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Adult Type 2 Diabetes Insulin Guidelines INTRODUCTION

Adult Type 2 Diabetes Insulin Guidelines INTRODUCTION

Adult Type 2 Guidelines INTRODUCTION

Background pharmacists, nurses, and dietitians from across Sutter Health. This More than 29 million American adults have diabetes, which is the 4th revision of the original guideline first written in 2008. is approximately 9.1% of adults in the United States. Diabetes This guideline is based on a primary review of the literature. doubles the risk of heart disease and strokes.3 Uncontrolled The identification and rating of the literature to support this diabetes is the leading cause of adult-onset blindness, kidney Adult Insulin Guideline followed a multi-step disease and lower-limb amputations.3 There has been an process. Pertinent articles for review were identified by a Medline substantial increase in the prevalence of diabetes. Over the last search including the key words: Diabetes Mellitus, Type 2/drug 30 years the number of patients with diabetes has quadrupled. If therapy, Hypoglycemic Agents, Insulin, Algorithms, Titrat,* the prevalence continues to increase, one out of every three adults Bolus and Basal. The search was limited to 2005 to June 1st 2016, will have diabetes by 2050.4 Despite the increase in prevalence language English, and Adult 19+. Older clinical trials evaluating of diabetes, the clinical management of diabetes has improved Human were included, since none were available over time. The mean A1C has improved from 1999 to 2010 from from 2005-2016. The guideline team then reviewed the list of 7.6% to 7.2% which has led to an improvement in cardiovascular articles and included those that were identified as clinical trials disease outcomes and a substantial decrease in the number of examining the initiation and titration of insulin in an ambulatory patients with end stage microvascular complications. That said, setting in adults. The most recent American Diabetes Association only 33-49% of patients with diabetes currently have their diabetes (ADA) and American Association of Clinical Endocrinologists targets for , and control at goal, (AACE) consensus guidelines, the most recent American Family and only 14% have all three targets at goal.1 Medicine review summary, and the most recent ADA position Approximately 5-10% of diabetes is . 90-95% of statements and technical reviews on diabetes care topics were also diabetes is type 2 diabetes.3 Type 1 diabetes is due to insulin included. Insulin package insert recommendations were obtained deficiency, and must be treated with insulin. Type 2 diabetes is from Lexi-Comp, Online. The recommendations for this guideline initially due to , but relative insulin deficiency are based on the information from these articles above. develops over time. Many patients with type 2 diabetes The insulin guideline is intended for adults with type 2 diabetes eventually need to take insulin to manage their condition. in an ambulatory setting. It is not intended for patients with This clinical practice guideline is written to support clinicians type 1 diabetes, patients with ketosis or acute insulin deficiency, who care for patients with type 2 diabetes using insulin. pregnant patients, hospitalized patients, children or adolescents. It is intended to help clinicians, educators, care managers and Clinical Practice Guidelines Benefit patients make decisions about insulin, oral, and non-insulin A clinical practice guideline (CPG) can help improve consistency injectable diabetes according to standard clinical of best practice care in a health care organization. It allows all practice. It should not take the place of clinical decision-making members of a care team to screen, diagnosis, monitor, treat and skills of individual clinicians. All decisions should be made within educate patients using standard recommendations. It also allows the context of the specific situation for each patient, including an organization to measure clinical outcomes in the population current health, current medications, risk of , quality using metrics consistent with the CPG treatment algorithm. It of life, , and patient preference. provides a template to translate the organization’s diagnosis and This guideline is divided into the following sections: treatment recommendations into embedded decision support General recommendations ...... 2 tools within the electronic health record and into patient-friendly Basal insulin ...... 4 information and handouts. It provides a means to efficiently adjust care consistently across the organization when new evidence Prandial insulin ...... 6 emerges about disease management in the health care literature. Premixed insulin ...... 8 Switching back and forth from analog to human . . .9 Sutter Health Adult Type 2 Diabetes Switching back and forth from basal/prandial to Insulin Guidelines premixed insulin ...... 10 The following Sutter Health Adult Type 2 Diabetes Insulin Pre-operative insulin recommendations ...... 11 Clinical Practice Guideline was written by a multi-disciplinary Additional information ...... 12 team including internists, family physicians, endocrinologists, Adult Type 2 Diabetes Insulin Guidelines

General Recommendations For type 2 diabetes patients with A1C and glucose levels above goal despite optimal use of other oral diabetes medications, consider -like -1 Receptor Agonists (GLP1 RAs) or insulin.1 GLP1 RAs can be equally or more effective than insulin, and are associated with less weight gain and less hypoglycemia.1,5,15,19,22,26,30 Consider GLP1 RAs for patients who desire , have no contraindications to GLP RAs and who do not have signs or symptoms of severe , significant insulin deficiency, or history of (DKA). GLP1 RAs include below • (Byetta®) • Exenatide ER (Bydureon®) • (Victoza®) • (Trulicity®) • (Tanzeum®) Insulin is ideal for patients who have evidence of significant hyperglycemia, a history of DKA, need to avoid weight loss, have contraindications to GLP1 RAs, and/or cannot tolerate GLP1 RAs. • Start with BASAL INSULIN and follow initiation and titration guidelines below for most type 2 diabetes adult patients.1,5 • Consider start with FULL INSULIN REPLACEMENT (simultaneous basal and prandial insulin at physiologic doses) for patients with suspected type 1 diabetes, acute very high blood , severe symptoms (polyuria, polydipsia, weight loss), evidence of ketoacidosis, or suspicion of severe insulin deficiency—in collaboration with a specialized diabetes provider. Note: all patients should have additional diabetes education when starting injectable or insulin medications1 Note: two basal Insulin and GLP1RAs combinations are FDA approved for once daily injection: • Soliqua™ 100/33 ( 100 Units/mL & 33 mcg/mL injection) • Xultophy® 100/3.6 (degludec 100 units/mL and liraglutide 3.6 mg/mL injection)

Rev. May, 2017 Adult Type 2 Diabetes Insulin Guidelines | 2 17-SYSCOM-0008379 Consider the following goals when adjusting medications:1 ADA A1C Goals*: • A1C < 7.0% is general goal • A1C < 8.0% goal may be appropriate if: Longstanding diabetes Limited life expectancy Known CVD or advanced complications Extensive co-morbid conditions Difficult to control despite use of insulin Severe hypoglycemia *Alternate A1C goals may be suggested based on individualized characteristics1,5,6 ADA Glucose Goals—Individualized based on characteristics above (especially if high risk for hypoglycemia):1,5,6 and pre-meal glucose • For most people: 80-130 mg/dL* • For older adults consider 1. If healthy: 90-130 mg/dL 2. If complex/intermediate health status (ie. multiple chronic conditions): 90-150 mg/dL 3. If very complex/poor health status (ie. end stage chronic conditions): 90-180 mg/dL Peak post-meal glucose (1-2 hours after meal) • < 180 mg/dL • Difference between pre-meal and post-meal glucose < 50 mg/dL

Adult Type 2 Diabetes Insulin Guidelines | 3 BASAL INSULIN: Long-acting: Glargine 100 units/ml (Lantus,® Basaglar®) Glargine 300 units/ml (Toujeo®) Detemir 100 units/ml (Levemir®) Degludec 100 units/ml or 200 units/ml (Tresiba®)

Intermediate-acting: NPH 100 units/ml NPH insulin has elevated risk of hypoglycemia so use with extra caution 1,5,8,24,27,32,35,49,56

