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 Type 2 diabetes accounts for 90-95% of patients with diabetes CDC. National diabetes fact sheet. 2005 available at www.cdc.gov/diabetes/pubs/pdf/ndfs_2005.pdf
In 2002 total indirect and direct medical costs for diabetes = $132 billion
Risk factors for type 2 diabetes 1 st degree relative with diabetes Gestational diabetes or delivering a baby >9 lbs 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
Diagnosis of diabetes Symptoms of diabetes + casual plasma glucose ≥ 200 mg/dl OR OR
Oral glucose tolerance test (OGTT): 2-h postload glucose ≥ 200 mg/dl
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/m 2 Screen patients < 45 years old if they are overweight + an additional risk factor FPG should be done initially
Repeat screening every 3 years
Metformin hepatic glucose production, intestinal glucose absorption, insulin sensitivity Diarrhea, abdominal bloating, nausea
Titrate dose at weekly intervals to minimize AEs
Contraindications to Metformin Renal impairment SCr >1.5 for men, >1.4 for women Age >80 unless normal GFR 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 Primary outcome: all-cause mortality at 1 year and end of follow-up Eurich DT, et al. Diabetes Care. 2005;28:2345-51
Secondary outcome: all-cause hospitalizations at 1 year and end of follow-up
Improved Clinical Outcomes Associated with Metformin in Patients with Diabetes and Heart Failure Eurich DT, et al. Diabetes Care. 2005;28:2345-51 0.86 (0.77-0.96) 0.83 (0.70-0.99) 1.0 Combined endpoint 0.93 (0.83-1.05) 0.87 (0.73-1.05) 1.0 Adjusted all-cause hospitalization, HR (95% CI) 0.61(0.52-0.72) 0.70 (0.54-0.91) 1.0 Adjusted all-cause mortality, HR (95% CI) Combination therapy (n=852) Metformin monotherapy (n=208) Sulfonylurea monotherapy (n=773)
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 Eurich DT, et al. Diabetes Care. 2005;28:2345-51
Cannot prove that metformin is efficacious in this population
Sulfonylureas ↑ insulin secretion from pancreatic β -cells Not recommended if CrCl < 50 ml/min (use a different sulfonylurea) Not recommended if CrCl < 10 ml/min 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
Thiazolidenediones (TZDs) Insulin Sensitizers TZDs are PPAR- gamma receptor activators Primarily in the peripheral tissue Effect may not be seen for 4 weeks Rosiglitazone (Avandia ® ) Initial dose 4 mg/day, Max dose 8 mg/day
Initial dose 15-30 mg/day, Max dose 45 mg/day
Adverse Effects/Contraindications of TZDs Fluid retention and peripheral edema Fluid retention is a major contributor Redistribution of adipose tissue 2-3% when combined with insulin ALT > 2.5 x upper limit of normal Granberry MC, et al. Am J Health-Syst Pharm. 2007;64:931-6
HF NYHA class III or IV (see following slides)
TZD Use In 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 Nesto RW, et al. Diabetes Care. 2004;27:256-63
Do not use TZDs in patients with NYHA class III or IV HF
Meta-analysis of MI Risk With Rosiglitazone 42 trials comparing rosiglitazone with placebo 15,560 patients received rosiglitazone 12,283 patients assigned to comparator groups 24-52 week duration of trials Nissen SE, et al. N Engl J Med. 2007;356:1-15
Mean baseline A1C 8.2% for both groups
Meta-analysis of MI Risk With Rosiglitazone Nissen SE, et al. N Engl J Med. 2007;356:1-15 0.06 1.64 (0.98-1.74) 22 39 Death from CV causes # events 0.03 1.43 (1.03-1.98) 72 86 Myocardial Infarction # events P value Odds Ratio (95% CI) Control n= 11,634 Rosiglitazone n= 14,371
PROactive Trial Primary objective: Determine if pioglitazone reduces CV morbidity and mortality in patients with diabetes ↓ Triglycerides 11% vs. 1.8% ↑ Dormandy JA, et al. Lancet. 2005;366:1279-89
Non-significant reduction in the primary endpoint
PROactive Sub-analysis 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 Erdmann E, et al. J Am Coll Cardiol. 2007;49:1772-80
