disclosure guideline updates 1 48th annual meeting navigating the oceans of opportunity pour some...

7/19/2014

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48th Annual Meeting

Navigating the Oceans of Opportunity

Pour Some Sugar On Me –Diabetes Updates for the

Practicing Pharmacist Karen R. Sando, Pharm.D., BCACP, CDE

Clinical Assistant ProfessorUniversity of Florida, College of Pharmacy

Gainesville, FL

Disclosure

I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation

I have lived with T1DM since age 8 and use the following devices to manage my diabetes: Animas Ping Insulin Pump

Dexcom G4 Platinum Continuous Glucose Monitor

One Touch Mini Glucose meter

Disclosure

Objectives

Explain updates to widely used guidelines for diabetes management (e.g. ADA)

Describe new therapeutic agents for management of diabetes mellitus and current role in therapy.

Describe new technologies (e.g. new continuous glucose monitors, insulin pumps, apps) for management of diabetes mellitus.

Discuss clinical controversies in diabetes management and provide clinical pearls for navigating controversies in practice.

Guideline Updates

Diabetes and Related Guideline Updates

Nov 2013

• ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults – Focus on Individuals with DM

Dec 2013

• 2014 Evidence-Based Guidelines for Management of High Blood Pressure in Adults (JNC 8) – HTN goals for individuals with DM

Jan 2014

• 2014 American Diabetes Association Standards of Care in Diabetes Mellitus

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Foreigner – Double Vision (Look Similar to 2013)

2014 ADA Standards of Care

Diagnosis of Diabetes

Screening for T1DM

Detection and Diagnosis of Gestational Diabetes Mellitus

Glucose Monitoring

Neuropathy

Pharmacological Therapy for Hyperglycemia in T2DM

Medical Nutrition Therapy

Nephropathy

Retinopathy

Diabetes Care in Specific Populations (thyroid and celiac screening)

Diabetes Care in the Hospital

ADA Standards of Care in DM

Diabetes Care January 2014 37:S4

ADA Levels of Evidence Grading System

LOE Description

A Clear evidence from well-conducted, generalizable RCTs that are adequatelypowered

B Supportive evidence from well-conducted cohort or case control studies

C Supportive evidence from poorly controlled or uncontrolled studies OR Conflicting evidence with the weight of evidence supporting the recommendation

E Expert consensus or clinical experience

Diabetes Care January 2014 37:S14-S80

Pharmacologic Therapy in T2DM

2013 - If noninsulin monotherapy at maximal tolerated dose does not achieve or maintain the A1C target over 3–6 months, add a second oral agent, a glucagon-like peptide-1 (GLP-1) receptor agonist, or insulin. (LOE=A)

3 months

2014


Clinical Inertia with Treatment Intensification People with diabetes often experience prolonged

(> 5 years) poor glycemic control (A1c >8%) before insulin therapy is initiated

UK data estimates from NICE - takes mean of 7.7 years to initiate insulin after last OAD started (on ≥ 2 OADs)

Bottom line – therapy intensification should be considered every 3 months if not achieving A1c goals

NICE=National Institute for Health and Care Excellence Diabetes Care 2013, 36:3411-3417

Nephropathy

“Microalbuminuria” and “macroalbuminuria” will no longer be used “Persistent albuminuria” at levels 30–299 mg/24 h and

levels ≥ 300 mg/24 h

Normal albumin excretion = < 30 mg/24 h.

ACEI or ARB for primary prevention of diabetic kidney disease is not recommended in those with normal blood pressure and albumin excretion (<30 mg/24 hours) (LOE=B)


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Nephropathy

For people with DM and diabetic kidney disease (albuminuria >30 mg/24 hour) reducing dietary protein below usual intake is NOT recommended (LOE=A) Previous guidelines recommended limiting protein

intake to 0.8 to 1.0 g/kg body weight/day

Does not alter glycemic measures, cardiovascular risk measures, or GFR decline

May consider if GFR continues to decline despite BP/glucose control and ACEI/ARB on board


Diabetes Care in the Hospital

The sole use of sliding scale insulin in the inpatient hospital setting is discouraged (LOE=E)

Sliding scale insulin in the inpatient setting Reactionary vs. proactive

Higher frequency of hyperglycemia

Greater length of stay

“Recommend more physiological regimen including basal, prandial, and correctional insulin is recommended”.

