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Joslin Diabetes Center & Joslin Clinic
Clinical Guideline for Pharmacological Management of Type 2 Diabetes
10 28 2011

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)
 Random 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 OR
 Glycated Hemoglobin (A1C) > 6.5%** .
* These tests should be confirmed by a repeat test, on a different day, unless unequivocally high
** Only an A1C test that has been referenced to an accepted laboratory method (standardized) should be utilized for diagnostic purposes
Goals of Glycemic Control for People with Diabetes 1
Biochemical Index
Fasting Plasma Glucose or Preprandial Glucose (mg/dl)
70 – 130
2 hours Post-prandial (mg/dl)
Bedtime Glucose (mg/dl)
90 – 150
A1C (%) sustained
< 7% 3
Copyright 2011 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, 617-309-5815. Please refer to Joslin’s web site, 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 characteristics listed within each box)

 Marked hyperglycemia OR
Mild Intermediate
Mild or no symptoms AND
FPG > 150 mg/dl4 OR
 Significant weight loss OR
 Negative ketones AND
 Random > 250 mg/dl4
 Severe/significant symptoms OR
AND/OR
No acute concurrent illness AND
 2+ or greater ketonuria OR
 A1C > 7.0%
A1C < 7.0%
 DKA/ hyperosmolar state OR
 Does not meet criteria for
 Severe intercurrent illness or surgery
mild or severe
Start insulin immediately 5
If after 6-8 weeks,
Start MNT and physical
Start metformin.
target not met
activity and consider
Choose alternate drug if

addition of metformin
metformin is contraindicated
See page 5 – Add Insulin
See next page: CONSIDERATIONS FOR SELECTING
NON-INSULIN GLUCOSE LOWERING MEDICATIONS
Copyright 2011 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, 617-309-5815. Please refer to Joslin’s web site, www.joslin.org, for the most current version of our Clinical Guidelines. CONSIDERATIONS FOR SELECTING NON-INSULIN GLUCOSE LOWERING MEDICATIONS
INITIAL THERAPY
ADJUNCT THERAPY
Metformin
Insulin Secretagogue
-Glucosidase
Thiazolidinediones
Dipeptidyl
GLP-1 agonist
Bile Acid Sequestrant
Centrally Acting
(sulfonylurea or
Inhibitor
Peptidase IV
(colesevelam)
meglitinide)
Inhibitors
(bromocriptine
mesylate)
Contraindicated
with:
Contraindicated:
 Chronic intestinal  Consider risk for Contraindicated:
Contraindicated:
Contraindicated:
Contraindicated:
Contraindicated:
See footnotes 8, 9,
13 for CV and
other risks
the setting of personal or fm hx of medullary thyroid cancer or patients with MEN2 Titrate dose over 1-6 months
Reinforce MNT and physical activity
If A1C >7% OR
Fasting plasma glucose >130mg/dl OR
2 hour postprandial glucose >180mg/dl
Add second oral glucose lowering medication OR GLP-1 agonist OR insulin
See next page
Copyright 2011 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, 617-309-5815. Please refer to Joslin’s web site, www.joslin.org, for the most current version of our Clinical Guidelines. ADVANCING GLUCOSE LOWERING MEDICATION THERAPY
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
GLP-1 agonist10
glucose lowering
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, or 70/30 human  Suggested starting dose for 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:
 Adding pre-meal rapid or short-acting insulin (e.g. aspart, glulisine, lispro or regular) to bedtime intermediate or  Adding 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  Changing to multidose insulin therapy using combination of rapid, short, intermediate, or long-acting insulin  Adding oral glucose lowering medication to improve glycemic control if already on insulin (metformin, TZDs 13, sulfonylureas or meglitinides, sitagliptin, -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 Copyright 2011 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, 617-309-5815. Please refer to Joslin’s web site, www.joslin.org, for the most current version of our Clinical Guidelines. GLUCOSE LOWERING MEDICATION COMBINATIONS
Suggested well-studied combinations based on results of clinical studies.
These do not preclude other combinations:

 metformin and insulin secretagogue **  metformin and dipeptidyl peptidase IV inhibitors **  metformin and thiazolidinediones **, 9  metformin and colesevelam  sulfonylurea and -glucosidase inhibitor  sulfonylurea and dipeptidyl peptidase IV inhibitors  sulfonylurea and GLP-1 agonists  sulfonylurea and colesevelam  dipeptidyl peptidase IV inhibitors and pioglitazone  pioglitazone and sulfonylurea**, 9  pioglitazone and repaglinide 9  pioglitazone and GLP-1 agonists 9

