Special Diabetes Program for Indians: Competitive Grant Program Treatment of Cardiovascular Risks in Patients with Diabetes: Reaching Goals

Objectives: Review the pharmacologic treatment of hyperglycemia, hypertension and high cholesterol in patients with type 2 diabetes. Appreciate the benefits of good control on risk factors for cardiovascular outcomes.

Modifiable CHD Risk Factors High blood pressure Dyslipidemia Elevated total cholesterol and LDL-C Elevated triglycerides Low HDL-C Tobacco smoke Obesity Physical inactivity Diabetes mellitus

CVD Risk Reduction Hyperglycemia Hypertension Control Lipid Control Daily Aspirin Lifestyle Changes Weight loss, healthy foods, Increased activity Smoking Cessation

A1c < 7% Medications Healthy Food Choices Increased Physical Activity HYPERGLYCEMIA

Impact on Complication with Glucose Control Macrovascular Microvascular Other factors must be targeted Statton IM et al. BMJ 2000; 321:

ADA and ACE Glycemic Goals American Diabetes Association. Diabetes Care. 2004;26:S33-S50. American College of Endocrinology Consensus Statement on Guidelines for Glycemic Control  6.5 < 7.0< 6.0HgbA 1c (%) TargetGoalNormalBiochemical Index ACEADA  ADA Updated recommendations: "more stringent goals (i.e., a normal A1C, <6%) can be considered in individual patients"

2004 AI/AN Diabetic Patients with HbA1c < 7% IHS Standards of Care Audit Data 2004 IHS 2003 Average 34%

Minneapolis, International Diabetes Center, Can the Course of Type 2 Diabetes Be Altered? Glucose (mg/dL) Relative Function (%) Years of Diabetes Uncontrolled Hyperglycemia 50 – 100 – 150 – 200 – 250 – 300 – 350 – 0 – 50 – 100 – 150 – 200 – 250 – Fasting Glucose Post-meal Glucose ObesityIFG*Diabetes Insulin Resistance  -cell Failure

Type 2 Diabetes: Who Is Your Typical Patient? Patients typically present with: –A 1c ? _____________ –Approximately _______ % reduction in beta-cell function? –Degree of Insulin Resistance? ________ –Complications?_____________ –Other conditions?_____________

Hyperglycemia *Primary site(s) of action. DeFronzo RA. Ann Intern Med. 1999;131(4): Inzucchi SE. JAMA. 2002;287(3): Pancreas Sulfonylureas Repaglinide Nateglinide Liver Metformin* Rosiglitazone Pioglitazone Adipose Tissue Rosiglitazone* Pioglitazone* Gut Acarbose Miglitol Muscle Rosiglitazone* Pioglitazone* Metformin Oral Therapy for Type 2 Diabetes: Sites of Action

Choosing An Oral Agent 1.What is the current degree of control? 2.How long has the patient been diagnosed? 3.Is the patient overweight? 4. Does the patient have dyslipidemia?

Choosing An Oral Agent 5.What is the kidney and liver function like? 6.Does the patient have known heart disease? 7.How does the patient feel about taking meds?

BLDHSB Meals NPH/Lantus Insulin Effect ADDING INSULIN Bedtime intermediate or long acting insulin plus oral agent(s)

premixed 70/30 premixed 70/30 BLDHSB Meals Insulin Effect Rapid-acting mixture (NPH/R or lispro) before dinner plus oral agent(s)

Combination Therapy With Insulin 1 injection a day Convenience (usually given at night) Slow, safe, and simple titration Low dosage compared to a full insulin regimen Limited weight gain Effective improvement in glycemic control by suppressing hepatic glucose production

BP< 130/80 Medications Healthy Food Choices Increased Physical Activity HYPERTENSION

Goals for Control ADA:Target Blood Pressure is < 130/80 IHS: Target Blood Pressure is  130/80 Additional protection against complications, including renal failure, may be obtained by lowering BP further to 125/75

2004 AI/AN Diabetic Patients with BP < 130/80 IHS Standards of Care Audit Data 2004 IHS 2003 Average 34%

Average Number of Antihypertensive Agents Needed Per Diabetic Patient to Achieve Target BP UKPDSDBP<85 ABCDDBP<75 VDRDMAP<92 HOTDBP<80 AASKMAP<92 Number of Antihypertensive Agents Trail Target BP mm Hg

JNC-7 Algorithm for the treatment of hypertension in patients with diabetes Lifestyle Modifications: Weight reduction, diet high in fruits & vegetables, low fat dairy produces, and decreased total and saturated fats; Na+ restriction to 2gr/day; regular aerobic exercise; and moderation of alcohol intake Drug Monotherapy: Consider ACE or ARB as first line Compelling indications for individual classes: ACEs, ARBs, thiazides,  -blockers, CCBs Optimize dosing or add additional agents until BP goal achieved NOT AT BP GOAL < 130/80

ACE & ARBS Limits nephropathy and Lower CVD risk Thiazide  -Blocker*  Blocker Ca++CB Step-wise progression to controlling Blood pressure

Thiazide Diuretics ALLHATT Study Excellent second agent in patient’s with diabetes Start at 12.5 mg/day and increase to 25 mg/day if needed No benefit of a higher dose

ß-blockers Used in patients with known cardiovascular disease Risk of masking hypoglycemia Side effect can be limiting factor, taper down slowly if needed

