; 32(suppl 1):S1-S201. CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2008;32(suppl 1):S1-S201.

Insulin Deficiency Insulin Resistance Other Antihyperglycemic Agents
Secretagogue DPP-4 Inhibitor GLP-1 RA Insulin Resistance Metformin TZD Other Acarbose Having reviewed the various classes of oral antihyperglycemic agents, we can group them based on their mechanism of action. The two primary defects in type 2 diabetes are insulin resistance and relative insulin deficiency. Metformin and TZDs work to reduce insulin resistance. Insulin, secretagogues and DPP-IV inhibitors work to increase insulin levels. Acarbose does not address either of the defects, but instead delays absorption of carbohydrates. References: Cheng AY, Fantus IG. Oral antihyperglycemic therapy for type 2 diabetes mellitus. CMAJ 2005; 172(2): Palalau AI, Tahrani AA, Piya MK, et al. DPP-4 inhibitors in clinical practice. Postgrad Med 2009; 121(6): Cheng AYY, Fantus IG. CMAJ 2005; 172: Palalau AI, et al. Postgrad Med 2009; 121(6):

What is your level of comfort in discussing the pros and cons of the various classes?
Uncomfortable Somewhat uncomfortable Neutral Comfortable Very comfortable

Pros and Cons Insulin Deficiency Insulin Resistance Other Insulin
Secretagogue DPP-4 Inhibitor GLP-1 RA Insulin Resistance Metformin TZD Other Acarbose Having reviewed the various classes of oral antihyperglycemic agents, we can group them based on their mechanism of action. The two primary defects in type 2 diabetes are insulin resistance and relative insulin deficiency. Metformin and TZDs work to reduce insulin resistance. Insulin, secretagogues and DPP-IV inhibitors work to increase insulin levels. Acarbose does not address either of the defects, but instead delays absorption of carbohydrates. References: Cheng AY, Fantus IG. Oral antihyperglycemic therapy for type 2 diabetes mellitus. CMAJ 2005; 172(2): Palalau AI, Tahrani AA, Piya MK, et al. DPP-4 inhibitors in clinical practice. Postgrad Med 2009; 121(6): Cheng AYY, Fantus IG. CMAJ 2005; 172: Palalau AI, et al. Postgrad Med 2009; 121(6):

When selecting the next agent after metformin, which of the following statements best describe you?
I use the same second-line agent for all patients unless there is a contraindication I like having multiple options and consider all of them before selecting the best one for the patient I use one of 2 classes only

What is your level of comfort in individualizing therapy?
Uncomfortable Somewhat uncomfortable Neutral Comfortable Very comfortable

What is the degree of hyperglycemia?
Questions to Consider When Individualizing … What is the degree of hyperglycemia? Is the patient at risk for hypoglycemia? Does the patient have a drug plan? Other Considerations: Contraindications, weight, glycemic durability, side effects, comfort, preference These three questions can help one decide on the most appropriate second agent for any given patient. The first question is: What is the degree of hyperglycemia? If the blood sugars are very high or the patient is symptomatic from hyperglycemia, then one would select an agent that could bring down the blood sugars quickly and effectively. However, if the blood sugars are only slightly elevated and the patient has no symptoms, then one can choose an agent that brings down blood sugars more slowly.

↓↓↓ ↓↓ ↓ A1c FAST MOD SLOW Glucose Lowering Insulin Secretagogue DPP-4
GLP-1 RA TZDs ↓ Acarbose The different classes have the ability to lower glucose to different extents and at different rates. The fastest are insulin and secretagogues. The others are slower. 2008 CDA guidelines. 2008 CDA Guidelines

What is the degree of hyperglycemia?
Questions to Consider When Individualizing … What is the degree of hyperglycemia? Is the patient at risk for hypoglycemia? Does the patient have a drug plan? Other Considerations: Contraindications, weight, glycemic durability, side effects, comfort, preference The next consideration is the patient’s risk for hypoglycemia, since the different classes of oral agents carry different hypoglycemia tendencies.

Low High Risk of Causing Hypoglycemia Acarbose Insulin DPP-4 Inhibitor
Secretagogue Low Acarbose DPP-4 Inhibitor GLP-1 RA Metformin TZDs The different agents, listed here alphabetically, have different propensities for causing hypoglycemia. Reference: CDA Clinical Practice Guidelines Expert Committee. CDA 2008 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2008; 32(suppl 1):S1-S201 CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2008;32(suppl 1):S1-S201.

Who is at Risk for Hypoglycemia?
Risk factors for hypoglycemia Variable eating Variable activity Poor recognition of hypoglycemia (elderly, dementia) Chronic kidney disease High-risk consequences of hypoglycemia Bus driver, pilot, truck driver, etc. Living alone When determining a patient’s risk for hypoglycemia, one needs to consider the presence of risk factors that increase the risk of hypoglycemia as well as other variables that place the patient at risk of adverse consequences if they experience hypoglycemia. The risk factors for hypoglycemia include variable eating schedule, variable activity level or poor recognition of hypoglycemia. People at high risk of bad outcomes from hypoglycemia include those in occupations that involve public safety (bus driver, pilot, truck driver, etc.) and those living alone.