Continued on next page
Copyright 2011 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, 617-309-5815. Please refer to Joslin’s web site, www.joslin.org, for the most current version of our Clinical Guidelines. ORAL GLUCOSE LOWERING MEDICATIONS AVAILABLE IN THE USA
Biguanides
Dipeptidyl
Bile Acid
Centrally
(Thiazolidinediones)
Glucosidase
Secretagogues
Peptidase IV
Sequestrant
Combinations
Inhibitors
Inhibitors
(DPP-4 Inhibitors)
Sulfonylureas
 colesevelam  bromocriptine  metformin and glipizide Meglitinides
D-phenylalanine
Derivatives
Continued on next page
Copyright 2011 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, 617-309-5815. Please refer to Joslin’s web site, www.joslin.org, for the most current version of our Clinical Guidelines. INJECTABLE DIABETES MEDICATIONS AVAILABLE IN THE USA
INSULINS

Insulin Type
Duration
Rapid-Acting
Short-Acting
Intermediate-Acting
Long-Acting
Premixed Insulin Combinations
Insulin Type
50% lispro protamine suspension, 50% lispro 75% lispro protamine suspension, 25% lispro 70% aspart protamine suspension, 30% aspart *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
Incretin mimetic that enhances glucose-dependent insulin secretion and several other Liraglutide (Victoza) Incretin mimetic that enhances glucose-dependent insulin secretion and several other 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 2011 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, 617-309-5815. Please refer to Joslin’s web site, 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 i On September 23, 2010, the Food and Drug Administration (FDA) announced regulatory actions with respect to products containing rosiglitazone: Avandia® (rosiglitazone maleate) Tablets, Avandamet® (rosiglitazone maleate and metformin hydrochloride) Tablets and Avandaryl® (rosiglitazone maleate and glimepiride) Tablets. The FDA is requiring GlaxoSmithKline (GSK) to implement restrictions on the use of these products through a program to assure their safe use (i.e., Risk Evaluation and Mitigation Strategy or REMS) and additional safety labeling changes in response to the agency’s review of data that suggest an elevated risk of cardiovascular events. GSK will be working with the FDA to implement the agency’s requirement for a REMS and additional labeling changes. Additional information will be communicated when these measures are finalized. It will take several months to put the REMS program in place. Until the REMS program is in place, the FDA's decision allows current or potential users of rosiglitazone to continue or start using the medication after consultation with their health care provider about treatment options. Once the REMS program is in place a) Health care providers will need to be enrolled in the program in order to prescribe rosiglitazone containing products. b) Pharmacists will need to be enrolled in order to dispense rosiglitazone containing products. c) Patients will need to be enrolled in the program by their physician in order for them to begin or continue receiving rosiglitazone. d) Health care providers will have to attest to and document their patient's eligibility if they believe that their patient is a candidate for rosiglitazone. e) Patients will have to review statements describing the cardiovascular safety concerns with rosiglitazone and sign an acknowledgment of their understanding of the information. f) Current users of rosiglitazone will only be able to continue using the medication if they acknowledge and document that they understand the risks associated with the drug. g) Patients not already taking rosiglitazone can receive the medicine only if they are unable to achieve glycemic control on other medications and, in consultation with their health care provider, decide not to take pioglitazone for medical reasons. 9 ii According to FDA advisory issued on June 15, 2011 re: potentially increased risk of bladder cancer with Pioglitazone use: a. Do not use pioglitazone in patients with active bladder cancer. b. Use pioglitazone with caution in patients with a prior history of bladder cancer. The benefits of glycemic control versus unknown risks for cancer recurrence with pioglitazone should be considered in patients with a prior history of bladder cancer. 10 If therapeutic goals are not met, consider starting insulin. Stop exenatide when starting insulin other than glargine. 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. Copyright 2011 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, 617-309-5815. Please refer to Joslin’s web site, www.joslin.org, for the most current version of our Clinical Guidelines. 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.
Guideline Authors: Om Ganda, MD, Martin Abrahamson, MD, Jason Gaglia, MD, Richard Beaser, MD, Elizabeth Blair, ANP-BC, CDE, Alissa Segal Pharm D, CDE
Approved by Joslin Clinical Oversight Committee on 10/27/2011

