CHAPTER 5. Clinical Guideline for Pharmacological Management of Adults With Type 2 Diabetes

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Evidence-Based Diabetes Management, June 2018, Volume 24, Issue 7

From the Adult Diabetes and Clinical Research Sections, Joslin Diabetes Center, Harvard Medical School. Approved May 10, 2016; updated April 24, 2018. For the Figure and Tables, download the PDF at the end of the chapter.

Objective: The objective of the Joslin Diabetes Center Clinical Guideline for Pharmacological Management of Adults with Type 2 Diabetes is to support clinical practice, influence clinical behavior to improve outcomes, and to assure quality of care according to accepted standards. The guideline was established after careful review of current evidence, literature, and clinical practice. This guideline is reviewed periodically and modified to reflect changes in clinical practice and available pharmacological information.

5.1.0 DIABETES MELLITUS: DIAGNOSTIC CRITERIA (NONPREGNANT ADULTS)

This 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 nonpregnant patient population. The guideline is not a substitution for full prescribing information. Refer to Joslin’s Clinical Guideline for Adults with Diabetes (Chapter 1) as well as Joslin’s Guideline for the Care of Older Adults With Diabetes (Chapter 4) for additional, more comprehensive information on diabetes care and management.

  • Random plasma glucose (PG) ≥200 mg/dl and symptoms of diabetes (polyuria, polydipsia, ketoacidosis, or unexplained weight loss) or
  • Glycated hemoglobin (A1C) ≥6.5%a or
  • Fasting plasma glucoseb ≥126 mg/dl or
  • Results of a 2-hour 75-g oral glucose tolerance test ≥200 mg/dL at 2 hours

aOnly an A1C test that has been referenced to an accepted laboratory method (standardized) should be utilized for diagnostic purposes. Consider evaluation for hemoglobin variant if A1C is discordant from PG values.

5.2.0 GOALS OF GLYCEMIC CONTROL FOR INDIVIDUALS WITH DIABETES (TABLE 1)

5.3.0 INITIAL TREATMENT STRATEGY (FIGURE)

5.3.1 Advancing antidiabetes medications:

bThese tests should be confirmed by a repeat test, on a different day, unless unequivocally high.

5.4.0 CONSIDERATIONS FOR SELECTING NONINSULIN GLUCOSE-LOWERING MEDICATIONS

5.4.1 First-line add-on to metformin or use as monotherapy if metformin is contraindicated: see table SP256

5.5.0 PREFERRED CONSIDERATIONS IN PATIENTS WITH T2D AND ESTABLISHED CARDIOVASCULAR DISEASE

TABLE 3. Preferred Considerations in Patients With T2D and Established Cardiovascular Disease

5.6.0 ORAL GLUCOSE-LOWERING MEDICATIONS (TABLE 4)

5.6.1 Examples of fixed-dose medications: (Table 4)

5.7.0 INJECTABLE ANTIDIABETES MEDICATIONS (INCRETIN MIMETICS AND NONINSULIN ANALOGUES) (TABLE 5)

5.8.0 INSULIN PRODUCTS (TABLE 6)

5.8.1 Premixed insulin combinations:

TABLE 2. Considerations for Selecting Noninsulin Glucose-Lowering MedicationsTABLE 7. Premixed Insulin Combinations

