Management of the Patient with Type 2 Diabetes

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Management of the Patient with Type 2 Diabetes. Gretchen M. Ray, Pharm.D. Cardiovascular Pharmacotherapy Resident University of New Mexico College of Pharmacy. Objectives. Provide diabetes screening criteria for adults
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Management of the Patient with Type 2 Diabetes Gretchen M. Ray, Pharm.D. Cardiovascular Pharmacotherapy Resident University of New Mexico College of Pharmacy Objectives
  • Provide diabetes screening criteria for adults
  • Describe available pharmacologic treatment options for type 2 diabetes including advantages/disadvantages of therapy and contraindications
  • Given a patient case recommend appropriate lifestyle modifications and pharmacotherapy to achieve glycemic goals
  • Objectives
  • Distinguish between microvascular and macrovascular complications
  • Provide screening criteria for nephropathy, neuropathy, and retinopathy
  • Provide treatment strategies for the prevention and treatment of micro and macrovascular complications
  • Epidemiology of Type 2 DM
  • In 2005 20.8 million people (7% of the US population) had diabetes
  • 14.6 million diagnosed
  • 6.2 million undiagnosed
  • Type 2 diabetes accounts for 90-95% of patients with diabetes
  • In 2002 total indirect and direct medical costs for diabetes = $132 billion
  • CDC. National diabetes fact sheet. 2005 available at www.cdc.gov/diabetes/pubs/pdf/ndfs_2005.pdf Risk factors for type 2 diabetes
  • Physically inactive
  • 1st degree relative with diabetes
  • Minority ethnic groups
  • Gestational diabetes or delivering a baby >9 lbs
  • Hypertension
  • HDL <35 mg/dL and/or triglycerides >250 mg/dL
  • Polycystic ovary syndrome
  • Previous impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)
  • History of vascular disease
  • Psychiatric illness
  • Diagnosis of diabetes
  • Symptoms of diabetes + casual plasma glucose ≥ 200 mg/dl
  • FPG ≥ 126 mg/dl
  • Oral glucose tolerance test (OGTT): 2-h postload glucose ≥ 200 mg/dl
  • OR OR Definition of “pre-diabetes”
  • Impaired fasting glucose (IFG) = FPG 100-125 mg/dl
  • Impaired glucose tolerance (IGT) = 2-h post load glucose 140-199 mg/dl
  • IFG and IGT indicate a risk factor for diabetes and cardiovascular disease
  • Diabetes Screening
  • Screening identifies asymptomatic patients who might have diabetes
  • Consider in patients ≥ 45 years especially if their BMI ≥ 25 kg/m2
  • Screen patients < 45 years old if they are overweight + an additional risk factor
  • FPG should be done initially
  • Repeat screening every 3 years
  • Oral Therapies Metformin
  •  hepatic glucose production,  intestinal glucose absorption,  insulin sensitivity
  • Efficacy:  A1C 1.5%
  • Adverse effects
  • Primarily GI (up to 50%)
  • Diarrhea, abdominal bloating, nausea
  • Titrate dose at weekly intervals to minimize AEs
  • Give with meals
  • Lactic acidosis- rare
  • Monitor SCr
  • Contraindications to Metformin
  • Renal impairment SCr >1.5 for men, >1.4 for women
  • Radiocontrast studies
  • Age >80 unless normal GFR
  • Hypoxia
  • Liver dysfunction
  • Alcoholism
  • Heart Failure requiring pharmacologic therapy
  • According to package insert
  • Should heart failure be a contraindication to metformin?
