Saint Anselm CollegeContinuing Nursing Education

Manchester, NH

Diabetic PharmacologyFaculty: Deb Boles, MS, RPh

Clinical Pharmacy Manager, Lowell General HospitalLowell, MA

Contact hours: 2

This online program is available until December 31, 2016In order to receive contact hours, you must:

1)Listen to entire program2)Complete the post-test and the evaluation3)Once you have submitted your evaluation, you will then be sent your certificate of completion.

Thank you!

Disclosure:

The presenter has no financial or other interest in any commercial company which could influence the content of this presentation. There is no commercial support for this program. The planning committee has nothing to disclose.

DIABETES

Deb Boles, MS,RPh

Clinical Pharmacy Specialist

Objectives

Distinguish the three types of known diabetes

Discuss the different types of insulin including new therapies

List potential therapies for type 2 diabetes

Diabetes impact

Effects 15 million americans (8% of the population)

3rd leading cause of death behind cancer

Estimated 12 million people have it and don’t know it

Incidence of Diabetes in the US

Centers For Disease Control and Prevention. Diabetes Data and Trends. .http://apps.nccd.cdc.gov/DDT_STRS2/NationalDiabetesPrevalenceEstimates.aspx?mode=DBT

Glucose and Insulin Production

Normal insulin function

Blood glucose increases after meal

Pancreas secretes insulin to help glucose enter cells

Negative feedback loop

Fasting state slow release of insulin

3 Major Classifications of DiabetesCause Incidence

Type 1 Auto-immune mediated destruction of insulin-producing beta cells in the pancreas

Less than 10% of patients with diabetes

Type 2 Peripheral insulin resistance and a relative deficiency of insulin

More than 90% of patients with diabetes

Gestational Insulin resistance caused by pregnancy; increases risk for type 2 diabetes later in life

3-5% of pregnancies

Type 1 (IDDM)

Only accounts for 5-10% of all cases

Strong genetic component

Environmental trigger

Insulin dependent

Type 1 Pathogenesis

Beta-cells in pancreas are destroyed leading to total insulin deficiency

Abnormal activation of T-cells mediated immune system

In general destruction is more rapid when occurs at younger age

Management of Type 1

Appropriate insulin delivery

Self monitor of blood glucose concentrations

Nutritional planning

Avoidance of hypo or hyperglycemia

Screening for treatment of diabetes-related complications

History of insulin

For decades – only animal source

1980’s recombinant technology

Utilizes E. Coli

Insulin producing genes

Insulin PropertiesType of Insulin Onset Peak Duration

Rapid ActingAspart (Novolog®)Lispro (Humalog®)Glulisine (Apidra®)

15-30 minutes 90 minutes 3-5 3-53-5

Short ActingRegular

30-60 minutes 2-3 hours 6-10

Intermediate ActingNPH

2-3 hours 4-10 hours 12-18 hours

Long-ActingDetemir (Levemir®)Glargine (Lantus®)

2-3 hours2-3 hours

No pronounced peakNo pronounced peak ~24 hours

~24 hours

Roach P. New Insulin Analogues and Routes of Delivery; Pharmacodynamic and Clinical Considerations. 2008;47(9):595-610.

Rapid acting

Three agentsLispro(Humalog)

Aspart (Novolog)

Glulisine (Apridra)

Higher levels earlier

Short duration of action

Helps reduce post-prandial hyperglycemia

Increase patient compliance

Insulin glulisine (Apridra)

Two amino acid changes

Bind to Insulin receptors affecting glucose transfer across cells

12 week study premeal versus postmeal

Insulin aspart (Novolog)

Single amino acid change

Glucose lowering effects better than regular

Better post-prandial control

Comparable to lispro

Rapid acting mixes

Rapid acting can’t be mixed with NPH

Mixes are plain with protamine bound product

Lispro 25/75 or 50/50

Aspart 30/70 or 50/50

Rapid Acting vs. Regular insulinBenefits of Regular Insulin

Rapid-ActingExpensive

Given prior to high-fat meal, potential increased risk of early post-meal hypoglycemia

Short duration may provide gaps in insulin supply between meals

Regular

Less expensive

Provides some basal activity which must be taken into account if switch to rapid-acting insulin

Roach P. New Insulin Analogues and Routes of Delivery; Pharmacodynamic and Clinical Considerations. 2008;47(9):595-610.

