Diabetes Update 2017 · Diabetes Update—2017 Timothy C. Evans, MD PhD FACP Department of Medicine...

Diabetes Update—2017

Timothy C. Evans, MD PhD FACP

Department of Medicine

and MEDEX Northwest

University of Washington

NCCPA Disclaimer

• I am on the Board of Directors (BOD) of NCCPA.

• The BOD is involved with strategic direction and policy.

• The BOD does not develop or review the exams.

• I have never taken nor seen the PANCE, PANRE, or

individual test items.

• In this lecture I am not speaking on behalf of the

NCCPA, nor with any knowledge of specific exam test

items.

Topics

• Diagnosis/Standards of Care

• Diabetic Foot Evaluation

• Rx including New Drugs

• A Word About Thiazolidinediones

• What Should the Glucose Goal Be?

• Metabolic Syndrome and DM prevention

• What’s Next?

Types of Diabetes

• Type 1—Autoimmune, insulin deficient, DKA

prone

• Type 2—Familial, insulin resistance and

abnormal insulin secretion

• Gestational

• Other—Drug induced, endocrinopathies,

genetic

Diagnostic Criteria

• FPG ≥ 126 mg/dL

• Random PG ≥ 200 mg/dL in a patient with Sx of

hyperglycemia

• 2-hr PPG ≥ 200 mg/dL during OGTT

• ADA Rec: Screen high risk pts q 3 yrs

• HbA1c (2010, became an official diagnostic criterion)

– Prediabetes, 5.7–6.4%

– Diabetes, 6.5% or greater

Who to Screen

• BMI > 25 kg/m2 (> 23 kg/m2 Asian Amer) and:

– Phys inact; +1st deg rel with DM; Hx GDM; HBP;

HDL < 35 mg/dL and/or TG > 250 mg/dL; women

with PCOS; HbA1c > 5.7%, IGT, IFG; cond assoc

with ins resist (severe obesity, acanthosis nigricans);

Hx CVD.

– Start at age 45 yrs

– Repeat q3yrs, more freq for pre-DM or other risks

Standards of Care

• Diabetes Care (journal) Supplement, each

January

• Accessible at www.diabetes.org

• SoC 2016, Abridged for Primary Care

Providers at:

• http://clinical.diabetesjournals.org/site/misc/

2016Abridged-SOC.pdf

Normal Goal

Additional

Action

Suggested

Whole blood values

Average preprandial glucose (mg/dl) <100 80–130 <80 or >140

Average bedtime glucose (mg/dl) <110 100–140 <100 or >160

Plasma values

Average preprandial glucose (mg/dl) <110 90–130 <90 or >150

Average bedtime glucose (mg/dl) <120 110–150 <110 or >180

HbA1c (%) <6 <7 >8

Standards of Care Glycemic Control

Standards of Care Weight and Diet

• Diet: 50+% calories from carbohydrate,

< 30% calories from fat (mostly

monounsaturated, < 7% sat, < 200 mg chol, min

trans FA), 15-20% from protein (0.8 g/kg)

• Weight control for overwt or obese: 500–1000

kcal/d deficit. Inc insulin sensitivity in type 2.

• Bariatric surgery consider in BMI > 35kg/m2

Standards of Care Exercise

• Attention to micro and macrovascular dis

• Gradual increase

• ETT if ≥ 10% 10-yr cardiac event risk

• 150+ min/wk mod ex (50–70 % max ht rt)

• Or 90+ min/wk vigorous aerobic ex (> 70% max ht rt)

• Spread over at least 3 d/wk, no more than 2 consecutive days of inactivity

Prevention of Complications Hypertension

• Goal < 140/90 (lower?, JNC 8)

• Regimen should include ACEI or ARB,

esp if also nephropathy

• Add CCB, thiazide, others

• Lifestyle—smoking cessation, diet

(DASH, mod EtOH, sodium < 2.4 g/d),

physical activity (mod-vig 3-4 days/wk,

40 min/session)

