Practical Diabetes Management - Welcome to CCEHS · PDF file · 2017-03-24Practical...

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Mary Korytkowski M.D.

Professor of Medicine

University of Pittsburgh

Practical Diabetes Management

Choosing the Right Medication

Mary Korytkowski MD

Honoraria

British Medical Journal Diabetes Research and Care

Advisory Board Member Novo Nordisk

Other

ABIM Endocrinology & Metabolism Test-Writing Committee

No exam content will be disclosed

Disclosure of Financial Relationships

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Biguanides: Metformin

Insulin secretogogues: Sulfonylureas, meglitinides

Sodium glucose cotransporter 2 (SGLT2) inhibitors

Thiazolidinediones (TZD)

Incretins — Dipeptidyl peptidase IV inhibitors (DPP-IV)

— Glucagon like peptide agonists

_________________________________

Alpha glucosidase inhibitors

Other agents — Bile acid sequestrants

— Bromocriptine

Amylin agonists

Non-insulin therapy for treatment of diabetes

Pharmacologic Approaches to Glycemic Treatment

4 Diabetes Care 2017;40(Suppl. 1):S64–S74

Efficacy

Risk for hypoglycemia

Weight

Side effects

Cost

Factors to consider in choosing the right medication

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Metformin

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Efficacy Reduces A1c by 1.5-2.0%

Risk for hypoglycemia Low

Weight Neutral / Mild weight loss

Side effects B12 Deficiency (monitor B12 levels periodically)

Gastrointestinal (5% of patients)*

Lactic acidosis (rare)

Cost Low

*Can be minimized by using extended release formulations and taking after a meal

Insulin secretogogues:

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Efficacy

Reduces A1c by 1.5-2.0%


Moderate

Weight

Neutral / gain

Side effects

Hypoglycemia

Cost

Low

Sulfonylureas: glipizide and glimepiride

Glinides: repaglinide and meglitinide

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Glyburide

https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiTxvPI6OrSAhWn6oMKHTwBA3oQjRwIBw&url=https://commons.wikimedia.org/wiki/File:Simple_Prohibited.svg&psig=AFQjCNED9MtbRChP5CZduZuCIGQVEkJEDg&ust=1490296319798159

Thiazolidinediones: Pioglitazone, Rosiglitazone

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Efficacy

High


Low

Weight

Weight gain

Side effects

Edema

CHF

Bone loss and fractures

Cost

Low

Sodium Glucose Transporter (SGLT) 2 Inhibitors

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Efficacy

Intermediate (Reduce A1C by ~ 0.8-1.0%)


Low

Weight

Weight loss

Side effects

Genito-urinary infections

Dehydration

Fracture risk (canagliflozin)

Cost

High

dapagliflozin , canagliflozin, empagliflozin

Dipeptidyl Peptidase Inhibitors

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Efficacy

Intermediate (Reduce A1C by ~ 0.8-1.0%)


Low

Weight

Weight neutral

Side effects

Infrequent

Increase in nasopharyngitis/URI/UTI

Headache, myalgias / arthralgias

Rarely LFT elevations

Case reports of acute pancreatitis

Rare case reports severe hypersensitivity reactions with

anaphylaxis, angioedema, exfoliative skin conditions

Cost

High

Sitagliptin / Saxagliptin / Alogliptin / Linagliptin

Glucagon Like Peptide 1 (GLP1) Receptor Agonists

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Efficacy

High


Low

Weight

Weight loss

Side effects

Gastrointestinal (nausea, vomiting) Post-marketing reports of pancreatitis and acute renal failure

Cost

High

exenatide, liraglutide, albiglutide, dulaglutide

The reported low risk for hypoglycemia reported with

TZDs, , GLP1 agents, DPP4 and SGLT2 inhibitors

increases when these agents are used in combination

with insulin secretogogues or insulin

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82 year old male with 20 year history type 2 diabetes and osteopenia

Microvascular complications: Background DR, Neuropathy, CKD

Macrovascular complications: CAD s/p CABG

Home glucose: FBG 110-218 mg/dl

Hypoglycemia: none reported

Medications

Glipizide 5 mg BID

Metformin 500 mg bid

Pravastatin 20 mg

Ramipril 10 mg qd

Atenolol 12.5 mg

Vitamin D 1000 IU

PE: Wt 210 lbs HT 5”9” BMI 312 kg/m

BP 146/80 HR 70

Extremities 1+ pitting edema

Absent KJ / AJ DTRs

Vibration decreased 50% MF testing normal

Laboratory Studies

HA1c 8.4% (increased from 7.8%)

Creatinine 1.6 mg/dl eGFR 46 ml/min

LFTs normal

LDL 89

25 Vitamin D 35 ng/ml

Patient Case

Management of Atherosclerotic Cardiovascular Disease Risk Factors in the Older Adult Patient With Diabetes

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Korytkowski M and Forman DE Diabetes Care April 2017.