  • Improved Clinical Outcomes Associated with Metformin in Patients with Diabetes and Heart Failure
  • Investigate the association between metformin and clinical outcomes in patients with HF and diabetes
  • Retrospective study
  • Primary outcome: all-cause mortality at 1 year and end of follow-up
  • Secondary outcome: all-cause hospitalizations at 1 year and end of follow-up
  • Eurich DT, et al. Diabetes Care. 2005;28:2345-51 Improved Clinical Outcomes Associated with Metformin in Patients with Diabetes and Heart Failure Eurich DT, et al. Diabetes Care. 2005;28:2345-51 Improved Clinical Outcomes Associated with Metformin in Patients with Diabetes and Heart Failure
  • Lower all-cause mortality with metformin
  • No increase in hospitalizations associated with metformin
  • Observational study
  • Cannot prove that metformin is efficacious in this population
  • Eurich DT, et al. Diabetes Care. 2005;28:2345-51 Sulfonylureas Patients with Diabetes and Heart Failure
  • ↑ insulin secretion from pancreatic β-cells
  • Efficacy: ↓ A1C 1.5%
  • Glyburide
  • Not recommended if CrCl < 50 ml/min (use a different sulfonylurea)
  • Glipizide
  • Not recommended if CrCl < 10 ml/min
  • Glimepiride
  • Not recommended if CrCl < 22 ml/min
  • Response of sulfonylureas plateaus after half the max dose
  • Reduced GI absorption if blood glucose > 250 mg/dL
  • Sulfonylureas Adverse Effects Patients with Diabetes and Heart Failure
  • Hypoglycemia
  • Elderly patients
  • Hepatic/renal impairment
  • Combination therapy
  • Weight gain
  • Thiazolidenediones (TZDs) Insulin Sensitizers Patients with Diabetes and Heart Failure
  • TZDs are PPAR- gamma receptor activators
  • ↑ insulin sensitivity
  • Primarily in the peripheral tissue
  • Efficacy:  A1C 0.5-1.4%
  • Effect may not be seen for 4 weeks
  • Rosiglitazone (Avandia®)
  • Initial dose 4 mg/day, Max dose 8 mg/day
  • Pioglitazone (Actos®)
  • Initial dose 15-30 mg/day, Max dose 45 mg/day
  • AE’s Patients with Diabetes and Heart Failure Fluid retention and peripheral edema Weight gain Fluid retention is a major contributor Redistribution of adipose tissue New-onset heart failure < 1% 2-3% when combined with insulin CI’s ALT > 2.5 x upper limit of normal Hepatic disease Alcohol Abuse HF NYHA class III or IV (see following slides) Adverse Effects/Contraindications of TZDs Granberry MC, et al. Am J Health-Syst Pharm. 2007;64:931-6 TZD Use In Heart Failure Patients with Diabetes and Heart Failure
  • Use of TZDs in patients with NYHA class I or II HF
  • May be used with initiation of treatment at the lowest dosage (rosiglitazone 2 mg daily or pioglitazone 15 mg daily)
  • Observe for weight gain, edema, or exacerbation of HF
  • Do not use TZDs in patients with NYHA class III or IV HF
  • Nesto RW, et al. Diabetes Care. 2004;27:256-63 Meta-analysis of MI Risk With Rosiglitazone Patients with Diabetes and Heart Failure
  • 42 trials comparing rosiglitazone with placebo
  • 15,560 patients received rosiglitazone
  • 12,283 patients assigned to comparator groups
  • 24-52 week duration of trials
  • Mean baseline A1C 8.2% for both groups
  • Nissen SE, et al. N Engl J Med. 2007;356:1-15 Meta-analysis of MI Risk With Rosiglitazone Patients with Diabetes and Heart Failure Nissen SE, et al. N Engl J Med. 2007;356:1-15 PROactive Trial Patients with Diabetes and Heart Failure
  • Primary objective: Determine if pioglitazone reduces CV morbidity and mortality in patients with diabetes
  • Pioglitazone vs. placebo
  • ↓ Triglycerides 11% vs. 1.8% ↑
  • ↑ LDL 7.2% vs. 4.9%
  • ↓ LDL/HDL 9.5% vs. 4.2%
  • Non-significant reduction in the primary endpoint
  • Dormandy JA, et al. Lancet. 2005;366:1279-89 PROactive Sub-analysis Patients with Diabetes and Heart Failure
  • Evaluated same endpoints in patients with prior MI
  • Significant ↓ in fatal/nonfatal MI excluding silent MI with pioglitazone
  • 5.3% pioglitazone vs. 7.2% placebo p=0.0453
  • Results for rosiglitazone and pioglitazone recently confirmed with two new meta-analyses
  • Erdmann E, et al. J Am Coll Cardiol. 2007;49:1772-80 HF in PROactive Patients with Diabetes and Heart Failure Dormandy JA, et al. Lancet. 2005;366:1279-89 FDA Updates- August 14, 2007 Patients with Diabetes and Heart Failure