Calcium Channel Blocker May add reno-protective benefit Syst-Euro study, HOT study showed a reduction in cardiovascular events in hypertensive diabetic patients Offers elderly patients with isolated systolic hypertension good protection against cardiovascular events

SUMMARY Treatment of Hypertension in Diabetes Blood pressure goal in diabetes < 130/80 –Level of blood pressure more important that type of therapy –Reduces rates of both micro and macrovascular disease ACE/ARB based therapies: 1 st Line Choice –Reduces CVD complication and offers reno- protection Multi-drug therapy often needed Aggressive treat essential, if CVD present ideal goal is lower: 125/75 Arch Intern Med, Vol 160, Sep 11, 2000,

LDL < 100 TR < 150 HDL: Men >45 Women > 55 Medications Healthy Food Choices Increased Physical Activity HYPERLIPIDEMA

Treatment Decisions Based on LDL Cholesterol Levels in Adults With Diabetes Diabetes Care, Volume 28, Supplement 1, January 2005 *

Goals for Control LDL < 100 mg/dL, 70 mg/dL for patients at high risk HDL**: Men > 45 mg/dL HDL**: Women > 55 mg/dL Triglycerides < 150 mg/dL **There is no clear consensus on the use of drug therapy to raise HDL

Considerations in Therapy Diet and exercise are key Hyperglycemia itself will lead to increased TG: try to improve sugars first Metformin will decrease LDL Glitazones will decrease TG, increase HDL Check TFTs in initial work-up Metamucil, increased dietary fiber

Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults: 1. LDL cholesterol lowering - Lifestyle interventions - HMG CoA reductase inhibitor (statin) - Cholesterol absorption inhibitior (ezetimibe) - Bile acid binding resin or fenofibrate 2. HDL cholesterol raising - Lifestyle interventions (weight loss, physical activity, smoking cessation) - Nicotinic acid or fibrates Adapted from ADA. Diabetes Care 2004;27(suppl 1):S68

3.Triglyceride lowering - Lifestyle interventions - Glycemic control - Fibric acid derivative (gemfibrozil, fenofibrate) - Niacin - High-dose statin therapy (in those who have high LDL-C) 4. Combined hyperlipidemia - First choice: Improved glycemic control plus high dose statin - Second choice:Improved glycemic control plus statin plus fibrate - Third choice: Improved glycemic control plus statin plus nicotinic acid Adapted from ADA. Diabetes Care 2004;27(suppl 1):S68

Testing Lipid panel annually, more often is medication adjustments are made Consider direct LDL if TG >250 mg/dL or if specimen is non-fasting All diabetic patients with LDL > 100 mg/dL need medical, dietary and lifestyle intervention

First Line Therapy: Statins Effect in lowering LDL Marginal benefit on HDL and TG Generally well tolerated, mild GI side effects May potentiate effect of oral anticoagulation In high doses with other meds, may cause myalgia

Fibrates Best for lowering TG May increase LDL is TG very high May increase incidence of choleilithiasis Generally well tolerated with some GI side effects May potentiate the effects of oral anticogaulants

2004 AI/AN Diabetic Patients LDL Tested LDL < 100 IHS Standards of Care Audit Data 2004 IHS 2003 Average 35%

Procoagulant State in Patients with Diabetes Platelets are overly sensitive to platelet aggregating agents High levels of Thromboxane, a potent vasoconstrictor Decreased fibrinolytic activity Increased levels of Plasminogen Activitor Inhibitor-1 Clot lysis cannot precede normally

Aspirin Therapy in Diabetes “Aspirin - the poor man’s statin” Reduces risk of MI by ~ 15-60% Treat all high risk patients with diabetes over the age of 35 Use 162 – 325 mg/day The Lancet IHS Standards of Care for Patients with Type 2 Diabetes

2004 AI/AN Diabetic Patients prescribed Aspirin IHS Standards of Care Audit Data 2004 IHS 2003 Average 65%

Smoking Cessation Smoking doubles the risk of CVD in patients with diabetes Attenuates the benefit of gained from modifying other risks MRFIT: independent and  ing risk of CVD based on the # cigarettes/day

Putting It All Together Updating the Approach to Treatment to Improve Cardiovascular Risks

The Traditional Treatment: “Treatment to Failure Approach” Treatment is initiated with a trial of diet and exercise If glycemic control not achieved, start mono-therapy Maximize therapy If glycemic control not achieved, start 2 nd agent: repeat pattern Little if no attention paid to cardiovascular risk

Updated Approach to Treatment Goal: to help patients achieve earlier and better control Initiation of medical nutritional therapy, increased activity, diabetes self-management Evaluate other cardiovascular risk factors: hypertension, cholesterol, smoking, aspirin use.

Updated Approach to Glycemic Treatment Early initiation on monotherapy Rapid progression to combination therapy when glycemic control not attained or maintained Therapy directed at multiple defects Self glucose monitoring and frequent HgbA1c checks (Q 3 months) while gaining control

Putting It All Together: Address other aspects of CVD risk at each visit Multiple approaches to treatment GOAL: pushes the plan forward quickly and consistantly

How Can We Help Improve Cardiovascular Outcomes? 1.Improve patient’s awareness of risks 2.Address emotional barriers 3.Empower the patient through education, motivation, and self advocacy

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