diabetes management in the outpatient setting

Diabetes Management in the Outpatient Setting

Diagnostic Criteria(before 2010)

•FPG≥126 mg/dl.•Prediabetes (IFG)≥100 mg/dl.

•75 gram OGTT 2 hour-value≥200 mg/dl.•Prediabetes (IGT)≥140 mg/dl.

•Random blood glucose≥200 mg/dl + symptoms (polyuria, polydipsia, unexplained weight loss).

International Expert Committee Report on the Role of A1C in the Diagnosis of Diabetes

6.5%

THE INTERNATIONAL EXPERT COMMITTEE. Diabetes Care 2009;32:1327

NORMAL IFG or IGT DIABETES

FPG < 100 mg/dl IFG

FPG > 100 - 125 mg/dl

FPG > 126 mg/dl

2-h PG < 140 mg/dl IGT

2-h PG > 140 -

199 mg/dl

2-h PG > 200 mg

Random PG > 200 + symptoms

A1C 5.7% to 6.4% ≥ 6.5%

2010 Diagnosis of Diabetes and Categories of Increased Risk for Diabetes

ADA, Diabetes Care 33: Suppl. 1, S11-S61, 2010

• A1c does not require patients to be fasting.• HbA1c reflects longer-term glycemia than does plasma

glucose.• Relatively unaffected by acute (e.g., stress or illness

related) perturbations in glucose levels.• Currently used to guide management and adjust therapy.• HbA1c laboratory methods are now well standardized and

reliable.

J Clin Endocrinol Metab 93: 2447–2453, 2008Diabetes Care 32 (7):1327-1334, 2009

Main factors in support of using HbA1C as a screening and diagnostic test

• Greater cost• Limited availability of A1C testing in certain

regions of the developing world• Incomplete correlation between A1C and average

glucose • Misleading in patients with anemia and

hemoglobinopathies.

Limitations of the Use of A1C for the Diagnosis of Diabetes

Factors influencing A1c

Recommendation of the International Expert Committee for the diagnosis of diabetes

• Diabetes should be diagnosed when A1C is ≥6.5%• Diagnosis should be confirmed with a repeat A1C test• Confirmation is not required in symptomatic subjects

with plasma glucose levels >200 mg/dl

• If A1C testing is not possible, previously recommended diagnostic methods (e.g., FPG or2HPG, with confirmation) are acceptable.

DIABETES CARE, VOLUME 32, NUMBER 7, JULY 2009

Who To Screen

•No major risk factors, FPG every 3 years beginning at 45 y.o.•Any risk factors, screen earlier and more often:

•Overweight (BMI>25 kg/m2).•First degree relative with T2DM.•High risk ethnic group.•Hypertension (≥140/90 mmHg).•HDL≤35 mg/dl and/or triglycerides≥250 mg/dl.•History of gestational diabetes or delivered baby ≥9lb.•Polycystic ovary syndrome.•History of vascular disease.•Habitual physical inactivity.

Treatment Goals for Type 2 Diabetes

Guidelines for Glycemic, BP, & Lipid Control American Diabetes Assoc. Goals

HbA1C < 7.0% (individualization)

Preprandial glucose 70-130 mg/dL (3.9-7.2 mmol/l)

Postprandial glucose < 180 mg/dL

Blood pressure < 130/80 mmHg

Lipids

LDL: < 100 mg/dL (2.59 mmol/l) < 70 mg/dL (1.81 mmol/l) (with overt CVD)HDL: > 40 mg/dL (1.04 mmol/l) > 50 mg/dL (1.30 mmol/l)TG: < 150 mg/dL (1.69 mmol/l)

ADA. Diabetes Care. 2012;35:S11-63HDL = high-density lipoprotein; LDL = low-density lipoprotein; PG = plasma glucose; TG = triglycerides.

Standard of Care-Multifactorial Therapy

•DCCT (1993) and UKPDS (1998) established role for better glycemic control on prevention of microvascular complications. •Studies that improved BP or lipids generally showed lower CAD in type 2 diabetes.•Steno 2 trial (2003) showed a marked lowering of both micro and macrovascular events when all 3 utilized.