  • Rosiglitazone and pioglitazone received a “boxed warning” regarding CHF
  • www.fda.gov Actos prescribing information. August 2007 FDA Updates: November 19, 2007 Patients with Diabetes and Heart Failure
  • MI risk added to rosiglitazone boxed warning
  • Avandia prescribing information. November 2007 Sitagliptin (Januvia Patients with Diabetes and Heart Failure®)
  • DPP-4 inhibitor
  • Prevents the degradation of endogenous GLP-1
  • Results in a rise in postprandial endogenous GLP-1 levels
  • Sitagliptin Lauster CD et al. Am J Health Syst Pharm. 2007;64:1265-73 Sitagliptin (Januvia Patients with Diabetes and Heart Failure®)
  • Efficacy: A1C 0.5-0.7%
  • 100 mg PO once daily
  • CrCl 30-50 ml/min 50 mg/day
  • CrCl <30 ml/min 25 mg/day
  • Approved for monotherapy or combination therapy
  • Weight neutral
  • Side effects similar to placebo
  • No contraindications identified yet
  • Non-Oral Therapies Patients with Diabetes and Heart Failure Glucagon-like peptide 1 (GLP-1) agonists Patients with Diabetes and Heart Failure
  • Exenatide (Byetta®)
  • Glucagon-like-peptide-1 (GLP-1) analog
  • Incretin mimetic
  • Resistant to degradation by dipeptidyl peptidase-4 (DPP-4)
  • Suppresses high glucagon levels
  • Delays gastric emptying (can affect absorption of other medications)
  • Efficacy: ↓ A1C 0.5-1%
  • Dosing:
  • 5 mcg SC twice daily within 60 min of meals
  • Increase to 10 mcg bid after 4 weeks
  • FDA approved for type 2 diabetes in patients on metformin, sulfonylurea, TZD, or a combination who are not at goal
  • Not yet approved for use with basal insulin
  • GLP-1 Physiology Patients with Diabetes and Heart Failure AE’s Patients with Diabetes and Heart Failure N/V, diarrhea (30-45%) Modest weight loss (a good side effect) Hypoglycemia especially in combination with sulfonylureas Anti-exenatide antibodies Monitoring Renal function A1C in 3 months CI’s Type 1 diabetes Precautions CrCl < 30 ml/min Gastroparesis Hypoglycemia Exenatide adverse effects/contraindications Pramlintide (Symlin Patients with Diabetes and Heart Failure®)
  • Synthetic analog of human amylin
  • Suppresses glucagon secretion
  • Suppression of endogenous glucose from liver
  • Slows gastric emptying
  • Less rapid glucose appearance in the circulation
  • Regulates food intake due to central modulation of appetite
  • Weight loss
  • Pramlintide (Symlin Patients with Diabetes and Heart Failure®)
  • FDA approved for Type 1 or 2 diabetes in patients on optimal insulin therapy who are still not at goal
  • With or without metformin and/or sulfonylurea therapy
  • Efficacy: A1C ~0.1-0.4% in type1 and 0.3-0.7% in type 2
  • 60 mcg (10 units) SC titrate to 120 mcg (20 units) before major meals (Type 2 dosing)
  • Dosed in mcg but drawn up in an insulin syringe
  • www.symlin.com/7522-Type-2-Dosing.aspx
  • Administered in conjunction with mealtime insulin
  • Adverse Effects Patients with Diabetes and Heart Failure Insulin-Induced Severe Hypoglycemia: Hypoglycemia will occur within 3 hours of injection Must reduce pre-meal insulin by 50% at initiation to prevent serious reactions Further reduction in insulin may be needed as dosage of pramlintide is adjusted Contraindications Diagnosis of gastroparesis Hypoglycemia unawareness A1C > 9.0% Recurrent severe hypoglycemia requiring assistance during past 6 months Using other medications that stimulate gastrointestinal motility Pediatrics Pramlintide (Symlin®) Glycemic Goals Patients with Diabetes and Heart Failure ADA Guidelines Patients with Diabetes and Heart Failure A1C < 7.0% <6.5 may further reduce complications Fasting glucose 90-130 mg/dl Peak postprandial glucose <180 mg/dl 1-2 hours after the start of the meal AACE Guidelines A1C < 6.5% Fasting glucose < 110 mg/dl 2-h postprandial glucose <140 mg/dl Glycemic Control A1C and Meal Plasma Glucose Levels Patients with Diabetes and Heart Failure
  • A1C should be as close to normal for the individual patient
  • Use less intensive goals for patients with risk for hypoglycemia
  • Target postprandial glucose if A1C goals not met after reaching preprandial goals
  • Target fasting glucose first!