Consensus Development Conference on

Diabetes in Older Adults A Framework for Considering Treatment Goals

Kirkman et al. JAGS. Special Report-Diabetes in Older Adults: A Consensus Report 2012, 1-15.

American Geriatric Society:

A1c Recommendations 2013 for 65+

• 7.5 - 8% in general for the older adults

• 7% - 7.5% may be appropriate if it can be safely achieved in healthy older adults with few comorbidities and good functional status

• 8% - 9% is appropriate for older adults with multiple comorbidities, poor health, and limited life expectancy (IIA)

• Potential harm in lowering A1C to < 6.5% in older adults with type 2 DM (IIA)

American Geriatrics Society (AGS) Panel . Guidelines for Improving the Care of the Older Person with Diabetes Mellitus. J Am Geri Soc 2013; 51:S265-S280

? Increase dose of metformin

? Stop metformin

? Increase dose of glipizede

? Stop glipizide

? Add an SGLT2 inhibitor

? Add pioglitazone

? Add a DPP-IV inhibitor

? Add a GLP1 receptor agonist

? Add a basal insulin

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What is the correct medication for this patient?

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Updated Metformin–CKD Prescribing Guidelines (April 2016)

• Obtain eGFR before starting metformin and annually, more

frequently in those at risk for renal impairment (e.g., elderly).

• Metformin contraindicated in patients with an eGFR <30.

• Starting metformin in patients with an eGFR between 30-45 not

recommended.

• If eGFR falls <45, assess the benefits and risks of continuing

treatment. D/C if eGFR falls <30.

• Hold metformin at the time of / before iodinated contrast

procedure if eGFR 30-60; if h/o liver disease, alcoholism, or heart

failure; or if intra-arterial contrast. Recheck eGFR 48 hrs after

procedure and restart if renal function stable. http://www.fda.gov/Drugs/DrugSafety/ucm493244.htm (accessed 4-8-16)

http://www.fda.gov/Drugs/DrugSafety/ucm493244.htm

0

1

2

3

4

5

6

7

8

9

SU only SU + eGFR<30ml/min

SU +eGFR 30-59ml/min

SU +eGFR >60ml/min

Hazard Ratio (HR) for hypoglycemia with current SU therapy according to eGFR

Risk of Hypoglycemia with Sulfonylureas compared with metformin in relation to renal function

21 Van Dalem J et al BMJ 2016;354:i3625

Results adjusted for age and sex


? Stop metformin

? Increase dose of glipizide

? Stop glipizide


? Add pioglitazone




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SGLT2-Inhibitors: Mechanism of action

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Sodium-Glucose Cotransporter 2 Inhibitors

Advantages

• Effective

• Do not cause hypoglycemia when used alone or in combination with metformin

• Associated with weight loss, reductions in BP, and CVD events

Disadvantages: Expensive

May offer unique cardiovascular benefit

Empagliflozin recently approved for use

Original Article Empagliflozin, Cardiovascular Outcomes, and

Mortality in Type 2 Diabetes

Bernard Zinman, M.D., Christoph Wanner, M.D., John M. Lachin, Sc.D., David Fitchett, M.D., Erich Bluhmki, Ph.D., Stefan Hantel, Ph.D., Michaela Mattheus, Dipl.

Biomath., Theresa Devins, Dr.P.H., Odd Erik Johansen, M.D., Ph.D., Hans J.

Woerle, M.D., Uli C. Broedl, M.D., Silvio E. Inzucchi, M.D., for the EMPA-REG OUTCOME Investigators

N Engl J Med Volume 373(22):2117-2128

November 26, 2015

7070 subject with T2D at high risk for CVD randomized to Placebo,

Study Drug 10 or 25 mg for ~ 3.1 years

Mean age of subjects ~63 ± 9 years

Mean BMI ~30 ± 5 kg/m2

Emplagliflozin Study: HbA1c Levels

Zinman B et al. N Engl J Med 2015;373:2117-2128

Subject treated with study drug had

decreases in SBP of 4 mm Hg, DPB 1.5 mm

Hg, weight 2 kg, and waist circumference

Cardiovascular Outcomes and Death

Zinman B et al. N Engl J Med 2015;373:2117-2128

CVD death, nonfatal MI or CVA

Sodium-Glucose Cotransporter 2 Inhibitors Disadvantages:

• Increase in risk for “euglycemic DKA”

