Rational Goal-Setting and Management of Diabetes in the Elderly

Michael Shannon, MD Medical Director, Accountable Care, PMG SWR

PMG Endocrinology, Olympia WA

Presenter Disclosure Information

In compliance with accrediting board policies, the American Diabetes Association requires the following

disclosure to participants:

Michael Shannon, MD: Speaker’s Bureau: Novo Nordisk, Inc. Consultant: Eli Lilly, Novo Nordisk, Inc.

Outline of Talk

Challenges of diabetes care in the elderly Goal setting and A1c targets in elderly Interpret studies for diabetes agents

cardiovascular safety, released in last 12 months Current guidelines (ADA-EASD, AACE) and

review of treatment options for elderly

Disclosure: Speaker and Consultant, Novo Nordisk

Epidemiology of Diabetes in Elderly

Estimated at 26% for those aged 65+ Long term care (2007):

24% in nursing homes 22% in assisted living facilities

Unique Challenges in Managing These Patients

Hypoglycemia in the Elderly

Presentation overlaps other frailty syndromes Confusion, word-finding errors, altered LOC Tremors / dizziness No one goes wrong getting a UA and Fingerstick

Limited ability to self-manage hypoglycemia Limited vision/transfer ability to self-rescue Increased fall risk, sedation from other medication In institution, limited access to self-correction

Hyperglycemia in the Elderly

Symptomatic hyperglycemia Polyuria: glycosuria load, UTI risk Dehydration (impaired thirst, impaired access) Blurry vision (increased falls) Impaired wound healing

Unlike hypoglycemia, these are more subtle and slower to emerge -> need more vigilance

Polypharmacy and Complex PMH

Increases Hyperglycemia Steroids Antipsychotics Infections / immobility

Increases Hypoglycemia Sedative Agents Renal impairment Poor nutrition Cirrhosis (limited synthesis)

Diabetes Assessment in the Elderly

Goal-Setting for General Diabetes Plan

Physical Assessment Nutritional Assessment

Physical Assessment

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Nutritional Assessment

Malnutrition Poverty / isolation Dentition WWII Widower

Depression Cognitive Impairment

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Physical Assessment

Ophthalmic Higher rates of cataracts, glaucoma and macular

degeneration. Dexterity/Hands:

Vials vs pens, choice of meters General Home Safety Eval (cords, rugs, cats)

A1c Goals in the Elderly

STANDARDS OF MEDICAL CARE IN DIABETES—2016

• Lowering A1C to below or around 7% has been shown to reduce microvascular complications and, if implemented soon after the diagnosis of diabetes, is associated with long-term reduction in macrovascular disease. Therefore, a reasonable A1C goal for many nonpregnant adults is <7% B

Recommendations: Glycemic Goals in Adults (1)

ADA. 6. Glycemic Targets. Diabetes Care 2015;38(suppl 1):S35

• Providers might reasonably suggest more stringent A1C goals (such as <6.5%) for selected individual patients, if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Appropriate patients might include those with short duration of diabetes, long life expectancy, and no significant CVD C

Recommendations: Glycemic Goals in Adults (2)

ADA. 6. Glycemic Targets. Diabetes Care 2015;38(suppl 1):S35

Recommendations: Glycemic Goals in Adults (3)

• Less stringent A1C goals (such as <8%) may be appropriate for patients with B – History of severe hypoglycemia, limited life expectancy,

advanced microvascular or macrovascular complications, extensive comorbid conditions

– Those with longstanding diabetes in whom the general goal is difficult to attain despite DSME, appropriate glucose monitoring, and effective doses of multiple glucose lowering agents including insulin

ADA. 6. Glycemic Targets. Diabetes Care 2015;38(suppl 1):S35

Approach to the Management of Hyperglycemia

ADA. 6. Glycemic Targets. Diabetes Care 2015;38(suppl 1):S37. Figure 6.1; adapted with permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149

Elderly DM Goals: My 3 Levels

For those with good functional status, same as others post-ACCORD study (probably about 7-7.5% depending on CV disease)

For life expectancy < 5 years, < 8% For palliative care patients: avoid symptoms

Glucose > 180 = glycosuria, dehydration, UTIs Glucose over ~225 = poor wound healing,

increased decubitus ulcers

Diabetes: Recent CV Outcome Trials

Landmark Trials for Elderly DM

DCCT: For DM1, enrolled people < 39 years of age

UKPDS: did not enroll past 59 years of age

Last round of trials without CV benefit include ACCORD (mean age 62), VADT (mean age 60), and ADVANCE (mean age 66) but few > 75 years old

No outcome trial focused on elderly (no HYVET)

No major trials at all for frail/institutionalized elderly

Recent trials of newer glucose-lowering agents have been neutral on the primary CV outcome

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SAVOR-TIMI 53

EXAMINE

HR: 1.0 (95% CI: 0.89, 1.12)

HR: 0.96 (95% CI: UL ≤1.16)

TECOS

HR: 0.98

(95% CI: 0.88, 1.09)