Prevention of Complications Dyslipidemia—ATP 4

• Four statin benefit groups

– Clinical ASCVD

– LDL > 190 mg/dL

– DM, 40-75 yrs, LDL 70-189 mg/dL

– 40-75 yrs, LDL 70-189 mg/dL, 10-yr risk 7.5%

or higher, no DM or ASCVD

New Risk Calculator

• 10-yr risk for ages 40-75 years

• Similar risk factors to Framingham

– Sex, age, race, total cholesterol, HDL-

cholesterol, systolic BP, Rx for HBP, diabetes,

smoking

• Diabetes not an automatic ASCVD risk

equivalent

• http://clincalc.com/Cardiology/ASCVD/Poo

ledCohort.aspx

Statin Intensity

• High—lowers LDL by > 50%

– atorv 40-80 mg, rosuv 20-40 mg

• Moderate—lowers LDL by 30 to < 50%

– atorv 10-20, rosuv 5-10, simva 20-40, similar

moderate doses for the other statins

• Low—lowers LDL by < 30%

– simva 10 mg, similar low doses other statins,

no atorv or rosuv

ASCVD Risk

• 50 y/o, Tchol 250 mg/dL, HDL 38 mg/dL,

SysBP 145 mmHg, HTN Rx yes, smoker no

• DM no, 10-yr ASCVD risk 9.1%

• DM yes, 10-yr ASCVD risk 16.8%

ASCVD Risk


SysBP 145 mmHg, HTN Rx yes, smoker no



ASCVD Risk


SysBP 125 mmHg, HTN Rx no, smoker no



Prevention of Complications Smoking Cessation & ASA Use

• Smoking—quit all tobacco products

• 1/4–1/2 ASA for 2º CVD prevention

• Use for 1º prevention in:

– > 50 y/o with other RF (+ FH, HBP, smoking,

dyslipidemia, albuminuria), or

– Pts with 10-yr CHD risk ≥ 10%

Prevention of Complications Retinopathy

• Dilated exam by specialist

– Type 1 within 3-5 yrs of Dx

– Type 2 at Dx

– Before, during, and after pregnancy for

preexisting DM

Mohamed, Q. et al. JAMA 2007;298:902-916.

Nonproliferative and Proliferative Diabetic Retinopathy

A: Moderate nonproliferative diabetic

retinopathy with microaneurysms,

retinal hemorrhages, and macular

edema characterized by increased

vascular permeability and deposition

of hard exudates at the central retina.

B: Proliferative diabetic

retinopathy with new vessels and

fibrous tractional bands arising

from the optic disc.

Prevention of Complications Nephropathy

• Annual microalbuminuria and eGFR

– Type 1 after 5 years

– Type 2 at Dx

• Rx micro or macroalbuminuria

– ACEI or ARB

– Dietary protein, 0.8 mg/kg (~ 10% daily cal)

• Control BP also with ACEI, ARB, diuretics, CCB

Prevention of Complications Neuropathy

• At Dx in type 2, after 5 yrs in type 1

• Foot exam

• Autonomic screening—hypoglycemic

unawareness, resting tachycardia, exercise

intolerance, orthostatic hypotension,

constipation, gastroparesis, erectile dysfunct

• Pain can be treated with pregabalin,

duloxetine, and tapentadol. For more severe:

amitriptyline, venlafaxine, gabapentin, opioids.

Prevention of Complications Foot Care

• Exam — 10-gram monofilament;

vascularization; vibration; proprioception;

palpation; visual exam for callus, skin

atrophy or ulceration, infection, nail care,

hair distribution, deformity

• Pt education, glycemic control, D/C

smoking, orthotics

Likelihood of Osteomyelitis

• Visible bone or ability to probe to bone

• Ulcer > 2 x 2 cm

• Ulcer duration > 1–2 wks

• ESR > 70 mm/hr

The Primary Cause of Amputations

• Shoes and socks at clinic visits

• The time to take them off

• You can save limbs if you look at feet.

• Efficiency—Get the shoes and socks off before

you come into the room

– Train your patients

– Instruct the office staff

Treatment—Insulin

• Type 1 DM—Multiple daily injections of

insulin, basal and prandial, with

individualization, multiple SMBG

• Type 2 DM—for very high blood sugars, as

augmentation for oral agents, basal or

multiple duration insulin. Individualize.

Insulin should be used more often than it is.