  • Self-Monitoring of Blood Glucose (SMBG) Patients with Diabetes and Heart Failure
  • At least 3 times/day if on insulin injections
  • If on orals, just use SMBG to help them achieve their glycemic goals
  • Use the data to make decisions on what therapy to add
  • Diabetes Care 2007;30(Suppl 1) Patients with Diabetes and Heart Failure
  • Lifestyle + Metformin- Step 1 Patients with Diabetes and Heart Failure
  • Titrate metformin to max dose over 1-2 months
  • TZDs and sitagliptin are also approved for monotherapy
  • Consider adding other oral medications if there is persistent hyperglycemia
  • Lifestyle Modifications Patients with Diabetes and Heart Failure Diet Patients with Diabetes and Heart Failure
  • Weight loss will reduce insulin resistance
  • Saturated fat < 7 % of total daily calories
  • Carbohydrates should be from fruits, vegetables, whole grains, legumes, low fat milk
  • Low carb diets < 130 g/day not recommended for weight loss
  • Recommend sugar alcohols and nonnutritive sweeteners
  • Limit alcohol to 1 drink/day for women 2 drinks/day for men
  • If on insulin or a secretagogue drink alcohol with food to avoid hypoglycemia
  • Exercise Patients with Diabetes and Heart Failure
  • 150 min/week of moderate-intensity aerobic activity (50-70% of max heart rate)
  • 90 min/week of vigorous aerobic exercise (>70% of max heart rate)
  • Resistance exercise 3 times a week
  • Improves glycemia
  • OR Diabetes Self-Management Education (DSME) Patients with Diabetes and Heart Failure
  • All patients with diabetes should receive DSME after diagnosis
  • Teaches patients about the disease and how to improve self care
  • Should be conducted by either a CDE or health care professional with recent experience in diabetes management
  • Additional Medications - Step 2 Patients with Diabetes and Heart Failure
  • Add within 2-3 months of initiation of therapy
  • Sulfonylurea
  • Cheapest option
  • TZDs
  • More expensive
  • Cardiac risk with rosiglitazone
  • Insulin
  • Most effective option
  • Consider in patients with A1C >8.5% or symptoms of hyperglycemia
  • Initiate with basal insulin
  • Step-2 Alternatives Patients with Diabetes and Heart Failure
  • Sitagliptin
  • Glinides
  • Exenatide
  • Step-3 Initiate or intensify insulin therapy Patients with Diabetes and Heart Failure
  • Start or intensify insulin if lifestyle + metformin + a 2nd medication have not attained goal A1C
  • Third oral medication can be considered if A1C is close to goal <8.0%
  • Expensive, not as effective as insulin
  • Exenatide could be used at this step
  • D/C insulin secretagogues (sulfonylurea or glinides) when pre-prandial rapid insulin is started
  • Long Acting Insulin 10 units or 0.2 units/kg Patients with Diabetes and Heart Failure Increase dose 2 units q 3 days until fasting levels 70-130 mg/dl A1C ≥ 7% after 2-3 months? Check pre-meal BG & add 2nd injection ~4 units before meal Yes No Continue regimen Check A1C q 3 months Pre-Bed high: Add rapid acting at dinner Pre-Lunch BG high: Add rapid acting at breakfast Pre-Dinner high: Add rapid acting at lunch A1C ≥ 7% after 2-3 months? Nathan DM, et al. Diabetes Care 2006;29 A1C Patients with Diabetes and Heart Failure≥ 7% after 2-3 months? No Yes Recheck pre-meal BG and add another injection. Check 2-h postprandial BG and adjust pre-prandial insulin dose Continue regimen and check A1C q 3 months Nathan DM, et al. Diabetes Care 2006;29 TZD Patients with Diabetes and Heart Failure Sitagliptin Exenatide Exenatide Pramlintide CASE 1 Patients with Diabetes and Heart Failure
  • JK is a 59 year old male presenting for a follow-up visit to the diabetes clinic.
  • Past Medical History
  • Type 2 diabetes
  • Hypertension
  • Coronary artery disease
  • Chronic renal insufficiency
  • Medications Patients with Diabetes and Heart Failure Metformin 1000 mg BID Glyburide 10 mg BID Pioglitazone 45 mg once daily Metoprolol XL 50 mg once daily Fosinopril 20 mg once daily Aspirin 81 mg once daily Labs (fasting) Glucose 170 mg/dL A1C 9.0% SCr 1.7 mg/dL CrCl 70 ml/min CASE 1 CASE 1 Patients with Diabetes and Heart Failure
  • Which diabetes medication on his profile is contraindicated and should be discontinued?
