Developing a Type 2 Diabetes Treatment Algorithm Marc Cornier, MD Division of Endocrinology, Metabolism and Diabetes University of Colorado Denver Denver Health Medical Cener [email protected]

“The Problem” • >24 Million In US With Diabetes – ~10% of adult US population

• >57 million with “pre-diabetes” • • • • •

Increasing at a rate of 7% per year Type 2 occurring at younger age 1in 3 chance of diabetes for a child born in 2000 ~7 years of life lost (primarily from CVD) Annual cost = $174 billion – $13,000 (vs $2500 w/out DM ) Mokdad AH et al. JAMA 2003, 289:76. Narayan et al. JAMA. 2003,290:1884.

Worsening Trends in Diabetes and Obesity Diabetes

Obesity 35 30

7

25 20

6

15

5

10 19 98

20 00

19 96

19 94

20 00

19 98

19 96

19 94

19 92

10

4 19 92

Prevalence (%)

8

ADA Criteria for the Diagnosis of Diabetes Test

Normal

Increased Diabetes Risk

FBG

< 100

100-125


126

2-hr PG

< 140

140-199


200

?


200 + Sx

Random BG HbA1c

?

< 5.7

5.7-6.4


6.5 Diabetes Care 33:S1, 2010

How should we best treat this patient?

Creating an Algorithm for the Management of Type 2 Diabetes • What do we need to consider? – Pathophysiology – Treatment goals – Treatment options • in general • for your patient population

– Costs and Resources – Patient and provider “buy in” – Reminder: “one right way” to do things

Pathogenesis of Type 2 Diabetes Normal Insulin Resistance

Genes

Environment

Decreased Insulin Secretion

Type 2 Diabetes CR Kahn Diabetes 43:1066-1084, 1994

Natural History of Type 2 Diabetes Years from diagnosis

-10

0

-5

10

5

15

Insulin resistance Insulin secretion

Postprandial glucose Fasting glucose

Pre-diabetes

Type 2 diabetes

Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789; Nathan DM. N Engl J Med. 2002;347:1342-1349

Type 2 Diabetes: Pathophysiology
Glucose Islet-Cell Pancreas Dysfunction

_ Glucagon Liver

_ Insulin Muscle _ glucose Insulin Resistance uptake

_ Hepatic _ glucose

Glucose production Output


Glucose

Goals for the Management of Type 2 Diabetes • Acute: – Reverse the acute symptoms of hyperglycemia

• Chronic: – Glycemic Control: • Prevent microvascular complications • Prevent macrovascular complication?

– BP control: < 130/80 – Treatment of Metabolic Dyslipidemia – Other CRFs: smoking, ASA

Intensive Diabetes Treatment Microvascular Complications Study

A1c%

Retinopathy Nepropathy

DCCT

9 vs 7

_ 76%

_ 54%

UKPDS

8 vs 7

_ 20%

_ 30%

Kumamoto

9 vs 7

_ 69%

_ 70%

Advance

7.3 vs 6.5

Neuropathy

_ 60%

_ 21%

Intensive Diabetes Treatment Macrovascular Complications Study

A1c%

CVD Events

Mortality

DCCT/EDIC

9 vs 7

_ 42%

_ 6% (ns)

UKPDS-10yr

8 vs 7

_ 15-33%

_ 13-27%

ACCORD

7.5 vs 6.4

_ 10% (ns)

_ 22%

Advance

7.3 vs 6.5

_ 6% (ns)

_ 7% (ns)

VADT

8.4 vs 6.9

_ 13% (ns)

_ 26% (ns)

ADA Recommendations Glycemic Control Goals • HbA1C – Desirable: < 7% – Selected patients: • Lower A1c goals may be reasonable if attainable without significant adverse effects such as hypoglycemia • Less stringent A1c goals may be appropriate

• Preprandial Plasma Glucose: 90-130 mg/dl • Postprandial Plasma Glucose: < 180 mg/dl Diabetes Care 33:S1, 2010

Management of Type 2 Diabetes • Education • Lifestyle Modification – Diet • What is the best diet?