• High risk for volume depletion, hypotension and dehydration

Use carefully, if at all, in the elderly or those receiving diuretics

• Contraindicated in patients with advanced kidney disease

Effect declines as eGFR declines

Minimal effect with eGFR < 50 ml/min

• These are very new drugs for which long term safety has yet

to be established

Concern for an increase in bladder and breast neoplasms raised in

preclinical trials

• (I would not use this in any male suspected of having

prostatic hyperplasia)

Efficacy of SGLT-2 inhibitors (dapagliflozin) is reduced with declining eGFR.

van Bommel EJM et al. Clin J Am Soc Neph March 2017 doi:10.2215/CJN.06080616 ©2017 by American Society of Nephrology

Effect of the SGLT2i Canagliflozin on Fracture Risk

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Watts NB et al J Clin Endocrinol Metab 2016;101:157

Pooled analysis of data from 3 large preclinical trials

CANagliflozin cardioVascular Assessment Study (CANVAS) was primary

contributor to observed increase in fracture risk

4330 patients with T2D with elevated CVD risk Mean age 62±8 years


? Stop metformin


? Stop glipizide


? Add pioglitazone




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• Weight gain (up to 10 kg in some patients)

• Reductions in bone density with increase risk of fractures

• Exacerbation of CHF

– Use with caution in patients with pre-existing CHF

• Significant questions raised regarding CV safety of

rosiglitazone (2011)

• Increased bladder cancer risk with pioglitazone

demonstrated in some but not all studies

TZDS: Considerations for Use

Kernan WN et al. N Engl J Med 2016;374:1321

U.S. National Institute of Neurological Disorders and Stroke

(Grant # U01NS044976)

February 17, 2016DOI: 10.1056/NEJMoa1506930

IRIS Secondary Outcomes Pioglitazone

(N=1939)

Placebo

(N=1937)

Outcome* % (No.) % (No.)

Hazard Ratio

(95% CI) P

ACS 5.0 (96) 6.6 (128) 0.75 0.11

Stroke/MI/HF 10.6 (206) 12.9 (249) 0.82 0.11

DM 3.8 (73) 7.7 (149) 0.48 <.0001

Death 7.0 (136) 7.5 (146) 0.93 0.52

*ACS=Acute coronary syndrome (unstable angina or MI).

*HF=heart failure

IRIS Serious Adverse Events

# Participants

Pioglitazone

(N=1939)

Placebo

(N=1937)

Event % (N) P

Bone fracture† 5.1 (99) 3.2 (66) <0.01

Heart failure† 2.6 (51) 2.2 (42) 0.35

Incident cancer 6.9 (133) 7.7 (150) 0.29

†Previously reported to be associated with pioglitazone or drugs in its class.

IRIS Non-Serious Adverse Events

Pioglitazone

(N=1939)

Placebo

(N=1937)

Event % (No. Participants) P

Weight Gain†

at Year 4, mean 2.6 kg -0.5 kg <0.01

New or worse edema†

691 (36%)

483 (25%)

<0.01

New or worse SOB†

342 (18%)

292 (15%)

0.03

†Previously reported to be associated with pioglitazone or drugs in its class.


? Stop metformin


? Stop glipizide


? Add pioglitazone




_________________________________


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• Can be taken with or without food

• Once-daily dosing

• Side effects are infrequent

Increase in upper respiratory infections/UTI

Headache

Case reports of acute pancreatitis

Rare case reports severe hypersensitivity reactions with anaphylaxis, angioedema, and exfoliative skin conditions

• No evidence of macrovascular risk reduction

• Increased CHF exacerbations with saxagliptin

Dipeptidyl Peptidase-IV Inhibitors

DPP-IV Inhibitors

Initial dose Maximum

dose

Δ A1c Half life (hr) Duration

(hr)

Sitagliptin 100 mg 100 mg -0.8% 12

~16

Saxagliptin 2.5 mg 5 mg -0.6% 2.5 24

Linagliptin 5 mg 5 mg -0.7% 12 ~ 100 *

Alogliptin 25 mg 25 mg - 0.6% 21

Renal dose

adjustment

Hepatic

dose adj.