•DCCT (1993) and UKPDS (1998) established role for better glycemic control on prevention of microvascular complications. •Studies that improved BP or lipids generally showed lower CAD in type 2 diabetes.•Steno 2 trial (2003) showed a marked lowering of both micro and macrovascular events when all 3 utilized.•Memory effect-longterm micro and macrovascularprotection years after stopping the trial-in DCCT, UKPDS, and Steno 2 trials.

Standard of Care-Multifactorial Therapy

But…then the role of intensive glucose control management came under active debate.

ConclusionsIntensive treatment of glycemia in the ACCORD cohort did not reduce the risk of

composite measures of advanced microvascular outcomesrenal failure: initiation of dialysis or ESRD, or renal transplant, or a rise of

serum creatinine above 3.3 mg/dLretinal photocoagulation or vitrectomy to treat diabetic retinopathy, or development of neuropathy

Intensive therapy delayed the onset of albuminuria and some measures of eye complications and neuropathy

Microvascular benefits of intensive therapy should be weighed against increase in total and CVD-related mortality, increased weight gain, and high risk for severe hypoglycemia

Figure 1 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print](Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)

++

peripheralglucose uptake

hepatic glucose production

pancreatic insulinsecretion

pancreatic glucagonsecretion

Main Pathophysiological Defects in T2DM

gutcarbohydratedelivery &absorption

incretineffect

HYPERGLYCEMIAHYPERGLYCEMIA

?

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Antihyperglycemic AgentsPlasma glucosePlasma glucose

Major Sites of ActionMajor Sites of Action

Glucosidase Inhibitors Glucosidase Inhibitors

Muscle/Fat Muscle/Fat GI tractGI tract

Carbohydrate AbsorptionCarbohydrate Absorption

Glucose UptakeGlucose Uptake

Liver Liver

Glucose Production Glucose Production

Injected InsulinInjected Insulin

InsulinSecretion InsulinSecretion

Pancreas Pancreas InsulinSecretion InsulinSecretion

Sulfonylureas MeglitinidesSulfonylureas Meglitinides

(-)

(+)(+)

1. Hines SE. Intensive management of type 2 diabetes. Patient Care.April 30, 2000:91-107.2. Kelley DB, ed. Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:56-72.

(-) (-)

(+)

MetforminGlitazonesMetforminGlitazones

Natural History of Type 2 DMPlasmaGlucosePlasmaGlucose

Relative-CellFunction

Relative-CellFunction

Postmeal glucosePostmeal glucose

Fasting glucoseFasting glucose

Insulin resistanceInsulin resistance

Insulin secretionInsulin secretion

126mg/dL126mg/dL

Years of DiabetesYears of Diabetes-20-20 -10-10 00 1010 2020 3030-30-30

DeFronzo RA. Pathogenesis of type 2 diabetes: Implications for metformin. Drugs. 1999;58 (suppl 1):29-30.

Management of Hyperglycemia in T2DM

ANTI-HYPERGLYCEMIC THERAPY

•Therapeutic options: Lifestyle

-Weight optimization

-Healthy diet

- Increased activity levelDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]



• Therapeutic options: Oral agents & non-insulin injectables

- Metformin

- Sulfonylureas

- Thiazolidinediones

- DPP-4 inhibitors

- GLP-1 receptor agonists

- Meglitinides

- -glucosidase inhibitors

- Bile acid sequestrants

- Dopamine-2 agonists

- Amylin mimetics

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ClassClass MechanismMechanism AdvantagesAdvantages DisadvantagesDisadvantages CostCostBiguanides • Activates AMP-kinase

• Hepatic glucose production

• Extensive experience• No hypoglycemia• Weight neutral• ? CVD

• Gastrointestinal• Lactic acidosis• B-12 deficiency• Contraindications

Low

SUs / Meglitinides

• Closes KATP channels• Insulin secretion

• Extensive experience• Microvasc. risk

• Hypoglycemia• Weight gain• Low durability• ? Ischemic preconditioning

Low

TZDs • PPAR- activator• insulin sensitivity

• No hypoglycemia• Durability• TGs, HDL-C • ? CVD (pio)

• Weight gain• Edema / heart failure• Bone fractures• ? MI (rosi)• ? Bladder ca (pio)

High

-GIs • Inhibits glucosidase• Slows carbohydrate absorption

• No hypoglycemia• Nonsystemic• Post-prandial glucose• ? CVD events

• Gastrointestinal• Dosing frequency• Modest A1c

Mod.

Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ClassClass MechanismMechanism AdvantagesAdvantages DisadvantagesDisadvantages CostCostDPP-4inhibitors

• Inhibits DPP-4• Increases GLP-1, GIP

• No hypoglycemia• Well tolerated

• Modest A1c • ? Pancreatitis• Urticaria

High

GLP-1 receptor agonists

• Activates GLP-1 R• Insulin, glucagon• gastric emptying• satiety

• Weight loss• No hypoglycemia• ? Beta cell mass• ? CV protection

• GI• ? Pancreatitis• Medullary ca• Injectable

High

Amylin mimetics

• Activates amylin receptor• glucagon• gastric emptying• satiety

• Weight loss• PPG

• GI• Modest A1c • Injectable• Hypo w/ insulin• Dosing frequency

High

Bile acid sequestrants

• Bind bile acids• Hepatic glucose production

• No hypoglycemia• Nonsystemic• Post-prandial glucose• CVD events

• GI• Modest A1c• Dosing frequency

High

Dopamine-2agonists

• Activates DA receptor• Modulates hypothalamic control of metabolism• insulin sensitivity

• No hypoglyemia• ? CVD events

• Modest A1c• Dizziness/syncope• Nausea• Fatigue

High


ClassClass MechanismMechanism AdvantagesAdvantages DisadvantagesDisadvantages CostCostInsulin • Activates insulin

receptor• peripheral glucose uptake

• Universally effective• Unlimited efficacy• Microvascular risk

• Hypoglycemia• Weight gain• ? Mitogenicity• Injectable• Training requirements• “Stigma”

Variable




•Implementation strategies:

-Initial therapy

-Advancing to dual combination therapy

-Advancing to triple combination therapy

-Transitions to & titrations of insulin



CONSIDERATIONS•Age•Weight•Sex / racial / ethnic / genetic differences•Comorbidities

-Coronary artery disease-Heart Failure-Chronic kidney disease-Liver dysfunction-Hypoglycemia



CONSIDERATIONS•Age: Older adults

-Reduced life expectancy-Higher CVD burden-Reduced GFR-At risk for adverse events from polypharmacy-More likely to be compromised from hypoglycemia

Less ambitious targetsHbA1c <7.5–8.0% if tighter

targets not easily achievedFocus on drug safety

Less ambitious targetsHbA1c <7.5–8.0% if tighter

targets not easily achievedFocus on drug safety



CONSIDERATIONS•Weight

-Majority of T2DM patients overweight / obese-Intensive lifestyle program-Metformin-GLP-1 receptor agonists-? Bariatric surgery-Consider LADA in lean patients



CONSIDERATIONS•Sex/ethnic/racial/genetic differences

-Little is known-MODY & other monogenic forms of diabetes-Latinos: more insulin resistance-East Asians: more beta cell dysfunction-Gender may drive concerns about adverse effects (e.g.,

bone loss from TZDs)


T2DM Anti-hyperglycemic Therapy: General RecommendationsDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Adapted Recommendations: When Goal is to Avoid Weight GainDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]


CONSIDERATIONS•Comorbidities

-Coronary Disease

-Heart Failure

-Renal disease

-Liver dysfunction

-Hypoglycemia

Metformin: CVD benefit (UKPDS) Avoid hypoglycemia ? SUs & ischemic preconditioning ? Pioglitazone & CVD events ? Effects of incretin-based

therapies

Metformin: CVD benefit (UKPDS) Avoid hypoglycemia ? SUs & ischemic preconditioning ? Pioglitazone & CVD events ? Effects of incretin-based

therapies




-Coronary Disease

-Heart Failure

-Renal disease

-Liver dysfunction

-Hypoglycemia

Metformin: May use unless condition is unstable or severe

Avoid TZDs ? Effects of incretin-based

therapies

Metformin: May use unless condition is unstable or severe

Avoid TZDs ? Effects of incretin-based

therapies




-Coronary Disease

-Heart Failure

-Renal disease

-Liver dysfunction

-Hypoglycemia

Increased risk of hypoglycemia Metformin & lactic acidosis

US: stop @SCr ≥ 1.5 (1.4 women)

UK: dose @GFR <45 & stop @GFR <30

Caution with SUs (esp. glyburide) DPP-4-i’s – dose adjust for most Avoid exenatide if GFR <30