EMPA-REG OUTCOME®

ELIXA

HR: 1.02

(95% CI: 0.89, 1.17)

Empagliflozin

DPP-4 inhibitors*

Lixisenatide

CV, cardiovascular; HR, hazard ratio; DPP-4, dipeptidyl peptidase-4 *Saxagliptin, alogliptin, sitagliptin Adapted from Johansen OE. World J Diabetes 2015;6:1092-96

2013 2014 2015

Key inclusion and exclusion criteria

• Key inclusion criteria – Adults with type 2 diabetes – BMI ≤45 kg/m2 – HbA1c 7–10%* – Established cardiovascular disease

• Prior myocardial infarction, coronary artery disease, stroke, unstable angina or occlusive peripheral arterial disease

• Key exclusion criteria

– eGFR <30 mL/min/1.73m2 (MDRD)

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BMI, body mass index; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease *No glucose-lowering therapy for ≥12 weeks prior to randomisation or no change in dose for ≥12 weeks prior to randomisation or, in the case of insulin, unchanged by >10% compared to the dose at randomisation

Baseline characteristics Placebo (n=2333)

Empagliflozin 10 mg

(n=2345)

Empagliflozin 25 mg

(n=2342) Age, years 63.2 (8.8) 63.0 (8.6) 63.2 (8.6) Male 1680 (72.0) 1653 (70.5) 1683 (71.9) Region

Europe 959 (41.1) 966 (41.2) 960 (41.0) North America* 462 (19.8) 466 (19.9) 466 (19.9) Asia 450 (19.3) 447 (19.1) 450 (19.2) Latin America 360 (15.4) 359 (15.3) 362 (15.5) Africa 102 (4.4) 107 (4.6) 104 (4.4)

Data are n (%) or mean (SD) in patients treated with ≥1 dose of study drug

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*Includes Australia and New Zealand

Patients with event/analysed

Empagliflozin Placebo HR (95% CI) p-value

3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382

CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001

Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189

Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638

0.25 0.50 1.00 2.00

CV death, MI and stroke

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Favours empagliflozin Favours placebo

Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI

CV death

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HR 0.62 (95% CI 0.49, 0.77)

p<0.0001

Cumulative incidence function. HR, hazard ratio

3-point MACE: subgroup analysis Empagliflozin Placebo

All patients 4687 2333 Age, years 0.01 <65 2596 1297 ≥65 2091 1036

Sex 0.81 Male 3336 1680 Female 1351 653

Race 0.09 White 3403 1678 Asian 1006 511 Black/African-American 237 120

HbA1c, % 0.01 <8.5 3212 1607 ≥8.5 1475 726

Body mass index, kg/m2 0.06 <30 2279 1120 ≥30 2408 1213

eGFR, mL/min/1.73m2 0.20 ≥90 1050 488 60 to <90 2425 1238 <60 1212 607

p-value for interaction

0.25 0.50 1.00 2.00 4.00Favours empagliflozin Favours placebo

For the test of homogeneity of the treatment group difference among subgroups with no adjustment for multiple tests. eGFR, estimated glomerular filtration rate (according to Modification of Diet in Renal Disease equation)

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HR (95% CI)

Hospitalisation for heart failure

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HR 0.65 (95% CI 0.50, 0.85)

p=0.0017

Cumulative incidence function. HR, hazard ratio

All-cause mortality

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HR 0.68 (95% CI 0.57, 0.82)

p<0.0001

Kaplan-Meier estimate. HR, hazard ratio

0.25 0.50 1.00 2.00

Patients with event/analysed Empagliflozin Placebo

HR 95% CI p-value

All-cause mortality 269/4687 194/2333 0.68 (0.57, 0.82) <0.0001

CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001

Non-CV death 97/4687 57/2333 0.84 (0.60, 1.16) 0.2852

All-cause mortality, CV death and non-CV death

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Favours empagliflozin Favours placebo

Cox regression analysis. CV, cardiovascular; HR, hazard ratio

Adverse events consistent with genital infection

Rate = per100 patient-years

Placebo (n=2333)

Empagliflozin 10 mg

(n=2345)

Empagliflozin 25 mg

(n=2342)

n (%) Rate n (%) Rate n (%) Rate

Events consistent with genital infection

42 (1.8%)

0.73 153 (6.5%)

2.66 148 (6.3%)

2.55

Serious events 3 (0.1%)

0.05 5 (0.2%)

0.08 4 (0.2%)

0.07

Events leading to discontinuation

2 (0.1%)

0.03 19 (0.8%)

0.32 14 (0.6%)

0.23

By sex

Male 25 (1.5%)

0.60 89 (5.4%)

2.16 77 (4.6%)

1.78

Female 17 (2.6%)

1.09 64 (9.2%)

3.93 71 (10.8%)

4.81

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Patients treated with ≥1 dose of study drug Based on 88 MedDRA preferred terms

EMPA-REG OUTCOME®: Summary

• Empagliflozin reduced risk for 3-point MACE by 14%

• Empagliflozin was associated with a reduction in HbA1c without an increase in hypoglycaemia, reductions in weight and blood pressure, and small increases in LDL cholesterol and HDL cholesterol

• Empagliflozin was associated with an increase in genital infections but was otherwise well tolerated

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MACE, Major Adverse Cardiovascular Event; HDL, high density lipoprotein; LDL, low density lipoprotein

EMPA-REG OUTCOME®: Summary

• Empagliflozin reduced hospitalisation for heart failure by 35%

• Empagliflozin reduced CV death by 38%

• Empagliflozin improved survival by reducing all-cause mortality by 32%

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CV, cardiovascular

LEADER - Analysis by Age

Diagnosis is a fairly soft endpoint, but death is unequivocal.