+ -

+ -

- -

+ -

CVD Safety of Sitagliptin in Older Adults

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2004 participants with T2D and CVD age 78 ± 3 years (all >75) randomly assigned

to sitagliptin or placebo

Study outcomes : Sitagliptin vs. Placebo (TECOS)

43 Bethel MA et al. Diabetes Care 2017;40:494


? Stop metformin


? Stop glipizide


? Add pioglitazone

Add a DPP-IV inhibitor: Reasonable Choice Sitagliptin 50 mg or Linagliptin 5 mg

Biggest concern: Cost



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DPP-IV Inhibitors

Approved Cost

Sitagliptin 2006 $361 (30)

Saxagliptin 2009 $354 (30)

Linagliptin 2011 $1083 (90)

Alogliptin 2013 $340 (30)

Initial

Dose Max Dose ΔA1c Weight

Loss (kg)*

Half Life

Exenatide 5 mcg 10 mcg BID -0.9% -2.9 ~ 2.4 hr

Exenatide ER 2 mg 2 mg Qwk -1.5% -2.0 ~ 2 week

Liraglutide 0.6 mg 1.8 mg QD -1.1% -2.5 ~ 13 hr

Albiglutide 30 mg 50 mg Qwk -0.9% -0.9 ~ 5 days

Dulaglutide 0.75 mg 1.5 mg Qwk -0.8% -2.3 ~ 5 days

Lixisenatide 10 mcg 20 mcg QD -0.8% -- --

Renal dose

adjustment

Hepatic dose

adj.

- -

- -

- -

- -

- -

Glucagon-Like Peptide 1 Agonists

Incretin therapy improves first phase insulin secretion in type 2 diabetes

Time (min) -180 -90 0 30 60 90 120

Intravenous glucose

Insu

lin (

pM

/kg/

min

) Exenatide

Placebo

The GLP1 analog exenatide reduces glucose and glucagon levels following a meal

Kolterman J Clin Endocrinol Metab. 2003;88:3082-3089

0 120 180 60 50

100

150

200

Glucagon (pg/mL)

Placebo Exenatide

Standardized Breakfast

Time (min)

Plasma Glucose (mg/dL)

90

180

270

360

Standardized Breakfast

0 60 120 180 240 300

Placebo Exenatide

GLP-1RA in Older Adults: GetGoal-O

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350 participants with T2D and CVD age 74 ± 4 years of age (37% > 75 and 11% >

80) (28% with eGFR 30-60 ml/min) randomly assigned to a GLP-1RA

(lixesenatide) or placebo

30% on insulin / 30% on SU + metformin / 30% on other oral DM medications

HbA1c Glucose profile

Meneilly GS et al. Diabetes Care 2017;40:485

Frequency of Nausea in GetGoal-O

50 Meneilly GS et al. Diabetes Care 2017;40:485

Lixisenatide

Placebo

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Placebo Lixisenatide

< 59 mg/dl

Adverse Events : GetGoal-O

Meneilly GS et al. Diabetes Care 2017;40:485

Hypoglycemia was more frequent in lixisenatide group receiving SU (11.9% vs.

3.9% in placebo group) and less frequent in those receiving basal insulin in

combination with the GLP-1RA (5.4 vs. 12.7% of patients)


? Stop metformin


? Stop glipizide


? Add pioglitazone



Add a GLP1 receptor agonist Biggest concern: Cost (but would want to stop or lower dose SU)


_________________________________


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Progression to insulin therapy in type 2 diabetes

53 Diabetes Care 2017;40(Suppl 1):S64


? Stop metformin


? Stop glipizide


? Add pioglitazone



Add a GLP1 receptor agonist Biggest concern: Cost

Add a basal insulin: Starting dose 0.1 unit/kg or 6-10 units/day

_________________________________


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82 year old male with 20 year history type 2 diabetes and osteopenia

Microvascular complications: Background DR, Neuropathy, CKD

Macrovascular complications: CAD s/p CABG

Home glucose: 110-218 mg/dl

Hypoglycemia: none reported

Medications

Glipizide 5 mg BID

Metformin 500 mg bid

Pravastatin 20 mg

Ramipril 10 mg qd

Atenolol 12.5 mg

Vitamin D 1000 IU

PE: Wt 210 lbs HT 5”9” BMI 312 kg/m

BP 146/80 HR 70

Extremities 1+ pitting edema

Absent KJ / AJ DTRs

Vibration decreased 50% MF testing normal

Laboratory Studies

HA1c 8.4% (increased from 7.8%)

Creatinine 1.6 mg/dl eGFR 46 ml/min

LFTs normal

LDL 89

25 Vitamin D 35 ng/ml

Patient Case Summary

• Metformin:

– No need to DC therapy based on current guidelines

– Would not increase dose further with eGFR < 50 ml/min

• Sulfonylurea

– No need to lower dose or DC as no evidence hypoglycemia unless

additional medication started that could increase risk

• TZDS

– Raise risk for worsening of LE edema, CHF, and fractures

• SGTL2 inhibitors

– While he may benefit from CVD risk reduction, low eGFR may limit efficacy

• DPP4 inhibitor or GLP-1RA

– Demonstrated efficacy and safety in elderly population

• Add basal insulin with progression of dosing according to home

BG monitoring

Summary

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