Introduction
Role of the Pharmacist in Diabetes Care
Insulin Formulations in the Management of T2D
Product | Onset (h) | Duration (h) | Dosage forms and strengths | Insulin units per vial/pen | Maximum single-injection dose for pen devices (U) | Median cost [6]a (USD) | Storage days at room temperature (in use) |
---|---|---|---|---|---|---|---|
Insulin glargine 100 U/mL [30] | 2–4 | 24 | 3 mL cartridges | 300 | 80 | 298 | 28 |
10 mL vials | 1000 | ||||||
3 mL prefilled pens | 300 | ||||||
Follow-on insulin glargine 100 U/mL [31] | NA | 24 | 3 mL prefilled pens | 300 | 80 | 253 | 28 |
Insulin glargine 300 U/mL [32] | 6 | 24 | 1.5 mL prefilled pens | 450/900 | 80/160 | 298 | 42 |
Insulin degludec 100 or 200 U/mL [33] | 1 | > 42 | 3 mL prefilled pens containing either 100 or 200 U/mL | 300/600b | 80/160b | 355 | 56 |
Insulin detemir 100 U/mL [34] | 0.8–2 [48] | < 24 | 10 mL vials | 1000 | 80 | 323 | 42 |
3 mL prefilled pens | 300 |
NPH Insulin
Premixed Insulin Formulations
Basal Insulin Analogs
First-Generation Basal Insulin Analogs
Gla-100
IDet
Second-Generation Basal Insulin Analogs
Gla-300
IDeg
Treatment Algorithms
Study | Study details | Target | Titration algorithm | Titration frequency | Insulin starting dose | Insulin dose at EOS | HbA1c, % baseline | HbA1c, % at EOS | Hypoglycemia |
---|---|---|---|---|---|---|---|---|---|
Riddle 2003 [42] | Gla-100 or NPH once daily for 24 weeks n = 756 | ≤ 100 mg/dL | Dose adjustment based on mean of self-monitored FPG values from preceding 2 days: ≥ 180 mg/dL ↑ 8 U insulin; 140–180 mg/dL ↑ 6 U; 120–140 mg/dL ↑ 4 U; 100–120 mg/dL ↑ 2 U | Weekly | 10 U | Gla-100 47.2 U; NPH 41.8 U | Gla-100 8.61; NPH 8.56 | Gla-100 6.96; NPH 6.97 | Gla-100 9.2/patient year; NPH 12.9/patient year |
LANMET Yki-Järvinen 2006 [66] | Gla-100 or NPH once daily before bedtime for 36 weeks n = 110 | 72–100 mg/dL | Dose adjustment based on mean pre-breakfast SMPG over 3 consecutive days: > 100 mg/dL ↑ 2 U; > 180 mg/dL ↑ 4 U | Not stated | 10 U for patients using metformin alone; 20 U if patients had used both sulfonylurea and metformin | Gla-100 68 U (0.69 U/kg); NPH 70 U (0.66 U/kg) | Gla-100 9.13; NPH 9.26 | Gla-100 7.14; NPH 7.16 | Gla-100 5.4/patient year; NPH 8.0/patient year |
Hermansen 2006 [50] | Insulin detemir or NPH twice daily for 24 weeks n = 476 | ≤ 108 mg/dL (pre-breakfast and pre-dinner) | Dose adjustment based on average of 3 preceding SMPG levels on consecutive days: > 180 mg/dL ↑ 10 U (responders and non-responders); 163–180 mg/dL ↑ 6 U (responders) ↑ 8 U (non-responders); 145–162 mg/dL ↑ 4 U (responders) ↑ 6 U (non-responders); 127–144 mg/dL ↑ 2 U (responders) ↑ 4 U (non-responders); 109–126 mg/dL ↑ 2 U (responders and non-responders); if one pre-breakfast plasma glucose: 56–72 mg/dL ↓ 2; < 56 mg/dL ↓ 4 | At least weekly for 12 weeks and at least fortnightly thereafter | 10 U per injection | Detemir 36.1 U pre-breakfast and 29.5 U in the evening; NPH 25.3 U pre-breakfast and 19.7 U in the evening | Detemir 8.6; NPH 8.5 | Detemir 6.8; NPH 6.6 | Detemir 8.6/patient year; NPH 15.95/patient year |
