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Joslin Diabetes CenterJoslin Diabetes Forum 2013: The Impact of Comorbidities on Glucose ControlMedications to Treat Type 2 Diabetes: Matching the Options to Needs

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Medications to Treat Type 2 Diabetes:

Matching the Options to Needs

22.3 million people ( ̴ 7% of the population) have diagnosed DM• Additional 6.3 million undiagnosed

The number is growing by > 1 million per year

A major cause of mortality and morbidity

Cost (direct and indirect) $245 billion per year• 1 in 5 U.S. healthcare dollars spent

on diabetes

Diabetes in the U.S. Today: An Epidemic

Diabetes Care. 2013; 36(4):1033-1041

45% of Patients With Diabetes Are Still Not at ADA A1C Goal <7%*

49

50

51

52

53

54

55

56

A1c < 7% BP < 130/80 LDL < 100

*Ford ES. J Diabetes. 2011;3:337-347.

19% metall 3 goals

1



Natural History of Type 2 Diabetes

Kendall DM, Bergenstal RM ©2003 International Diabetes Center, Minneapolis, MN. All rights reserved.

Prediabetes (IFG, IGT)Metabolic syndrome

Years

Glucose(mg/dL)

Relative Function

Clinical diagnosis

-10 -5 0 5 10 15 20 25 30

50

100

150

200

250

300

350

Insulin resistance

-cell function

Fasting glucose

Postmeal glucose

Onset ofDiabetesOnset ofDiabetes

0

50

100

150

200

250

126 mg/dL

7.0 mM

Adapted from Holman RR. Diab Res Clin Pract. 1998;40(suppl):S21-S25.

Years

-cell function(% of normal by HOMA)

0

20

40

60

80

100

-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6

Time of diagnosis

HOMA=homeostasis model assessment

Decline of -Cell Function in the UKPDS Illustrates Progressive Nature of Diabetes

1Chan JM et al. Diabetes Care. 1994;17:961-969.2Colditz G et al. Ann Intern Med. 1995;122:481-486.

Age-adjusted relative risk of type 2 diabetes

Obesity Is the Primary Risk Factorfor Type 2 Diabetes

0

10

20

30

40

50

1.02.2

12

42

0

25

50

75

100

1.08.1

40

93

<23 25 31 35 <22 25 31 35

Men1 Women2

BMI

2



DPPOS Incidence of Diabetes

Risk Reduction18% with metformin34% with lifestyle

DPP: Diabetes Prevention Program; DPPOS: Diabetes Prevention Program Outcomes Study

DPPRG. Lancet. 2009 Nov 14;374(9702):1677-1686.

American Diabetes Association. Diabetes Care. 2013;36(suppl 1):S11-S66. American College of Endocrinology, Medical Guidelines for Clinical Practice for Developing a Diabetes Mellitus Comprehensive Care Plan. Endocrine Practice. 2011;17(suppl 2):1-52.

A1C is “gold standard” measure of diabetes control over the previous 2–3 months

AMERICAN DIABETES ASSOCIATION (ADA) GOAL

A1C (%) < 7 Preprandial plasma glucose (mg/dL) 70–130

Peak postprandial plasma glucose (mg/dL) < 180

Aggressive Control of Diabetes: Glycemic Goals of Treatment

AMERICAN ASSOCIATION OF CLINICALENDOCRINOLOGISTS (AACE)

A1C (%) ≤ 6.5Preprandial plasma glucose (mg/dL) < 110 2-hour postprandial glucose < 140

ADA: Individualizing Therapeutic Goals

A1C ≤ 7% for most

A1C < 6.5% for selected patients, if safe

A1C < 8% for high-risk patients:

• History of severe hypoglycemia

• Short life expectancy / advanced age

• Advanced micro-/macrovascular complications and comorbidities such as:

– Heart disease

– Renal dysfunction

– Liver disease

• Longstanding diabetes

Consider weight management needs and goals in medication selection

ADA/EASD, Management of Hyperglycemia in Type 2 Diabetes: A patient-Centered Approach Diabetes Care 2012; 35:1364-1379. ADA, Diab Care 2013, 36(Suppl 1):S11.

