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Fasting bg > 140

Joslin Diabetes Center & Joslin Clinic
Clinical Guideline for Pharmacological Management of Type 2 Diabetes
1/09/2009

The objective of the Joslin Diabetes Center & Joslin Clinic Clinical Guideline for Pharmacological Management of Type 2 Diabetes is to support
clinical practice and influence clinical behavior to improve outcomes and assure quality of care according to accepted standards. The Guideline was
established after careful review of current evidence, literature and clinical practice. This Guideline will be reviewed periodically and modified to reflect
changes in clinical practice and available pharmacological information.
This Clinical Guideline is not intended to serve as a mandatory standard, but rather to provide a set of recommendations for patient care management.
These recommendations are not a substitute for sound and reasonable clinical judgment or decision-making and do not exclude other options. Clinical
care must be individualized to the specific needs of each patient and interventions must be tailored accordingly. The Guideline has been created to
address initial presentations and treatment strategies in the adult non-pregnant patient population. The Guideline is not a substitution for full prescribing
information. Refer to Joslin's Clinical Guideline for Adults with Diabetes for additional, more comprehensive information on diabetes care and
management.
Diabetes Mellitus – Diagnostic Criteria (Non-Pregnant Adults)
• Casual plasma glucose > 200 mg/dl and symptoms of diabetes (polyuria, polydipsia, ketoacidosis, or unexplained weight loss) OR
• Fasting plasma glucose (FPG)* >126 mg/dl OR
• Results of a 2-hour 75-g Oral Glucose Tolerance Test (OGTT)* > 200 mg/dl
* These tests should be confirmed by a repeat test, on a different day, unless unequivocally high
Goals of Glycemic Control for People with Diabetes
Biochemical Index
Fasting Plasma Glucose or Preprandial Glucose (mg/dl)
70 – 130
Postprandial 2 hours (mg/dl)
Bedtime Glucose (mg/dl)
90 – 150
A1C (%) - sustained
< 7% 3
Copyright 2009 by Joslin Diabetes Center. All rights reserved. Any reproduction of this document, which omits Joslin's name or copyright notice is prohibited. This document may be reproduced for personal use only. It may not be distributed or sold. It may not be published in any other format without the prior, written permission of Joslin Diabetes Center, Publications Department, 617-226-5815. Please refer to Joslin's website, www.joslin.org, for the most current version of our Clinical Guidelines. INITIAL TREATMENT STRATEGY
Medical nutrition therapy (MNT), physical activity, blood glucose monitoring and patient education are the cornerstones of diabetes management for all
patients. Pharmacological management should be used in combination with MNT and physical activity. Current weight status and lifestyle should be
considered when choosing initial pharmacological therapy.
Initial Presentation (Based on presentation of the items listed within each box)

Mild or no symptoms AND
FPG > 150 mg/dl4 OR
Marked hy
perglycemia OR
• Negative ketones AND
• Random > 250 mg/dl4
• Significant weight loss OR
• No acute concurrent illness AND
AND/OR
Severe/significant symptoms OR
• A1C < 7.5%
• A1C > 7.5%
• 2+ or greater ketonuria OR
• Does not meet criteria
• DKA/ hyperosmolar state OR
for mild or severe
• Severe intercurrent illness or surgery