Results for rosiglitazone and pioglitazone recently confirmed with two new meta-analyses
HF in PROactive Dormandy JA, et al. Lancet. 2005;366:1279-89 0.634 22 (1%) 22 25 (1%) 25 Fatal HF 0.007 108 (4%) 153 149 (6%) 209 HF with hospital admission 0.003 90 (3%) 117 132 (5%) 160 HF w/o hospital admission <0.0001 198 (8%) 302 281 (11%) 417 Any report of HF # Patients (%) # Events # Patients (%) # Events P value Placebo n = 2633 Pioglitazone n = 2605
FDA Updates- August 14, 2007 www.fda.gov Actos prescribing information. August 2007
Rosiglitazone and pioglitazone received a “boxed warning” regarding CHF
FDA Updates: November 19, 2007 Avandia prescribing information. November 2007
MI risk added to rosiglitazone boxed warning
Sitagliptin (Januvia ® ) Prevents the degradation of endogenous GLP-1 Lauster CD et al. Am J Health Syst Pharm. 2007;64:1265-73 Sitagliptin
Results in a rise in postprandial endogenous GLP-1 levels
Sitagliptin (Januvia ® ) CrCl 30-50 ml/min 50 mg/day CrCl <30 ml/min 25 mg/day Approved for monotherapy or combination therapy Side effects similar to placebo
No contraindications identified yet
Glucagon-like peptide 1 (GLP-1) agonists Glucagon-like-peptide-1 (GLP-1) analog Resistant to degradation by dipeptidyl peptidase-4 (DPP-4) Suppresses high glucagon levels Delays gastric emptying (can affect absorption of other medications) 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
Exenatide adverse effects/contraindications Modest weight loss (a good side effect) Hypoglycemia especially in combination with sulfonylureas
Pramlintide (Symlin ® ) Synthetic analog of human amylin Suppresses glucagon secretion Suppression of endogenous glucose from liver Less rapid glucose appearance in the circulation
Regulates food intake due to central modulation of appetite
Pramlintide (Symlin ® ) 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
Pramlintide (Symlin ® ) 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 Diagnosis of gastroparesis Recurrent severe hypoglycemia requiring assistance during past 6 months
Using other medications that stimulate gastrointestinal motility
Glycemic Control <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 Fasting glucose < 110 mg/dl
2-h postprandial glucose <140 mg/dl
A1C and Meal Plasma Glucose Levels 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 345 12 310 11 275 10 240 9 205 8 170 7 135 6 Mean Plasma glucose mg/dl A1C
Target fasting glucose first!
Self-Monitoring of Blood Glucose (SMBG) 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)
Lifestyle + Metformin- Step 1 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
Diet 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 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) OR
Resistance exercise 3 times a week
Diabetes Self-Management Education (DSME) 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 Add within 2-3 months of initiation of therapy Cardiac risk with rosiglitazone Consider in patients with A1C >8.5% or symptoms of hyperglycemia
Initiate with basal insulin
Step-3 Initiate or intensify insulin therapy Start or intensify insulin if lifestyle + metformin + a 2 nd 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 Increase dose 2 units q 3 days until fasting levels 70-130 mg/dl A1C ≥ 7% after 2-3 months? No Continue regimen Check A1C q 3 months Check pre-meal BG & add 2 nd injection ~4 units before meal Yes Pre-Lunch BG high: Add rapid acting at breakfast Pre-Dinner high: Add rapid acting at lunch Pre-Bed high: Add rapid acting at dinner A1C ≥ 7% after 2-3 months? Nathan DM, et al. Diabetes Care 2006;29
A1C ≥ 7% after 2-3 months? Yes Recheck pre-meal BG and add another injection. Check 2-h postprandial BG and adjust pre-prandial insulin dose No Continue regimen and check A1C q 3 months Nathan DM, et al. Diabetes Care 2006;29
Pramlintide Exenatide Sitagliptin TZD Exenatide
CASE 1 JK is a 59 year old male presenting for a follow-up visit to the diabetes clinic.