Rapid Acting vs. Regular insulinBenefits of Rapid-Acting Insulin

Rapid-Acting

Smaller increases in blood glucose concentrations

Lower frequency of hypoglycemia and severe hypoglycemia in type 1 diabetes

ConvenienceInject right before meal

Can inject after meal

Regular

Absorbed too slowly to match rate of glucose after meals

Postprandial hyperglycemia

Inject 30 to 45 minutes prior to meal

Relatively prolonged duration of action

Late post-meal hypoglycemia

Roach P. New Insulin Analogues and Routes of Delivery; Pharmacodynamic and Clinical Considerations. 2008;47(9):595-610.

MealSC injection

0 30 60

Time (min)90 120 180 210150 240

Lispro

0 50 100

Time (min)150 200 300250

Pla

sm

a i

ns

uli

n)

Pla

sm

a i

ns

uli

n

MealSC injection

Short-Acting Insulin Analogs Aspart

RegularRegular

Heinemann, et al. Diabet Med. 1996;13:625–629;Mudaliar, et al. Diabetes Care. 1999;22:1501–1506

Side effects

Site irritationLocal itching and redness

10/1394 (0.7%)

Hypoglycemia75-95% of all type 1 report at least one minor episode

Insulin glargine (Lantus)

First to market

Similar A1C decreases as NPH

Decreased hypoglycemic events

No peak

Once daily vs bid dosing

Long-Acting vs. Intermediate Acting

Glargine Flat vs. peak seen with NPH

Recent studies show may not be completely flat– Especially at higher doses

Does not appear to be any overlap or accumulation

However, gradual increase in activity followed by slow decline after long use

Equal or less patient variabilityRoach P. New Insulin Analogues and Routes of Delivery; Pharmacodynamic and Clinical Considerations. 2008;47(9):595-610.

Glargine vs. NPH

Glargine does not always provide 24 hour coverage in all patients

25% of patients may present with rising glucose levels the following eveningConsider twice daily dosing at 12 hour intervals

Clinical trials glargine vs. NPHLess hypoglycemiaLower fasting blood glucose No difference found in A1c between agents

Roach P. New Insulin Analogues and Routes of Delivery; Pharmacodynamic and Clinical Considerations. 2008;47(9):595-610.

Lepore, et al. Diabetes. 1999;48(suppl 1):A97.

0 10

Time (hr)

20 30

GlargineNPH

Pla

sma

insu

linGlargine vs NPH Insulin

NPH

Glargine

Insulin detemir (Levemir)

Ultra long acting

Elimination of peak

Binds to albumin subq and in blood

Better reproducibility than NPH

Duration is dose dependent

Once daily or twice daily dosing

Decrease risk of wt gain

Decrease risk of hypoglycemia

Action is 12-18 hours

Can you mix?

Detemir vs. NPHDuration of action similar to or slightly longer than NPH but shorter than glargine

30-50% of patients require twice daily dosing

Less patient variabilityPossibly smaller peak

Not well demonstrated in patients with type I diabetesA clear difference has been shown with insulin glargine

Roach P. New Insulin Analogues and Routes of Delivery; Pharmacodynamic and Clinical Considerations. 2008;47(9):595-610.

Insulin Initiation

Diabetes is a chronic progressive diseaseUltimately ends in loss of β-cell function

10 units OR 0.15 units/kg of glargine, NPH or detamir at bedtime

Type 2 patients may require higher doses than patients with Type 1 due to resistanceIncrease in insulin by 1 unit may have drastic result with type 1 but not effect with type 2 patient

Mayfield JA., White RD. Insulin Therapy for Type 2 Diabetes: Rescue, Augmentation, and Replacement of Beta Cell Function. American Family Physician. 2004;70(3):489-500.

Insulin Dosing

Example titration schedule

Several studies have also shown patient involvement in titration is

successfulIncrease daily insulin dose by 2 units every 3 days if fasting glucose was above target (72-100mg/dL)

Barnett A. Dosing of Insulin Glargine in the Treatment of Type 2 Diabetes. Clinical Therapeutics. 2007;29(6):987-999.