Start MNT and Physical
Activity and Consider
Start Oral
If after 6-8 weeks,
Addition of Metformin
Start Insulin Immediately 5
target not met
Continued on next page
Copyright 2009 by Joslin Diabetes Center. All rights reserved. Any reproduction of this document, which omits Joslin's name or copyright notice is prohibited. This document may be reproduced for personal use only. It may not be distributed or sold. It may not be published in any other format without the prior, written permission of Joslin Diabetes Center, Publications Department, 617-226-5815. Please refer to Joslin's website, www.joslin.org, for the most current version of our Clinical Guidelines. CONSIDERATIONS FOR SELECTING INITIAL NON-INSULIN ANTIHYPERGLYCEMIC THERAPY6
Metformin
Thiazolidinediones
Dipeptidyl Peptidase
Bile Acid Sequestrant
• *Overweight/obese* Inhibitor
IV Inhibitors
• Renal/liver function • *Overweight/obese, (sulfonylurea or
• Milder presentation (DPP-4 Inhibitors) • Adjunct to other treatment signs of insulin • Use if postprandial • Use if postprandial hyperglycemia is the hyperglycemia is the • Modest effect on A1C. Also • Creatinine > 1.4 • Liver function normal: • Normal/overweight need to follow LFT • Repaglinide or Note: Reduces gastric absorption • Creatinine > 1.5 monitoring schedule7 of some drugs. If known • Can be used in renal useful for patients • No GI symptoms • Weight neutral interaction or unknown impairment but may with postprandial • Reduce dose in renal interaction with narrow increase fluid retention hyperglycemia or • Chronic intestinal therapeutic index drug, • Alcohol excess • Consider risk for bone with hypoglycemia administer 1 hour prior or 4 > 80 years age loss and fracture None known at this time
hours after colesevelam (unless creatinine Note: Full effect of clearance allows) initiation or titration of • Sulfonylureas in • Acarbose and • Bowel obstruction therapy may take 2-4 miglitol in renal • Serum triglyceride > 500mg/dl *Defuned in glossary months to be seen • Hx of hypertriglyceridemia- (creatinine > 2.0) induced pancreatitis • Class III or IV CHF • LFT > 2.5 times upper • See footnotes 8, 9 for GLP-1 agonist
• Administered subcutaneously Titrate Dose over 1 –6 months
Reinforce MNT and Physical Activity
Use if postprandial hyperglycemia predominates • To avoid hypoglycemia if If A1C > 7.0% OR
using with a sulfonylurea, Fasting Plasma Glucose > 130 mg/dl OR
consider initially decreasing 2 Hour Postprandial Glucose > 180 mg/dl
Add second oral antihyperglycemic OR GLP-1 agonist OR insulin
associated with weight loss • Gastroparesis requiring (See next page)
• History of pancreatitis Copyright 2009 by Joslin Diabetes Center. All rights reserved. Any reproduction of this document, which omits Joslin's name or copyright notice is prohibited. This document may be reproduced for personal use only. It may not be distributed or sold. It may not be published in any other format without the prior, written permission of Joslin Diabetes Center, Publications Department, 617-226-5815. Please refer to Joslin's website, www.joslin.org, for the most current version of our Clinical Guidelines. CEMIC THERAPY , continued

Suggested well-studied combinations based on results of
clinical studies. These do not preclude other combinations:

• Insulin secretagogue and metformin** • Sulfonylurea and α-glucosidase inhibitor • Thiazolidinediones and sulfonylurea** • Thiazolidinediones and metformin** • Thiazolidinediones and repaglinide • Thiazolidinediones and exenatide • Sulfonylurea and exenatide • Metformin and exenatide • Dipeptidyl Peptidase IV Inhibitors and sulfonylurea • Dipeptidyl Peptidase IV Inhibitors and metformin** • Dipeptidyl Peptidase IV Inhibitors and pioglitazone • Colesevelam and sulfonylurea • Colesevelam and metformin ** Also available in fixed combinations Continued on next page
Copyright 2009 by Joslin Diabetes Center. All rights reserved. Any reproduction of this document, which omits Joslin's name or copyright notice is prohibited. This document may be reproduced for personal use only. It may not be distributed or sold. It may not be published in any other format without the prior, written permission of Joslin Diabetes Center, Publications Department, 617-226-5815. Please refer to Joslin's website, www.joslin.org, for the most current version of our Clinical Guidelines. ANTIHYPERGLYCEMIC THERAPY, continued
A1C > 7.0% OR Fasting Plasma Glucose > 130 mg/dl OR 2 Hour Postprandial Plasma Glucose > 180 mg/dl Additional Oral
or Insulin 10,11,12 or
Consider starting with. agonist10
Medication
° Intermediate-acting insulin (NPH) once or twice daily as part of a conventional program of Different Class10
Long-acting insulin (detemir or glargine) once or twice daily for basal therapy Pre-supper insulin mixture (75/25 lispro, 50/50 lispro, 50/50 aspart, 70/30 aspart, 70/30 human insulin, or 50/50 human insulin) • Suggested starting dose for injectable insulin: 0.1-0.2 units/kg ideal body weight
• Titrate/adjust insulin dosage to achieve glucose goals