Questions to Consider When Individualizing …
What is the degree of hyperglycemia? Is the patient at risk for hypoglycemia? Does the patient have a drug plan? Other Considerations: Contraindications, weight, glycemic durability, side effects, comfort, preference Finally, economic considerations must also be taken into account because the presence or absence of drug coverage will influence one’s final decision.

Absence of contraindications Glycemic durability Weight effects
Other Considerations Absence of contraindications Glycemic durability Weight effects Side effects Comfort of prescriber Patient preference Usually, with the first three questions, one has narrowed the possibilities down to one, two or three agents. These final considerations will then make the decision. Contraindications are obvious to consider. The table on the following slide compares the available agents in terms of these other considerations.

+ Neutral Loss None Rare Poor ?? 2-year New WEIGHT GAIN
Secretagogue Insulin Acarbose TZD DPP-4 Inhibitors GLP-1 RA WEIGHT GAIN + Neutral Loss FLUID RETENTION / CHF None Rare FRACTURES GI INTOLERANCE GLYCEMIC DURABILITY Poor ?? LONG-TERM EXPERIENCE 2-year New PRESCRIBER COMFORT PATIENT PREFERENCE © Alice Y.Y. Cheng 2010

Summary Pros and cons of each class
Hypoglycemia, weight, side effects, degree of control, etc. What is the degree of hyperglycemia? Is the patient at risk for hypoglycemia? Does the patient have a drug plan? Other: contraindications, glycemic durability, weight, side effects, comfort, preference In summary, consideration of these three main questions and the other factors listed here provide the basis for decision-making in adding a second antihyperglycemic agent in patients whose A1C is not adequately controlled with lifestyle changes and metformin therapy.

Interactive Case: Leon
Module 5 Interactive Case: Leon

Leon 70-year-old hypertensive for 15 years with type 2 diabetes for 10 years Presents to emergency with acute hypoglycemia His blood sugar is 2.8

What we know….. eGFR 40 ml/min Blood Pressure 144/92 mmHg
Waist Circumference 104 cm ACR 24 mg/mmol Uric Acid 420 µmol/L LDL 2.4 mmol/L

Leon’s Medications Metformin 1,000 mg BID Glyburide 5 mg BID Ramipril
10 mg OD Atorvastatin

Leon’s ACR of 24 requires therapy targeted to reduce this value in order to reduce future CV events
True False Correct Answer 2 (False)

Incidence per 100 patient-years
Cardiovascular risk is greatest when both diabetes and nephropathy are present x 2.1 x 1.7 x 2.5 Incidence per 100 patient-years x 2.2 Among patients with both CKD and diabetes, the rate of CV events is more than twice the rate among patients with diabetes alone. Relative to healthy individuals, patients with CKD and diabetes have a 79% increased risk of congestive heart failure, 41% increased risk of atherosclerotic vascular disease, a 79% increased risk of congestive heart failure, and a 56% increased risk of death (P< for all comparisons). These results are from a sample of the United States Medicare population from 1998 and 1999 (N=1,091,201) who were divided according to diabetes and CKD status: no diabetes, no CKD (79.7%); diabetes, no CKD (16.5%); CKD, no diabetes (2.2%); both CKD and diabetes (1.6%). Reference: Foley RN, et al. “Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999” J Am Soc Nephrol 2005;16:489–95. Foley RN, et al. J Am Soc Nephrol. 2005;16:489–495.

Age-standardized event rate (per 100 person-yr)
Relationship Between eGFR and Clinical Outcomes Death from any cause Total events = 51,424 Cardiovascular events Total events = 139,011 Any hospitalization Total events = 554,651 Age-standardized event rate (per 100 person-yr) The slide shows the longitudinal glomerular filtration rate (GFR) in a study of 1,120,295 adults in the Northern California Kaiser Permanante healthcare system. Patients were included if their serum creatinine had been measured between 1996 and 2000. Age-standardized rates of death from any cause, cardiovascular events, and hospitalization are shown here according to corresponding estimated GFR. A cardiovascular event was defined as hospitalization for coronary heart disease, heart failure, ischemic stroke, or peripheral arterial disease. eGFR (mL/min/1.73 m2) Go AS, et al. N Engl J Med. 2004;351:

4 Risk Classification of CKD Proteinuria ≥ 90 60-89.9 45 – 59.9
Normal ACR < 30 mg/g or urine dipstick negative Mild ACR mg/g or urine dipstick trace or 1+ Heavy ACR > 300 mg/g or urine dipstick ≥ 2+ Alternate System eGFR, mL/min/1.73 m2 Risk Category 0 (No CKD) Risk Category 1 Risk Category 3 ≥ 90 Risk Category 1 Risk Category 2 Risk Category 4 Risk Category 2 Risk Category 3 Key point: Alternative classification systems take proteinuria into account. FACILITATOR NOTES: Because of the limitations of the widely used KDOQI classification system for CKD, Tonelli et al developed and validated a 5-category classification based not only on eGFR but also on presence and degree of proteinuria (as shown on this slide), as determined by dipstick urinalysis or urinary albumin:creatinine ratio (ACR). Normal proteinuria: ACR < 30 mg/g or urine dipstick negative Mild proteinuria: ACR mg/g or urine dipstick trace or 1+ Heavy proteinuria: ACR > 300 mg/g or urine dipstick ≥ 2+ These authors used data from a provincial laboratory registry in Alberta and a sample of noninstitutionalized adults in the US, and found that over a median follow-up of 38 months, the alternate system shown above classified fewer individuals as having higher-stage disease than the KDOQI system. The alternate system was more accurate in reclassifying subjects who did not develop a composite renal outcome of kidney failure or doubling of serum creatinine levels, and also more accurate when proteinuria was determined using ACR rather than dipstick testing. With increasing risk category, there was a graded increase in risk of the renal outcome. Reference: Tonelli M, Muntner P, Lloyd A, et al; Alberta Kidney Disease Network. Using proteinuria and estimated glomerular filtration rate to classify risk in patients with chronic kidney disease: a cohort study. Ann Intern Med 2011;154:12-21. 45 – 59.9 30 – 44.9 Risk Category 3 Risk Category 4 15 – 29.9 Tonelli M, et al. Ann Intern Med. 2011;154:12.