More evidence is needed Diabetes Care January 2014 37:S14-S80

Phil Collins – “I Don’t Care Anymore” (about LDL goals)

2013 ACC/AHA Lipid Guidelines

Lipid Management (Before)

ATP III; JAMA. 2001;285:2486-2497

AHA/ACC 2013 Lipid Guidelines

Four statin benefit groups: Clinical ASCVD

LDL ≥190 mg/dL

Diabetes Mellitus (T1 or T2)

10-yr ASCVD risk ≥ 7.5%

Guideline Comparison

2013 ACC/AHA Lipid Guidelines 2014 ADA Standards of DM Care

Diabetes is 1 of 4 statin benefit Groups1. Clinical ASCVD2. LDL ≥ 190 mg/dL3. Diabetes T1 or T2 (40 to 75 yrs of age) 4. 10-yr ASCVD risk ≥ 7.5%

Statin therapy should be considered regardless of baseline LDL levels in: -with overt CVD -without CVD and over age 40 with one ore more CVD risk factors (family history of CVD, HTN, smoking, dyslipidemia, or albuminuria

Calculate 10-yr ASCVD risk in those withoutclinical ASCVD

LDL goal <100 mg/dL (without overt CVD)LDL < 70 mg/dL (with overt CVD, optional)

If 10-yr ASCVD risk is ≥ 7.5% initiate high intensity statin therapy (lowers LDL by ≥ 50%)

Combination therapy has been shown not to provide additional cardiovascular benefit above statin therapy alone and is not generally recommended Non-statin therapy not recommended in

addition to statins except in certain clinical situations

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Bottom Line – Lipids in DM

Statin therapy should be initiated regardless of baseline lipid levels Substantial evidence supporting reduced CVD events

Select appropriate statin intensity based on 10-yr ASCVD risk and clinical history

Non-statin therapies no longer favored except in certain clinical situations

LDL reduction is primary goal of therapy

Monitor lipid levels 4 to 12 weeks after statin initiation for anticipated therapeutic response

Queen – “Under (Less) Pressure”

2014 Hypertension Guidelines (JNC 8)

JNC 8 Guidelines

Bottom Line – HTN in DM

For most patients treat to goal of <140/90 mm Hg Lower goals for those at higher risk of stroke (ADA)

Higher goals for elderly (>60 or >80 yo ?)

For those without CKD or albuminuria, can consider initiating CCB or thiazide-diuretic as first-line therapy African Americans – Low renin, salt-sensitive (CCB,

thiazides)

Caucasians – renin-mediated (ACEI, ARB)

Increase doses to achieve goal and intensify with a second agent of a differing mechanism for best results

Led Zeppelin – The Song (and therapeutic class) Remains the Same

New Diabetes Medications

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Dapagliflozin (Farxiga)

SGLT-2 Inhibitor

Glucose is eliminated in the

urine C. Chao, MD E. SGLT2 Inhibitors: FDA Approval of Canagliflozin for Type 2 Diabetes Therapy. In: Brunton LL. eds. Goodman & Gilman Online Updates. New York, NY: McGraw-Hill; 2011


Dosing Starting dose= 5 mg daily

May increase to 10 mg daily if additional glucose control needed

Special Populations Renal Impairment – Do not initiate if eGFR

< 60 ml/min/1.73m2

Hepatic Impairment – No dose adjustment needed

Geriatric (≥65 years of age)

Dapagliflozin (Farxiga) Package Insert. Available at http://packageinserts.bms.com/pi/pi_farxiga.pdf. Accessed 2014 May 28


Dapagliflozin (Farxiga) Package Insert. Available at http://packageinserts.bms.com/pi/pi_farxiga.pdf. Accessed

2014 May 28


Dapagliflozin (Farxiga) Package Insert. Available at http://packageinserts.bms.com/pi/pi_farxiga.pdf. Accessed

2014 May 28

Dapagliflozin BP Reduction


Dapagliflozin Weight Reduction


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Adverse effects Female genital mycotic infections (6.9% - 9.4% vs.