– Physical Activity - Exercise – Weight Loss • Lifestyle modification • Medications • Bariatric Surgery

Management of Type 2 Diabetes • Pharmacotherapy: – Oral Agents • • • •

Secretagogues: Sulfonylureas, Meglitinides Biguanides: Metformin Thiazolidinediones: Rosi- and Pioglitazone
-Glucosidase Inhibitors: Acarbose

• DPP-4 Inhibitors: Sitagliptin, Saxagliptin

– Non-Insulin Injectable Agents • Incretin Mimetics: Exenatide, Liraglutide • Amylin analogs: Pramlintide

– Insulin

Type 2 Diabetes: Pharmacotherapy Secretagogues

Incretin Based Therapies
Glucose Islet-Cell Pancreas Dysfunction

Metformin _ Glucagon

Insulin TZDs

_ Insulin

Liver

Muscle _ glucose Insulin Resistance uptake

_ Hepatic _ glucose

Glucose production Output


Glucose

Secretagogues • Mechanism of Action: enhanced insulin secretion • Sulfonylureas: Glyburide, Glipizide, Glimepiride – Pros: they work, inexpensive – Cons: hypoglycemia, weight gain, hyperinsulinemia?, increased CVD?, enhanced -cell destruction?

• Meglitinides: Repaglinide, Nateglinide – Rapid acting insulin secretagogues – Taken with meals – Pros: good for post-prandial hyperglycemia and in renal insufficiency – Cons: hypoglycemia, expensive

Metformin • Mechanism of Action: – reduces hepatic glucose production – some direct effect on insulin sensitivity?

• Pros: effective, relatively inexpensive, no weight gain, no hypoglycemia*

• Cons: GI side effects (bloating, diarrhea), Lactic Acidosis • Contraindications: CRI: Cr > 1.5 or GFR < ~50, significant cardiopulmonary or liver dz, hypotension, binge drinking

Thiazolidinediones • Pioglitazone and Rosiglitazone • Mechanism of Action: “Insulin sensitizers” • Pros: Effective, no hypoglycemia, CVD/endothelial benefits?

• Cons: Expensive, weight gain, edema, CHF, fractures

• Remember: little clinical effect for ~6 weeks

DPP-4 Inhibitors • Sitagliptin, Saxagliptin • Mechanism of Action: – Blocks DPP-4 resulting in increased levels of active incretins _ enhanced insulin secretion and glucagon suppression

• Pros: effective, no hypoglycemia, no weight gain, best for post-prandial hyperglycemia • Cons: Expensive, less clinical experience • Dosing: once daily, renal adjustment

GLP-1 Mimetics • Exenatide and Liraglutide • Mechanism of Action: – Increase insulin secretion and glucagon suppression – Reduced energy intake – Reduced gastric empyting

• Pros: effective, no hypoglycemia, weight loss, best for post-prandial hyperglycemia • Cons: expensive, injections, nausea • Dosing: – Exenatide: 5 μg to 10 μg BID – Liraglutide: 0.6 mg to 1.2 mg to 1.8 mg daily

Human Insulin and Analogs Typical Times of Action Insulin Preparations

Onset of Action

Peak

Duration of Action

Aspart, Glulisine, Lispro

~15 minutes

1 hours

2–4 hours

Human Regular

30–60 minutes 2–4 hours

4–6 hours

Human NPH

1–4 hours

6–10 hours

12–20 hours

Detemir, Glargine

1-2 hours

Relatively Flat up to 24 hours

Stepwise Management of Type 2 Diabetes 5 4 3 2 1

Insulin

Oral + Insulin

Oral ComboTx or Orals+GLP1 mimetics

Oral Monotherapy

Diet & exercise Adapted from Williams G. Lancet 1994; 343: 95-100.

How should we start?

Algorithm for Type 2 Diabetes ADA/EASD Consensus Statement Tier 1: well-validated core therapies Diagnosis: Lifestyle + Metformin

Step 1

Lifestyle + Metformin + Intensive insulin

Lifestyle + Metformin + Basal insulin Lifestyle + Metformin + Sulfonylurea

Step 2

Step 3

Tier 2: less well-validated core therapies Lifestyle + Metformin + Pioglitazone

(no hypoglycemia /edema (CHF)/ bone loss)

Lifestyle + Metformin + GLP-1 agonist (no hypoglycemia/weight loss /nausea/vomiting )

Lifestyle + Metformin + Pioglitazone + Sulfonylurea Lifestyle + Metformin + Basal insulin

Nathan DM, et al. Diabetes Care 2008;31(12):1-11.