Approximately 40% of type 2 diabetes patients have renal complications†
Diabetic nephropathy is a leading cause of chronic kidney disease. In fact, diabetes is responsible for 30-40% of all end-stage renal disease (ESRD) cases in the United States. To estimate the prevalence of Chronic Kidney Disease in the United States, the CDC analyzed the most recent data from the National Health and Nutrition Examination Survey (NHANES). The study clearly showed that people with diabetes had a greater prevalence of CKD than healthy individuals. CKD prevalence was greater among persons with diabetes than among those without diabetes (40.2% versus 15.4%). By disease stage, the prevalence for CKD Stages 1, 2 and 3 were below were 5.7%; 5.4%; and 5.4%, respectively in the normal population –lower than the figures shown in the table for diabetes patients. For diabetes patients, the prevalence of late-stage CKD was over 2%, whereas in the normal population the prevalence was 0.4%. In summary, CKD prevalence is high in diabetes patients, with around 40% of all diabetes patients affected by some degree of declining renal function. Koro CE, et al. Clin Ther. 2009;31:2608–17 Coresh J, et al. JAMA. 2007;298(17): CKD prevalence was greater among people with diabetes than among those without diabetes (40.2% versus 15.4%) * No signs of kidney damage ** Albuminuria – kidney damage †Based on data from 1,462 patients aged ≥20 years with T2DM who participated in the Fourth National Health and Nutrition Examination Survey (NHANES IV) from 1999 to 2004.

ACCOMPLISH: Diabetes Subset ACEI + CCB better than ACEI + HCTZ
Non-Diabetes All Diabetes High-Risk Diabetes Proportion of patients 0.24 0.18 0.12 0.06 B + A (events = 245) B + H (events = 296) HR = 0.82 (0.69–0.97; p = 0.020) B + A (events = 307) B + H (events = 383) HR = 0.79 (0.68–0.92; p = 0.003) B + A (events = 195) B + H (events = 244) HR = 0.77 (0.64–0.93; p = 0.007) B + H 2,293 2,172 2,087 2,012 1,937 1,839 1, B + H 3,468 3,310 3,186 3,069 2,954 2,815 1, B + H 1,410 1,333 1,263 1,197 1,145 1, Key point: In the ACCOMPLISH trial, compared to adding HCTZ, adding the CCB amlodipine to benazepril significantly reduced the risk of vascular events in patients with diabetes as well as nondiabetic patients. FACILITATOR NOTES: One of the prespecified analyses in the ACCOMPLISH trial1 (discussed in main module of this slide deck) concerned the effects of benazepril + amlodipine versus benazepril + HCTZ in patients with diabetes. In the study cohort were 6,946 patients with diabetes, including 2,842 at very high risk because of previous CV or stroke events. The primary end point was a composite of CV death, MI, stroke, hospitalization for angina, resuscitated arrest, and coronary vascularization. As shown here, all those with diabetes as well as those with high-risk diabetes benefitted from reduced relative risk with the ACEI/CCB treatment, compared with the ACEI/HCTZ treatment. References: Jamerson K, Weber MA, Bakris GL, et al; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359: Weber MA, Bakris GL, Jamerson K, et al. Cardiovascular events during differing hypertension therapies in patients with diabetes. J Am Coll Cardiol 2010;56:77-85. Weber MA, et al. J Am Coll Cardiol. 2010;56:77.

Major Atherosclerotic Events
SHARP: Major Atherosclerotic Events Animated Slide The Lancet, 377 (9784); , 25 June 2011

Leon’s proteinuria is……….
A predictor for stroke and CHD events A target for therapy to reduce CV events A strong predictor of future progression of his CKD All of the above 1 and 3 1 and 2 Correct answer is 5

Proteinuria as a Predictor of Stroke and CHD Events in Type 2 Diabetes
1.0 40 p<0.001 Incidence (%) 0.9 A CV Mortality 30 B 0.8 0.7 20 C 0.6 10 0.5 In type 2 diabetes, there is a correlation between the extent of proteinuria and the risk of stroke and coronary artery disease. p<0.001 20 40 60 80 Stroke CHD events Months A: U-Prot < 150 mg/l B: U-Prot mg/l C: U-Prot > 500 mg/l Mietinen H, et al. Stroke. 1996;27:

Individualized follow-up and treatment
Identify Patients in Your Practice At High Risk For Chronic Kidney Disease Patients with hypertension Patients with diabetes mellitus Patients with atherosclerotic coronary, cerebral, or peripheral vascular disease Patients with heart failure Patients with unexplained anemia Patients with a family history of end-stage renal disease First Nations peoples eGFR <30 eGFR 30-60 eGFR >60 Consider reversible factors: Individualized follow-up and treatment CKD is diagnosed in this group only if other renal abnormalities are present (i.e. proteinuria, hematuria, anatomical) Medication Volume Depletion Intercurrent illness Obstruction Repeat tests in weeks eGFR <30 eGFR 30-60 Nephrology referral recommended Follow eGFR at 3 months, then serially Assess for persistent significant proteinuria Implement risk reduction eGFR < 30 or progressive decline in eGFR or persistent significant proteinuria or inability to attain treatment targets Stable eGFR and no significant proteinuria Canadian Society of Nephrology - Société Canadienne de Néphrologie -

40 ml/min 144/92 mmHg 104 cm 24 mg/mmol 420 µmol/L 2.4 mmol/L
What we should aim for……. eGFR 40 ml/min Blood Pressure 144/92 mmHg Waist Circumference 104 cm ACR 24 mg/mmol Uric Acid 420 µmol/L LDL 2.4 mmol/L <130/80 <94 Animated Slide <360 <2.0

Interactive Case: Catherine
Module 6 Interactive Case: Catherine

About Catherine European Origin Family history: Social history:
64 years old Family history: Mother: diabetes, amputation age 70 years Father: MI age 69 years Social history: Married with 2 children and 4 grandchildren Non-smoker 30-minute walk 3 times/wk

Catherine’s Medical History
Type 2 diabetes for 5 years and hypertension for 3 years SU added to metformin 3 months ago Mild hypoglycemia 6 times in last 2 months, related to delayed or smaller meal or exercise One severe episode required help from her husband SMBG: fasting ; ac supper 6.4 to 8.9

Catherine’s Medications
Metformin 1,000 mg BID Gliclazide MR 30 mg OD Ramipril 10 mg OD

Catherine’s Exam and Labs
Weight: 75 kg Height: 1.6 m BMI: 29 kg/m2 Waist Circumference: 95 cm Heart Rate: 76 bpm BP: 142/84 mmHg No carotid bruit Pedal pulse palpable Optic fundi normal Laboratory Creatinine: 109 µm/l eGFR: 54 Urine: ACR 20.4 (N < 2.8) FPG: 7.6 A1C: 7.6% Cholesterol: 6.4 HDL-C: 1.1 LDL-C: 4.4 TG: 1.9, TC: HDL-C: 5.8 ECG: normal

How would you determine Catherine’s risk for CVD?
Eyeball based on risk factors Put her in high risk category because all patients with DM are high risk Use a risk-assessment tool (e.g., Framingham) Use CDA Guideline criteria for who is at high risk

Diabetes and High Risk for Cardiovascular Events
The following individuals with diabetes should be considered at high risk for cardiovascular events: Men aged ≥ 45 years, women aged ≥ 50 years [Grade B, Level 2] Men < 45 years and women < 50 years with ≥ 1 of the following [Grade D, Consensus]: macrovascular disease (e.g., MI, peripheral arterial disease, or cerebrovascular disease) microvascular disease (nephropathy and retinopathy) multiple additional risk factors extreme level of single risk (e.g., LDL-C > 5.0 mmol/L, SBP > 180 mmHg) duration of diabetes > 15 years with age > 30 years The Canadian Diabetes Association (CDA) Guidelines recommendations are that all men older than 45 years and women older than 50 years with diabetes be viewed to be at high risk for CV events and have the application of vascular protective measures (specifically, the use of statins, angiotensin-converting enzyme inhibitors [ACEIs]/angiotensin receptor blockers [ARBs] or acetylsalicylic acid [ASA]) considered. For younger patients with diabetes, the presence of CAD, CVD, or peripheral arterial disease (PAD)—whether clinically apparent or subclinical (silent event or detected by imaging)—or the presence of microvascular disease (nephropathy or retinopathy) will place the individual into a high-risk category. Multiple other risk factors, such as smoking, hypertension, hyperlipidemia, extreme levels of one risk factor, or duration of diabetes beyond 15 years will increase the CVD risk to a higher-risk category. The age cut-offs are based upon the findings of the Ontario Diabetes study (Booth et al. Lancet 2006; 368:29-36) and are consistent with the current American Diabetes Association (ADA) recommendations. CDA Guidelines 2008.

Vascular Protection in the Patient with Diabetes
For patients at high risk of a CV event ACE inhibitor or ARB therapy (independent of BP) Lipid-lowering therapy (primarily statins) Antiplatelet therapy (as recommended) For all patients with diabetes: Lifestyle modification achievement and maintenance of healthy body weight healthy diet regular physical activity smoking cessation 2. Optimize blood pressure control 3. Optimize glycemic control The Canadian Diabetes Association (CDA) Guidelines recommendations are that all men older than 45 years and women older than 50 years with diabetes be viewed to be at high risk for CV events and have the application of vascular protective measures (specifically, the use of statins, angiotensin-converting enzyme inhibitors [ACEIs]/angiotensin receptor blockers [ARBs] or acetylsalicylic acid [ASA]) considered. For younger patients with diabetes, the presence of CAD, CVD, or peripheral arterial disease (PAD)—whether clinically apparent or subclinical (silent event or detected by imaging)—or the presence of microvascular disease (nephropathy or retinopathy) will place the individual into a high-risk category. Multiple other risk factors, such as smoking, hypertension, hyperlipidemia, extreme levels of one risk factor, or duration of diabetes beyond 15 years will increase the CVD risk to a higher-risk category. The age cut-offs are based upon the findings of the Ontario Diabetes study (Booth et al. Lancet 2006; 368:29-36) and are consistent with the current American Diabetes Association (ADA) recommendations. CDA Guidelines 2008.