Mean FBG (mg/dL) Weekly Increase in Insulin Dose

≥100 - <120 2

≥ 120 - <140 4

≥ 140 - < 180 6

≥180 8

Insulin DosingIf glycemic control remains inadequate with basal insulin alone:

Switch to twice daily insulin

Advancement to basal-bolus insulin• Initiate bolus insulin at doses of 4 to 10 units before

the meal with the greatest pre-prandial glucose level

• Monitor and titrate to other meals where post prandial glucose is not at goal

Barnett A. Dosing of Insulin Glargine in the Treatment of Type 2 Diabetes. Clinical Therapeutics. 2007;29(6):987-999.

Alternative Insulin Delivery

• Insulin pump– Composed of a pump reservoir and battery operated pump– Size of beeper– Canula under the skin

• Change every 2 days– Set basal rate– Bolus with meals– Next goal – pump to sense blood glucose and administer dose

Insulin Sensors

Insulin Pump with Sensor

Medications affecting glucose

• Increase glucose– Steroids– Diuretics– Estrogens– HIV medications– Antipsychotics

• Decrease glucose– ACE inhibitors– MAOI’s– Aspirin

Close monitoring of glucose levels and insulin adjustments will be needed

Type 2 (NIDDM)

• Can still produce insulin but inadequately• Lack of sensitivity to insulin by cells • Mechanisms

– Insulin resistance (target cells)– Beta-cell dysfunction (pancreas)

Pathophysiology of Type 2 Diabetes

Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661-1669.

Peripheral TissuesPeripheral Tissues(Muscle)(Muscle)

GlucoseGlucose

LiverLiver

Impaired insulin Impaired insulin secretionsecretion

Increased glucose Increased glucose productionproduction

Receptor +Receptor +postreceptor defectspostreceptor defects

InsulinInsulinresistanceresistance

PancreasPancreas

Risk factors for Type 2

• Genetic component– Family history confers 2.4 fold risk increase

• Obesity– Risk doubles for every 20% increase in ideal weight

• Ethnic background– Hispanic > asian> african > caucasian

• History of gestational diabetes• Increased age

Risk factors for insulin resistance

• Overweight• Waist

– >40 inches in men– >35 inches in women

• >40 yrs of age• Ethnicity• Gestational diabetes

• High BP• High TG• Low HDL• Polycystic ovarian

disease• History of type 2 in

family

Diagnosis of DiabetesA1C FBG (mg/dL) OGTT (mg/dL) Casual

Diabetes ≥6.5% ≥126 ≥200; test performed 2 hours after 75 g glucose load

≥200mg/dL AND symptoms of hyperglycemia (polyuria, polydipsia, weight loss)

Pre-DiabetesImpaired fasting glucose (IFG)

Impaired glucose tolerance (IGT)

5.7%-6.4% 100 to 125

N/A

N/A

140 to 199

N/A

N/A

American Diabetes Association. Standards of Medical Care in Diabetes-2011. Diabetes Care. 2011;34(s1):s11-s61.

ABCs of Diabetes CareParameter ADA Goal

A1c <7%

Preprandial plasma glucose

90-130mg/dL

Postprandial plasma glucose

<180mg/dL

Blood Pressure <130/80

Cholesterol LDL <100mg/dLHDL >40mg/dL (M) > 50mg/dL (F)TG <150mg/dLTC <200mg/dL

American Diabetes Association. Standards of Medical Care in Diabetes-2011. Diabetes Care. 2011;34(s1):s11-s61.

ADA and ACE glycemic goals

ADA ACE

Biochemical Index Normal goal goal

Fasting pre-prandial <100 90-130 <110

Post-prandial <140 <180 <140

A1C <6 <7 <6.5

A1c and Daily Blood Glucose

A1C (%) Mean plasma glucose (mg/dl)

6 126

7 154

8 183

9 212

10 240

11 269

12 298

American Diabetes Association. Standards of Medical Care in Diabetes-2011. Diabetes Care. 2011;34(s1):s11-s61.