Notes for Figure and Tables

  1. Goals should be individualized based on factors that include the following: comorbidities, age, duration of diabetes, hypoglycemic awareness.
  2. If diet history reveals markedly excessive carbohydrate intake, consider initial trial of nutrition therapy and physical activity before initiating oral antidiabetes medications, even if glucose levels are above thethresholds listed.
  3. Some patients with T2D initially stabilized on insulin may be considered for transition to noninsulin antidiabetes medications as blood glucose control permits.
  4. May need to taper and discontinue some or all oral antidiabetes medications as insulin is initiated and adjusted, particularly if using short- or rapid-acting and basal insulins.
  5. Pre- and postprandial blood glucose should be checked. Frequency of checking may vary; it can be 1 to 4 times/day depending on individual patient and status of glycemic control.
  6. There is an increased risk for edema when insulin and a thiazoli-dinedione are used together. Rosiglitazone should not be used in combination with insulin.
  7. FDA requirements for LFT monitoring for thiazolidinediones (TZDs): If initial alanine aminotransferase (ALT) is >2.5 times normal, do not start this medication. 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 or 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. On September 23, 2010, the 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. These FDA actions required GlaxoSmithKline to implement restrictions on the use of these products through a Risk Evaluation and Mitigation Strategy (REMS) program to assure their safe use and through additional safety labeling changes in responseto the agency’s review of data that suggested an elevated risk ofcardiovascular events. However, based on additional data review, the REMS program was removed as of December 16, 2015. Rosiglitazone now has the same indications for prescribing as pioglitazone.

9.b. According to the FDA advisory issued on June 15, 2011, regarding potential increased risk of bladder cancer with pioglitazone use: (1) Do not use pioglitazone in patients with active bladder cancer. (2) 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. Risks of acute pancreatitis or pancreatic cancer have not been confirmed in clinical trials. The FDA is currently monitoring clinical reports via the Adverse Event Reporting System.

11. Diabetic ketoacidosis (DKA) with SGLT-2 inhibitors: Rare but sometimes serious cases have been reported. Check for DKA if symptomsdevelop, even if glucose levels are not elevated.

12. The potential benefits of SGLT-2 inhibitors in preventing progression of early renal disease are being investigated.

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89. Kernan WN, Viscoli CM, Furie KL, et al; IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374(14):1321-1331. doi: 10.1056/NEJMoa1506930.

Bile Acid Sequestrants

90. 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. doi: 10.1001/archinte.168.18.1975.

91. Fonseca VA, Rosenstock J, Wang AC, Truitt KE, Jones MR. Colesevelam HCl improves glycemic control and reduces LDL cholesterol in patients with inadequately con- trolled type 2 diabetes on sulfonylurea-based therapy. Diabetes Care. 2008;31(8):1479- 1484. doi: 10.2337/dc08-0283.

92. 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. doi: 10.1001/ archinte.168.14.1531.

93. Fonseca VA, Handelsman Y, Staels B. Colesevelam lowers glucose and lipid levels in type 2 diabetes: the clinical evidence. Diabetes Obes Metab. 2010;12(5):384-392. doi: 10.1111/j.1463-1326.2009.01181.x.

Combination Therapy With Insulin

94. Aviles-Santa L, Sinding J, Raskin P. Effects of metformin in patients with poorly controlled insulin-treated type 2 diabetes mellitus. a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1999;131(3):182-188.

95. Belcher G, Lambert C, Goh KL, Edwards G, Valbuena M. Cardiovascular effects of treatment of type 2 diabetes with pioglitazone, metformin and gliclazide. Int J Clin Pract. 2004;58(9):833-837.

96. Goudswaard AN, Furlong NJ, Rutten GE, Stolk RP, Valk GD. Insulin monotherapy versus combinations of insulin with oral hypoglycaemic agents in patients with type 2 diabetes mellitus. Cochrane Database Sys Rev. 2004;(4):CD003418.

97. 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. 2003;5(3):163-170.

98. 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. 2005;27(10):1535-1547.

99. 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. 2006;29(3):554- 559. doi: 10.2337/diacare.29.03.06.dc05-0695.

100. Yki-Jarvinen H, Kauppinen-Makelin R, Tiikkainen M, et al. Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study. Diabetologia. 2006;49(3):442-451.

101. Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in basal insulin— treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med.2011;154(2):103-112. doi: 10.7326/0003-4819-154-2-201101180-00300.

Insulin

102. Davidson J, Vexiau P, Cucinotta D, Vaz J, Kawamori R. Biphasic insulin aspart 30: literature review of adverse events associated with treatment. Clin Ther. 2005;27(suppl B):S75-S88.