What is your target A1C for Catherine?
≤ 6.5% ≤ 7.0% ≤ 7.5% ≤ 8.0%

2008 CDA Guidelines1: Recommended Glycemic Targets
A1C (%)* FPG or preprandial PG (mmol/L) 2-hour postprandial PG (mmol/L) Type 1 and type 2 diabetes ≤ 7.0 4.0 – 7.0 5.0 – 10.0 (5.0 – 8.0 if A1C targets not being met) * Treatment goals and strategies must be tailored to the individual with diabetes, with consideration given to individual risk factors. Attain A1C target within 6 to 12 months. In 2008, the Canadian Diabetes Association (CDA) published its updated, evidence-based Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. The guidelines include recommended targets for glycemic control: an A1C of 7% or lower; fasting and preprandial plasma glucose between 4 and 7 mmol/L and a 2-hour postprandial plasma glucose (PPG) between 5 and 10 mmol/L. If, however, the A1C target is not being met, the recommended 2-hour PPG target is between 5 and 8 mmol/L. These guidelines also emphasized the importance of individualized glycemic targets taking into account the risk:benefit of improved glycemic control. Evidence from the Diabetes in Canada Evaluation (DICE) study, or the more recent DRIVE trial, has shown that approximately half of all Canadians with type 2 diabetes do not achieve their A1C goals. References: CDA Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2008; 32(suppl 1):S1-S201. Harris SB, Ekoé JM, Zdanowicz Y, et al. Glycemic control and morbidity in the Canadian primary care setting (results of the Diabetes in Canada Evaluation study). Diabetes Res Clin Pract 2005; 70(1):90-7. 3. Braga M, Casanova A, Dawson K, et al. Diabetes management in Canada: evidence of an ongoing care gap. Presented at the American Diabetes Association 68th Scientific Sessions 2008, San Francisco. Evidence shows that approximately half of Canadian patients do not achieve their A1C targets (DICE2 and DRIVE3 studies) CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes 2008; 32(suppl 1):S1-S201. Harris SB, et al. Diabetes Res Clin Pract 2005; 70(1):90-7. Braga M, et al. Presented at the American Diabetes Association 68th Scientific Sessions 2008, San Francisco.

Determining Glycemic Targets
Ismail-Beigi F, et al. Ann Inttern Med. 2011;154:

Catherine is having episodes of hypoglycemia
Catherine is having episodes of hypoglycemia. These episodes can be associated with which of the following? Higher mortality rate Higher rate of microvascular complications Higher rate of cardiovascular complications All of the above 1 and 3 Correct Answer is 4

Severe Hypoglycemia Significantly Increases the Risk for Adverse Outcomes in Patients With T2DM
Hazard ratios represent the risk of an adverse cardiovascular outcome or death among patients reporting severe hypoglycemia (<2.8 mmol/L)* as compared with those not reporting severe hypoglycemia Clinical Outcome and Interval After Hypoglycemia Hazard Ratio (95% CI)† Microvascular events 2.07 ( )‡ Macrovascular events 3.45 ( )‡ Death from any cause 3.30 ( )‡ Death from non-CV cause 2.86 ( )‡ Death from CV cause 3.78 ( )‡ Severe Hypoglycemia Significantly Increases the Risk for Adverse Outcomes in Patients With T2DM Key message: Severe hypoglycemia was associated with significant risk for microvascular events, macrovascular events, death from any cause, death from cardiovascular cause, and death from noncardiovascular cause. This study evaluated the association between severe hypoglycemia and risk for diabetes-related complications in patients with T2DM (N=11,140). Methods: Patients were recruited from 215 centers in 20 countries and were included if they had a diagnosis received after the age of 30 years with a history of microvascular or macrovascular disease or at least one other cardiovascular risk factor. Glucose control was not part of entry criteria, but patients were excluded if they had a clear indication for long-term insulin use at entry. Patients were randomized to receive blood-pressure lowering medication or placebo and either standard or intensive glucose control with extended-release gliclazide or a standard guideline-based treatment strategy. Severe hypoglycemia was defined as blood glucose <50 mg/dL and transient dysfunction of the central nervous system where patients were unable to treat themselves and required help from another person. Results: Various clinical outcomes and death were followed after the hypoglycemic event and compared with patients who did not have a hypoglycemic event. Severe hypoglycemia was associated with a significant increase (P<.01) for all comparisons, even after adjusting for treatment assignment and multiple covariates listed above. Reference Zoungas S, Patel A, Chalmers J, et al; ADVANCE Collaborative Group. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010;363(15): *Severe hypoglycemia blood glucose <2.8 mmol per liter with transient dysfunction of the CNS, without other apparent cause, during which the patient was unable to administer treatment (requiring help from another person). †Adjusted for multiple covariates: sex, duration of diabetes, treatment assignment, presence or absence of a history of macrovascular disease, presence or absence of a history of microvascular disease, and smoking status at baseline. Time-dependent covariates during follow-up included age; level of glycated hemoglobin; body-mass index; creatinine level; ratio of urinary albumin to creatinine; systolic blood pressure; use or non-use of sulfonylurea, metformin, thiazolidinedione, insulin, or any other diabetes drug; and use or non-use of antihypertensive agents. ‡p< CI=confidence interval. Zoungas S.N, Engl J Med. 2010;363(15):