Rosenstock 2008 [67] | Insulin detemir (once or twice daily) or Gla-100 (once daily) for 52 weeks n = 582 | ≤ 108 mg/dL | Dose adjustments in 2-U steps in the evening according to average pre-breakfast SMPG and response to previous dose adjustment; morning dose adjustment according to average pre-dinner SMPG in some insulin detemir patients | Daily | 12 U | Detemir 0.78 U/kg (once daily 0.52 U/kg, twice daily 1.00 U/kg); Gla-100 0.44 U/kg | Detemir 8.64; Gla-100 8.62 | Detemir 7.16 (once daily 7.12, twice daily 7.06); Gla-100 7.12 | Detemir 5.8/patient year; Gla-100 6.2/patient year |
BEGIN ONCE LONG Zinman 2012 [61] | IDeg 100 U or Gla-100 100 U once daily for 52 weeks Inadequately controlled with OADs n = 1030 | 70–88 mg/dL | Dose adjustment on the basis of the average of pre-breakfast SMPG values of 3 consecutive days preceding a visit (full details not given) | Not reported | 10 U | IDeg 0.59 U/kg; Gla-100 0.60 U/kg | 8.2 for both | IDeg 7.1; Gla-100 7.0 | IDeg 1.52/patient year; Gla-100 1.85/patient year |
BEGIN LOW VOLUME Gough 2013 [62] | IDeg 200 U or Gla-100 100 U once daily for 26 weeks n = 457 | < 90 mg/dL | Dose adjustment according to the average of 3 consecutive preceding pre-breakfast SMPG levels: < 56 mg/dL ↓ 4 U; 56–69 mg/dL ↓ 2 U; 70–89 mg/dL no change; 90–125 mg/dL ↑ 2 U; 126–143 mg/dL ↑ 4 U; 144–161 mg/dL ↑ 6 U; ≥ 162 mg/dL ↑ 8 U | Weekly | 10 U | IDeg 0.53 U/kg; Gla-100 0.60 U/kg | IDeg 8.3; Gla-100 8.2 | Mean HbA1c decreased by 1.3% in both treatment groups | IDeg 1.22/patient year; Gla-100 1.42/patient year |
BEGIN FLEX Meneghini 2013 [63] | IDeg 100 U once-daily in a pre-specified dosing schedule (8–40-h intervals between injections) or IDeg 100 U once-daily IDeg at the main evening meal or Gla-100 at the same time each day for 26 weeks Insulin-naive or -experienced n = 610 | 70–90 mg/dL | Dose adjustment according to the average of 3 consecutive preceding pre-breakfast SMPG levels: < 56 mg/dL ↓ 4 U; 56–69 mg/dL ↓ 2 U; 70–89 mg/dL no change; 90–125 mg/dL ↑ 2 U; 126–143 mg/dL ↑ 4 U; 144–161 mg/dL ↑ 6 U; ≥ 162 mg/dL ↑ 8 U | Weekly | 10 U in insulin-naive patients | 0.6 U/kg for all groups in insulin-experienced patients; 0.5 U/kg for all groups in insulin-naive patients | IDeg flexible dosing 8.5; IDeg fixed 8.4; Gla-100 8.4 | IDeg flexible dosing mean decrease by 1.28; IDeg fixed 1.07; Gla-100 1.26 | IDeg flexible dosing 3.6/patient year; IDeg fixed 3.6/patient year; Gla-100 3.5/patient year |
Meneghini 2013 [68] | Insulin detemir or Gla-100 for 26 weeks n = 457 | ≤ 90 mg/dL | Dose adjustment based on mean of 3 consecutive pre-breakfast SMPG measurements: 92–144 mg/dL ↑ 2 U; for each 18 mg/dL above that range (but ≤ 180 mg/dL), ↑ 2 U, with a maximum of 8 U added if mean FPG was >180 mg/dL. No dose adjustment was made if mean FPG was > 71 to ≤ 90 mg/dL, with no value ≤ 71 mg/dL without an obvious explanation The dose was to be reduced by 2 U if ≥ 1 fasting SMPG readings were 56–71 mg/dL and by 4 U if < 56 mg/dL | Weekly | 10 U | Detemir 57 U (0.7 U/kg); Gla-100 51 U (0.61 U/kg) | Detemir 7.96; Gla-100 7.86 | Detemir 7.48; Gla-100 7.13 | Detemir 3.19/patient year; Gla-100 4.41/patient year |