3



Sulfonylureas__________

Generalized insulin

secretagogues

Type 2 Diabetes

-Glucosidase

Inhibitors________

Delay carbohydrate absorption

Biguanide________

Reduces hepatic insulin

resistance

TZDs________

Reduce peripheral

insulin resistance

InsulinReplacement

Therapy

DPP-4 Inhibitors

Restore GLP-1 levels

Meglitinides __________

Restore postprandial

insulin patterns

ColesevelamMechanism unknown

SGLT2 Inhibitors Renal glucose

excretion

Quick-releaseBromocriptine

Central mechanismGLP-1

AnalogsStimulate cells

Glucagon

Pharmacotherapy Tailored for the Multiple Defects of Type 2 Diabetes

Classification Based on Target Pathology

Insulin Resistance• Biguanides (metformin)• Thiazolidinediones (pioglitazone)

β-Cell Dysfunction/Failure• Sulfonylureas (SU) • DPP-4 inhibitors (DPP-4-i)• Short-acting secretagogues (meglitinides/“glinides”)• GLP-1 receptor agonists (GLP-1-RA)• Insulin

Other Mechanisms• α-Glucosidase inhibitors (GI glucose absorption)• Colesevelam (hepatic, but exact mechanism not clear)• Bromocriptine (rapid-acting; dopaminergic mechanisms)• SGLT-2 inhibitors (renal glucose excretion)

Classification Based on Predominant Blood Glucose Effects Postprandial Glucose

• DPP-4 inhibitors

• α-Glucosidase inhibitors (AGI)

• Short-acting secretagogues (“glinides”)

• Short-acting insulin

Fasting Glucose• Biguanides (metformin)

General Glucose Reductions• Sulfonylureas

• Thiazolidinediones (pioglitazone)

• Bromocriptine (rapid-acting)

• Colesevelam

• SGLT-2 inhibitors

• Intermediate and long-acting Insulin

• GLP-1-RA

4



Actions of Diabetes Medications

Drug Name Class How It WorksWhere It Works

Hypo-glycemia?

Metformin Biguanides Hepatic

glucose production

Liver Rare

SulfonylureasRepaglinideNateglinide

Secretagogues Insulin

secretionPancreas Yes

Pioglitazone Thiazolidinediones Insulin

sensitivityMuscle Rare

AcarboseMiglitol

α-GlucosidaseInhibitors

Slows CHOabsorption

Intestines Rare

Pramlintide Amylin analogs

Gastric emptying

Glucagon Satiety

Activates amylin receptor

With insulin

ADA/EASD. Management of Hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care. 2012;35:1364-1379. Data reported in package inserts.

Actions of Diabetes Medications (cont.)

Drug Name Class How It WorksWhere It Works

Hypo-glycemia?

ColesevelamBile Acid Sequestrants

Binds bile acids

Hepatic glucose production

Intestines Rare

ExenatideLiraglutide

GLP-1 agonists

Activates GLP-1 R Insulin Glucagon Gastric emptying Satiety

Pancreas;Stomach

Rare

SaxagliptinSitagliptinLinagliptinAlogliptin

DPP-4 inhibitors

Inhibits DPP-4 GLP-1, GIP Insulin Glucagon

Pancreas Rare

CanagliflozinSGLT-2inhibitors

Increases renalglucose excretion

Kidneys Rare


Medications and Pharmacology

Description Action Examples

Medicationsimproving insulin action

Decrease insulin resistance Increase insulin sensitivity

Biguanide (metformin)Thiazolidinediones

Medicationsaugmenting the Incretin effect

Increase prandial insulinGLP-1 agonistsDPP-4 inhibitors

Insulin secretagoguesIncrease basal and/orprandial insulin

SulfonylureasShort-acting secretagogues

Other mechanisms

Renal glucose reabsorptionGI glucose absorptionHepatic glucose metabolismDopaminergic mechanisms

SGLT-2 inhibitorsα-Glucosidase inhibitorsColesevelamQuick-release bromocriptine


5



Estimated Reduction of A1C in Response to Monotherapy of Available Diabetes Medications

Adapted from Nathan DM. N Engl J Med. 2007;365:437-440. Package Inserts for canagliflozin, bromocriptine, colesevelam.