Glossary and Common Abbreviations
A1C: glycohemoglobin (hemoglobin A1C)
ALT: alanine aminotransferase
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 gastrointestinal 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
MEN2: Multiple endocrine neoplasia type 2
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.
Rx: treatment
TZDs: thiazolidinediones
Joslin Clinical Oversight Committee
Martin J. Abrahamson, MD, ex officio Copyright 2011 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, 617-309-5815. Please refer to Joslin’s web site, 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 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 Pharmacotherapy
1. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2. Beaser, RS and Staff of Joslin Diabetes Center. Joslin’s Diabetes Deskbook for Primary Care Providers. Updated Second edition. Joslin Diabetes Center, 3. Diabetes Prevention and Control Program, Diabetes Guidelines Work Group. Massachusetts guidelines for adult diabetes care. Boston (MA): Massachusetts 4. Institute for Clinical Systems Improvement (ICSI). Management of type 2 diabetes mellitus. Bloomington (MN): Institute for Clinical Systems Improvement 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. Kahn SE, Haffner SM, Heise MA, et. al. Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy. New England Journal of Medicine 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 7. Rodbard H, Jellinger P, Davidson JA, Einhorn D, Garber AJ, Grunberger G, Handelsman Y, Horton ES, Lebovitz H, Levy P, Moghissi ES, Schwartz SS. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: An algorithm for glycemic control. Endocr Pract 2009;15: 540–559. Copyright 2011 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, 617-309-5815. Please refer to Joslin’s web site, www.joslin.org, for the most current version of our Clinical Guidelines. 8. 8. Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R et al. Comparative Effectiveness and Safety of Medications for Type 2 Diabetes: An Update Including New Drugs and 2-Drug Combinations. Annals of Internal Medicine 2011; 154(9):602-613. 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 4:73- 2. Cryer DR, Nicholas SP, Henry DH, Mills DJ, Stadel BV. Comparative outcomes study of metformin intervention versus conventional approach. Diabetes Care 3. 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. 4. 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, 1996. 5. Holstein A, Stumvoll M. Contraindications can damage your health--is metformin a case in point? Diabetologia 48:2454-9, 2005. 6. Inzucchi SE. Metformin and heart failure: innocent until proven guilty. Diabetes Care 28:2585-2587, 2005. 7. Johansen K. Efficacy of metformin in the treatment of NIDDM. Meta-analysis. Diabetes Care 22:33-7, 1999. 8. McCormack J, Johns K, Tildesley H. Metformin's contraindications should be contraindicated. CMAJ 173:502-4, 2005. 9. UKPDS Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 10. Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database of 11. 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 12. Sulkin TV, Bosman D, Krentz AJ. Contraindications to metformin therapy in patients with NIDDM. Diabetes Care 20:925-8, 1997.
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. Davidson JA, Perez A, Zhang J, The Pioglitazone 343 Study Group. Addition 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. Copyright 2011 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, 617-309-5815. Please refer to Joslin’s web site, www.joslin.org, for the most current version of our Clinical Guidelines. 3. Kulenovic I. Impact of rosiglitazone on glycaemic control, insulin levels and blood pressure values in patients with type 2 diabetes. Med Arh 60:179-81, 2006. 4. Miyazaki Y, Mahankali A, Matsuda M et al. Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone. 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 9. GlaxoSmithKline. GSK regulatory update on Avandia following EMA and FDA reviews: issued Thursday 23 September 2010. Available at: http://www.gsk.com/media/pressreleases/2010/2010_pressrelease_10103.htm. Accessed September 2010. 10. U.S. Food and Drug Administration. Postmarketing drug safety information for patients and providers. Q&A: Avandia (rosiglitazone). Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm226976.htm. Accessed September 2010.* 11. Woodcock J. United Stated Food and Drug Administration, Center for Drug Evaluation and Research. Decision on continued marketing of rosiglitazone (Avandia, Avandamet, Avandaryl). Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM226959. Accessed October 2010.* 12. Piccinni, C, Motola, D, Marchesini,D, Poluzzi, E Assessing the association of pioglitazone use and bladder cancer through drug adverse reporting. Diabetes Care 13. FDA Drug Safety Communication: Update to ongoing safety review of Actos (pioglitazone) and increased risk of bladder cancer; June 15, 2011
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. Copyright 2011 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, 617-309-5815. Please refer to Joslin’s web site, www.joslin.org, for the most current version of our Clinical Guidelines. 6. Shapiro MS, Abrams Z, Lieberman N. Clinical experience with repaglinide in patients with non-insulin-dependent diabetes mellitus. Isr Med Assoc J. 2005