103. Hirsch IB, Bergenstal RM, Parkin CG, Wright E, Buse JB. A real-world approach to insulin therapy in primary care practice. Clin Diabetes. 2005;23(2):78-86. doi: 10.2337/ diaclin.23.2.78.

104. Kennedy L, Herman WH, Strange P, Harris A; 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: the Glycemic Optimization with Algorithms and Labs at Points of Care (GOAL A1C) Trial. Diabetes Care. 2006;29(1):1-8. doi: 10.2337/diacare.29.01.06.dc05-1058.

105. Riddle MC. The Treat-to-Target trial and related studies. Endocr Pract. 2006;12(suppl1):71-79. doi: 10.4158/EP.12.S1.71.

106. Siebenhofer A, Plank J, Berghold A, et al. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Database Syst Rev. 2006;(2):CD003287.

107. Valensi P, Cosson E. Is insulin detemir able to favor a lower variability in the action of injected insulin in diabetic subjects? Diabetes Metab. 2005;31(4 Pt 2):4S34-4S39.

108. Davidson MB, Raskin P, Tanenberg RJ, Vlajnic A, Hollander P. A stepwise approach to insulin therapy in patients with type 2 diabetes mellitus and basal insulin treatment failure. Endocr Pract. 2011;17(3):395-403. doi: 10.4158/EP10323.OR.

109. Rossetti P, Ampudia-Blasco FJ, Ascaso JF. Old and new basal insulin formulations: understanding pharmacodynamics is still relevant in clinical practice. Diabetes Obes Metab. 2014;16(8):695-706. doi: 10.1111/dom.12256.

110. de la Pena A, Riddle M, Morrow LA, et al. Pharmacokinetics and pharmacodynamics of high-dose human regular U-500 insulin versus human regular U-100 insulin in healthy obese subjects. Diabetes Care. 2011;34(12):2496-2501. doi: 10.2337/dc11-0721.

111. Segal AR, Vootla T, Beaser RS. Insulin: making sense of current options. Endocrinol Metab Clin North Am. 2016;45(4):845-874. doi: 10.1016/j.ecl.2016.06.009.

Inhaled Insulin

112. Pittas AG, Westcott GP, Balk EM. Efficacy, safety, and patient acceptability of Techno- sphere inhaled insulin for people with diabetes: a systematic review and meta-analysis.Lancet Diabetes Endocrinol. 2015;3(11):886-894.

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113. Leahy JL. Technosphere inhaled insulin: is faster better? Diabetes Care.2015;38(12):2282-2284. doi: 10.2337/dci15-0002.

Pramlintide

114.Hollander P, Ratner R, Fineman M, et al. 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. 2003;5(6):408-414. doi: 10.1046/j.1463-1326.2003.00295.x.

115. Hollander PA, Levy P, Fineman MS, 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. 2003;26(3):784-790. doi: 10.2337/ diacare.26.3.784.

116. Weyer C, Gottlieb A, Kim DD, et al. 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. 2003;26(11):3074-3079. doi: 10.2337/ diacare.26.11.3074.

117. Whitehouse F, Kruger DF, Fineman M, et al. 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. 2002;25(4):724-730. doi: 10.2337/ diacare.25.4.724.

Bromocriptine

118. Holt RI, Barnett AH, Bailey CJ. Bromocriptine: old drug, new formulation and new indication. Diabetes Obes Metab. 2010;12(12):1048-1057. doi: 10.1111/j.1463- 1326.2010.01304.x.

119. DeFronzo R. Bromocriptine: a sympatholytic, d2-dopamine agonist for the treatment of type 2 diabetes. Diabetes Care. 2011:34(4):789-794. doi: 10.2337/dc11-0064.

120. Gaziano JM, Cincotta AH, O’Connor CM, et al. Randomized clinical trial of quick- release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes. Diabetes Care. 2010;33(7):1503-1508. doi: 10.2337/dc09-2009.

121. Scranton R, Cincotta A. Bromocriptine—unique formulation of a dopamine agonist for the treatment of type 2 diabetes. Expert Opin Pharmacother. 2010;11(2):269-279. doi: 10.1517/14656560903501544.