Medication Reduction in A1C

Insulin Injection 2.5

Metformin 1–1.5

Sulfonylureas 1–1.5

Short-acting secretagogues 1–1.5

Thiazolidinediones 1–1.3

GLP-1 analog 0.6–1.0

Α-Glucosidase inhibitors 0.5–0.8

Amylin analog 0.6–0.8

SGLT-2 inhibitors 0.6–0.7

DPP-4 Inhibitors 0.5–0.7

Bromocriptine (short-acting) 0.4–0.6

Colesevelam 0.4–0.5

Combination Therapy: Improvements in Glycemic Control When Adding a 2nd Medication

Regimen A1C FBG

Metformin + glyburide ~1.3% ~63 mg/dL

Metformin + repaglinide ~1.1% ~35 mg/dL

Metformin + exenatide ~0.9% ~24 mg/dL

Metformin + canagliflozin ~0.8% ~40 mg/dL

Metformin + pioglitazone (30 mg) ~0.8% ~38 mg/dL

Metformin + acarbose ~0.7% ~40 mg/dL

Metformin + sitagliptin ~0.7% ~17 mg/dL

Sulfonylurea + bromocriptine ~0.5% ~18 mg/dL

Metformin + colesevelam ~0.5% ~14 mg/dL

Insulin + antihyperglycemic meds. Open to target Open to target

Pivotal trial data reported in package inserts.

Antidiabetes Medications: Key Considerations in Advancing Therapy Metformin

• Usually first-line therapy with effective A1C reduction of 1–1.5 points

• No hypoglycemia or weight gain• Reduction in CV risk & mortality• Fasting glucose

Secretagogues (sulfonylureas, short-acting)• Good A1C impact: 1–1.5 point reduction• Inexpensive• Insulin secretion not glucose-dependent: general glucose-

lowering, short-acting, target postprandial• Potential for weight gain and hypoglycemia

α-Glucosidase inhibitors• Lesser efficacy (A1C 0.5–0.8 point reduction) but target

postprandial glycemia• Neutral effect on weight, lipids, and BP, but GI side effects• May prevent DM & reduce CV events (Stop-NIDDM Study)

Beaser RS. Joslin’s Diabetes Deskbook , 2nd updated ed. Boston, MA: Joslin Diabetes Center; 2010.

6



Antidiabetes Medications: Key Considerations in Advancing Therapy Thiazolidinediones

• A1C reduction 1–1.3 points• Reduced peripheral insulin resistance: targets rising glycemia

during the day• Reduction in visceral fat but potential for weight gain / fluid retention• No hypoglycemia, but concern about other adverse events

DPP-4 inhibitors• Modest impact on A1C: 0.5–0.7 point reduction• Glucose-dependent impact on postprandial glycemia• Neutral impact on weight, lipids

GLP-1 agonists• Glucose-dependent insulin secretion and suppression of glucagon

targets postprandial glycemia and general glycemic lowering• Slows gastric emptying, can have AE of nausea• Reduced food intake and weight loss• Injected

Beaser RS. Joslin’s Diabetes Deskbook , 2nd updated ed. Boston, MA: Joslin Diabetes Center; 2010.Package inserts.

Antidiabetes Medications: Key Considerations in Advancing Therapy Colesevelam

• Modest A1C reduction: 0.5 points• Dual effect on LDL-C and A1C• General glycemic-lowering• Neutral effect on weight• Large number of large pills or dissolved powder

Quick-release bromocriptine• Modest impact on A1C: 0.6 points• Generalized glycemic-lowering• Neutral impact on weight, lipids• Unclear mechanism of action, multiple tablets

• SGLT-2 inhibitors• Modest impact on A1C: 0.6 points• Generalized glycemic-lowering• Weight loss

Beaser RS. Joslin’s Diabetes Deskbook , 2nd updated ed. Boston, MA: Joslin Diabetes Center; 2010.Package inserts.

Treatment Considerations in Overweight People Issues:

• Majority of people with type 2 diabetes are overweight or obese

• Consider latent autoimmune diabetes in adults (LADA) in lean people

Clinical approaches:• Intensive lifestyle program• Metformin• GLP-1 receptor agonists• Consider bariatric surgery

ADA/EASD. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care. 2012;35:1364-1379.

7



Modest

Weight Gain Weight Neutral Weight Loss

Significant

Pioglitazone

SUsGlyburideGlipizide

InsulinNPHGlargineRegularAspartLisproGlulisine

SUsGlimepirideGlipizide XL

GlinidesRepaglinideNateglinide

InsulinDetemirGlulisine (PP)

Metformin

DPP-4 InhibitorsSitagliptinSaxaglipitinLinagliptin

α-Glucosidase InhibitorsAcarboseMiglitol

Colesevelam

Bromocriptine

GLP-1 AnalogsExenatideExenatide ERLiraglutide

Pramlintide

Modest

Based on Mitri J, Hamdy O. Expert Opin Drug Saf. 2009;8(5):573-584.