Onishi 2013 [64] | IDeg or Gla-100 100 U once daily for 26 weeks n = 435 | 70–90 mg/dL | Dose adjustment based on mean of 3 consecutive pre-breakfast SMPG measurements: < 56 mg/dL ↓ 4 U; 56–69 mg/dL ↓ 2 U; 70–89 mg/dL no change; 90–125 mg/dL ↑ 2 U; 126–143 mg/dL ↑ 4 U; 144–161 mg/dL ↑ 6 U; ≥ 162 mg/dL ↑ 8 U | Weekly | 10 U | IDeg 19 U (0.28 U/kg); Gla-100 24 U (0.35 U/kg) | IDeg 8.4; Gla-100 8.5 | IDeg 7.2; Gla-100 7.1 | IDeg 3.0/patient year; Gla-100 3.7/patient year |
BEGIN EASY AM; BEGIN EASY PM Zinman 2013 [53] | IDeg 200 U three times weekly, either before breakfast (AM) or with the evening meal (PM), or Gla-100 once daily n = 927 | 70–90 mg/dL | Based on mean pre-breakfast SMPG (lowest value from prior 3 consecutive days) IDeg: < 56 mg/dL ↓ 8 U; 56–69 mg/dL ↓ 4 U; 70–89 mg/dL no change; 90–125 mg/dL ↑ 4 U; 126– 143 mg/dL ↑ 8 U; 144–161 mg/dL ↑ 12 U; ≥ 162 mg/dL ↑ 16 U Gla-100: < 56 mg/dL ↓ 4U; 56–69 mg/dL ↓ 2 U; 70–89 mg/dL no change; 90–125 mg/dL ↑ 2 U; 126–143 mg/dL ↑ 4 U; 144–161 mg/dL ↑ 6 U; ≥ 162 mg/dL ↑ 8 U | Weekly | IDeg 20 U; Gla-100 10 U | IDeg AM 50 U; Gla-100 62 U IDeg PM 51 U; Gla-100 56 U (mean calculated dose for IDeg vs actual dose for Gla-100) | IDeg AM 8.2; Gla-100 8.3 IDeg PM 8.3; Gla-100 8.3 | IDeg AM mean decrease of 0.93; Gla-100 1.28 IDeg PM mean decrease of 1.09; Gla-100 1.35 | (Confirmed) IDeg AM 1.3/patient year; Gla-100 1.2/patient year IDeg PM 1.6/patient year; Gla-100 1.0/patient year |
EDITION 3 Bolli 2015 [55] | Gla-300 or Gla-100 once-daily for 6 months n = 878 | 80–100 mg/dL | SMPG > 100 and < 140 mg/dL ↑ 3 U; SMPG ≥ 140 mg/dL ↑ 6 U; SMPG ≥ 60 and < 80 mg/dL ↓ 3 U; SMPG < 60 mg/dL or if severe or multiple symptomatic hypoglycemia events occurred ↓ ≥ 3 U at investigator’s discretion | Weekly | 0.2 U/kg/day | Gla-300 0.62 U/kg; Gla-100 0.53 U/kg | Gla-300 8.49; Gla-100 8.58 | Gla-300 7.08; Gla-100 7.05 | ≥ 1 confirmed (≤ 3.9 mmol/L) or severe hypoglycemia event: Gla-300 46%; Gla-100 53% |
Study | Treatment | Titration goal | Titration algorithm | Titration frequency | Insulin starting dose | Insulin dose at EOS | HbA1c, % baseline | HbA1c, % EOS | Hypoglycemia (overall confirmed events) |
---|---|---|---|---|---|---|---|---|---|
AT.LANTUS Davies 2005 [69] | Gla-100 once daily for 24 weeks. Suboptimally controlled on insulin or OADs n = 4961 | ≤ 100 mg/dL | Based on mean of self-monitored FPG values from preceding 3 consecutive days Algorithm 1: ≥ 180 mg/dL ↑ 6–8 U insulin; 140–180 mg/dL ↑ 4 U; 120–140 mg/dL ↑ 2 U; ≥ 100–120 mg/dL ↑ 0–2 U Algorithm 2: ≥ 180 mg/dL ↑ 2 U insulin; 140–180 mg/dL ↑ 2 U; 120–140 mg/dL ↑ 2 U; ≥ 100–120 mg/dL ↑ 0–2 U | Algorithm 1: titration weekly; managed by physician Algorithm 2: titration every 3 days; managed by patient | Various depending on prior treatment | Reported in figure only | Algorithm 1 8.9; algorithm 2 8.9 | Algorithm 1 7.9; algorithm 2 7.7 | Algorithm 1 29.8%; algorithm 2 33.3% |