If target glucose not met after 2-4 months, consider:
•
Changing to multidose insulin therapy using combination of rapid, short, intermediate, or long-acting insulin Adding pre-meal rapid or short-acting insulin (e.g. aspart, glulisine, lispro or regular) pre-meals, to bedtime intermediate or long-acting insulin Adding bedtime basal insulin and adjusting the rapid or short-acting insulin as needed if taking pre-meal insulin and postprandial glucose targets are met, but fasting glucose is elevated • Adding oral antihyperglycemic medication to reduce insulin resistance or improve glycemic control if already on insulin (metformin, TZDs13, sulfonylureas, α-glucosidase inhibitors, and colesevelam are approved for use
in combination with insulin)
• If post-prandial excursions predominate, refer to endocrinologist for intensification of therapy or for consideration of pramlintide use Copyright 2009 by Joslin Diabetes Center. All rights reserved. Any reproduction of this document, which omits Joslin's name or copyright notice is prohibited. This document may be reproduced for personal use only. It may not be distributed or sold. It may not be published in any other format without the prior, written permission of Joslin Diabetes Center, Publications Department, 617-226-5815. Please refer to Joslin's website, www.joslin.org, for the most current version of our Clinical Guidelines. Oral Antihyperglycemic Medications Available in the USA
Biguanides
Insulin Secretagogues
Dipeptidyl Peptidase
Bile Acid
Glucosidase
IV Inhibitors
Sequestrant
Inhibitors
(DPP-4 Inhibitors)
• pioglitazone • sitagliptin (Januvia) • colesevelam • metformin and glipizide (Metaglip) (Precose) • glimepiride (Amaryl) (Welchol) • metformin and glyburide (Glucovance) • rosiglitazone • miglitol • glipizide (Glucotrol) • metformin and pioglitazone (Actoplus met) (Avandia) (Glyset) • glipizide extended • pioglitazone and glimepiride (Duetact) release (Glucotrol XL) • rosiglitazone and glimepiride (Avandaryl) (Glucophage) • glyburide • rosiglitazone and metformin (Avandamet) • metformin (Micronase, Diabeta) • sitagliptin and metformin (Janumet) • micronized glyburide • repaglinide and metformin (PrandiMet) (Glynase) (Glucophage (glimepiride, glipizide Fortamet, and glyburide are Glumetza) available as generic medications) (metformin and metformin ER available as • repaglinide (Prandin) medication) D-phenylalanine
Derivatives
formulation for • nateglinide (Starlix) patients unable to swallow pills Continued on next page
Copyright 2009 by Joslin Diabetes Center. All rights reserved. Any reproduction of this document, which omits Joslin's name or copyright notice is prohibited. This document may be reproduced for personal use only. It may not be distributed or sold. It may not be published in any other format without the prior, written permission of Joslin Diabetes Center, Publications Department, 617-226-5815. Please refer to Joslin's website, www.joslin.org, for the most current version of our Clinical Guidelines. INJECTABLE DIABETES MEDICATIONS
INSULIN CHART14
Insulin Type
Duration
Insulin aspart analog Insulin glulisine analog 10 – 30 minutes 30 minutes – 3 hours Insulin lispro analog Human NPH insulin 90 minutes – 4 hours up to 24 hours** Long-Acting
Insulin glargine 45 minutes -4 hours up to 24 hours *** Premixed Insulin Combinations
Insulin Type
50% NPH; 50% Regular Humulin 50/50 70% NPH; 30% Regular Humulin 70/30 70% NPH; 30% Regular 50% lispro protamine suspension, 50% lispro Humalog Mix 50/50 50% aspart protamine suspension, 50% aspart Novolog Mix 50/50 75% lispro protamine suspension, 25% lispro Humalog Mix 75/25 70% aspart protamine suspension, 30% aspart NovoLog Mix 70/30 *Usual clinical relevance can be less than 12 hours
** Usual clinical relevance can be less than 24 hours. Often requires twice daily dosing
*** Individual response may require twice daily dosing

INCRETIN MIMETICS AND NON-INSULIN SYNTHETIC ANALOGS
Mechanism of Action
Type of Diabetes
# of Injections Per Day
Exenatide (Byetta) Incretin mimetic that enhances glucose-dependent insulin secretion and several other antihyperglycemic actions of incretins. Pramlintide (Symlin) Synthetic analog of human amylin, a naturally occurring hormone made in the beta cells, which slows gastric emptying, suppresses glucagon secretion, and regulates food intake. A significant reduction in insulin dose may be required when insulin is used in conjunction with pramlintide. Copyright 2009 by Joslin Diabetes Center. All rights reserved. Any reproduction of this document, which omits Joslin's name or copyright notice is prohibited. This document may be reproduced for personal use only. It may not be distributed or sold. It may not be published in any other format without the prior, written permission of Joslin Diabetes Center, Publications Department, 617-226-5815. Please refer to Joslin's website, www.joslin.org, for the most current version of our Clinical Guidelines.
Footnotes:

1Laboratory methods measure plasma glucose. Most glucose monitors approved for home use calibrate whole blood glucose readings to plasma values. Plasma glucose
values are 10-15% higher than whole blood glucose values. It is important for people with diabetes to know whether their meters and strips record whole blood or
plasma results.
2 Goals should be individualized based on the following, including: co-morbidity, age, duration of diabetes, hypoglycemic awareness. 3The true goal of care is to bring the A1C as close to normal as safely possible. A goal of < 7% is chosen as a practical level for most patients using medications that may cause hypoglycemia to avoid the risk of that complication. Achieving normal blood glucose is recommended if it can be done practically and safely. 4If diet history reveals markedly excessive carbohydrate intake, may consider initial trial of MNT and physical activity before initiating oral agent therapy even though glucose levels are above the thresholds listed. 5Some patients with type 2 diabetes initially stabilized on insulin may be considered for transition to non-insulin anti-hyperglycemic therapy as blood glucose control permits. 6A combination of two drugs of different classes may be used as initial pharmacotherapy when there is marked hyperglycemia or when MNT and physical activity alone have not resulted in an A1C of < 7.0% 7FDA Requirements for LFT monitoring for thiazolidinediones (TZDs):
If initial ALT is > 2.5 times normal, do not start this medication
Once TZD is started, monitor ALT periodically thereafter according to clinical judgement.
If ALT is > 2.5 times normal during treatment, check weekly. If rise persists or becomes 3 times > normal, discontinue TZD.
8 Thiazolidinediones cause or exacerbate congestive heart failure in some patients. After initiation of TZDs and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of the TZD must be considered. TZDs are not recommended in patients with symptomatic heart failure or in patients with established NYHA Class III or IV heart failure. 9 A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total patients), most of which compared rosiglitazone to placebo, showed rosiglitazone to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction. Three other studies (mean duration 41 months; 14,067 total patients), comparing rosiglitazone to some other approved oral antihyperglycemic agents or placebo, have not confirmed or excluded this risk. In their entirety, the available data on the risk of myocardial ischemia are inconclusive. 10 If therapeutic goals are not met, consider starting insulin. Stop exenatide and DPP-IV inhibitor when starting insulin. 11May need to taper and discontinue some or all oral antihyperglycemic medications as insulin is initiated and adjusted, particularly if using short or rapid-acting and basal insulins. 12Pre- and postprandial blood glucose should be checked. Frequency of checking may vary between 1-4 times/day depending on individual patient and status of glycemic control. 13 There is an increased risk for edema when insulin and a thiazolidinedione are used together. Rosiglitazone should not be used in combination with insulin. 14The onset, peak and duration of any insulin type depends on many factors. Patients may experience variations in timing and/or intensity of insulin activity due to dose,
site of injection, temperature of the insulin, level of physical activity, in addition to other factors. Therefore, the time action profile (TAP) should be considered as only
reasonable estimates of the action of an insulin.
Guideline Authors: Martin Abrahamson, MD, Richard Beaser, MD, Elizabeth Blair, ANP-BC, Om Ganda, MD, James Rosenzweig, MD, Howard Wolpert, MD, Alissa
Segal Pharm D, CDE, Amy Campbell, MS, RD, CDE
Approved by Joslin Clinical Oversight Committee on 01/09/2009.
Copyright 2009 by Joslin Diabetes Center. All rights reserved. Any reproduction of this document, which omits Joslin's name or copyright notice is prohibited. This document may be reproduced for personal use only. It may not be distributed or sold. It may not be published in any other format without the prior, written permission of Joslin Diabetes Center, Publications Department, 617-226-5815. Please refer to Joslin's website, www.joslin.org, for the most current version of our Clinical Guidelines. Glossary and Common Abbreviations
A1C: glycohemoglobin (hemoglobin A1C)
ALT: alanine aminotransferase
BMI: body mass index; normal = 18.5-24.9 kg/m2; overweight = 25.0-29.9 kg/m2 (> 23 kg/m2 in Asian populations); obese = ≥ 30 kg/m2 (23-27 kg/m2 in Asian populations)
Casual plasma glucose: a random plasma glucose
CHF: congestive heart failure
CV: cardiovascular
DPP-4: Dipeptidyl Peptidase IV Inhibitors
FDA: Food and Drug Administration
FPG: fasting plasma glucose
G: gram
GLP-1: Glucagon-like peptide-1is secreted by the intestinal L cell in response to food intake, impacting glucose regulation.
HS: bedtime
Incretin: hormone produced by the gastronintestinal tract in response to food intake and necessary for glucose homeostasis
Incretin mimetics: a class of agents used for managing type 2 diabetes that mimics the enhancement of glucose-dependent insulin secretion and other glucoregulatory actions of naturally occurring incretins
Kg: kilogram
LDL-C: low density lipoprotein, cholesterol
LFT: liver function tests
Mg: milligram
Mg/dl: milligram per deciliter
MNT (Medical Nutrition Therapy): Begins with assessment of overall nutrition status, followed by individualized prescription for treatment. Registered dietitian considers food intake, physical activity, course
of any medical therapy, individual preferences and other factors.
Obesity: BMI ≥ 30 kg/m2
Overweight: BMI = 25.0-29.9 kg/m2
PFTs: pulmonary function tests
Rx: treatment
TAP: time action profile
TZDs: thiazolidinediones
Joslin Clinical Oversight Committee
Om Ganda, MD - Chairperson Melinda Maryniuk, MEd, RD, CDE Richard Beaser, MD Medha Munshi, MD Elizabeth Blair, MS, ANP-BC, CDE Kristi Silver, MD Patty Bonsignore, MS, RN, CDE Jo-Anne Rizzotto, MEd, RD, CDE Amy Campbell, MS, RD, CDE Susan Sjostrom, JD Cathy Carver, ANP-BC, CDE Kenneth Snow, MD Jerry Cavallerano, OD, PhD Robert Stanton, MD David Feinbloom, MD William Sullivan, MD Richard Jackson, MD Howard Wolpert, MD Lori Laffel, MD, MPH Martin J. Abrahamson, MD, ex officio Copyright 2009 by Joslin Diabetes Center. All rights reserved. Any reproduction of this document, which omits Joslin's name or copyright notice is prohibited. This document may be reproduced for personal use only. It may not be distributed or sold. It may not be published in any other format without the prior, written permission of Joslin Diabetes Center, Publications Department, 617-226-5815. Please refer to Joslin's website, www.joslin.org, for the most current version of our Clinical Guidelines. References for Joslin's Pharmacological Management of Type 2 Diabetes Guideline