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.
GLP-1 receptor agonists

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 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. 9. Russell-Jones D, Vaag A, Schmitz O, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 Met+SU): a randomised controlled trial. Diabetologia 2009; 52: 2046–55. Copyright 2011 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, 617-309-5815. Please refer to Joslin’s web site, www.joslin.org, for the most current version of our Clinical Guidelines. 10. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double- blind, parallel-treatment trial. Lancet 2009; 373: 473–81.
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. 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. 3. 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. 4. DeFronzo RA, Hissa MN, Garber AJ, et al. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care 2009; 32:1649–55. 5. Scott, LJ Linagliptin in type 2 diabetes mellitus . Drugs 2011; 71: 611-624 Bile Acid Sequestrants

1. Bays HE, Goldberg RB, Truitt KE, Jones MR. Colesevelam hydrochloride therapy in patients with type 2 diabetes mellitus treated with metformin: glucose and 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 131:182-88, 2. Belcher G, Lambert C, Goh1 KL, Edwards G, Valbuena1 M. Cardiovascular effects of treatment of type 2 diabetes with pioglitazone, metformin and glipazide. 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. Copyright 2011 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, 617-309-5815. Please refer to Joslin’s web site, www.joslin.org, for the most current version of our Clinical Guidelines. 5. Roberts VL, Stewart J, Issa M, Lake B, Melis R. 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. Rosenstock J, Sugimoto D, Strange P, Stewart JA, Soltes-Rak E, Dailey G. Triple 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. 8. Buse, JB et al Use of Twice-Daily Exenatide in Basal Insulin–Treated Patients With Type 2 Diabetes Ann Intern Med 2011; 154: 103-112. 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 21:1162-66, 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 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. 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, Ratner R, Fineman M, Strobel S, Shen L, Maggs D, Kolterman O, Weyer C. 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. Copyright 2011 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, 617-309-5815. Please refer to Joslin’s web site, www.joslin.org, for the most current version of our Clinical Guidelines. 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. Weyer C, Gottlieb A, Kim DD, Lutz K, Schwartz S, Gutierrez M, Wang Y, Ruggles JA, Kolterman OG, Maggs DG. Pramlintide 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. Whitehouse F, Kruger DF, Fineman M, Shen L, Ruggles JA, Maggs DG, Weyer C, Kolterman OG. 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. Bromocriptine
1. Holt, RI et al Bromocriptine: old drug, new formulation, and new indication Diabetes, Obesity, and Metabolism 2010; 12: 1048-1057. Copyright 2011 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, 617-309-5815. Please refer to Joslin’s web site, www.joslin.org, for the most current version of our Clinical Guidelines.

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