Goal HgbA1c < 7%

Non-pharmacological therapy

Optimize BG control

Consistent carbohydrate intake

Modify fat and calorie content

Space meals

Increase physical activity

Moderate weight loss

Monitor blood glucose

Therapy selection in Type 2

• Magnitude of change needed in BG• Co-existing medical conditions• Adverse effects• Contraindication• Issues with compliance• Cost to patient and healthcare system

Mechanisms of action

Sulfonylureasglyburide (Micronase™; Diabeta™), glipizide (Glucotrol™),

glimeperide (Amaryl™)

• Mechanism of action– Primary

• stimulates beta-cell secretion of insulin (release)– Secondary

• decreased rate of hepatic glucose production• increases insulin receptor sensitivity

• Efficacy– ↓ Hgb A1c 1-2%

• Common Adverse Events– Hypoglycemia– Weight gain– Rash

• Small chance of cross reactivity with sulfa antibioticsRaskin P. Why insulin sensitizers but not secretagogues should be retained when initiating insulin in type 2 diabetes. Diabetes Metab Res Rev. 2008;24:3-13.

Sulfonylureas• Hypoglycemia

– Older adults have a 36% ↑ risk – Risk factors

• Age-related decline in renal function

• Co-administration with insulin sensitizers

• Recent discharge from hospital

• >60 years

• Caloric restriction

• Use of 5 or more medicationsNeumiller JJ, Setter SM. Pharmacologic Management of the Older Patient with Type 2 Diabetes Mellitus. The American Journal of Geriatric Pharmacotherapy. 2009;7(6):324-342.

Sulfonylureas• Place in therapy:

– 75-90% initial response, failure over time due to loss of beta cells

– 25% “complete responders”, do not require additional agent

– Require functioning β-cells to work• May be ineffective in long term diabetes

– Combination with insulin not as effective as with metformin

– Alternative to insulin therapy (as monotherapy or additon to metformin)

Raskin P. Why insulin sensitizers but not secretagogues should be retained when initiating insulin in type 2 diabetes. Diabetes Metab Res Rev. 2008;24:3-13.

Metformin (Glucophage™)• Mechanism of action

– Primary• inhibits hepatic glucose production

– Secondary• increases insulin sensitivity, enhancing peripheral utilization of

glucose

• Efficacy– ↓ Hgb A1c 1-2%

• Common Adverse Events– GI side effects most common

• Typically transient – Weight loss

Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2009.

Metformin

• B-12 deficiency– Up to 22% of patients with type 2 diabetes – Often not clinically significant– May need to supplement with B-12– Calcium supplementation may reverse– Higher doses (>1g/day) and duration (>3 years) of

therapy increase risk

Vidal-Alaball J and Butler CC. Reduced serum vitamin B-12 in patients taking metformin. BMJ; 2010;340:2198.

Metformin• Precautions/Contraindications

– Renal disease or dysfunction• Serum creatinine ≥1.5 in men; ≥1.4 in women

– Acute or chronic metabolic acidosis– IV dye studies

• stop metformin day of study and do not resume until renal function returns to normal, usually 48 hours

– Age > 80 years– Impaired hepatic function– Excessive alcohol use– Medical condition that may predispose to metabolic

or lactic acidosis or hypoxemia • COPD, PVD, infections, surgery, CHF

Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2009.

Metformin

• Lactic Acidosis– Meta-analysis assessed incidence of fatal and non-

fatal lactic acidosis– Type 2 metformin treated patients vs. non-

metformin treated patients• no cases of lactic acidosis in 70,490 patient-years of

metformin use vs. 55,451 patient-years in non-metformin group

– No evidence that metformin is associated with an increased risk of lactic acidosis

Salpeter SR, Greyber E, Pasternak GA, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010. Apr 14(4).

Metformin

• Place in therapy– First line agent

• Only agent shown to decrease macrovascular complications

• Hypoglycemia rare when used as monotherapy

– Monotherapy or in combination with other oral agents and insulin

American Diabetes Association. Standards of Medical Care in Diabetes-2011. Diabetes Care. 2011;34(s1):s11-s61.

Glinidesrepaglinide (Prandin®), nateglinide (Starlix®)• Mechanism of action

– stimulates release of insulin from beta-cells• Bind to a different receptor than sulfonylureas• Glucose Dependent, unlike sulfonylureas

– Do not stimulate insulin secretion in absence of hyperglycemia• Very short duration of action

• Efficacy– ↓ Hgb A1c 0.5-1.5%

• Common Adverse Events– Hypoglycemia (greater than sulfonylurea)– Weight gain

Campbell RK. Type 2 diabetes: Where we are today: An overview of disease burden, current treatments, and treatment strategies. JAPhA. Sept/Oct 2009.s3-s9..