Insulin

Preparations

Onset of Action Peak Action Duration of

Action

Lispro/Aspart 5–15 minutes 1–2 hours 4–6 hours

Human Regular 30–60 minutes 2–4 hours 6–10 hours

Human NPH 1–2 hours 4–8 hours 10–20 hours

Glargine/Detemir 1–2 hours Flat ~24 hours

Insulin preparations

Treatment—Drugs

Oral Agents (type 2 DM):

• Insulin secretagogues

– Sulfonylureas

– Meglitinides

• Insulin sensitizers

– Metformin

– Thiazolidinediones

• Polysaccharide digestion inhibitors—alpha-glucosidase inhibitors

• Dipeptidyl peptidase IV (DPP-IV) inhibitors

• Sodium-glucose transporter 2 (SGLT 2) inhib

Expected HbA1c Decrease

• TLC 1-2%

• Metformin 1-2% (slow)

• Sulfonylureas 1-2% (fast)

• Insulins 1.5-3.5% (fastest)

• TZDs 0.5-1.4% (slowest)

• GLP-1 agonists 0.5-0.8%

• α-glucosidase inhibs 0.5-0.8%

• DPP-IV inhibs 0.5-0.8%

• SLGT-2 inhibs 1%

The Incretin Effect

• More rapid disposal of glucose load when

given by mouth than IV

• Greater insulin effect

• Glucagon inhibition

• Delayed gastric emptying

• Due to GI signaling and release of GI

hormones

GI Hormones

and an Enzyme Inhibitor

• Glucagon-like peptide 1 (GLP-1),

injectable, nausea

– exenatide, ER-exenatide, liraglutide

• Amylin (↓ gastric emptying, ↑ satiety),

injectable, nausea

– pramlintide

• Dipeptidyl peptidase IV (DPP-IV, rapidly

degrades GLP-1 and GIP) inhibitors, oral

– sitagliptin, saxagliptin, linagliptin, alogliptin

Na-Glucose Transporter Inhibitors

• SGLT-2 in proximal renal tubule

• Canagliflozin

• Accounts for 90% glucose reabsorption

• Decrease HbA1c by ~1%, BW and SBP

• Yeast vaginitis, UTI, polyuria, occas

hypoglycemia

• Contraindications—type 1 DM, severe renal

insufficiency

Thiazolidinediones

• Cardiac Effects

• Bones

Pioglitazone

• Pioglitazone meta-analysis

– 19 trials; 16,390 patients

– Decreased death, MI, CVA; HR 0.82 (0.72–0.94)

– Increased CHF; HR 1.41 (1.14–1.76)

– No change CHF mortality

• Prescribing information includes black box warning about CHF

JAMA. 2007;298:1180-88.

Rosiglitazone

• Rosiglitazone meta-analysis

– 4 RCTs; 14,391 patients

– Increased MI; HR 1.42 (1.06-1.91)

– CHF; HR 2.09 (1.52-2.88)

– No change cardiac mortality; HR 0.90 (0.63-1.26)

• Prescribing information includes black box warning about CHF and myocardial ischemia

JAMA. 2007;298:1189-95.

More Rosiglitazone

• Meta-analysis

– 42 trials

– Mean age 56 years

– Baseline HbA1c 8.2%

• MI odds ratio 1.43 (95% CI, 1.03-1.98,

P=0.03)

• CV death odds ratio 1.64 (95% CI, 0.98-

2.74, P=0.06) NEJM. 2007;356:2457-2471.

Rosiglitazone vs Pioglitazone

• 227,571 Medicare patients, mean age 74.4 yrs

– Rosiglitazone or Pioglitazone for 3 years

• Acute MI, CVA, CHF, all-cause mortality,

composite of all

• 8667 endpoints, Rosi > Pio for CVA, CHF, death

• Composite risk 1.68 (95% CI, 1.27-2.08)

• NNH 60 Rx’d for 1 year

JAMA. 2010;304:411-418.

JAMA. 2010;304:469-471.

Thiazolidinediones and Bones

• Risk of peripheral fractures

• Both pioglitazone and rosiglitazone

• FDA warnings in prescribing information

JAMA. 2007;297:1645.

Drug Saf. 2009;32:539-547.

Thiazolidinediones

For Now

• Avoid in NYHA Class III and IV CHF

• Use with caution in Class I and II

• Prudent to avoid rosiglitazone in patients at significant risk of ischemic ht disease and instead consider metformin, SUs, or insulin

• Consider fracture risk

How Low Should the Glucose Be?

• DCCT, UKPDS, and long-term benefits

• Steno-2 and long-term followup

• ACCORD—NEJM. 2008;358:2545-2559.

• ADVANCE—NEJM. 2008;358:2560-2572.

• VADT—NEJM. 2009;360:129-139.

DCCT—Type 1 DM

NEJM. 1993;329:977–986.

Epidemiology of Diabetes Interventions

and Complications (EDIC)

NEJM. 2005;353:2643–2653.