1.5% placebo)

Nasopharyngitis (6.3% vs. 6.2% placebo)

Urinary tract infections (4.3% - 5.7% vs. 3.7% placebo)

Medication Guide required Bladder cancer risk Across 22 clinical studies only 4 cases in treatment group

0.17% (dapagliflozin) vs. 0.03% in placebo/comparator



Significant drug interactions Not metabolized by CYP450 system

No clinically significant interactions

May cause hypotension due to intravascular volume depletion Caution in those on antihypertensives

Patient Counseling and Monitoring Experience increase urine volume

Hypoglycemia

Hemoglobin A1c and renal function


Place in therapy Consider as add-on therapy in patients who

do not achieve A1c goals on metformin monotherapy

Some beneficial effects on weight and BP –common comorbidities with diabetes

Avoid in renal impairment

Minimal risk of hypoglycemia

Cost $310 to $320 per 30-day supply (5 mg tablet)

Cost information available at www.goodrx.com. Accessed 2014 May 28

Albiglutide (Tanzeum)

Mechanism of Action - GLP-1 Agonist

Not recommended as initial monotherapy

Dosing 30 mg injected subcutaneously once weekly

May increase to 50 mg once weekly if inadequate response

Special Populations – no suggested renal/hepatic impairment dose adjustments

Albiglutide Monotherapy

Albiglutide (Tanzeum) Package Insert. Available at https://www.gsksource.com/gskprm/htdocs/documents/TANZEUM-PI-MG-IFU-COMBINED.PDF. Accessed

2014 May 28

Combination Therapy

Study Design Significant Results

104-Week RCT comparing add-ontherapy in those inadequately controlled on metformin (N=249)

-0.9% A1c reduction (vs. placebo + MET) -0.4% A1c reduction (vs. sitagliptin + MET) -0.3% A1c reduction (vs. glimepiride + MET) Lost significantly more body weight than those on glimepiride + MET (-1.2 kg)

52-week RCT comparing add-ontherapy in those inadequately controlled on pioglitazone (≥30 mg/day) (±metformin) (N=249)

-0.8% A1c reduction (vs. placebo + pioglitazone) -30 mg/dL FPG reduction (vs. placebo +pioglitazone

52-week RCT comparing add-on vs. pioglitazone in those uncontrolled on metformin + sulfonylurea (N=657)

-0.9% A1c reduction (vs. placebo+ MET + sulf) + 0.25% A1c increase (vs. PIO + MET + sulf) Did NOT meet non-inferiority margin for comparison with PIO Significantly more weight loss vs. PIO add-on (-4.9 kg)

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Comparison to Liraglutide

• MORE injection site reactions with albiglutide vs. liraglutide • LESS GI adverse effects with albiglutide vs. liraglutide

Comparison to Insulin Glargine

Adverse Effects

GI upset (N/V/D) – Discontinuation in 2% of patients in pooled placebo controlled trials

Injection site reactions

Cough

Back pain/arthralgias

Rare and Precautions Black box warning – thyroid C-cell, MTC, or MEN-2

tumors

Risk of pancreatitis (0.3% albiglutide vs. 0% placebo)

Slows gastric emptying

Albiglutide Patient Counseling

Step 1 –1. Twist Pen clockwise to mix

lyophilized powder with diluent

2. Rock pen side to side 5 times

Step 2 – Wait 15 minutes while solution mixes

Step 3 –1. Attach needle 2. Rock pen side to side 5 more

times3. Tap pen 2 to 3 times to remove

large air bubbles 4. Twist clockwise again to prime

Albiglutide Place in Therapy

Adds to available GLP-1 agonists Exenatide (Byetta) – twice a day, more GI side effects, not

recommended in significant renal impairment (CrCl <30 ml/min)

Liraglutide (Victoza) – once daily, no renal impairment dosing, less GI side effects vs. exenatide

Exenatide LAR (Bydureon) – once weekly, use not recommended with CrCl < 30 ml/min

Consider as add-on therapy in those inadequately controlled on metformin

Weight loss in overweight/obese patients

Cost ???

Beatles – When I’m Sixty-Four (turn my insulin pump off)

Devices, Apps, and the Future

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Combined insulin pump and continuous glucose monitor (CGM)

“Threshold Suspend” feature User controlled on/off

Threshold 60 to 90 mg/dL

Pump will suspend basal delivery for up to 2 hours

Medtronic MiniMed 530G

Study of Threshold Suspend Pump

Bergenstal RM et al. N Engl J Med 2013;369:224-232.