Glinides

• Place in Therapy– High post-prandial glucose levels

• Take (0-30 minutes) before meals• Skip a meal, skip the dose

– Useful in irregular meal pattern• elderly

– Useful if prone to hypoglycemia– Expensive

Thiazolidinedionesrosiglitazone (Avandia™), pioglitazone (Actos™)

• Mechanism of action– Primary

• Enhances peripheral uptake of glucose by increasing glucose/insulin receptors

• Enhance insulin sensitivity – Secondary

• Reduces hepatic glucose production• Efficacy

– ↓ Hgb A1c 0.5-0.8%• Common Adverse Events

– Edema– Weight gain

Campbell RK. Type 2 diabetes: Where we are today: An overview of disease burden, current treatments, and treatment strategies. JAPhA. Sept/Oct 2009.s3-s9.

ThiazolidinedionesEffects on Cholesterol

• LDL particle size– Small dense more closely associated with CHD– pioglitazone found to increase LDL size

• Reduces Triglycerides– pioglitazone > rosiglitazone

• Pio ↓10-20%• Rosi neutral to slight reduction

• Increasing HDL – Both increase by 3-9mg/dL– Newer evidence suggests pioglitazone > rosiglitazone

Rizzo M, Emanuel RC, Rini GB, et al. The differential effects of thiazolidindiones on atherogenic dyslipidemia in type 2 diabetes: what is the clinical significance?

Thiazolidinedione Prescribing Considerations

• Contraindications– Contraindicated in patients with NYHA Class III or IV heart failure

• Warning and Precautions– CHF– Edema– Hepatic– Fractures

• Increased incidence found in females– Hypoglycemia – Macular edema

Actos[package insert]. Deerfield, IL: Takeda Pharmaceutical America, Inc; 2011.

Cardiovascular Risk

• Data suggests that Rosiglitazone may increase risk of cardiovascular events– Pioglitazone does not appear to have the same risk

• Meta-analysis of 16 observational studies– Included 810,000 thiazolidinedione users– Compared to pioglitazone, rosiglitazone was

associated with a statistically significant increased risk of CHF, MI, death

Loke, YK, Kwok CS, Singh S. Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies. BMJ.2011;342:d1309.

Thiazolidinediones

• Place in therapy:– Losing place in therapy, no longer considered a

first line class– Maximum effect can take up to 8 weeks – Expensive– Recommend pioglitazone vs. rosiglitazone due

to safety concerns

Alpha-glucosidase inhibitorsacarbose (Precose®), miglitol (Glycet®)

• Mechanism of action– inhibits enzyme that hydrolyzes complex starches and sugars

into readily absorbable molecules, delaying absorption of glucose

• If hypoglycemic reaction need glucose source (not sucrose)

• Efficacy– ↓ Hgb A1c 0.5-0.8%

• Common Adverse Events– GI intolerance, cramping, flatulence

• titrate dose slowly• minimize carbohydrate intake at first• may resolve in 8-12 weeks as gut receptors adjust

Campbell RK. Type 2 diabetes: Where we are today: An overview of disease burden, current treatments, and treatment strategies. JAPhA. Sept/Oct 2009.s3-s9.

Alpha-glucosidase inhibitors

• Place in therapy:– for high post-prandial blood glucose– few drug interactions – hypoglycemia rare in monotherapy– does not cause weight gain– Do not use in patients with inflammatory

bowel disease or conditions with risk of bowel perforation

Combination Therapy

• Glucovance– Glyburide/metformin

• Avandamet– Rosiglitazone/metformin

• Metaglip– Glipizide/metformin

Pramlintide (Symlin)

• Synthetic analog of human amylin• Amylin hormone synthesized by beta-cell• Reduce post-prandial blood sugar• Reduce glucose fluctuations• Lower meal-time insulin requirements

– Lower insulin by ½ when starting

• Injectable – three times a day before meals• Side effects – nausea primarily

Pramlintide• Do not use in the following patients:

– Diagnosis of gastroparesis– Hypoglycemia unawareness– Poor compliance with insulin or self-blood glucose

monitoring– HgbA1c >9%– Recurrent, severe hypoglycemia requiring assistance during

the past 6 months– Require use of medications that stimulate gastrointestinal

motility– Pediatric patients

Symlin [package insert]. San Diego, CA: Amylin Pharmaceuticals, Inc.; 2008.