  • A. Metformin
  • B. Glyburide
  • C. Pioglitazone
  • CASE 1 Patients with Diabetes and Heart Failure
  • Why?
  • A. Coronary artery disease
  • B. Renal insufficiency
  • C. Drug Interaction
  • D. Non-adherence
  • CASE 1 Patients with Diabetes and Heart Failure
  • Which one of the following would be most appropriate to replace the discontinued medication? A. Glipizide XL 20 mg PO once daily B. Insulin aspart 4 units SC before breakfast C. Insulin glargine 10 units SC at bedtime D. Pramlintide 60 mcg SC before meals
  • Complications of Diabetes Patients with Diabetes and Heart Failure Complications of Uncontrolled Diabetes Patients with Diabetes and Heart Failure Hyperglycemia Continuous Spike Acute Toxicity Chronic Toxicity Tissue Lesions Diabetic Complications Microvascular Macrovascular Nephropathy Neuropathy Retinopathy PVD MI Stroke PPG HbA1C Hanefeld M, et al. Diabet Med. 1997;14(suppl 3):S6 Adjusted Incidence Patients with Diabetes and Heart Failure per 1000 person years 9 10 6 7 8 11 *Based on UKPDS 35 data Stratton IM, et al. BMJ. 2000;321:405-12. Relative Risk of Progression of Diabetic Complications by Mean HbA1c* Updated Mean HbA1c (%) Macrovascular Complications Patients with Diabetes and Heart Failure Macrovascular Complication Statistics Patients with Diabetes and Heart Failure
  • CVD and Stroke
  • Adults with DM have heart disease death rates 2-4x higher than non-diabetics
  • Risk for stroke is 2 to 4x higher and risk of death from stroke is 2.8x higher than in non-diabetics
  • U.S. Department of Health and Human Services, National Institute of Health, 2005. Macrovascular Complications Patients with Diabetes and Heart Failure ~ 80% of all diabetic mortality 75% from coronary atherosclerosis 25% from cerebral or peripheral vascular disease > 75% of all hospitalizations for diabetic complications > 50% of patients with newly diagnosed type 2 diabetes have CHD National Diabetes Data Group. Diabetes in America. 2nd. Ed. NIH; 1995. Insulin Resistance and Atherosclerosis Patients with Diabetes and Heart Failure Insulin resistance Hyperinsulinemia Impairedglucosetolerance HypertriglyceridemiaDecreased HDL-C Essentialhypertension Clinicaldiabetes Accelerated atherosclerosis Heart Disease and Diabetes Patients with Diabetes and Heart Failure Intensive treatment of hyperglycemia Therapy for insulin resistance Appropriate lipid management Aggressive blood pressure control Treatment of CVD in diabetes is similar to therapy for non-diabetic individuals, the risk of CVD is much higher and the benefits of therapy are greater Hypertension Patients with Diabetes and Heart Failure Defined as BP ≥ 140/90 mmHg GOAL BP: < 130/80 mmHg 20 – 60% of Diabetics have HTN Epidemiologic evidence from the UKPDS indicate that each 10 mmHg decrease in mean SBP results in:  12% any DM complication  15% any DM-related death  11% MI  13% microvascular complications American Diabetes Association. Diabetes Care. 2007;30:S4-S41. Hypertension Patients with Diabetes and Heart Failure Weight loss  1 kg results in  of MAP ~ 1 mmHg Sodium restriction In non-diabetic patients reduces SBP ~ 5 mmHg and DBP ~2 - 3 mmHg Drug Therapy (If SBP ≥ 140 mmHg or DBP ≥ 90 mmHg or lifestyle modification failure) 1st choice: ACE-I or ARB 2nd choice: Thiazide, β-Blocker, or Non-DCCB JNC 7 report. JAMA 2003;289:2560-72. Cholesterol Management Patients with Diabetes and Heart Failure Screening: Fasting lipid panel at least annually More often if needed to achieve goals In adults with low-risk lipid values, may obtain fasting lipid panel every 2 years Goals: LDL < 100 mg/dL Optional: LDL <70 mg/dL TG < 150 mg/dL HDL: > 40 mg/dL for males > 50 mg/dL for females American Diabetes Association. Diabetes Care .2007;30:S4-S41. Macrovascular C
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