UKPDS—Type 2 DM

UKPDS 10 Years Later

• HbA1c differences gone after 1 year

• RR decrease in SU/insulin aggressive Rx

– 9% any DM endpoint

– 24% microvascular disease

– 15% MI

– 13% any cause death

• RR decrease in metformin aggressive Rx

– 21% any DM endpoint

– 33% MI

– 27% any cause death

NEJM. 2008;359:1577-1589.

Steno-2 Study and Follow-Up

ACCORD

ADVANCE • 11,140 pts, RCT, HbA1c goal < 6.5%

• At 5 years—intensive 6.5%, std 7.3%

• Results

– Micro/macrovasc; HR 0.90 (0.82–0.98), 1º renal

– Major microvasc; HR 0.86 (0.77–0.97)

• 1º renal (HR 0.79; 0.66–0.93), no effect retinopathy

• No effect on major macrovasc, CV death, or any

cause death

• Gliclazide 90.5% vs 1.6%, TZD 16.8% vs 10.9%

• Insulin 40.5% vs 24.1%

Veterans Affairs Diabetes Trial

Glucose Control in the ICU

• Early studies showed benefit of tight control.

• More recent multicenter studies, in both

medical and surgical ICUs, show risk.

• Ideal is probably a compromise between risk of

out-of-control DM and hypoglycemia.

• 2016 SoC: 140-180 mg/dL in most critically ill

patients. Insulin is preferred treatment.

Recommendations for Now

• HbA1c 7% remains standard of care

– Probably more to be gained from getting uncontrolled pts down to 7% than from lowering tightly controlled pts further

• Attention to healthy lifestyle

– Diet, exercise, weight control

• Aggressive BP control

• Aggressive dyslipidemia control

• Discontinue tobacco

Metabolic Syndrome—NCEP (revised 2005, Circulation. 2005;112:2735-2752)

• Any three of five of the following

– Glucose intolerance/insulin resistance: FBS ≥ 110 mg/dL (≥ 100 mg/dL, or on drug Rx)

– Hypertension: BP ≥ 130/85 (or on drug Rx)

– Dyslipidemia

• TG ≥ 150 mg/dL (or on drug Rx)

• HDL < 40 mg/dL in men, < 50 mg/dL in women (or on drug Rx)

– Central adiposity: waist circ > 40” men, > 35” in women

Metabolic Syndrome Prevalence

Third NHANES, 1988-1994

Arch Int Med. 2003:427-436.

Metabolic Syndrome and

Cardiovascular Mortality JAMA. 2002;288:2709-2716.



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Finnish Diabetes Prevention Study

• Design

– 522 middle-aged overweight (BMI 31)

– 172 men and 350 women

– Mean duration 3.2 years

• Intervention Group: Individualized counseling

– Reducing weight, total intake of fat and saturated fat

– Increasing intake of fiber, physical activity

Tuomilehto J et al. N Engl J Med 2001;344:1343-1350.

Treating the Metabolic Syndrome

Goals

Intervention Controls

P value % of subjects

Wt reduction >5% 43 13 0.001

Fat intake < 30%

energy 47 26 0.001

Sat fat

<10% energy 26 11 0.001

Fiber

>15 g/1000 kcal 25 12 0.001

Exercise > 4

hr/wk 86 71 0.001

Tuomilehto J et al. N Engl J Med 2001;344:1343-1350..

Incidence of Diabetes during Follow-up

No. with Diabetes/Total no.

Intervention 5/13 10/66 9/69 2/38 0/25 0/24

Control 15/48 25/107 14/48 2/15 0/11 0/4

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NEJM. 2002;346:393–403.

ADA Recommendations

• For patients with IGT or IFG

• Lifestyle intervention is primary

– Modest wt loss 5–10%

– Moderate exercise, 30 min daily

– Smoking cessation

• For patients with both IGT and IFG consider

adding metformin

– Consider OGTT in pts with IFG less than 60 y/o

and with BMI > 35

Metabolic Syndrome

Summary

What’s Next?

• Non-invasive glucose monitoring

• Type 1 — Islet and stem cell transplantation

• Type 2

– Rx the epidemic of obesity

– Increased understanding of weight homeostasis

• Mechanism of insulin resistance and the

connection with visceral adiposity

• Genetics of diabetes

Diabetes Update 2017 · Diabetes Update—2017 Timothy C. Evans, MD PhD FACP Department of Medicine...

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