• Patients with T1DM and documented nocturnal hypoglycemia (N=247)

• Randomized to sensor-augmented pump with and without suspend feature for 3 months

Study Design

• Primary safety outcome – change in A1c • Primary efficacy outcome – AUC for nocturnal

hypoglycemic events

Primary and Secondary Outcomes

• Changes in A1c similar between two groups (no statistically significant difference)

• Mean AUC for hypoglycemia 37.5% lower in threshold-suspend group vs. control (p<0.001)

Results

Artificial Pancreas Project (JDRF)

Smart Insulin 2003 MIT chemical

engineer founded a company called SmartCells

2010 Merck has acquired SmartCells

Working to develop glucose-dependent insulin

Future Directions

Information available at www.jdrf.org. Accessed 2014 May 28

Logbooks Glooko Logbook

dLife Diabetes Companion

WaveSense diabetes manager

Carb-Counting My Glucose Buddy

Sanofi-Aventis Go Meals

Useful Apps

Information Available at: http://diabetes.ufl.edu/my-diabetes/diabetes-resources/diabetes-apps/. Accessed 2014 May 28

Peter Frampton – Show Me the Way

Clinical Controversies and Pearls

Common Clinical Controversies

Scenario #1 Maximized on metformin and sulfonylurea and not achieving

A1c goals

What should you add next?

Scenario #2 Oral agents + basal insulin and still not achieving goal

Should we think about mealtime insulin?

Scenario #3 Achieving previously set LDL goals but not on the

appropriate intensity statin

Should I stay or should I go (to a more potent statin)

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Scenario #1

BW is a 62 yo female with T2DM on metformin 1000 mg BID and glipizide 10 mg BID. Current A1c is 8.3% (last A1c 8.1% 3 months ago). BMP WNL, Wt=201 lbs (BMI=30.1). Her doctor wishes to add something to her diabetes regimen but isn’t sure what to do. He asks your advice.

“Hey, are you the pharmacist? Can I get some help with this

patient?”

“Hey, are you the pharmacist? Can I get some help with this

patient?”

ADA/EASD Treatment Algorithm

Inzucchi SE et al. Diabetologia. 2012 Jun;55(6):1577-96

AACE 2013 Algorithm

Comparison of Additional Therapy

Basal Insulin vs. GLP-1 RA

• Multicenter, open-label, randomized two-arm parallel trial design• 390 patients with T2DM aged ≥18 with suboptimal glucose control

despite maximum tolerated doses of metformin or metformin + sulfonylurea

• Randomized to insulin glargine initiated at 10 units daily and titrated vs. exenatide weekly 2 mg sub-Q

Study Design

• Change in A1c• % of patients achieving A1c <7.0 and <6.5%• Body weight• Incidence of hypoglycemia • Overall safety

Outcomes

• A1c decreased by -1.2% (EQW) vs. -1.0% (IG) (p=0.029) • Greater percentage of EQW treated patients achieved A1c <7% or ≤6.5% (p=0.084)

• EQW treated patients lost 2.1 kg vs. 2.4 kg gained in IG group (P<0.001) • Less hypoglycemia in metformin alone AND metformin + sulfonylurea EQW-

treated vs. IG-treated (p<0.001) • More diarrhea and nausea occurred in EQW vs. IG

Results

Diamant M et al. Diabetes Care 35:683–689, 2012

Scenario #1 Bottom Line

GLP-1 RA has advantage of weight loss and less hypoglycemia. GI ADE common, injectable

TZDS use caution in those with HF, also causes fluid retention/weight gain

DPP-IV neutral for weight loss, hypoglycemia, generally well-tolerated, linagliptin does not require renal dose adjustment

Basal insulin effective, large A1c reductions, weight gain, hypoglycemia

Bromocriptine moderate GI symptoms, high pill burden (0.8 mg tablets, may take up to 6 tabs/day)

SGLT2 inhibitors caution with renal impairment, increased risk of mycotic infections in female, cost/insurance coverage?

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Scenario #2

TG is a 56 yo male with T2DM x 15 years. Current meds include metformin 1000 mg BID, glimepiride 8 mg daily, sitagliptin 100 mg daily, insulin glargine 75 units QHS. Most recent A1c is 9.1%. Compliant with current meds. BMP WNL. Wt=100 kg. His physician refers TG to your diabetes clinic and asks you to figure out what is going on with his diabetes!!

When should we think about adding mealtime insulin?

Not meeting A1c goals despite 3-6 months titration of basal insulin to achieve fasting goal (70-130 mg/dL)

Significant post-prandial glucose excursions (>180 mg/dL)

Overnight lows or between meal lows when basal insulin increased

TDD of insulin exceeds 0.5 units/kg/day 75 units/100 kg=0.75 units/kg/day

A1c above goal of <7.0%Inzucchi SE et al. Diabetologia. 2012 Jun;55(6):1577-96

Initiation and titration

Option #1 Initiate fixed dose of prandial insulin before meal responsible for

largest glucose excursion

Add second injection, then third to other meals

Option #2 Initiate fixed dose of prandial insulin prior to each meal

Typically 10% of total daily basal dose recommended

For TG that would be 7 to 8 units

Option #3 Calculate carbohydrate ratio insulin sensitivity factor (ISF)

Carb ratios Written as 1 unit of

insulin: x grams of carbs

Calculate by dividing TDD (basal) into 500

ISF or correction factor Written as 1unit: x

mg/DL >target BG

Calculate using the “1800 rule”

Carb ratios and ISF

Let’s Do Some Math!