ACCORD: Mortality by Study Group and Hypoglycemia Occurrence
HR for mortality higher in those with hypoglycemia, regardless of treatment group STD (n = 175 w/events) INT (n = 528 w/events) HR INT vs. STD (95% CI) No severe hypoglycemia 1.0%/year 180 deaths 17,516 PYs 1.3%/year 220 deaths 17,031 PYs 1.25 ( ) At least one severe hypoglycemia event 4.9%/year 17 deaths 345 PYs 2.8%/year 34 deaths 1,208 PYs 0.55 ( ) HR (hypoglycemia vs. no hypoglycemia) (95% CI) 2.87 ( ) 1.28 ( ) In those with hypoglycemia, mortality rate lower in INT than STD group In the ACCORD study, symptomatic, severe hypoglycemia was associated with an increased risk of death within each study arm. The annual mortality rate among participants who had never experienced an HMA was higher among participants in the intensive arm than in those in the standard arm (1.3% per year vs. 1.0% per year; HR 1.25, 95% CI 1.03 to 1.52). When mortality among participants who had experienced an HMA event was compared, however, the annual mortality rate was lower in the intensive arm than in the standard arm (2.8% per year vs. 4.9% per year; HR 0.55, 95% CI 0.31 to 0.99), indicating a lower relative risk of death among those in the intensive arm who had experienced hypoglycemia than in those in the standard arm who had experienced hypoglycemia. PY = person-year. Adapted from: Bonds DE, et al. BMJ. 2010;340:b4909.

Risk Factors for Hypoglycemia
Older age Long duration of diabetes treatment Chronic Kidney Disease Prior episode of severe hypoglycemia Other glucose-lowering medications Glycemic control – inverse? or correlated? Hypoglycemia unawareness, especially during sleep Delayed, smaller, or missed meal Alcohol Recent moderate or intensive exercise Risk Factors for Hypoglycemia Key message: Multiple risk factors can lead to hypoglycemia in patients with diabetes. Age, long duration of diabetes treatment can be considered “non-modifiable”. Other risk factors can be modified through adjustments in treatment, targets, education and behavior References 1. CDA. Can J Diabetes 2008; 32:S29–S31. 2. Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 2005;28(5): 3. Frier BM. How hypoglycemia can affect the life of a person with diabetes. Diabetes Metab Res Rev. 2008;24(2):87-92. 4. Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes. 2008;57(12): 5. Murad H, Coto-Yglesias F, Wang A et al., Drug-Induced Hypoglycemia: A Systematic Review. J Clin Endocrinol Metab. 2009;94(3): 1. CDA. Can J Diabetes. 2008;32:S29–S31; 2. Workgroup on Hypoglycemia, American Diabetes Association, Diabetes Care. 2005;28(5): ; 3. Frier BM, Diabetes Metab Res Rev. 2008;24(2):87-92; 4. Cryer PE, Diabetes. 2008;57(12):

Pathophysiologic Cardiovascular Consequences of Hypoglycemia
CRP VEGF IL-6 Inflammation Neutrophil activation Blood coagulation abnormalities Endothelial dysfunction Hypoglycemia Platelet activation Vasodilation Sympathoadrenal response Pathophysiologic Cardiovascular Consequences of Hypoglycemia Key message: Hypoglycemia causes physiologic abnormalities that may increase the risk for cardiovascular events in patients with diabetes. Hypoglycemia may affect cardiovascular events through increased inflammation, endothelial dysfunction, abnormal sympathoadrenal responses, and blood coagulation abnormalities. Inflammatory responses trigger the release of multiple inflammatory markers (C-reactive protein, vascular endothelial growth factor, and interleukin-6) and increase the overall levels of inflammatory cytokines that can lead to endothelial injuries and abnormalities in coagulation. The activation of the fibrinolytic system and increased epinephrine levels can also lead to blood coagulation abnormalities through increased neutrophil activation, platelet activation, and increased factor VII. The sympathoadrenal response leads to increased catecholamine release, which increases myocardial contractility, workload, and cardiac output. Endothelial dysfunction can lead to decreased vasodilation and can place an even greater strain on the cardiovascular system and perpetuate the inability to meet oxygen demands. Reference Desouza CV, Bolli GB, Fonseca V. Hypoglycemia, diabetes, and cardiovascular events. Diabetes Care. 2010;33(6): Factor VII Hemodynamic changes Rhythm abnormalities  Adrenaline  Oxygen consumption  Contractility  Heart workload Heart rate variability CRP=C-reactive protein; IL-6=interleukin 6; VEGF=vascular endothelial growth factor. Desouza CV, et al. Diabetes Care. 2010;33(6):