Edwin AM Gale, Lancet 2003

Guidelines: ADA vs AACE (vs me)

Antihyperglycemic Therapy in Type 2 Diabetes

ADA. 7. Approaches to Glycemic Treatment. Diabetes Care 2015;38(suppl 1):S43. Figure 7.1; adapted with permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149

The Diabetes Toolbox 2016 Drug Class (First in Class) FDA Approval Insulin (subcutaneous) 1922 (first use) Sulfonylurea (chlorpropamide) 1958 Biguanide (metformin) 1995 Alpha-glucosidase inhibitors (acarbose) 1995 Thiazolidinedione (troglitazone) 1997 Meglitinide (repaglinide) 1997 Incretins (pramlintide, exenatide) 2005 DPP-IV Inhibitors (sitagliptin) 2006 Bile acid sequestrant (colesevelam) 2008 (DM) Dopamine agonist (bromocriptine QR) 2009 SGLT-2 inhibitor (canagliflozin) 2013

The Toolbox in 2016

Metformin: great – with new GFR guidance – please use metformin ER

Sulfonylureas: cheap, but risk of hypoglycemia; no more glyburide (and its evil metabolite norglyburide cleared through kidneys) -> now $4 monthly glimepiride

TZDs: no hypoglycemia but risks of edema, CHF, and possibly fractures and malignancies

Available for Q&A: colesevelam, bromocriptine

Metformin FDA (April 2016): “We have concluded

from the review of studies published in the medical literature that metformin can be used safely in patients with mild impairment in kidney function and in some patients with moderate impairment in kidney function.”

Label update: now “contraindicated” if eGFR is <30mL/min/1.73m2

2014 update from the International Society of Nephrology: metformin may still be appropriate for eGFR 14-29mL/min/1.73m2

GLP-1 Agonists

Modest benefit in HbA1c 0.7-1.1% and some weight loss as well but some nausea

Safety warnings about pancreatitis and medullary thyroid cancer

Cardiovascular studies nearing completion Can be used in combination with basal insulin

at same time of day, for probably best efficacy with reasonably low risk of hypoglycemia

DPP-IV Inhibitors

Sitagliptin, saxagliptin, linagliptin, alogliptin Modest decrease in HbA1c of 0.5% - 0.8%; Minimal side effects (possible more minor

infections) except saxagliptin showed increased congestive heart failure (seen in ADA guideline)

SGLT-2 Inhibitors

Approved starting in 2013 SGLT-2 inhibitor blocks renal re-absorption of

glucose and lowers blood sugars Associated with similar modest HbA1c decrease

of 0.5% - 0.7%) as DPP-IV inhbitors (UTDOL) Risks: infections and dehydration, DKA Independent of resistance (can use with insulin)

but limit dose eGFR 45-60 and don’t use < eGFR 45 or with hepatic impairment.

Final Words on Newer Agents

None of these have been in wide use for long Lessons of rosiglitazone: hemoglobin A1c is

a surrogate endpoint, not the true goal of care All the new drugs cost upwards of $10/day

Final Words on Newer Agents

None of these have been in wide use for long Lessons of rosiglitazone: hemoglobin A1c is

a surrogate endpoint, not the true goal of care All the new drugs cost upwards of $10/day For elderly, hypoglycemia safety probably is

main reason to use, or dosing convenience, with possible exception of empagliflozin and liraglutide b/c cardiovascular outcome study

Indications for Insulin Therapy

Severe hyperglycemia at diagnosis Hyperglycemia despite maximum doses of

non-insulin agents Decompensation of other organ systems that

limits use of other oral agents Early cost-effective potent treatment

Approach To Starting and Adjusting Insulin in Type 2 Diabetes

ADA. 7. Approaches to Glycemic Treatment. Diabetes Care 2015;38(suppl 1):S46. Figure 7.2; adapted with permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149

To Infinity and Beyond

Insulin Pens = KEY for elderly (easier than ever: CTS, visual impairment, neuropathy)

Insulin pumps appropriate if motivated and fulfill strict Medicare criteria

AMDA has excellent LTC guidelines for also incorporating multidiscipinary team

Conclusion

Diabetes is common in the elderly and care of these individuals is more challenging

ADA and AACE have slightly different goals of care and treatment pathways, and toolbox can be viewed with focus on elderly

The EMPA REG and LEADER study showed cardiovascular and all-cause mortality reduction with empagliflozin and liraglutide

Questions and Appreciation