Rational Goal-Setting and Management of Diabetes in the ... › ... › files › media ›...
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Rational Goal-Setting and Management of Diabetes in the Elderly
Michael Shannon, MD Medical Director, Accountable Care, PMG SWR
PMG Endocrinology, Olympia WA
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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.
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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
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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
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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
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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
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Polypharmacy and Complex PMH
Increases Hyperglycemia Steroids Antipsychotics Infections / immobility
Increases Hypoglycemia Sedative Agents Renal impairment Poor nutrition Cirrhosis (limited synthesis)
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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)
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A1c Goals in the Elderly
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STANDARDS OF MEDICAL CARE IN DIABETES—2016
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• 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
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• 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
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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
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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
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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
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Diabetes: Recent CV Outcome Trials
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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
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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
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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
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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
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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
25
Favours empagliflozin Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI
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CV death
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HR 0.62 (95% CI 0.49, 0.77)
p<0.0001
Cumulative incidence function. HR, hazard ratio
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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)
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Hospitalisation for heart failure
28
HR 0.65 (95% CI 0.50, 0.85)
p=0.0017
Cumulative incidence function. HR, hazard ratio
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All-cause mortality
29
HR 0.68 (95% CI 0.57, 0.82)
p<0.0001
Kaplan-Meier estimate. HR, hazard ratio
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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
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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
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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
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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
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LEADER - Analysis by Age
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Diagnosis is a fairly soft endpoint, but death is unequivocal.
Edwin AM Gale, Lancet 2003
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Guidelines: ADA vs AACE (vs me)
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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
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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
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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
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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
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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
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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)
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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.
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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
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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
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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
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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
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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
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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
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Questions and Appreciation