INSTRUCTIONS: Basal insulin is the best starting insulin choice for most patients (if fasting glucose is above goal).1,5,8 Start one of the intermediate-acting or long-acting insulins listed above.1,8 Basal insulin is usually started at night and given once daily.20,27,31,33,34,39,43,44,45,51,52,55,57,61 If patient is on only basal insulin, then in general patient should eat predictable carb consistent meal size at regular intervals. Basal insulin should be given at the same time daily, except for Degludec which is equally effective if taken at variable times during the day.46 Continuing non-insulin anti-diabetes medications when starting basal insulin helps maintain glucose control60 but may increase risk of hypoglycemia.1,7,8 The decision about using each particular in combination with basal insulin should be individualized.7 Note: if NPH causes nocturnal hypoglycemia, consider switching NPH to long-acting insulin.5,32,49,56, 63 Key characteristics of diabetes medications when used with basal insulin: : Prevents weight gain and should be continued if tolerated.1,5,8 : Increases risk of hypoglycemia and weight gain.5,8,38,56 (ie Prandin®, Starlix®): Target postprandial glucose levels. Can fit irregular meal schedule.8 (TZDs): Increase risk of CHF, edema and weight gain.5,8 Dipeptidyl peptidase-4 inhibitors (DPP4 inhibitors): Improve glycemic control without increasing weight. 5,8,11,53, 62 Alpha-glucosidase inhibitors: Target postprandial glucose levels. 41,42 Sodium-glucose Cotransporter-2 Inhibitors (SGLT2 Inhibitors): Improve glycemic control, stabilize insulin dosing and reduce weight.5,47,82 (note: cases of DKA have been reported in patients with type 1 and 2 diabetes receiving SGLT2 inhibitors.7 An AACE scientific consensus group reports that the incidence is infrequent.3) GLP1 RAs: Improve glycemic control and prevent weight gain/reduce weight.1,5,8,9,16,25,74,80

Starting Dose: 0.1-0.2 units per kg per day.1,5,7,10,37,40,55,59 or 10 units1,7,8,13,14,18,20,21,23,29,31,34,36,39,43,46,49,50

Use the lower end of the range dose if thin, elderly, renal insufficiency, hypertension, lower cognitive function, on sulfonylureas, A1C or fasting glucose close to goal, or high risk for hypoglycemia.28,32,34,37,48

Adult Type 2 Diabetes Insulin Guidelines | 4 Titration: Teach patient to increase by 1 unit every 1 day17,31 or by 2 units every 2-3 days1,5,8,20,21,57,61 until the fasting glucose is at goal (Inform patient to hold self-titration until further evaluation if develops any hypoglycemia) or Titrate 1 time per week such as per table below until average fasting glucose (mg/dL) at goal8,12,13,20,21,27,32,33,36,39,51,52 Fasting glucose > 180 mg/dL increase 8 units Fasting glucose 160-180 mg/dL increase 6 units Fasting glucose 140-160 mg/dL increase 4 units Fasting glucose 130-140 mg/dL increase 2 units Fasting glucose 80-130 mg/dL no change Fasting glucose < 80 mg/dL (individualized for patient) decrease 2-4 units or 10-20%1 Note: Titration is required for patient to reach glycemic goals

Frequent follow-up (such as weekly) during titration. To evaluate pattern, monitor glucose levels: fasting, premeal, postmeal/bed, middle of the night (if on NPH or risk of hypoglycemia)

STOP Titration and Evaluate: • When fasting glucose level reaches individualized fasting goal • or stop sooner for evaluation if Basal insulin dose > 0.5 units/kg (such as > 50 units in a person weighing 100 kg (220 lbs)) Bed or post-meal glucose levels are significantly more elevated than the fasting or pre-meal glucose levels (such as bed glucose level > 50 mg/dl higher than fasting glucose level) Patient has any hypoglycemia (glucose < 70 mg/dL)

Consider additional treatment options to target postprandial glucose elevations if patient does not reach glycemic goals on basal insulin: • Add GLP1 RA medication especially if desires weight loss and if patient has no contraindications to GLP1 RA. (Studies have shown that adding GLP1 RAs can be equally or more effective than adding prandial insulin to basal insulin with less hypoglycemia and weight gain.)1,5,7,8,9,16,25,69,74,79,80 Note: two basal Insulin and GLP1RAs combinations are FDA approved for once daily injection1 Soliqua™ 100/33 (insulin glargine 100 Units/mL & lixisenatide 33 mcg/mL injection) and Xultophy® 100/3.6 (degludec 100 Units/mL and liraglutide 3.6 mg/mL) • Add prandial insulin injection (especially if patient has very elevated glucose levels)1,5,8 • Switch to premixed insulin (if patient has fixed meal schedule and difficult to do multiple daily injections)1,5 • Add an oral medication (such as one of those that target post prandial glucose elevations)5,8,41

Adult Type 2 Diabetes Insulin Guidelines | 5 PRANDIAL INSULIN: Rapid acting: Lispro 100 units/ml (Humalog 100®) Lispro 200 units/ml (Humalog 200®) Aspart 100 units/ml (Novolog®) Glulisine 100 units/ml (Apidra®)

Short acting: Regular 100 units/ml Regular insulin has longer peak and extra risk of hypoglycemia so use with caution (especially in renal insufficiency)1,5,8,64

INSTRUCTIONS: Start one of the prandial insulins listed above.1,8 When adding prandial insulin: Continue metformin.1 Stop sulfonlyureas,1,5 meglitinides (ie Prandin®, Starlix®), and alpha-glucosidase inhibitors. May consider continue DPP-4 Inhibitor58,62,81 and SGLT2 inhibitors.1,47,78 Consider lower basal dose 10% (or more) when adding prandial insulin especially if A1C is < 8.0, fasting glucose levels are close to goal, or the patient is at risk for hypoglycemia.1,5 Give rapid-acting insulins within 15 minutes before meal.7,8 Give Regular insulin 30 minute before meals.7,8

Fixed Dose Starting Option: Adjusted Starting Option: 4-5 units1,5 7,66, 67,72,75 If meals vary in size and patient is accurate at counting carbs: or 10% of basal insulin dose1,5,7,68,70,72 Starting Dose: 65 Either start before each meal or with largest meal only* 1,5,58,66,68,75,76 1 unit for 15 grams carbs before meals Use lower dose if thin, elderly, renal insufficiency, hypertension, May consider calculate insulin to carbohydrate ratio (I:C) = 500 / lower cognitive function, on sulfonylureas, A1C or fasting glucose total daily dose (TDD) of insulin (500 rule)8 close to goal, or high risk for hypoglycemia. In general, patient can eat variable carb size meals at variable *Advance to all meals if needed 1,5 intervals May also consider add I:C ratio to snacks INSTRUCTIONS: In general, patient should eat carbohydrate (carb) consistent meals when starting, but can eat at variable intervals5 If on NPH twice daily, may hold lunch time prandial dose Prandial insulin dose should eventually be about 50% of total daily insulin dose (if all three meals)5,8 The ADA Standards of Medical Care in Diabetes 2017 also includes 0.1 units/kg with the largest meal as a starting dosing option1

Adult Type 2 Diabetes Insulin Guidelines | 6 Consider adding pre-meal Correction Factor (CF):7,8 Add 1 unit for each 50 mg/dL that the pre-meal glucose is above target Alternative method to determine pre-meal correction factor: Consider target of 100 to 150 mg/dl for correction Correction factor (CF) = 1800 / total daily dose of insulin (1800 rule)7,8