Obesity

Treatment Considerations in People With Renal Disease

Issues:• Increased risk of hypoglycemia

• Metformin and lactic acidosis

Clinical approaches:• US: Stop metformin @ SCr > 1.5 (men),

1.4 (women)

• UK: dose @ GFR <45, stop @ GFR < 30

• Caution using sulfonylureas (esp. glyburide)

• DPP-4 inhibitors: adjust doses (except linagliptin)

• Avoid exenatide if GFR < 30


Renal Disease (Slide 1 of 2)

Sulfonylureas Meglitinides -Glucosidase Inhibitors(Acarbose, Miglitol)

TZDs (Pioglitazone)

Do not use if:

eGFR<60 (nateglinide)

Cr>2 (~eGFR<30)

Other notes

Glipizide: less hypoglycemia

Repaglinide: no dose adjustment

Concerns re: fluid retention, edema, bone disease, bladder Ca

8



Renal Disease (Slide 2 of 2)

Biguanides (Metformin)

GLP-1 Agonists

DPP-4 Inhibitors

SGLT-2 Inhibitors

Use with caution if:

eGFR 45–60

Adjust dose if:

eGFR 30–45 (maximum 1000 mg/d)

eGFR ≤ 50 eGFR 45–60 (max 100 mg/d)

Do not use if:

eGFR <30 eGFR < 30 (exenatide)

eGFR < 45

Other notes

D/C for inpatients if lactic acidosis risk

Liraglutide: no dose adjustment

Treatment Considerations in People With Liver Dysfunction

Issues:• Most drugs not tested in advanced liver

disease

Clinical approaches:• Pioglitazone may help steatosis

• Insulin is the best option if disease is severe


Abnormal Liver Function

Ding X et al. Hepatology. 2006;43:173-181.Cusi K. Curr Opin Endocrinol Diabetes Obes. 2009;16:141-149.Williams KH et al. Endocr Rev. 2013;34(1):84-129.

Biguanides(metformin)

TZDs (pioglitazone) Incretins (exenatide,liraglutide)

Pros • Insulin sensitization

• Weight neutral• May improve

LFTs

• Insulin sensitization• May improve LFTs• May improve steatosis,

inflammation

• Weight loss• May improve

steatosis

Cons Potential for:• Weight gain• Edema• Heart failure

9



Coronary Artery Disease and Glycemic ControlACCORD

• Intensive (A1C < 6%) vs standard (7–8%)• Increased mortality in intensive arm• ? role of hypoglycemia

ADVANCE • Intensive (A1C < 6.5%) vs standard• No change in mortality

VADT• Intensive (A1C < 6%) vs standard• Longer DM duration less CVD benefit

Summarized in ADA Clinical Practice Recommendations, 2013.

Treatment Considerations in People With Heart Disease Coronary artery disease:

• Metformin has CVD benefit (UKPDS)• Avoid hypoglycemia• Sulfonylureas and ischemic preconditioning• Possible CVD effects with pioglitazone, incretin-

based therapies, α-glucosidase inhibitors, bromocriptine

Heart failure:• Metformin OK unless unstable or severe• Avoid thiazolidinediones• Incretin-based therapies ? CV protection


Preventing CVD Events

Measure Change in Measure CVD Risk Reduction

A1C 1% 14%

Systolic BP 10 mm Hg 11%

LDL-C 1 mmol/L (≈ 40 mg/dL) 25%

Stratton IM et al. Diabetologia. 2006 Aug;49(8):1761-1769. (based on UKPDS) Yusuf S. Lancet. 2002 Jul 6;360(9326):2-3. (based on MRC/BHF Heart Protection Study [HPS])

10



Coronary Artery Disease –Effects of Specific Meds

Metformin SUs TZDs (pioglit-azone)

DPP-4i GLP-1a

Lipid effects

↓TG, ↑HDL, ↔ LDL-C

None ↓↓TG, ↑↑HDL, ↔ LDL-C

↓post-prandial lipids

↓↓non-HDL

BP effects

None None None None ↓

CVD event rates

↓* ↓* ↓*

Davidson MH. Am J Cardiol. 2012;110[suppl]:43B–49B.Canagliflozin package insert.