Diagnosis

1. ADA Position Statement: Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2009; 32 ( suppl 1): S62-S67 2. Nathan, DM, Kuenen,J, Borg,H Translating the A1c assay into estimated average glucose values. Diabetes Care 2008; 31: 1473-1478
Goals of Glycemic Control and Phrmacotherapy
1. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2009; 32 ( suppl 1): S13-S 61 3. Beaser, RS and Staff of Joslin Diabetes Center. Joslin's Diabetes Deskbook for Primary Care Providers. Second edition. Joslin Diabetes Center, Boston; 2007. 4. Diabetes Prevention and Control Program, Diabetes Guidelines Work Group. Massachusetts guidelines for adult diabetes care. Boston (MA): Massachusetts Department of Public Health; 2005 Jun. 5. Institute for Clinical Systems Improvement (ICSI). Management of type 2 diabetes mellitus. Bloomington (MN): Institute for Clinical Systems Improvement (ICS); 2005 Nov. Oral Antihyperglycemic Therapy

1. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 287:360-72, 2002. 2. Kimmel B and Inzucchi S. Oral agents for type 2 diabetes: an update. Clinical Diabetes 23:64-76, 2005. 3. Krentz AJ, Bailey CJ. Oral antidiabetic agents. Drugs 2005; 65(3):385-411. 4. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 131:281-303, 1999. 5., et. al. Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy. New England Journal of Medicine
2006; 355: 2427-2443

6. Nathan, DM et al Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy. Diabetes Care
2008; 31: DOI : 10.2337/dc 08-9025
rig t 2009 by Joslin Diabetes Center. All rights reserved. Any reproduction of this document, which omits Joslin's name or copyright notice is prohibited. This document may be reproduced for personal use only. It may not be distributed or sold. It may not be published in any other format without the prior, written permission of Joslin Diabetes Center, Publications Department, 617-226-5815. Please refer to Joslin's website, www.joslin.org, for the most current version of our Clinical Guidelines. Metformin