Titrate: Titrate: Titrate 1-2 units every 2-3 days1,5,58,65,67,70 Adjust insulin to carbohydrate ratio as appropriate per below until 65 or post-meal glucose at goal 10-15% of dose 1-2 times per week1,5 until post-meal glucose levels 1 unit for 15 g carbs at goal 5,65,67 1 unit for 12 g carbs If post-meal pattern 1 unit for 10 g carbs If post-meal pattern INSTRUCTIONS: is low blood glucose is high blood glucose, 1 unit for 7 g carbs Next pre-meal glucose level may be used as a proxy for 1-2 hour peak (hypoglycemia), move down the scale post-meal glucose level when titrating insulin move up the scale 1 unit for 5 g carbs May consider different doses for different meals 1 unit for 4 g carbs May adjust insulin dose to match variable size and content of meals 1 unit for 3 g carbs If pattern of hypoglycemia, then decrease dose for that particular meal Alternate adjustment: by 10-20%1,5 Adjust insulin to carb ratio per 500 rule8 Several clinical trials have demonstrated effective self-titration of prandial insulin70,71,77

Adult Type 2 Diabetes Insulin Guidelines | 7 PREMIXED INSULIN: 75/25 Lispro Mix (Humalog® Mix) or 50/50 Lispro Mix (Humalog® Mix) 70/30 Aspart Mix (Novolog® Mix) 70/30 Degludec/Aspart (Ryzodeg®) 70/30 NPH/Regular Note: 70/30 NPH/Regular insulin has elevated risk of hypoglycemia so use with extra caution 1,5,89,102

INSTRUCTIONS: Premixed insulin is an option for patients who are unable to do multiple injections and who have fixed meal schedules5 In general, patients on premixed insulin should eat predictable carb-consistent meal size at regular intervals, with at least 8-10 hours between first and last meal (if premix is 70/30 NPH/Regular then 3 meals required) Premixed insulin may cause more hypoglycemia and weight gain compared to basal and prandial insulin 1,5, 27,34,51,84,88,95,99,100 When adding premixed insulin: Continue Metformin. Stop sulfonlyureas, meglitinides (ie Prandin®, Starlix®), and alpha-glucosidase inhibitors. May consider continuing DPP-4 inhibitors and SGLT-2 inhibitors.

Starting Dose: 5-10 units before BREAKFAST and before DINNER 84,88,90,91,97,99,100 May consider start with one meal per day (especially for Degludec/Aspart.)

Alternate starting dose: 40-50% of previous total daily insulin dose before BREAKFAST and before DINNER1,73,87,92

Use lower dose if thin, elderly, renal insufficiency, hypertension, lower cognitive function, on sulfonylureas, A1C or fasting glucose close to goal, or high risk for hypoglycemia.93

Titrate BREAKFAST dose until pre-dinner glucose Titrate DINNER dose until pre-breakfast glucose at goal: at goal: 1-2 units every 2-3 days1,88,101 1-2 units every 2-3 days1,88,101 or or 10-15% 1-2 times per week1 10-15% 1-2 times per week1

Note: may also take post-breakfast glucose levels into consideration Note: may also take post-dinner glucose levels into consideration when adjusting dose. when adjusting dose. If hypoglycemia, then decrease dose by 10-20%1 If hypoglycemia, then decrease dose by 10-20%1

• May require different doses for pre-breakfast and pre-dinner injections • Several clinical trials have demonstrated effective and safe self-titration of mixed insulin44,95,100 • May consider switch to Humalog® 50/50 Mix if patient needs proportionally less basal insulin (such as if nocturnal hypoglycemia)86,90 • May consider switch to premixed insulin before each meal if prandial insulin coverage needed for all 3 meals daily.1,103 Note: may consider switch to Humalog® 50/50 when using for all 3 meals.

Adult Type 2 Diabetes Insulin Guidelines | 8 Switching Insulin Types: Important note: Make decision about new insulin dose based on glucose patterns. Consider relatively higher dose if patient’s current glucose levels are high, and lower dose if patient is at risk of hypoglycemia. Switching from NPH to long-acting basal insulin (such as Lantus®/Levemir®/ Degludec®/etc.): Consider if patient has nocturnal hypoglycemia or persistent hyperglycemia. Start long-acting basal insulin before bed at 50%-80% of total daily NPH dose then titrate per basal insulin guideline. Switching from long-acting basal insulin (such as Lantus®/Levemir®/ Degludec®/etc) to NPH: Consider if patient needs to switch due to cost or availability. Start NPH before bed at 40-50% of current long-acting basal insulin dose. Also consider start NPH before breakfast at 40-50% of long-acting basal insulin dose – individualize decision based on current prandial insulin use, daytime glucose pattern, and estimate of basal needs during the day. Switching from Regular to Humalog®/Novolog®/Apidra®: Consider if patient has daytime hypoglycemia. Start Humalog®/Novolog®/Apidra® at 80-100% of current Regular Insulin mealtime dose then titrate per prandial insulin guideline. Switching from Humalog®/Novolog®/Apidra® to Regular Insulin: Consider if patient needs to switch due to cost. Start Regular Insulin at 80-100% of current mealtime Humalog®/Novolog®/Apidra® dose then titrate per prandial insulin guideline. Caution: • Watch for daytime hypoglycemia • Need to take Regular Insulin injection 30 minutes before meals

Adult Type 2 Diabetes Insulin Guidelines | 9 Switching from PREMIXED INSULIN to BASAL/PRANDIAL INSULIN: Selection of Patients: • Patient has persistent hypoglycemia episodes, or • Patient wants a more flexible meal schedule • Patient has excess glucose variability, or

• Determine total daily premixed insulin dose (TDD) (may adjust based on expected patient daily insulin needs) • Stop premixed insulin • Start basal insulin before bed and prandial insulin before meals.

Starting dose of BASAL INSULIN: Starting dose of PRANDIAL INSULIN: 50% TDD (total daily premixed insulin dose) before bed 10-15% TDD (total daily mixed insulin dose) before meals Note: This is essentially = to 80% of the current basal component of Note: This is similar to the current prandial component of mixed insulin. premixed insulin Note: May adjust dose based on size of each meal

Titrate per BASAL Titrate per PRANDIAL insulin guideline insulin guideline

Switching from BASAL or BASAL/PRANDIAL INSULIN to PREMIXED INSULIN: Selection of Patients: • Difficulty taking multiple injections daily • Stable glucose pattern and no hypoglycemia episodes • Stable consistent meal schedule

• Determine total daily insulin dose (TDD) (may adjust based on expected patient daily insulin needs) • Stop both Basal and Prandial insulin • Start premixed insulin before breakfast and before dinner.

Starting BREAKFAST Dose: Starting DINNER Dose: 40-50% of total daily insulin dose73,87,92 40-50% of total daily insulin dose73,87,92 Target glucose for titration is pre-dinner glucose. 88,91,94 Target glucose for titration is fasting glucose. 88,91,94 (may also consider post-breakfast glucose when titrating dose) (may also consider post-dinner glucose when titrating dose)

Titrate per PREMIXED insulin guideline

Adult Type 2 Diabetes Insulin Guidelines | 10 Pre-Operative Diabetes Guidelines: Please see accompanying patient handout at end. Please note that instructions may need to be modified for clear liquid diets/bowel prep.

Day before surgery: Non-insulin medications: • Diabetes oral medications: Take usual oral diabetes medications, except hold SGLT2 Inhibitors • Injectable non-insulin therapy: Take as usual Insulin: • Basal Insulin: Take 80% of usual evening dose • Prandial Insulin: Take as usual • Premixed Insulin: Take 80% of usual dinner dose • Pump: Set temporary basal rate to 80% of usual basal rate the night before surgery for overnight and 2 hours after anticipated end of surgery • Change insertion site the day before surgery (avoid location of planned surgery)

Day of surgery: Non-insulin medications: • Diabetes oral medications: Hold • Injectable non-insulin therapy: Hold Insulin: • Basal Insulin: Take 80% of usual morning dose (if patient takes basal insulin in morning) • Prandial Insulin: Hold off mealtime doses until eating is resumed • Premixed Insulin: Either hold or, for patients at higher risk for hyperglycemia, consider giving 50% of the intermediate acting component of premixed insulin as NPH or basal insulin (e.g. glargine or detemir). • Pump: Keep temporary basal rate set at 80%. Tell staff about pump on arrival. Bring additional pump supplies (tubing, reservoirs, pods) for two site changes.