Pramlintide specifics:

♦ Injectable- insulin syringe♦ Starting dose Type 1 DM 15 mcg (2.5 units)♦ Starting dose Type 2 DM 60 mcg (10 units)♦ Titrate as tolerated every 3 days

♦ Symlin® pens (60 and 120 mcg)♦ Use at the time of a meal (250 cal)♦ Separate injection from insulin♦ Decrease dose of prandial insulin by 50%♦ Potentially less nausea than with exenatide

Incretin mimetics

• New class of antihyperglycemics• Incretin hormone (GLP-1) stimulates glucose

dependent insulin secretion and slows GI motility• GLP-1 levels are decreased in diabetics• Agents

– Exenatide (Byetta)– Liraglutide (Victoza)– Tasoglutide (R1583) – phase III trials

Exenatide (Byetta)

• Gila monster saliva• MOA• Role in adjunct

therapy• Dosing• Side effects• Weight reduction

benefit

Liraglutide (Victoza)

• FDA approved 2010• Similar to Byetta• Once daily instead of

twice• Weight reduction

benefit• Dosing • Side effects

Comparing GLP-1 AnalogExenatide Liraglutide

Dosing Twice daily Once daily

Efficacy ↓in A1C of 1% (Ranges in studies 0.4-1%)

1-1.5%

Weight Reduction

2-3kg 3-4kg •not significantly different vs. exenatide

Nausea 57% 10-15% (often described as mild)•Overall, significantly fewer adverse events vs. exenatide

Boxed Warnings

No boxed warning Causes thyroid C-cell tumors at clinically relevant exposures inrodents

Dosage adjustments

CrCl 30-50 mL/min: Use caution when initiating or escalating doses.CrCl <30 mL/min: Not recommended.

No dosage adjustments; use with caution due to insufficient studies in this population

Grossman S. Differing Incretin Therapies Based on Structure, Activity, and Metabolism: Focus on Liraglutide. Pharmacotherapy.2009;29:25s-32s.

Exenatide and Liraglutide

• Place in therapy:– Not recommended as first line therapy for

patients inadequately controlled on diet and exercise

– Not for treatment of type 1 diabetes– Not indicated in combination with insulin

• Some endocrinologists use

– May use as adjunctive therapy with oral agents– May be useful in patients who are overweight

DPP-4 Inhibitors

• DPP-4 quickly inactivates GLP-1

• Oral agents• Agents

– Saxagliptin (Onglyza)– Sitagliptin (Januvia)– Linaglitpin (Tradjenta)

Sitagliptin Januvia®

Saxagliptin Onglyza™

LinaglitpinTradjenta™

Efficacy Monotherapy A1C 0.36 to 0.76%With metformin A1C 0.7%With pioglitazone A1C 0.85%With glimepiride A1C 0.45%

Monotherapy A1C 0.43 to 0.54%With metformin A1C 0.6 to 0.7%With thiazolidinedion A1C 0.9%With glyburide A1C 0.6%

Monotherapy A1C 0.44 to 0.50%With metformin A1C 0.48 to 0.49%With thiazolidinedione A1C 1.06%

Renal Dosage Adjustments

Normal dose 100mg PO daily:CrCl 30-50 ml/min 50mg daily

CrCl < 30 ml/min 25mg daily

Normal dose 2.5 to 5 mg PO daily:CrCl ≤50ml/min 2.5mg daily

No dose adjustment necessary

Drug Interactions

Limited metabolism through CYP 3A4 & 2C8; no dosage recommendations

Metabolized by CYP3A4; warning placed to reduce dose if 3A4 inhibitors are used

Substrate for CYP3A4 & weak competitive inhibitor of 3A4; efficacy may be reduced if combined with 3A4 inducors

Neumiller JJ, Wood L, Campbell RK. Dipeptidyl Peptidase-4 Inhibitors for the Treatment of Type 2 Diabetes Mellitus. Pharmacotherapy.2010. 30(5):464-484.Scott LJ. Linagliptin: In type 2 Diabetes Mellitus. Drugs 2011;71(5):611-624.