*nonrandomized trials

Coronary Artery Disease –Effects of Specific Meds

Bile acid sequestrants (colesevelam)

SGLT-2 inhibitors

Meglitinides

Lipid effects ↓↓non-HDL ↑LDL None

BP effects ↓ None

CVD event rates

Unknown Unknown

Davidson MH. Am J Cardiol. 2012;110[suppl]:43B-49B. | Derosa G. J Clin Pharm Ther.2009 Feb;34(1):13-23. | Derosa G. Curr Med Res Opin. 2009 Mar;25(3):607-615.Canagliflozin package insert.

*nonrandomized trials

Treatment Considerations in Older Adults Issues:

• Reduced life expectancy• Higher cardiovascular disease (CVD) burden• Reduced GFR• At risk for adverse events from polypharmacy• More likely to be compromised from hypoglycemia

Clinical approaches:• Less ambitious targets• A1C < 7.5–8.0% if tighter targets not easily

achieved• Focus on drug safety

ADA/EASD. Management of hyperglycemia in type 2 diabetes: a patient-centered approach Diabetes Care. 2012;35:1364-1379.

11



Elderly (slide 1 of 2)

Medication Hypoglycemia Risk

Advantages Cautions

Metformin Low • Cardiovascular benefits• Reduced dose safe for

eGFR ≥ 45

• GI side effects• Unintended weight loss• Renal insufficiency

Sulfonylureas(glipizide)

Higher • Well tolerated • Inconsistent meals lead to hypoglycemia

Nonsulfonylurea secretagogues (glinides)

Lower than SUs • May skip dose if meal is skipped

• Multiple doses (error-prone)

• Expensive

glucosidase inhibitors

Low • GI side effects are common

Germino, FW. Clin Ther. 2011;33(12):1868-1882.

Elderly (slide 2 of 2)

Medication Hypoglycemia Risk

Advantages Cautions

DPP-4 inhibitors Low • Expensive

GLP-1 agonists Low • Unintended weight loss• Expensive• Needs injections

Thiazolidinediones(pioglitazone)

Low • Possible bladder cancer risk• Leg edema, CHF

SGLT-2 inhibitors Low • Limit to 100 mg/day if >75years

Insulin Higher • Well tolerated • Complex regimen can lead to errors

Germino, FW. Clin Ther. 2011;33(12):1868-1882.

Principles of Starting and Advancing Therapy

AACE and ADA Guidelines

12



ADA/EASD Position Statement

From Inzucchi S et al. ADA EASD position statement. Diabetes Care. 2012;35:1364-1379.]

Healthy eating, weight control, increased physical activity

Initial drug monotherapy

2-drug combinations

Metformin

Efficacy

Hypoglycemia

Weight

Cost

Side effects

Efficacy A1CHypoglycemiaWeight

CostSide effects

HighLow riskNeutral / lossGI / lactic acidosisLow

If A1C not at goal at 3 months, proceed to 2 drugs. (No specific order)

Met + Met + Met + Met + Met +SU TZD DPP-4i GLP-1-RA Insulin High High Intermediate High HighestModerate risk Low risk Low risk Low risk High risk

Gain Gain Neutral Loss GainHypo-glycemia

Edema, CHF, Fx Rare GI Hypo-

glycemiaLow High High High Variable

13



ADA/EASD Position StatementHealthy eating, weight control, increased physical activity

3-drug combin-ations

More complex insulin strategies

Met + Met + Met + Met + Met +

SU TZD DPP-4i GLP-1-RA Insulin

+ + + + +

TZD SU SU SU TZD

or DPP-4-I or DPP-4i or TZD or TZD or DPP-4i

or GLP-1-RA or GLP-1-RA or Insulin or Insulin or GLP-1-RA

or Insulin or Insulin

If A1C not at goal at 3–6 months, proceed to a more complex insulin strategy + 1–2 noninsulin agents

Insulin (multiple daily doses)

If A1C not at goal after 3 months, proceed to 3-drug combination (no specific order)

From Inzucchi S et al. ADA EASD position statement. Diabetes Care. 2012;35:1364-1379.]

Treatment of Type 2 Diabetes:Key Points Individualize treatment targets and methods,

consider comorbidities (esp. CVD, renal, liver) and age-related issues

Consider weight management needs and goals in designing treatments

Nutrition, exercise, education: foundation of any treatment program

Metformin is first-line pharmacotherapy—unless there is a contraindication

After metformin, advance to 1–2 medications that are most appropriate for the patient

Treatment of Type 2 DM:Key Points

Ultimately many patients will require insulin, alone or in combination with other medications

Make all treatment decisions with the patient, focusing on her or his preferences, needs, and values

Comprehensive CV risk reduction is vital!

14

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