Notes: • Consider alternate insulin doses than above if low or high glucose levels or A1C on current insulin dose. • Instruct patient to check sugars every 4 hours after waking up on the morning of surgery until arrival for procedure. • Instruct patient to use correction scale (if one is available) for blood > 200 mg/dL. • Instruct patient to treat any hypoglycemia with 15 grams of glucose gel or glucose tabs or 4 ounces of clear juice such as apple, and to tell staff upon arrival for the procedure. • Instruct patient to discuss pump before surgery, remind staff upon arrival, and to bring extra pump supplies.

Adult Type 2 Diabetes Insulin Guidelines | 11 Additional Information: in combination with insulin Below is general information about the use of other classes of diabetes medications in combination with insulin—but these notes do not include all information that needs to be considered when making clinical decisions Note: all oral and non-insulin injectable medications may increase the risk of hypoglycemia when used with insulin.7 Metformin: Continue if possible with both basal and prandial insulin because it improves glycemic control, helps prevent weight gain and maintain lower dose of insulin when combined with insulin.1,5 8 Sulfonylureas: Individualize decision about continuing when using basal insulin. Sulfonylureas help maintain glucose control in patients on basal insulin though substantially increase risk of hypoglycemia and weight gain when used with basal insulin. Generally discontinue when using prandial insulin.1,5,8,38,54,56 TZDs: Discontinue TZDs when starting basal and prandial insulin due to risk of side effects (including CHF, edema, and weight gain) when combined with insulin.1,8 Meglitinides (ie. Prandin®, Starlix®), alpha-glucosidase inhibitors: May consider using with basal insulin since these medications target post-prandial glucose excursions. Generally discontinue when using prandial insulin.8,41,42 DPP-4 inhibitors: May consider using with basal insulin because targets post-prandial glucose excursions. May improve glycemic control for patients on prandial insulin as well.5,11,58,62,67,81 GLP-1 RA medications: May consider using with basal and prandial insulin because targets post-prandial glucose excursions, improves glycemic control, lowers insulin dose and prevents weight gain.1,5,9,16,25,74,80 SGLT-2 inhibitors: May consider using with basal and prandial insulin because improves glycemic control, reduces amount of insulin needed and decreases weight.1,5,47,78,82 note: cases of DKA have been reported in patients with type 1 and 2 diabetes receiving SGLT2 inhibitors7. An AACE scientific consensus group reports that the incidence is infrequent3.

Note: once patient’s glucose levels are controlled with insulin, occasionally it may be possible to stop insulin and continue or switch to oral medications or other non-insulin injectables, depending on the stage of the diabetes and changes in other individual patient characteristics.

Adult Type 2 Diabetes Insulin Guidelines | 12 Fig. 01: Individualizing A1C Goals

From article Standards of Medical Care in Diabetes—2017. Adapted with permission from Inzucchi et al. “Depicted are patient and disease factors used to determine optimal A1C targets. Characteristics and predicaments toward the left justify more stringent efforts to lower A1C; those toward the right suggest less stringent efforts.”

Fig. 02: Glycemic Goals in Older Adults1,6 Table represents a consensus framework for considering treatment goals for glycemia, blood pressure, and dyslipidemia in older adults with diabetes.

Pre-meal Glucose Bedtime Glucose Health Status Description Rationale A1C Goal (%) Goals (mg/dL) Goal (mg/dL)

Healthy • Few coexisting chronic illnesses • Longer remaining life expectancy < 7.0 90-130 90–150 • Intact cognitive and functional status

Complex/ • Multiple coexisting chronic llnesses* • Intermediate remaining life expectancy < 8.0 90-150 100-180 Intermediate • 2+ instrumental ADL impairments • high treatment burden • mild to moderate cognitive impairment • hypoglycemia and fall risk

Very complex/ • Long-term care or end-stage illnesses** • Limited remaining life expectancy < 8.5† 100-180 110-200 Poor health • moderate to severe cognitive impairment • 2+ ADL dependencies from American Diabetes Association Standards of Medical Care in Diabetes—20166

“The patient characteristic categories are general concepts. Not every patient will clearly fall into a particular category. Consideration of patient and caregiver preferences is an important aspect of treatment individualization. Additionally, a patient’s health status and preferences may change over time ADL, activities of daily living.”

Adult Type 2 Diabetes Insulin Guidelines | 13 ‡A lower A1C goal may be set for an individual if achievable without recurrent or severe hypoglycemia or undue treatment burden. *Coexisting chronic illnesses are conditions serious enough to require medications or lifestyle management and may include arthritis, cancer, congestive heart failure, depression, emphysema, falls, hypertension, incontinence, stage 3 or worse , myocardial infarction, and stroke. By “multiple,” we mean at least three, but many patients may have five or more. **The presence of a single end-stage chronic illness, such as stage 3-4 congestive heart failure or oxygen- dependent lung disease, chronic kidney disease requiring , or uncontrolled metastatic cancer, may cause significant symptoms or impairment of functional status and significantly reduce life expectancy. †A1C of 8.5% (69mmol/mol) equates to an estimated average glucose of 200 mg/dL (11.1 mmol/L). Looser A1C targets above 8.5% (69 mmol/mol) are not recommended as they may expose patients to more frequent higher glucose values and the acute risks from glycosuria, , hyperglycemic , and poor wound healing.6

Fig. 03: Examples Example of correction factor using 1800 rule when starting prandial insulin: A patient is on 60 units of basal insulin (before starting prandial insulin). So initial Total Daily Dose (TDD) of insulin is 60 units. Correction Factor (CF) would be: 1800 / 60 = 30. If pre-meal glucose = 240, blood glucose is 90 mg/dl above target of 150; Correction is 90/30 = 3 units. Give 3 units insulin as correction. Example of carbohydrate ratio using 500 rule when starting prandial insulin: A patient on 50 units basal insulin daily (before starting prandial insulin). So initial Total Daily Dose (TDD) is 50 units. Insulin to Carbohydrate Ratio (I:C Ratio): 500/50 = 1:10 units. For a 60 gm carbohydrate meal = 60/10 = take 6 units.

Pre-meal Prandial Glucose Level (mg/dL) Insulin Dose Example of Insulin with fixed prandial dose of 80-150 4 units 4 units and correction 151-200 5 units factor of 1 unit per 50 201-250 6 units mg/dl glucose (1:50) 251-300 7 units correcting to a target of 301-350 8 units 150 mg/dl glucose: 351-400 9 units >401 10 units

Adult Type 2 Diabetes Insulin Guidelines | 14 Mealtime Advice2,7,8 Take rapid acting prandial and analog premixed insulins (Novolog® 70/30, Humalog® 75/25, etc.) just before a meal. At restaurants, only take insulin once food actually arrives at table. Take Regular and NPH/Reg 70/30 insulin 30 minutes before meals.

General meal relationship to type of insulin If patient is on only basal insulin, then in general patient should eat predictable, carb- consistent meal size at regular intervals If patient is on premixed insulin, then patient should eat predictable, carb-consistent meal size at regular intervals, with at least 8-10 hours between first and last meal (if premix is NPH/Regular then 3 meals required) If patient is on prandial insulin with fixed dose, then in general patient should eat predictable, carb-consistent meal size, but can eat at variable intervals If patient is on prandial insulin using a carb ratio, then in general patient can eat variable, carb-size meals at variable intervals If patient is on analog insulin, snacks are usually not needed If patient is on NPH or Regular insulin, snacks may be needed

Identification Carry personal ID and wear medical ID.