1. Charpentier G, Riveline JP, Varroud-Vial M. Management of drugs affecting blood glucose in diabetic patients with renal failure. Diabetes Metab 26 Suppl 2. Cryer DR, Nicholas SP, Henry DH, Mills DJ, Stadel BV. Comparative outcomes study of metformin intervention versus conventional approach. Diabetes Care 28:539-543, 2005. 3. Dornan TL, Heller SR, Peck GM, Tattersall RB. Double-blind evaluation of efficacy and tolerability of metformin in NIDDM. Diabetes Care. 14: 342-343, 4. Garber AJ, Duncan TG, Goodman AM, Millis DJ, Rohlf JL Efficacy of Metformin in Type II Diabetes: Results of a Bouble-Blind, Placebo-controlled, Dose- Response Trial. Am J Med 103:491-497, 1997. 5. Grant PJ. The effects of high and medium dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care 19: 64-66, 6. Holstein A, Stumvoll M. Contraindications can damage your health--is metformin a case in point? Diabetologia 48:2454-9, 2005. 7. Inzucchi SE. Metformin and heart failure: innocent until proven guilty. Diabetes Care 28:2585-2587, 2005. 8. Johansen K. Efficacy of metformin in the treatment of NIDDM. Meta-analysis. Diabetes Care 22:33-7, 1999. 9. McCormack J, Johns K, Tildesley H. Metformin's contraindications should be contraindicated. CMAJ 173:502-4, 2005. 10. UKPDS Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352: 854-865, 1998. 11. Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2006 Issue 4. 12. Salpeter S., Greyber E, Paternak G., Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Sys Rev 2006 Issue 4. 13. Sulkin TV, Bosman D, Krentz AJ. Contraindications to metformin therapy in patients with NIDDM. Diabetes Care 20:925-8, 1997. Copyright 2009 by Joslin Diabetes Center. All rights reserved. Any reproduction of this document, which omits Joslin's name or copyright notice is prohibited. This document may be reproduced for personal use only. It may not be distributed or sold. It may not be published in any other format without the prior, written permission of Joslin Diabetes Center, Publications Department, 617-226-5815. Please refer to Joslin's website, www.joslin.org, for the most current version of our Clinical Guidelines.
Thiazolidinediones
1. Charbonnel1B, Roden M, Urquhart , Mariz S, Johns D, Mihm M, Wide M, Tan M. Pioglitazone elicits long-term improvements in insulin sensitivity in patients with type 2 diabetes: comparisons with glipazide-based regimens. Diabetologia 48:553-60, 2005. 2. , dition of pioglitazone to stable insulin therapy in patients with poorly controlled type 2 diabetes: results of a double-blind, multicentre, randomized study. Diabetes Obes Metab 8:164-74, 2006. 3. mpact of rosiglitazone on glycaemic control, insulin levels and blood pressure values in patients with type 2 diabetes. Med Arh 60:179-81, 4. Miyazaki Y, Mahankali A, Matsuda M et al. Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone. Diabetes Care 24:710-719, 2001. 5. Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, Le Winter M, Porte D, Semenkovich CF, Smith S, Young LH, Kahn R. American Heart Association; American Diabetes Association. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Circulation 108:2941-8, 2003. 6. Mazzone T, Meyer PM, Feinstein SB, Davidson MH, Kondos GT, D'Agostino RB, Sr. et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA 2006; 296(21):2572-2581. 7. Yki-Jarvinen, H. Thiazolidinediones. New England Journal of Medicine 2004; 351: 1106-1118 8 Nissen, SE, Wolski, K . Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. New England Journal of Medicine 2007; 356: 2457-2471 Insulin Secretagogues

1. Bailey CJ, Day C. Antidiabetic drugs. Br J Cardiol 10:128-36, 2003. 2. Del Prato S, Heine RJ, Keilson L, Guitard C, Shen SG, Emmons RP. Treatment of patients over 64 years of age with type 2 diabetes: experience from nateglinide pooled database retrospective analysis. Diabetes Care 26:2075-80, 2003. 3. Dornhorst M. Insulotropic meglitinide analogues. Lancet 358:1709-15, 2001. 4. Hazama Y, Matsuhisa M, Ohtoshi K, Gorogawa S, Kato K, Kawamori D, Yoshiuchi K, Nakamura Y, Shiraiwa T, Kaneto H, Yamasaki Y, Hori M. Beneficial effects of nateglinide on insulin resistance in type 2 diabetes. Diabetes Res Clin Pract 71:251-5, 2006. 5. Plosker, Gl, Figgitt, DP.Repaglinide: a pharmacoeconomic review of its use in type 2 diabetes mellitus. PharmacoEconomics 22:389-411, 2004. 6. Shapiro MS, Abrams Z, Lieberman N. Clinical experience with repaglinide in patients with non-insulin-dependent diabetes mellitus. Isr Med Assoc J. 2005 Copyright 2009 by Joslin Diabetes Center. All rights reserved. Any reproduction of this document, which omits Joslin's name or copyright notice is prohibited. This document may be reproduced for personal use only. It may not be distributed or sold. It may not be published in any other format without the prior, written permission of Joslin Diabetes Center, Publications Department, 617-226-5815. Please refer to Joslin's website, www.joslin.org, for the most current version of our Clinical Guidelines.
Alpha-Glucosidase Inhibitors