Treatment Algorithm for Patients with Type 2 Diabetes Diet-Exercise-Weight Loss

Metformin* Sulfonylurea, TZD, DPP-IV Inhibitor, GLP-1 mimetic, Insulin

*ADA recommends considering Metformin at time of diagnosis especially if HbA1c > 6.5%

Case: Initial Management • • • • • •

Diet Activity/Exercise Add oral monotherapy – metformin? Treat Lipids and BP “to goal” ASA Screen for diabetic eye, kidney, nerve disease

Glycemic Control Over Time - UKPDS

HbA1c (%)

9

Conventional Insulin Chlorpropamide Glibenclamide Metformin

8

7

6 0

0

2

4

6

8

10

Years from randomization Adapted from The Lancet 352:856-867, September 12, 1998

Treatment Algorithm for Patients with Type 2 Diabetes Diet-Exercise-Weight Loss A1c > 6.5%

Metformin (SU, TZD, DPP-IV inhibitor, GLP-1 mimetic, Insulin) A1c
7%

Sulfonylurea, TZD, DPP-IV inhibitor, GLP-1 mimetic, Insulin (Metformin) *ADA recommends considering 2 nd agent if HbA1c > 7

Case: “Follow-up” Management • Diabetes – poor control on “monotherapy” – Reinforce Lifestyle Modification – Step therapy • Oral “Double Therapy”: add TZD, DPP-4 I, sulfonylurea? • Add GLP-1 mimetic? • Add or switch to insulin?

• • • •

Obesity HTN Hyperlipidemia Cardiac Risks?

Hemoglobin A1C Plasma Glucose (mg/dL)

300

24 hour Glucose

200

Postprandial Hyperglycemia Fasting Hyperglycemia

100

Normal A1C 4%-6%

0 06.00

12.00

18.00

24.00

06.00

Time of Day (h)

How Do We Choose? • Ideal World: – What is primary pathophysiology? • Severe insulin resistance? • Fasting hyperglycemia or increased HGO? • Postprandial hyperglycemia or insulin secretory defect?

– Benefits vs risks?

• Real Life: – What’s on formulary? – Are there any contraindications to certain agents or class of agents?

• Individualize

Case (f/u): Assessment/Plan • Type 2 Diabetes: poor control on metformin and SU – Reinforce Lifestyle Modification and weight loss – Step therapy • Oral “Triple Therapy”: Add a TZD or DPP-4 Inhibitor? • Add GLP-1 mimetic? • Add or switch to insulin?

• Don’t forget other problems: – HTN, Hyperlipidemia, Cardiac Risks?

Treatment Algorithm for Patients with Type 2 Diabetes Diet-Exercise-Weight Loss

Metformin , SU, TZD, DPP-IV inhibitor, Insulin Meformin, SU, TZD, DPP-IV inhibitor, GLP-1 mimetic, Insulin Triple “non-insulin” Therapy

Basal Insulin

Basal-Bolus Insulin vs Other Combinations

Indications for Insulin Therapy in Type 2 Diabetes • • • • •

Poor control on oral agents Cannot take/tolerate oral agents Severe hyperglycemia Hyperosmolar State and/or Ketoacidosis Pregnancy

Profiles of Insulin Preparations Aspart, Glulisine, Lispro Regular NPH Glargine Detemir

Plasma insulin levels

0

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Hours

Adding/Starting Insulin Therapy in Type 2 Diabetes • Basal insulin: – NPH at bedtime/BID vs Detemir or Glargine – Especially good for persistent fasting hyperglycmia

• Basal+Bolus Therapy: – Basal + Bolus or Mealtime Rapid-Acting or Regular insulin – Especially good post-prandial hyperglycemia – Premixed insulins?

• • • •

Add insulin to previous regimen or to “insulin sensitizers”? Change to insulin mono-therapy Most will require insulin after 10 years. Insulin is not a failure – it is not a penalty!

Starting/Titrating Basal Insulin • Start with 10-15 units at bedtime • Weekly titration: FBG (mg/dl) > 180 160-180 140-160 120-140 100-120 70-120