Hypoglycemia1 Tell patient to carry rapidly absorbed carbohydrate source at all times and teach friends and family about how to treat low glucose. Treat low glucose (<70 mg/dL) as per Rule of 15’s: Give 15 grams of rapidly absorbed carbohydrate (ie: 1/2 cup juice or 4 glucose tabs). Recheck glucose level in 15 minutes. Give another 15 gm of carbohydrate if glucose still < 70 mg/dL. Repeat until the glucose level is higher than 70 mg/dL. Once glucose level returns to normal, consider following with a snack or meal. Inform provider of hypoglycemia episodes at next appointment. If severe hypoglycemia (unconscious, seizures) call 911 and give glucagon kit as instructed if available. Prescribe glucagon kit for high risk patient to have at home.

Steroid Use When patients start steroid medications or are given steroid injections, blood glucose levels often increase significantly. In general, diabetes medications (including insulin) need to be increased to manage the hyperglycemia. Also note that as the steroid medications are tapered, the diabetes medications (including insulin) can often be gradually reduced to their previous level.

Insulin Device8 Consider insulin pen if able for patients with vision, dexterity or cognition difficulties or for patient convenience. Note insulin pens cost more than insulin vials. However, total cost of insulin pen is potentially lower than vial if patient’s daily insulin dose is low (since less unused insulin needs to be discarded at end of month). Insulin pens may not be covered by insurance.

Adult Type 2 Diabetes Insulin Guidelines | 15 Syringes and Needles2,7,8 For insulin pens consider using pen needles that are 31 gauge 5 mm or 32 gauge 4 mm. For vials consider using syringes that are 0.3-1.0 cc (depending on insulin dose) with 31 g 6 mm (15/64”) syringes. Instruct patient to leave needle in for 5-10 seconds after injection completed. A new pen needle or syringe must be used for each injection. Pen needles should not be left on the pen between injections.

Storage2,7 Refrigerate insulin until opened. Discard after expiration date. Once opened, insulin can be kept at room temperature for varying lengths of time depending upon type and brand of insulin. Avoid heat.

Education1 All patients should receive Diabetes Self-Management Education and Support (DSMES) and Medical Nutrition Therapy (MNT) by Certified Diabetes Educators if possible.

Exercise1,5 Encourage patients to continue exercising even when starting insulin. Note: Low glucose levels may occur during or after exercise. Carry glucose source when exercising. Check glucose before and during exercise. If patient has low glucose levels associated with exercise: consider decreasing preceding prandial insulin dose (if within several hours before exercise) and/or taking extra before or during exercise.

Weight Loss1,5 Strongly encourage weight loss for patients who are overweight or obese. Consider referral to a weight loss program.

Referral Consider referral to an expert in diabetes care if patient unable to reach glucose goals or has medical conditions or complications that make insulin management more difficult to manage. Diabetes experts may consider use of treatment options such as continuous glucose monitors, insulin pumps, concentrated insulin such as Reg U500, or complex medication combinations.

Adult Type 2 Diabetes Insulin Guidelines | 16 ABBREVIATIONS:

A1C A1c CPG Clinical practice guideline ADA American Diabetes Association AACE American Association of Clinical Endocrinologists GLP1 RA Glucagon-like peptide-1 receptor agonists DKA Diabetic ketoacidosis FDA Food and Drug Administration CVD NPH Neutral protamine Hagedorn insulin TZD DPP-4 inhibitors Dipeptidyl Peptidase-4 Inhibitors SGLT-2 inhibitors Sodium-glucose co-transporter 2 inhibitors carbs Carbohydrates I:C Insulin to carbohydrate ratio TDD Total daily dose CF Correction factor CHF Congestive heart failure ADL Activities of daily living ID Identification DSMES Diabetes self-management education and support MNT Medical nutrition therapy Reg Regular insulin

Adult Type 2 Diabetes Insulin Guidelines | 17 REFERENCES: General Information 1 American Diabetes Association Standards of medical care in diabetes--2017. Diabetes Care Volume 40, Supplement 1, S1-135. January 2017 2 American Diabetes Association. Insulin administration. Diabetes Care. 2004 Jan;27 Suppl 1:S106-9. 3 Chronic Disease Prevention and Health PromotionPublications. At A Glance Fact Sheets. Diabetes https://www.cdc.gov/chronicdisease/resources/publications/aag/diabetes.htm February 17 2016 4 Centers for Disease Control and Prevention. Diabetes Report Card 2014. Atlanta, GA: Centers for Disease Control and Prevention, US Dept of Health and Human Services; 2015. https://www.cdc.gov/diabetes/pdfs/ library/diabetesreportcard2014.pdf 5 Garber AJ, et al. American Association of Clinical Endocrinologists (AACE).; American College of (ACE). Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2017 executive summary. Endocr Pract. 2017;23(2): 207-238. 6 Kirkman, MS, et. al. Diabetes in Older Adults. Diabetes Care. Vol 35, December 2012. 2650-2664. 7 Lexi-Comp, Online. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2017 http://www. wolterskluwercdi.com/lexicomp-online/ 8 Petznick, A. Insulin Management of Type 2 Diabetes Mellitus. American Family Physician. July 15, 2011 Volume 84, Number 2 183-190

Basal Insulin 9 Arnolds, S, et al. “Further improvement in postprandial glucose control with addition of exenatide or to combination therapy with insulin glargine and metformin: a proof-of-concept study.” 2010. Diabetes Care 33(7): 1509-1515. 10 Aschner P, et al. EASIE investigators. Insulin glargine versus sitagliptin in insulin-naive patients with type 2 diabetes mellitus uncontrolled on metformin (EASIE): a multicentre, randomised open-label trial. Lancet. 2012 Jun 16;379(9833):2262-9 11 Barnett AH, et al. for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial. Lancet. 2013 Oct 26;382(9902):1413-23. 12 Bergenstal RM, et al. Adjust to target in type 2 diabetes: comparison of a simple algorithm with carbohydrate counting for adjustment of mealtime . Diabetes Care. 2008 Jul;31(7):1305-10. 13 Bretzel RG, et al. Once-daily basal insulin glargine versus thrice-daily prandial in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial. Lancet. 2008 Mar 29;371(9618):1073-84. 14 Buse JB, et al. DURAbility of basal versus lispro mix 75/25 insulin efficacy (DURABLE) trial 24-week results: safety and efficacy of insulin lispro mix 75/25 versus insulin glargine added to oral antihyperglycemic drugs in patients with type 2 diabetes. Diabetes Care. 2009 Jun;32(6):1007-13. 15 Buse JB, et al. Is insulin the most effective injectable antihyperglycaemic therapy? Obes Metab. 2015 Feb;17(2):145-51. 16 Buse JB, et al. (DUAL-II) Trial Investigators.. Contribution of liraglutide in the fixed-ratio combination of and liraglutide (IDegLira). Diabetes Care. 2014 Nov;37(11):2926-33. 17 Dailey G, et al. Comparison of three algorithms for initiation and titration of insulin glargine in insulin-naive patients with type 2 diabetes mellitus. Diabetes. 2014 Mar;6(2):176-83. 18 Dale, J, et al. (2010). “Insulin initiation in primary care for patients with type 2 diabetes: 3-year follow-up study.” Prim Care Diabetes 4(2): 85-89 19 D’Alessio D, et al. EAGLE Investigators. Comparison of insulin glargine and liraglutide added to oral agents in patients with poorly controlled type 2 diabetes. Diabetes Obes Metab. 2015 Feb;17(2):170-8. 20 Davies M, et al. AT.LANTUS Study Group. Initiation of insulin glargine therapy in type 2 diabetes subjects suboptimally controlled on oral antidiabetic agents: results from the AT.LANTUS trial. Diabetes Obes Metab. 2008 May;10(5):387-99. 21 Davies M, et al. ATLANTUS Study Group. Improvement of glycemic control in subjects with poorly controlled type 2 diabetes: comparison of two treatment algorithms using insulin glargine. Diabetes Care. 2005 Jun;28(6):1282-8. 22 Davies M, et al. Once-weekly exenatide versus once- or twice-daily : randomized, open- label, of efficacy and safety in patients with type 2 diabetes treated with metformin alone or in combination with sulfonylureas. Diabetes Care. 2013 May;36(5):1368-76.