1. Balfour JA, McTavish D. Acarbose. An update of its pharmacology and therapeutic use in diabetes mellitus. Drugs 46:1025-54, 1993. 2. Carlson RF. Miglitol and hepatotoxicity in type 2 diabetes mellitus. Am Fam Physician 62:315 -318, 2000. 3. Hanefeld M, Cagatay M, Petrowitsch T, Neuser D, Petzinna D, Rupp M. Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta- analysis of seven long-term studies. Eur Heart J 25:10-6, 2004. 4. Van de Laar FA, Lucassen PL, Akkermans RP, Van de Lisdonk EH, Rutten GE, Van Weel C. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev 18; (2):CD003639, 2005.
Exenatide

1. DeFronzo RA et al. Effects of exenatide (Exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 28:1092-1100, 2005. 2. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27:2628-35, 2004. 3. Fineman MS, Bicsak TA, Shen LZ, Taylor K, Gaines E, Varns A, Kim D, Baron AD. Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care 26:2370-7, 2003. 4. Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG; GWAA Study Group. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med 143:559-69, 2005. 5. Iltz JL, Baker DE, Setter SM, Keith Campbell R. Exenatide: an incretin mimetic for the treatment of type 2 diabetes mellitus. Clin Ther 28:652-65, 2006. 6. Kendall, DM et al. Effects of exenatide (Exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 28:1083-1091, 2005. 7. Linnebjerg H, Kothare PA, Skrivanek Z, de la Pena A, Atkins M, Ernest CS, Trautmann ME. Exenatide: effect of injection time on postprandial glucose in patients with type 2 diabetes. Diabet Med 23:240-5, 2006. 8. Poon T, Nelson P, Shen L, Mihm M, Taylor K, Fineman M, Kim D. Exenatide improves glycemic control and reduces body weight in subjects with type 2 diabetes: a dose-ranging study. Diabetes Technol Ther 7:467-77, 2005. Copyright 2009 by Joslin Diabetes Center. All rights reserved. Any reproduction of this document, which omits Joslin's name or copyright notice is prohibited. This document may be reproduced for personal use only. It may not be distributed or sold. It may not be published in any other format without the prior, written permission of Joslin Diabetes Center, Publications Department, 617-226-5815. Please refer to Joslin's website, www.joslin.org, for the most current version of our Clinical Guidelines. DPP-IV Inhibitors

1. Chia CW, Egan JM. Incretin-based therapies in type 2 diabetes mellitus. J Clin Endocrinol Metab 2008; 93(10):3703-3716.
2. Fonseca VA, Rosenstock J, Wang AC, Truitt KE, Jones MR. Colesevelam HCl improves glycemic control and reduces LDL cholesterol in patients with inadequately controlled type 2 diabetes on sulfonylurea-based therapy. Diabetes Care 2008; 31(8):1479-1484. 3. Miller S, St Onge EL. Sitagliptin: a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Ann Pharmacother 2006; 40(7-8):1336-1343. 4. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care 2007; 30(8):1979-1987.
Bile Acid Sequestrants

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lipid effects. Arch Intern Med 2008; 168(18):1975-1983. 2. Fonseca VA, Rosenstock J, Wang AC, Truitt KE, Jones MR. Colesevelam HCl improves glycemic control and reduces LDL cholesterol in patients with inadequately controlled type 2 diabetes on sulfonylurea-based therapy. Diabetes Care 2008; 31(8):1479-1484. 3. Goldberg RB, Fonseca VA, Truitt KE, Jones MR. Efficacy and safety of colesevelam in patients with type 2 diabetes mellitus and inadequate glycemic control receiving insulin-based therapy. Arch Intern Med 2008; 168(14):1531-1540. Combination Therapy with insulin