Increased risk of hypoglycemia Metformin & lactic acidosis

US: stop @SCr ≥ 1.5 (1.4 women)

UK: dose @GFR <45 & stop @GFR <30

Caution with SUs (esp. glyburide) DPP-4-i’s – dose adjust for most Avoid exenatide if GFR <30




-Coronary Disease

-Heart Failure

-Renal disease

-Liver dysfunction

-Hypoglycemia

Most drugs not tested in advanced liver disease

Pioglitazone may help steatosis Insulin best option if disease

severe

Most drugs not tested in advanced liver disease

Pioglitazone may help steatosis Insulin best option if disease

severe




-Coronary Disease

-Heart Failure

-Renal disease

-Liver dysfunction

-Hypoglycemia Emerging concerns regarding

association with increased mortality

Proper drug selection in the hypoglycemia prone

Emerging concerns regarding association with increased mortality

Proper drug selection in the hypoglycemia prone


T2DM Anti-hyperglycemic Therapy: General Recommendations Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Adapted Recommendations: When Goal is to Avoid HypoglycemiaDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Adapted Recommendations: When Goal is to Minimize Costs Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Physiologic Insulin Secretion :Basal/Bolus Concept

Breakfast Lunch Supper

Insu

lin(µ

U/m

L)

Glu

cose

(mg

/dL

)

Basal Glucose

150

100

50

07 8 9 1011 12 1 2 3 4 5 6 7 8 9

A.M. P.M.

Time of Day

Basal Insulin

50

25

0

Prandial Glucose

Prandial Insulin

Suppresses Glucose Production Between Meals & Overnight

Basal 50% of Daily Needs


Long (Detemir)

Rapid (Lispro, Aspart, Glulisine)

Hours

Long (Glargine)

0 2 4 6 8 10 12 14 16 18 20 22 24

Short (Regular)

Hours after injection

Insu

lin le

vel


Therapeutic options: Insulin

Intermediate (NPH)

Initial calculation of basal dose•BW in kilograms x sensitivity index (0.15 – 0.2 )

Or•Body Weight in pounds x 0.1

From BID NPHTake total NPH dose and decrease by 20% for starting dose

Establishing Basal Requirement for Glargine

•Sequential increase•Increase every 2-3 days by

4 U if FBG>140 mg/dL2 U if FBG=120mg/dL to 140 mg/dLOR

•Mean of am BG after five days•Add to initial Glargine by formula

(Average BG-100)/10•Example: 200 pounds on 20 units glargine q hs, mean am BG is200 on 6th and 7th day

Add (Av BG -100)10 to glargine, (200-100/10)

i.e. increase from 20 to 30 units q hs• 2nd week--average 130 ,increase glargine from 30 to 33

Establishing Basal Requirement for Glargine

Sequential Insulin Strategies in T2DM Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]


ANTI-HYPERGLYCEMIC THERAPY•Glycemic targets

- HbA1c < 7.0% (mean PG 150-160 mg/dl [8.3-8.9 mmol/l])

- Pre-prandial PG <130 mg/dl (7.2 mmol/l)

- Post-prandial PG <180 mg/dl (10.0 mmol/l)

- Individualization is key: Tighter targets (6.0 - 6.5%) - younger, healthier Looser targets (7.5 - 8.0%+) - older, comorbidities,

hypoglycemia prone, etc.

- Avoidance of hypoglycemiaPG = plasma glucose Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]


KEY POINTS

• Glycemic targets & BG-lowering therapies must be individualized.

• Diet, exercise, & education: foundation of any T2DM therapy program

• Unless contraindicated, metformin = optimal 1st-line drug.

•After metformin, data are limited. Combination therapy with 1-2 other oral / injectable agents is reasonable; minimize side effects.

•Ultimately, many patients will require insulin therapy alone / in combination with other agents to maintain BG control.

•All treatment decisions should be made in conjunction with the patient (focus on preferences, needs & values.)

• Comprehensive CV risk reduction - a major focus of therapy.

diabetes management in the outpatient setting

Documents

diabetes care

diabetes management

american diabetes

prediabetes igt140 mgdl

prediabetes ifg100 mgdl

hourvalue200 mgdl

role of a1c

use of a1c