Adult Type 2 Diabetes Insulin Guidelines | 18 23 Del Prato S, et al. ELEONOR Study Group. Telecare Provides comparable efficacy to conventional self- monitored blood glucose in patients with type 2 diabetes titrating one injection of insulin glulisine-the ELEONOR study.Diabetes Technol Ther. 2012 Feb;14(2):175-82. 24 Delgado E; LAUREL Spain study investigators. Outcomes with insulin glargine in patients with type 2 diabetes previously on NPH insulin: evidence from clinical practice in Spain. Int J Clin Pract. 2012 Mar;66(3):281-8. 25 DeVries JH, et al. Liraglutide-Detemir Study Group. Sequential intensification of metformin treatment in type 2 diabetes with liraglutide followed by randomized addition of basal insulin prompted by A1C targets. Diabetes Care. 2012 Jul;35(7):1446-5 26 Diamant M, et al. Exenatide once weekly versus insulin glargine for type 2 diabetes (DURATION-3): 3-year results of an open-label randomised trial. Lancet Diabetes Endocrinol. 2014 Jun;2(6):464-73. 27 Fajardo Montañana C, et al. Less weight gain and hypoglycaemia with once-daily insulin detemir than NPH insulin in intensification of insulin therapy in overweight Type 2 diabetes patients: the PREDICTIVE BMI clinical trial. Diabet Med. 2008 Aug;25(8):916-23. 28 Gerstein HC, R, et al. ORIGIN Trial Investigators, Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012 Jul 26;367(4):319-28. 29 Gough SC, et al. Low-volume insulin degludec 200 units/ml once daily improves glycemic control similarly to insulin glargine with a low risk of hypoglycemia in insulin-naive patients with type 2 diabetes: a 26-week, randomized, controlled, multinational, treat-to-target trial: the BEGIN LOW VOLUME trial. Diabetes Care. 2013 Sep;36(9):2536-42. 30 Grimm M, Li Y, et al. Exenatide once weekly versus daily basal insulin as add-on treatment to metformin with or without a sulfonylurea: a retrospective pooled analysis in patients with poor glycemic control. Postgrad Med. 2013 Sep;125(5):101-8. 31 Harris S, et al. Can family physicians help patients initiate basal insulin therapy successfully?: randomized trial of patient-titrated insulin glargine compared with standard oral therapy: lessons for family practice from the Canadian INSIGHT trial. Can Fam Physician. 2008 Apr;54(4):550-8. 32 Hermansen K, et al. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care. 2006 Jun;29(6):1269-74. Erratum in: Diabetes Care. 2007 Apr;30(4):1035. 33 Hollander P, et al. A 52-week, multinational, open-label, parallel-group, noninferiority, treat-to-target trial comparing insulin detemir with insulin glargine in a basal-bolus regimen with mealtime in patients with type 2 diabetes. Clin Ther. 2008 Nov;30(11):1976-87. 34 Holman RR, et al. 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med. 2009 Oct 29;361(18):1736-47. 35 Home PD, et al. Modulation of insulin dose titration using a hypoglycaemia-sensitive algorithm: insulin glargine versus neutral protamine Hagedorn insulin in insulin-naïve people with type 2 diabetes.Diabetes Obes Metab. 2015 Jan;17(1):15-22. Author information: 36 Janka HU, et al. Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes. Diabetes Care. 2005 Feb;28(2):254-9. 37 Kadowaki T, et al. One Potential formula for the calculation of starting and incremental insulin glargine doses: ALOHA subanalysis. 2012;7(8) 38 Karl DM, Gill J, Zhou R, Riddle MC. Clinical predictors of risk of hypoglycaemia during addition and titration of insulin glargine for type 2 diabetes mellitus. Diabetes Obes Metab. 2013 Jul;15(7):622-8. 39 Kennedy L, et al. GOAL AIC Team. Impct 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 Point of Care (GOAL A1C) trial. Diabetes Care. 2006 Jan;29(1):1-8. 40 Kerlan, V,et al. (2012). “Insulin initiation in elderly patients with type 2 diabetes in France: a subpopulation of the LIGHT study.” Curr Med Res Opin 28(4): 503-511. 41 Kim MK, et al. Diabetes and for postprandial glucose control after optimizing fasting glucose with insulin glargine in patients with type 2 diabetes. Res Clin Pract. 2011 Jun;92(3):322-8 42 Lee MY, et al. Comparison of acarbose and in diabetes patients who are inadequately controlled with basal insulin treatment: randomized, parallel, open-label, active-controlled study. J Korean Med Sci. 2014 Jan;29(1):90-7. 43 Liebl A, et al. PREFER Study Group. Comparison of insulin analogue regimens in people with type 2 diabetes mellitus in the PREFER Study: a randomized controlled trial. Diabetes Obes Metab 2009 Jan;11(1):45-52. 44 Masuda H, et al. Comparison of twice-daily injections of biphasic insulin lispro and basal-bolus therapy: glycaemic control and quality-of-life of insulin-naïve type 2 diabetic patients. Diabetes Obes Metab. 2008 Dec;10(12):1261-5. 45 Meneghini L, et al. The usage of a simplified self-titration dosing guideline (303 Algorithm) for insulin detemir in patients with type 2 diabetes--results of the randomized, controlled PREDICTIVE 303 study.Diabetes Obes Metab. 2007 Nov;9(6):902-13.