Catherine’s A1C is 7.6% with metformin 1,000 mg bid and gliclazide MR 30 mg od. She is reporting episodes of hypoglycemia. Her eGFR is 54. How would you manage her antihyperglycemic agents? Reduce dose of metformin and increase dose of gliclazide Reduce dose of metformin, stop gliclazide, and add another agent Continue metformin and increase dose of gliclazide Continue metformin, stop gliclazide, and add another agent Continue metformin and gliclazide and add another agent Add basal insulin and consider stopping gliclazide Other

You Decide on Option 4: Continue Metformin, Stop Gliclazide, and Add Another Agent This New Agent Would Be? An alpha-glucosidase inhibitor A DPP-4 inhibitor A GLP-1R agonist A meglitinide A thiazolidinedione

Second-Line Agents in CDA 2008 Guidelines
Add an agent best suited to the individual based on its advantages/disadvantages Class A1C Hypoglycemia Other advantages Other disadvantages Alpha-glucosidase inhibitor Rare Improved postprandial control Weight neutral GI side effects Incretin agent: DPP-4 inhibitor GLP-1R agonist* to to Improved postprandial control Weight neutral Improved postprandial control Weight loss New agent (unknown long-term safety) Injectable, nausea and vomiting, new agent Insulin Yes No dose ceiling Many types, flexible regimens Weight gain Insulin secretagogue: Meglitinide Sulfonylurea to Yes** Improved postprandial control Newer sulfonylureas (gliclazide, glimeripide) are associated with less hypoglycemia than glyburide Requires TID to QID dosing TZD Durable monotherapy Requires 6-12 weeks for maximal effect Edema, rare CHF, rare fractures in female Rosi: may CV risk Pio: may bladder Ca risk Weight-loss agent None Weight loss GI side effects (orlistat) ↓ = <1.0% decrease in A1C; ↓↓ = 1.0 – 2.0% decrease in A1C; ↓↓↓ = >2.0% decrease in A1C *GLP-1R agonists were not available when 2008 CDA Guidelines were published. **Less hypoglycemia in the context of missed meals. Adapted from 2008 CDA Clinical Practice Guidelines, Canadian Journal of Diabetes. 2008;32(Suppl 1):S1-S201.

What is the Ideal First Add-on to Metformin
What is the Ideal First Add-on to Metformin? Network Meta-analysis Comparing Non-Insulin Antihyperglycemic Drugs With PBO as Add-on to Metformin Change in A1C Goal Change in Overall A1C (%) Achieved Body Weight (kg) Hypoglycemia Mean Diff. RR PBO (Ref) 1 Sulfonylureas -0.79 2.49 2.06 4.57 Meglitinides -0.65 2.25 1.77 7.50 TZDs -0.85 2.71 2.08 0.56 AGIs -0.64 ND -1.80 0.42 DPP-4 inhibitors -0.78 2.51 -0.14 0.63 GLP-1R agonists -0.97 3.20 -1.74 0.89 Phung OJ, et al. JAMA. 2010;303: Published online April 14, 2010.

Efficacy of Add-on Therapy to Metformin + SU:
Clinical Trials of Incretin Agents Indicated as Add-on to Metformin + SU Nauck M, et al. Diabetes Care. 2009;32:84-90. Kendall D, et al. Diabetes Care. 2005;28: Hermansen K, et al. Diabetes, Obesity & Metabolism. 2007;9: Owens DR, et al. Diabetic Medicine 2011.

Catherine has an LDL-C of 4.4 mmol/L. How would you manage this?
Start atorvastatin 10 mg or 20 mg and titrate as necessary Start atorvastatin 40 mg and titrate as necessary Start atorvastatin 80 mg Start rosuvastatin 10 mg and titrate as necessary Start rosuvastatin 20 mg and titrate as necessary Start rosuvastatin 40 mg Start a statin with ezetimibe Other

Canadian Cardiovascular Society Guidelines on Dyslipidemia 2009
Risk categories and treatment recommendations Genest J et al. Can. J Cardiol 2009; 25:

Would you treat Catherine with low-dose ASA?
Yes No

Aspirin for Primary Prevention of CV Events in
People with Diabetes: Meta-analysis of 6 Randomized Trials (N=10,117) Major CV events: OR = 0.90 ( ) Myocardial infarction: OR = 0.86 ( ) Stroke: OR = 0.83 ( ) CV Death: OR = 0.94 ( ) All cause Mortality: OR = 0.93 ( ) De Berardis G, et al. BMJ. 2009;339:b4531.

Antiplatelet Recommendations For Primary Prevention in Diabetes
CDA 2008: The decision to prescribe antiplatelet therapy for primary prevention of CV events should be based on individual clinical judgement [Grade D, Consensus] CCS 2011: For patients with diabetes aged >40 years and at low risk for major bleeding, low-dose ASA ( mg daily) may be considered for primary prevention in patients with other CV risk factors for which its benefits are established [Class IIb, Level B] CDA Guidelines 2008. CCS Guidelines Can J Cardiol. 27:S1-S59.