Chronic renal insufficiency
CASE 1 Pioglitazone 45 mg once daily Metoprolol XL 50 mg once daily
Fosinopril 20 mg once daily
Which diabetes medication on his profile is contraindicated and should be discontinued?
A . Coronary artery disease
CASE 1 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
Complications of Uncontrolled Diabetes Hanefeld M, et al. Diabet Med. 1997;14(suppl 3):S6 HbA 1C PPG Hyperglycemia Spike Continuous Chronic Toxicity Acute Toxicity Tissue Lesions Diabetic Complications Microvascular Macrovascular Nephropathy Neuropathy Retinopathy PVD MI Stroke
Relative Risk of Progression of Diabetic Complications by Mean HbA 1c * Updated Mean HbA 1c (%) Stratton IM, et al. BMJ. 2000;321:405-12. Adjusted Incidence per 1000 person years 6 7 8 9 10 11 *Based on UKPDS 35 data
Macrovascular Complication Statistics Adults with DM have heart disease death rates 2-4x higher than non-diabetics U.S. Department of Health and Human Services, National Institute of Health, 2005.
Risk for stroke is 2 to 4x higher and risk of death from stroke is 2.8x higher than in non-diabetics
Macrovascular Complications ~ 80% of all diabetic mortality 75% from coronary atherosclerosis 25% from cerebral or peripheral vascular disease > 75% of all hospitalizations for diabetic complications National Diabetes Data Group. Diabetes in America. 2 nd . Ed. NIH; 1995.
> 50% of patients with newly diagnosed type 2 diabetes have CHD
Insulin Resistance and Atherosclerosis Accelerated atherosclerosis Clinical diabetes Hyperinsulinemia Impaired glucose tolerance Hypertriglyceridemia Decreased HDL-C Essential hypertension Insulin resistance
Heart Disease and Diabetes Intensive treatment of hyperglycemia Therapy for insulin resistance Appropriate lipid management 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
Aggressive blood pressure control
Hypertension Defined as BP ≥ 140/90 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 American Diabetes Association. Diabetes Care. 2007;30:S4-S41.
13% microvascular complications
Hypertension 1 kg results in of MAP ~ 1 mmHg 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) 1 st choice: ACE-I or ARB JNC 7 report. JAMA 2003;289:2560-72.
2 nd choice: Thiazide, β -Blocker, or Non-DCCB
Cholesterol Management Fasting lipid panel at least annually More often if needed to achieve goals American Diabetes Association. Diabetes Care .2007;30:S4-S41.
In adults with low-risk lipid values, may obtain fasting lipid panel every 2 years
Macrovascular Complications Aspirin Therapy: 75 – 162 mg/day Primary prevention in those with ↑ CVD risk : Lipids: TC >200; LDL >100; HDL < 45 (or 55) & TG >200 Secondary prevention in those with DM + CVD American Diabetes Association. Diabetes Care .2007;30:S4-S41.
Not recommended for patients < 30 years-old
Macrovascular Complications Advise all patients not to smoke American Diabetes Association. Diabetes Care .2007;30:S4-S41.
Provide smoking cessation counseling and other forms of treatment if needed
Management Summary for Macrovascular Complications American Diabetes Association. Diabetes Care .2007;30:S4-S41. Macrovascular Complications Goals Hypertension Dyslipidemia Treatment
Relative Risk of Progression of Diabetic Complications by Mean HbA 1c * Skyler JS ,et al. Endocrinol Metab Clin North Am . 1996;25:243-54. Relative risk 6 7 8 9 10 11 12 15 13 11 9 7 5 3 1 HbA 1c (%) Diabetic retinopathy Nephropathy Neuropathy Microalbuminuria *Based on DCCT data
Diabetic Nephropathy Occurs in 20 to 40% of diabetics Most common cause of ESRD ESRD develops in 50% of type 1 patients with overt nephropathy within 10 years American Diabetes Association. Diabetes Care. 2007;30:S4-S41.