Adult Type 2 Diabetes Insulin Guidelines | 19 46 Meneghini L, et al. (BEGIN FLEX) Trial Investigators. The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: a 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes. Diabetes Care. 2013 Apr;36(4):858-64. 47 Neal B, et al. CANVAS Trial Collaborative Group. Efficacy and safety of , an inhibitor of sodium- glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes Care. 2015 Mar;38(3):403-11. 48 ORIGIN Trial Investigators. Predictors of nonsevere and severe hypoglycemia during glucose-lowering treatment with insulin glargine or standard drugs in the ORIGIN trial. Diabetes Care. 2015 Jan;38(1):22-8. 49 Philis-Tsimikas A, et al. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther. 2006 Oct;28(10):1569-81. 50 Philis-Tsimikas A, et al. Insulin degludec once-daily in type 2 diabetes: simple or step-wise titration (BEGIN: once simple use). Adv Ther. 2013 Jun;30(6):607-22. 51 Raskin P, et al. Comparison of insulin detemir and insulin glargine using a basal-bolus regimen in a randomized, controlled clinical study in patients with type 2 diabetes. Diabetes Metab Res Rev. 2009 Sep;25(6):542-8. 52 Rosenstock J, et al. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia. 2008 Mar;51(3):408-16. 53 Sheu WH, et al. Linagliptin improves glycemic control after 1 year as add-on therapy to basal insulin in Asian patients with type 2 diabetes mellitus. Curr Med Res Opin. 2015 Mar;31(3):503-12 54 Suzuki D, et al. Effectiveness of basal-supported oral therapy (BOT) using insulin glargine in patients with poorly controlled type 2 diabetes. J Exp Clin Med. 55 Swinnen SG, et al. A 24-week, randomized, treat-to-target trial comparing initiation of insulin glargine once- daily with insulin detemir twice-daily in patients with type 2 diabetes inadequately controlled on oral glucose- lowering drugs Diabetes Care. 2010 Jun;33(6):1176-8. 56 Swinnen SG, et al. Continuation versus discontinuation of insulin secretagogues when initiating insulin in type 2 diabetes. Diabetes Obes Metab 2010 Oct;12(10):923-5 57 Swinnen SG, et al. Rationale, design, and baseline data of the insulin glargine (Lantus) versus insulin detemir (Levemir) Treat-To-Target (L2T3) study: A multinational, randomized noninferiority trial of basal insulin initiation in type 2 diabetes. Diabetes Technol Ther. 2009 Nov;11(11):739-43. 58 Takahara M, et al. Efficacy of adding once-daily insulin glulisine in Japanese type 2 diabetes patients treated with insulin glargine and sitagliptin. Diabetes Technol Ther. 2014 Oct;16(10):633-9. 59 Tsai, S. et al. First insulinization with basal insulin in patients with Type 2 diabetes in a real-world setting in Asia. 2011 J Diabetes 3(3): 60 Vora J, et al. SOLVE study group. Effect of once-daily insulin detemir on oral antidiabetic drug (OAD) use in patients with type 2 diabetes.J Clin Pharm Ther. 2014 Apr;39(2):136-43. 61 Wang XL, et al. Evaluation of the superiority of insulin glargine as basal insulin replacement by continuous glucose monitoring system.Diabetes Res Clin Pract. 2007 Apr;76(1):30-6. 62 Yki-Järvinen H, et al. Effects of adding linagliptin to basal insulin regimen for inadequately controlled type 2 diabetes: a ≥52-week randomized, double-blind study. Diabetes Care. 2013 Dec;36(12):3875-81. 63 Zdarska DJ, et al. Comparison of glucose variability assessed by a continuous glucose-monitoring system in patients with type 2 diabetes mellitus switched from NPH insulin to insulin glargine: the COBIN2 study. Wien Klin Wochenschr. 2014 Apr;126(7-8):228-37.

Adult Type 2 Diabetes Insulin Guidelines | 20 Prandial Insulin 64 Anderson JH et al. Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin-analog treatment. Multicenter Insulin Lispro Study Group. Diabetes Feb 1997 46 (2) p265-70. 65 Bergenstal RM, et al. Adjust to target in type 2 diabetes: comparison of a simple algorithm with carbohydrate counting for adjustment of mealtime insulin glulisine. Diabetes Care. 2008 Jul;31(7):1305-10. 66 Blackberry ID, et al. An exploratory trial of basal and prandial insulin initiation and titration for type 2 diabetes in primary care with adjunct retrospective continuous glucose monitoring: INITIATION study. Diabetes Res Clin Pract. 2014 Nov;106(2):247-55. 67 Bretzel RG, et al. Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial. Lancet. 2008 Mar 29;371(9618):1073-84. 68 Davidson MB, et al. Stepwise approach to insulin therapy in patients with type 2 diabetes mellitus and basal insulin treatment failure. Endocr Pract 17(3): 395-403. 69 Digenio A, et al. Prandial insulin versus glucagon-like peptide-1 added to basal insulin: comparative effectiveness in the community practice setting. Postgrad Med. 2014 Oct;126(6):49-59. 70 Edelman SV, et al. AUTONOMY: the first randomized trial comparing two patient-driven approaches to initiate and titrate prandial insulin lispro in type 2 diabetes. Diabetes Care. 2014 Aug;37(8):2132-40. 71 Harris SB, et al. Does a patient-managed insulin intensification strategy with insulin glargine and insulin glulisine provide similar glycemic control as a physician-managed strategy? Results of the START (Self- Titration With Apidra to Reach Target) Study: a randomized noninferiority trial.Diabetes Care. 2014;37(3):604-10. 72 Holman RR, et al. 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med. 2009 Oct 29;361(18):1736-47. 73 Levin, PA, et al. Glycemic control with insulin glargine plus insulin glulisine versus premixed insulin analogues in real-world practices: a cost-effectiveness study with a randomized pragmatic trial design. 2011 Clin Ther 33(7): 841-850 74 Mathieu C, et al. BEGIN: VICTOZA ADD-ON (NN1250-3948) study group.. A comparison of adding liraglutide versus a single daily dose of insulin aspart to insulin degludec in subjects with type 2 diabetes 75 Meneghini, L, et al. Comparison of 2 intensification regimens with rapid-acting insulin aspart in type 2 diabetes mellitus inadequately controlled by once-daily insulin detemir and oral antidiabetes drugs: the step- wise randomized study. 2011 Endocr Pract 17(5): 727-736 76 Owens, DR et al. Effects of initiation and titration of a single pre-prandial dose of insulin glulisine while continuing titrated insulin glargine in type 2 diabetes: a 6-month ‘proof-of-concept’ study. 2011 Diabetes Obes Metab 13(11): 1020-1027 77 Rodbard HW, et al. Treatment intensification with stepwise addition of prandial insulin aspart boluses compared with full basal-bolus therapy (FullSTEP Study): a randomised, treat-to-target clinical trial. Lancet Diabetes Endocrinol. 2014 Jan;2 (1):30-7. 78 Rosenstock J, et al. EMPA-REG MDI Trial Investigators. Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care. 2014 Jul;37(7):1815-23. 79 Rosenstock J, et al. Harmony 6 Study Group Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care. 2014 Aug;37(8):2317-25. 80 Rosenstock J, et al. GetGoal Duo-2 Trial Investigators.. Prandial Options to Advance Basal Insulin Glargine Therapy: Testing Lixisenatide Plus Basal Insulin Versus Insulin Glulisine Either as Basal-Plus or Basal-Bolus in Type 2 Diabetes: The GetGoal Duo-2 Trial. Diabetes Care. 2016 Aug;39(8):1318-28. 81 Shimoda S, et al. Efficacy and safety of sitagliptin as add-on therapy on glycemic control and blood glucose fluctuation in Japanese type 2 diabetes subjects ongoing with multiple daily insulin injections therapy. Endocr J. 2013;60(10):1207-14. Epub 2013 Aug 3. 82 Wilding JP, et al. 006 Study Group. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab. 2014 Feb;16(2):124-36.