Catherine has a BP of 142/84 while treated with ramipril 10 mg od
Catherine has a BP of 142/84 while treated with ramipril 10 mg od. How would you manage her BP? Add a thiazide-like diuretic Change to an FDC of an ACEi-diuretic Add a CCB Change to an ARB plus a thiazide-like diuretic Change to an FDC of an ARB-CCB Add an ARB Add a DRI Other

CHEP 2012: Treatment of Hypertension in Association with Diabetes Mellitus Summary
Threshold equal to or over 130/80 mmHg and TARGET below 130/80 mmHg A 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. Combining an ACEi and a DHP-CCB is recommended. with Nephropathy ACE inhibitor or ARB Diabetes 1. ACE inhibitor or ARB or 2. DHP-CCB or thiazide diuretic without Nephropathy > 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 for diabetic patients 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

ACCOMPLISH: Kaplan-Meier for Time to First Primary Composite Endpoint
CV Death, MI, Stroke, Hospitalized Angina, Cardiac Arrest, Coronary Revascularization N= 11,506 ; high-risk HTN BP  0.9/1.1 ACE/CCB vs. ACE/HCTZ ACEI / HCTZ ACEI / CCB 20% Risk Reduction Cumulative event rate HR: 0.80 ( ) P < 60% had diabetes (n=6,946) BP  1.2/1.1 ACE/CCB (131.5/72.6) vs ACE/HCTZ (132.7/73.7 HR: 0.79 ( ); p=0.003 1st CV morbidity/mortality (days) Jamerson K, et al. N Engl J Med. 2008; 359: Weber M, et al. JACC. 2010;56:77-85.

2012 CHEP Recommendations Regarding Drug Combinations
When combining drugs, use first-line therapies. Two drug combinations of beta blockers, ACE inhibitors and angiotensin receptor blockers have not been proven to have additive hypotensive effects. Therefore these potential two drug combinations should not be used unless there is a compelling (non blood pressure lowering) indication Combinations of an ACEI with an ARB do not reduce cardiovascular events more than the ACEI alone and have more adverse effects therefore are not generally recommended Caution should be exercised in combining a non dihydropyridine CCB and a beta blocker to reduce the risk of bradycardia or heart block. Monitor serum creatinine and potassium when combining K sparing diuretics, ACE inhibitors and/or angiotensin receptor blockers. If a diuretic is not used as first or second line therapy, triple dose therapy should include a diuretic, when not contraindicated. CHEP specifically recommends not to use the combination of an ACEI with an ARB in patients with hypertension without compelling indications, coronary artery disease who do not have heart failure, prior stroke, non proteinuric chronic kidney disease or diabetes mellitus without micro albuminuria.

2012 CHEP Recommendations Regarding Drug Combinations
Diabetes and Hypertension: Combination therapy using two first-line agents may also be considered as initial treatment of hypertension 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). 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 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). 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 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).

Take-Home Points Assess CV risk using CDA Guideline criteria for “high risk” Glycemic control significantly reduces the risk of diabetes complications, particularly microvascular complications Given the “legacy” benefits of early glycemic control, intervention to achieve and maintain glycemic targets is critical for the long-term prevention of diabetes complications A history of severe hypoglycemia is a predictor of poor outcomes Glycemic targets must be achieved safely while striving to minimize hypoglycemia In order to minimize CV risk, treat all CV risk factors according to guidelines for multifactorial vascular protection

Take-Home Points Patient education, which is essential for successful patient self-management, should be provided by a multidisciplinary diabetes care team “Clinical inertia” can be minimized by expanding roles of other healthcare providers

Take-Home Points The incretin agents are efficacious in monotherapy and in combination with other antihyperglycemic agents" Add a second bullet " Compared to other classes of antihyperglycemic agents the incretin agents offer the potential advantage of beneficial/neutral effects on body weight and a lack of hypoglycemia. The incretin agents vary in route of administration, effect on body weight, contraindications, and pharmacology, including dosing adjustments for patients with renal impairment

Take-Home Points When deciding which second agent to add, evaluate the pros and cons of each (including contraindications, glycemic durability, effect on body weight, side effects, patient and physician comfort), as well as: What is the degree of hyperglycemia? Is the patient at risk for hypoglycemia? Does the patient have a drug plan? Chronic kidney disease is common in diabetes and must also be considered in the selection of an appropriate antihyperglycemic agent In summary, consideration of these three main questions and the other factors listed here provide the basis for decision-making in adding a second antihyperglycemic agent in patients whose A1C is not adequately controlled with lifestyle changes and metformin therapy.

Take-Home Points Identification of CKD in diabetes requires screening for proteinuria, as well as an assessment of renal function (eGFR) All individuals with CKD should be considered at high risk for cardiovascular events and should receive treatments to reduce these risks The progression of renal damage in diabetes can be slowed through good glycemic control, good blood pressure control, and the use of medications that disrupt the renin- angiotensin-aldosterone system

Benefits of Mainpro-C You should have received your full Mainpro-C package from the CHRC, but in the meantime take a few moments to… Identify at least one thing you would like to change or verify about your practice Identify one question for which you still require an answer or clarification NOTE: If you choose not to complete the reflective exercise, you may claim Mainpro-M1 credits for your participation in this program (but may not claim Mainpro-C credits).

Questions… Contact the CHRC: Phone: 416-977-8010
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