500/75 units (TG’s basal dose) = ~6.7

1 unit: 7 grams of carbohydrate

1800/75 units (TG’s basal dose) =24

1 unit of insulin will lower TG’s blood sugar by ~24 mg/dL

Round to 25 mg/dl for easier math

Putting this into Practice

TG checked his blood sugar before lunch (result=175 mg/dL) and will eat 45 grams of carbohydrates. His target blood sugar before lunch is 100 mg/dL. How much prandial insulin should TG deliver before he eats lunch?

Carb ratio (1:7 grams)

45 grams ÷7 grams per unit of insulin=6.4 units6 units

ISF (1:25 mg/dL > 100 mg/dL)

175 mg/dL-100 mg/dL (target)=75mg/dL

75 mg/dL ÷ 25 mg/dL 3 units

Total to deliver is 9 units

Mealtime Insulin Titration

• Check blood glucose 2-hrs after start of meal OR• Check prior to each meal

• If above goal pre-lunch, increase breakfast prandial dose • If above goal pre-dinner, increase lunch prandial dose, etc.

Meneghini L et al. Endocr Pract. 2011; 17(5): 727-736

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Scenario #2 Bottom Line

The case of TG Metformin 1000 mg BID Continue

Glimepiride 8 mg daily Discontinue

Sitagliptin 100 mg daily Continue (for now)

Insulin glargine 75 units daily May reduce dose when initiating prandial insulin

Initiate insulin aspart/glulisine/lispro 7 units prior to meal with largest glucose excursion (usually

dinner OR breakfast)

Increase by 2 if pre-bedtime BG is >180 mg/DL

Scenario #3

HS is a 63 yo WF with T2DM, hyperlipidemia, and HTN that is managed by your lipid clinic. She has no history of ASCVD. She is in for follow-up today of her most recent lipid panel. Current cholesterol med=pravastatin 40 mg QHS

Lipid panel results are: TC=166 mg/dL, TG=162 mg/dL, HDL=41 mg/dL, LDL (calc)=92 mg/dL

BP 138/80 mm Hg

According to the new lipid guidelines, how should we manage this patient?

Scenario #3

HS is meeting previously established LDL treatment goal of <100 mg/dL (per ATP III and ADA 2014 guidelines)

However, is she on appropriate intensity statin?

Statin Intensity

Considering Risk

Globally consider risk for CVD Smoker?

Family history of CVD?

Blood pressure/DM controlled?

Calculate 10-yr ASCVD risk using online calculator http://tools.cardiosource.org/ASCVD-Risk-Estimator/

10-yr calculated risk=16.4% high-intensity statin

How much additional benefit will HS receive from switching to a high-dose statin?

Montori VM et al. JAMA. 2014;311(5):465-466

Statin decision aid

Available at http://staindecisionaid.mayoclinic.org

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Statin decision aid

Scenario #3 – Bottom Line

With established ASCVD, guidelines clearly recommend high-intensity statin

For those already established on statin therapy with T2DM: Is it appropriate intensity given their history? If low intensity statin –should likely increase to at least a

moderate-intensity statin (e.g. pravastatin 40 mg, simvastatin 20 mg)

If moderate-intensity –evaluate cardiac risk, will the patient gain additional benefit from high-intensity statin?

Involve patient in decision making (risks v benefits)

Conclusions

ADA guidelines minimally changed in 2014 but new BP and cholesterol guidelines impact the management of our patients with DM

New medications and devices are steadily added to our armamentarium of diabetes medications

When considering treatment changes for diabetes management or comorbidities involve patient in decision making process and clearly explain risks vs. benefits

48th Annual Meeting

Navigating the Oceans of Opportunity

Pour Some Sugar On Me –Diabetes Updates for the

Practicing Pharmacist Karen R. Sando, Pharm.D., BCACP, CDE

Clinical Assistant ProfessorUniversity of Florida, College of Pharmacy

Gainesville, FL

disclosure guideline updates 1 48th annual meeting navigating the oceans of opportunity pour some...

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