DPP-IV Inhibitorssitagliptin, saxagliptin, linaglitpin

• Place in therapy:– Tolerable side effect profile

• Considered weight neutral, hypoglycemia rare– Often similar to placebo group in clinical trials

– Add on therapy to first line oral hypoglycemic agents

– Special populations sensitive to hypoglycemia• Older adults

Canagliflozin (Invokana)• Approved for treatment of adults with type 2 Diabetes in conjunction

with lifestyle interventions

– Initiate at 100 mg PO daily, before first meal of the day

– Can increase to 300 mg PO daily if eGFR ≥ 60 mL/min (if less max dose = 100 mg/day)

• Contraindicated with hypersensitivity, ESRD, dialysis

– Avoid or discontinue if eGFR < 45 mL/min

• Additional Warnings include:

– Hypotension, hyperkalemia, hypoglycemia, mycotic genital infections, and increased LDL cholesterol

Invokana cont.• Significant Interactions

– Rifampin (UGT inducers)

• ~50% decrease in AUC

– Increased digoxin Cmax and AUC

• Pharmacokinetics

– ~ 65% absorption

– ~99% protein bound in plasma

– O-glucuronidation via UGT1A9 and UGT2B4 to inactive metabolites

– ~33% excreted in urine

– ~ 40 excreted unchanged in feces

• Common Adverse Events ( ≥ 5%)

– Urinary track infections (UTIs)

– Mycotic genital infections

– Increased frequency and/or volume of urination and nocturia

• Less common include:

– Hypersensitivity reaction

– Constipation

– Thirst

– Nausea and abdominal pain

Complications and co-morbid conditions

• Microvascular– Diabetic nephropathy

• 30% progress to end stage

– Diabetic retinopathy• 20-25% in type 1

diabetes• Close assoc with

nephropathy

– Diabetic neuropathy• Two major categories

• Macrovascular– CVD

• Accounts for 70% of deaths in type 2

Microvascular Complications

• Nephropathy• Retinopathy• Neuropathy

– Foot ulcers/lesions– Numbness, pain

• Sexual dysfunction• Gastroparesis

Macrovascular Complications

• Cardiovascular Diseases (CVD)– Coronary Artery Disease (CAD)– Myocardial Infarction (MI)– Stroke or transient ischemic attack (TIA)

• Peripheral Artery Disease (PAD)

Gestational diabetes

• Approx. 7% of pregnant women develop• Defined at high BG during pregnancy• All women some degree of glucose

intolerance• Placenta hormones – mother’s pancreas

usually compensates• Diagnosis

Risk factors

• Obesity prior to pregnancy• Ethnic group• Glucose in urine• Family history of diabetes• Previous birth of baby >9lbs• Previous birth of stillborn• Gestational diabetes in previous pregnancy• Too much amniotic fluid

Management of gestational diabetes

• Monitor BG 4x day• Urine ketone monitor• Dietary changes• Exercising• Insulin

References:• American Diabetes Association (ADA) Professional Practice Committee. Standards of medical care in diabetes - 2013.

Diabetes Care. 2013;36(1): S11-S66.• Centers for Disease Control and Prevention. Diabetes Report Card 2012. Atlanta, GA: Centers for Disease Control and

Prevention, US Department of Health and Human Services; 2012. Available at: www.cdc.gov/diabetes/pubs/pdf/DiabetesReportCard.pdf

• Centers for Disease Control and Prevention. National Diabetes Fact Sheet, 2011. Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; 2011. Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf.

• Diabetes Surveillance Report, Maine 2012. Augusta, ME: Diabetes Prevention and Control Program, Maine Center for Disease Control and Prevention; 2012. Available at: http://www.maine.gov/dhhs/mecdc/population‐health/dcp/statistics.htm

• Maine Center for Disease Control and Prevention. Maine Diabetes Prevention and Control Program, Health Fact Sheet: Diabetes in Maine. Maine Center for Disease Control and Prevention, Maine Department of Health and Human Services; 2011.

• Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach, Position Statement by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-79.

• Invokana (package insert). Janssen Pharmaceuticals, Inc. Titusville, NJ. March 2013; http://www.invokanahcp.com/. Accessed: 08/28/13.

• Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405-12.

• The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group. Effects of intensive glucose lowering in type 2 diabetes. NEJM. 2008;358(24):2545-59.

References:• Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes.

NEJM. 2009;360(2):129-39. • Ray KK, Kondapally Seshasai S, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes

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