1. Aviles-Santa L, Sinding J, Raskin P. Effects of metformin in patients with poorly controlled insulin-treated type 2 diabetes mellitus. Ann Intern Med 131:182- 2. Belcher G, Lambert C, Goh1 KL, Edwards G, Valbuena1 M. Cardiovascular effects of treatment of type 2 diabetes with pioglitazone, metformin and glipazide. Int J Clin Pract 58:833-7, 2004. 3. Goudswaard AN, Furlong NJ, Valk GD, Stolk RP, Rutten GEHM. Insulin monotherapy versus combinations of insulin with oral hypoglycaemic agents in patients with type 2 diabetes mellitus. Cochrane Database Sys Rev 2006 Issue 4. 4. Jones TA, Sautter M, Van Gaal LF, Jones NP. Addition of rosiglitazone to metformin is most effective in obese, insulin-resistant patients with type 2 diabetes. Diabetes Obes Metab 5:163-70, 2003. 5. Triple therapy with glimepiride in patients with type 2 diabetes mellitus inadequately controlled by metformin and a thiazolidinedione: results of a 30-week, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther 27:1535-47, 2005. 6. , ple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patients. Diabetes Care 29:554-9, 2006. 7. Yki-Jarvinen H et al. Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study. Diabetologia 3:1-10, 2006. Copyright 2009 by Joslin Diabetes Center. All rights reserved. Any reproduction of this document, which omits Joslin's name or copyright notice is prohibited. This document may be reproduced for personal use only. It may not be distributed or sold. It may not be published in any other format without the prior, written permission of Joslin Diabetes Center, Publications Department, 617-226-5815. Please refer to Joslin's website, www.joslin.org, for the most current version of our Clinical Guidelines. 1. Baker A, Ahmed E, Mallias J, Home PD. Optimization of evening insulin dose in patients using the short-acting insulin analog lispro. Diabetes Care 21:1162- 2. Davidson J, Vexiau P, Cucinotta D, Vaz J, Kawamori R. Biphasic insulin aspart 30: literature review of adverse events associated with treatment. Clin Ther 27:S75-88, 2005. 3. Hirsch B, Bergenstal RM, Parkin CG, Wright E, Buse JB. A real-world approach to insulin therapy in primary care practice. Clin Diabetes 23: 78-86, 2005. 4. Kennedy L, Herman WH, Strange P, Harris A for the GOAL A1C Team. Impact of active versus usual algorithmic titration of basal insulin and point-of-care versus laboratory measurement of HbA1c on glycemic control in patients with type 2 diabetes. Diabetes Care 29:1-8, 2006. 5. Kudva YC, Basu A, Jenkins GD, Pons GM, Quandt LL, Gebel JA, Vogelsang DA, Smith SA, Rizza RA, Isley WL. Randomized controlled clinical trial of glargine versus ultralente insulin in the treatment of type 1 diabetes. Diabetes Care 28:10-4, 2005. 6. Riddle MC. The Treat-to-Target Trial and related studies. Endoc Pract. 37:495-501, 2006. 7. Scholtz HE, Pretorious SG, Wessels DH, Becker RH. Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique. Diabetologia 48:1988-95, 2005. 8. Siebenhofer A, Plank J, Berghold A, Jeitler K, Horvath K, Narath M, Gfrerer R, Pieber TR. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD003287. 9. Taylor R, Davies R, Fox C, Sampson M, Weaver JU, Wood L. Appropriate insulin regimen for type 2 diabetes: a multicenter randomized crossover study. Diabetes Care 23:1612-18, 2000. 10. Valensi P, Cosson E. Is insulin detemir able to favor a lower variability in the action of injected insulin in diabetic subjects? Diabetes Metab 31:4S34-4S39, Pramlintide 1. Hollander P, aggs D,. Addition of pramlintide to insulin therapy lowers HbA1c in conjunction with weight loss in patients with type 2 diabetes approaching glycaemic targets. Diabetes Obes Metab 5:408-14, 2003. 2. Hollander PA et al. Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care 26:784-790, 2003. 3. , lintide reduces postprandial glucose excursions when added to regular insulin or insulin lispro in subjects with type 1 diabetes: a dose-timing study. Diabetes Care 26:3074-9, 2003. 4. , , A randomized study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy in type 1 diabetes. Diabetes Care 25:724-30, 2002. Copyright 2009 by Joslin Diabetes Center. All rights reserved. Any reproduction of this document, which omits Joslin's name or copyright notice is prohibited. This document may be reproduced for personal use only. It may not be distributed or sold. It may not be published in any other format without the prior, written permission of Joslin Diabetes Center, Publications Department, 617-226-5815. Please refer to Joslin's website, www.joslin.org, for the most current version of our Clinical Guidelines.

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