Adult Type 2 Diabetes Insulin Guidelines | 21 Mixed Insulin 83 Aschner P, et al..Insulin glargine compared with premixed insulin for management of insulin-naïve type 2 diabetes patients uncontrolled on oral antidiabetic drugs: the open-label, randomized GALAPAGOS study. J Diabetes Complications. 2015 Aug;29(6):838-45. 84 Buse JB, et al. DURAbility of basal versus lispro mix 75/25 insulin efficacy (DURABLE) trial 24-week results: safety and efficacy of insulin lispro mix 75/25 versus insulin glargine added to oral antihyperglycemic drugs in patients with type 2 diabetes. Diabetes Care. 2009 Jun;32(6):1007-13. 85 Clements MR, et. al. Improved glycaemic control of thrice-daily biphasic insulin aspart compared with twice-daily biphasic human insulin; a randomized, open-label trial in patients with type 1 or type 2 diabetes. Diabetes Obes Metab. 2008 Mar;10(3):229-37. 86 Farcasiu E, et al. Efficacy and safety of prandial premixed therapy using insulin lispro mix 50/50 3 times daily compared with progressive titration of insulin lispro mix 75/25 or biphasic insulin aspart 70/30 twice daily in patients with type 2 diabetes mellitus: a randomized, 16-week, open-label study. Clin Ther. 2011 Nov;33(11):1682-93 87 Fulcher GR, et al. BOOST: Intensify Premix I Investigators Comparison of insulin degludec/insulin aspart and biphasic insulin aspart 30 in uncontrolled, insulin-treated type 2 diabetes: a phase 3a, randomized, treat-to- target trial.. Diabetes Care. 2014 Aug;37(8):2084-90. 88 Holman RR, et al. 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med. 2009 Oct 29;361(18):1736-47. 89 Hussein Z, et al. Switching from biphasic human insulin to biphasic insulin aspart 30 in type 2 diabetes:

results from the ASEAN subgroup of the A1chieve study. Diabetes Res Clin Pract. 2013 Apr; 100 Suppl 1:S24-9. 90 Jain SM, et al. Prandial-basal insulin regimens plus oral antihyperglycaemic agents to improve mealtime glycaemia: initiate and progressively advance insulin therapy in type 2 diabetes. Diabetes Obes Metab. 2010 Nov;12(11):967-75. 91 Janka HU, et al. Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes. Diabetes Care. 2005 Feb;28(2):254-9. 92 Kaneko S, et al. BOOST: Intensify All Trial Investigators. Insulin degludec/insulin aspart versus biphasic insulin aspart 30 in Asian patients with type 2 diabetes inadequately controlled on basal or pre-/self-mixed insulin: a 26-week, randomised, treat-to-target trial. Diabetes Res Clin Pract. 2015 Jan;107(1):139-47. 93 Liao L, et al. Appropriate insulin initiation dosage for insulin-naive type 2 diabetes outpatients receiving insulin monotherapy or in combination with metformin and/or . Chin Med J 2010 Dec;123(24):3684-8 94 Liebl A, et al. PREFER Study Group. Comparison of insulin analogue regimens in people with type 2 diabetes mellitus in the PREFER Study: a randomized controlled trial. Diabetes Obes Metab 2009 Jan;11(1):45-52. 95 Ligthelm RJ. Self-titration of biphasic insulin aspart 30/70 improves glycaemic control and allows easy intensification in a Dutch clinical practice.Prim Care Diabetes. 2009 May;3(2):97-102. 96 Malone JK, et. al. Twice-daily pre-mixed insulin rather than basal insulin therapy alone results in better overall glycaemic control in patients with Type 2 diabetes. Diabet Med. 2005 Apr;22(4):374-81 97 Niskanen L, et al. Comparison of a soluble co-formulation of insulin degludec/insulin aspart vs biphasic insulin aspart 30 in type 2 diabetes: a randomised trial. Eur J Endocrinol. 2012 Aug;167(2):287-94. 98 Oyer DS, et al. INITIATEplus Study Group. A(1c) control in a primary care setting: self-titrating an pre-mix (INITIATEplus trial). Am J Med. 2009 Nov;122(11):1043-9. 99 Riddle MC, et al. Randomized, 1-year comparison of three ways to initiate and advance insulin for type 2 diabetes: twice-daily premixed insulin versus basal insulin with either basal-plus one prandial insulin or basal- bolus up to three prandial injections. Diabetes Obes Metab. 2014 May;16(5):396-402. 100 Robbins DC, et al. Mealtime 50/50 basal + prandial insulin analogue mixture with a basal insulin analogue, both plus metformin, in the achievement of target HbA1c and pre- and postprandial blood glucose levels in patients with type 2 diabetes: a multinational, 24-week, randomized, open-label, parallel-group comparison. Clin Ther. 2007 Nov;29(11):2349-64. 101 Schiel, R, et. al. Efficacy and treatment satisfaction of once-daily insulin glargine plus one or two oral antidiabetic agents versus continuing premixed human insulin in patients with Type 2 diabetes previously on long-term conventional insulin therapy: the SWITCH Pilot Study. Exp Clin Endocrinol Diabetes. 2008 Jan;116(1):58-64. 102 Soewondo P, et al. Clinical safety and effectiveness of biphasic insulin aspart 30 in type 2 diabetes patients

switched from biphasic human insulin 30: results from the Indonesian cohort of the A1chieve study. Res Clin Pract. 2013 Apr;100 Suppl 1:S41-6. 103 Yang W, et al. Biphasic insulin aspart 30 three times daily is more effective than a twice-daily regimen, without increasing hypoglycemia, in Chinese subjects with type 2 diabetes inadequately controlled on oral antidiabetes drugs. Diabetes Care. 2008 May;31(5):852-6.

Adult Type 2 Diabetes Insulin Guidelines | 22 PRE-OPERATIVE INSTRUCTIONS FOR PATIENTS WITH DIABETES:

Patient name: ______Date of surgery: ______

Blood sugar control is very important in helping to prevent complications from your surgery. If you are having blood sugars < 70 or > 200 mg/dL, you should see your diabetes care provider before undergoing elective surgery. Follow the general instructions below (unless advised differently by your own provider). For clear liquid diets/bowel preparation, these instructions may need to be modified. Discuss with your provider.

Day and evening prior to surgery: • Eat your normal (unless your surgeon has given you other instructions). • Take your regular diabetes pills except do not take Invokana, Jardiance or Farxiga (unless your surgeon has given you other instructions). • Take non-insulin injectable medications (e.g. Trulicity, Victoza, Byetta, etc.) as usual. Insulin instructions: • Background (Basal) insulin (e.g. Lantus, NPH, Levemir, Tresiba, Toujeo, etc.): take your usual dose during the day, but only take 80% of evening or bedtime dose. • Mealtime insulin (e.g. Humalog, Novolog, Apidra, Regular, etc.): take your usual doses of insulin with meals. • Premixed insulin (e.g. Novolog Mix 70/30, Humalog Mix 75/25, Humalog 50/50, NPH/Regular 70/30, etc.): take your usual morning dose, but take only 80% of your dinner dose.

Morning of surgery: • Follow any instructions you have received from your surgeon regarding food/liquid intake. • DO NOT take any diabetes pills. • DO NOT take non-insulin injectable medications (e.g. Trulicity, Victoza, Byetta, etc.). • Check your blood sugar (glucose) when you wake up on the morning of surgery and every 4 hours until you arrive at the hospital. • If your blood sugar is low during this time (under 70 mg/dL), take 15 grams of glucose gel or glucose tablets, if available. If not, drink 4 oz. (½ cup) of clear juice such as apple juice. Inform the surgical staff about this immediately when you arrive. Insulin instructions: • Background (Basal) insulin (e.g. Lantus, NPH, Levemir, Tresiba, Toujeo, etc.). Take 80% of your usual morning dose. • Do not take mealtime insulin. • If you have a correction scale, give insulin if blood sugar is above 200 mg/dL. • Premixed insulin (e.g. Novolog Mix 70/30, Humalog Mix 75/25, Humalog 50/50, NPH/Regular 70/30, etc.). Do not take premixed insulin, unless you have received other instructions from your provider.

Insulin pump instructions: • During your pre-op evaluation, discuss whether you can or cannot wear your pump during the procedure with your surgeon and anesthesiologist. If you are permitted to wear your pump, please follow guidelines below. • Change your insertion site and reservoir the day before surgery and bring extra supplies with you (insertion set, reservoir, extra batteries, insulin). • For surgeries involving the abdominal area, place the pump catheter in a site other than your abdomen (such as arm, hip, or thigh). • Starting the night before your procedure, set a temporary basal to 80% of your usual dose (minus 20%) until after your procedure and you are eating. • Remind the surgical staff that you are wearing an when you arrive.

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