ESRD develops in about 20% of type 2 patients with overt nephropathy within 20 years
Nephropathy: Diagnosis Category Spot Collection (albumin-to-creatinine) (mcg/mg) Normal < 30 Microalbuminuria 30 - 299 Clinical albuminuria > 300 Two of three specimens collected within a 3-6 month period should be abnormal before diagnosing . Exercise within 24 hr, infection, fever, CHF, marked hyperglycemia or HTN, pyuria, & hematuria may elevate urinary albumin excretion over baseline values American Diabetes Association. Diabetes Care. 2007;30:S4-S41.
Nephropathy: Screening DM 1: Within 5 years of diagnosis DM 1 and 2: Follow-up exams annually If (+) for microalbuminuria, test twice more over next 3 to 6 months If 2 of 3 tests are positive, they have microalbuminuria and should have treatment started American Diabetes Association. Diabetes Care. 2007;30:S4-S41
Serum creatinine should be measured at least annually for estimation of GFR
Nephropathy: Treatment Glycemic control: HbA 1c < 7% Blood pressure control: BP < 130/80 mmHg Decrease progression of microalbuminuria and slow rate of decline in GFR in patients with proteinuria Non-DCCBs, BB’s, or thiazide acceptable if intolerant to ACEI/ARB If ACE-I, ARBs, or thiazide used, monitor K + With presence of nephropathy American Diabetes Association. Diabetes Care. 2007;30:S4-S41
≤ 0.8 g/kg per day ( ~ 10% of daily calories)
Diabetic Neuropathy Syncope, fatigue, sustained heart rate Dysphagia, N/V, constipation, diarrhea ↓ bladder control, UTIs, ED, Dyspareunia Dry skin, calluses, limb hair loss
Depression, anxiety, sleep disorders
Diabetic Neuropathy Screening Assessment for protective sensation, foot structure and biomechanics, vascular status, and skin integrity. Neurologic status assessed with 5.07 (10-g) monofilament Also consider: pin-prick sensation, temperature and vibration perception (using tuning fork) Assess for history of claudication, and assess pedal pulses Assess skin integrity especially b/w toes and under metatarsal heads. Look for erythema, warmth, or callus formation (increased plantar pressure)
Bony deformities, limitation in joint mobility, and gait and balance should be assessed
Diabetic Neuropathy Treatment
Glycemic control: HbA 1c < 7%
Peripheral Neuropathy Treatment Wong M, et al. BMJ. 2007; 335; 1-10.
Optimal glycemic control: GOAL HbA 1c < 7%
Diabetic Retinopathy Leading cause of new cases of blindness among adults (20 to 74 years of age). Normal Vision Diabetic Retinopathy
Prevalence is strongly related to duration of diabetes.
Diabetic Retinopathy Screening Comprehensive dilated eye exam: DM 1: Within 3 to 5 years of diagnosis American Diabetes Association. Diabetes Care. 2007;30:S4-S41.
DM 1 and 2: Follow-up exams annually
Diabetic Retinopathy Management Tight glycemic control HbA 1C < 7% Tight blood pressure control <130/80 mmHg
Both shown to delay or prevent onset of retinopathy
Management Summary for Microvascular Complications Microvascular Complications Screening Nephropathy Neuropathy Retinopathy Treatment Everyone needs lifestyle modifications
Standards of Care in Diabetes Diabetes Care. 2007;30(suppl 1):S4-S41
Medical history during the 1 st evaluation Age and characteristics of onset of diabetes History of diabetes education Previous and current treatments
History of diabetes related complications
Patellar and achilles reflexes
Health Maintenance/Prevention of Complications Influenza vaccine annually Pneumococcal vaccine for all adults BP at every visit, goal < 130/80 mmHg Check lipids annually: Goal LDL <100 mg/dL, TG <150 mg/dL, HDL >40 for men >50 for women Annual test for microalbuminuria Annual eye exam to screen for retinopathy
Annual screening for peripheral and autonomic neuropathy
CASE 2 JT is a 58 year old male newly diagnosed with Type 2 diabetes
SH: Tobacco 1 pack/day x 30 years; Rare ETOH use; denies illicit drug use; diet is high in carbohydrates and sugars and low in vegetables; physical activity “little to none”
How much exercise should you recommend for JT?
CASE 2 Which of the following should be done at diagnosis?
B . Test for microalbuminuria
JT’s blood pressure is 150/90, what would be your recommendation for initial therapy?