GOAL A1C Kennedy 2006 [70] | Gla-100 once daily for 24 weeks n = 7893 | 70–100 mg/dL | Algorithm 1: usual titration of Gla-100 and laboratory HbA1c testing; algorithm 2: usual titration and POC HbA1c testing; algorithm 3: active titration and laboratory HbA1c testing; algorithm 4: active titration and POC HbA1c testing “Usual titration” defined as patient instruction at study visits every 6 weeks only (patient managed) “Active titration” defined as additional weekly patient contact (telephone, email, or fax) to reinforce insulin titration Based on mean fasting SMPG: insulin was increased by SMPG ≥ 100 to < 120 mg/dL ↑ 0–2 U; ≥ 120 to < 140 mg/dL ↑ 2; 140 to < 160 mg/dL ↑ 4; ≥ 160 to < 180 mg/dL ↑ 6; ≥ 180 mg/dL ↑ 8. If < 70 mg/dL ↓ previous lower dose. If severe hypoglycemia (e.g., SMPG < 36 mg/dL) occurred, upward titration was stopped for 1 week. If the HbA1c was > 8.0% after visit 1, Gla-100 dose could be increased, at the investigator’s discretion, by up to 5 additional units to meet glycemic targets at each subsequent study visit | Weekly | 10 U | Usual titration groups 50 U; active titration groups 55–56 U | Usual titration groups 8.9; active titration groups 8.8–8.9 | Usual titration groups 7.6; active titration groups 7.3 | Usual titration groups 3.7/patient year; active titration groups 6.0/patient year |
PREDICTIVE 303 Meneghini 2007 [71] | Insulin detemir for 26 weeks n = 5604 | ≤ 100 mg/dL | Algorithm 1 (patient-adjusted): Based on average of 3 fasting SMPG < 80 mg/dL, ↓ 3 U; 80–110 mg/dL, no change; > 110 mg/dL ↑ 3 U Algorithm 2 (physician adjusted): according to standard of care (variable) | Algorithm 1: every 3 days; algorithm 2: according to standard of care (variable) | On day 1: Algorithm 1 0.32 U/kg; algorithm 2 0.34 U/kg | Algorithm 1 0.68 U/kg; algorithm 2 0.53 U/kg | Algorithm 1 8.5; algorithm 2 8.5 | Algorithm 1 7.9; algorithm 2 8.0 | Algorithm 1 6.44/patient year; algorithm 2 4.95/patient year |
TITRATE Blonde 2009 [72] | Insulin detemir once daily for 2 weeks n = 244 | 70–90 or 80–110 mg/dL (3.9–5.0 or 4.4–6.1 mmol/L) | Using 3.9–5.0 mmol/L target: < 3.9 mmol/L ↓ 3 U; 3.9–5.0 mmol/L no adjustment; > 5.0 mmol/L ↑ 3 U Using 4.4–6.1 mmol/L target: < 4.4 mmol/L ↓ 3 U; 4.4–6.1 mmol/L no adjustment; > 6.1 mmol/L ↑ 3 U | Every 3 days | 0.1–0.2 U/kg or 10 U | 3.9–5.0 mmol/L treatment group 0.57 U/kg; 4.4–6.1 mmol/L group 0.51 U/kg | 3.9–5.0 mmol/L treatment group 7.99; 4.4–6.1 mmol/L group 7.94 | 3.9–5.0 mmol/L treatment group 6.77; 4.4–6.1 mmol/L group 7.00 | 3.9–5.0 mmol/L treatment group 7.73/patient year; 4.4–6.1 mmol/L group 5.27/patient year |
BEGIN: Once Philis-Tsimikas 2013 [73] | Simple use IDeg 100 U for 26 weeks n = 222 | “Simple” algorithm: 4-U dose adjustments based on a single pre-breakfast SMPG measurement; < 56 mg/dL ↓ 4 U; > 91 mg/dL ↑ 4 U). “Stepwise” algorithm: 2-U adjustments based on the lowest of 3 consecutive pre-breakfast SMPG readings (< 56 mg/dL ↓ 4 U; 56–70 mg/dL ↓ 2 U; 91–126 mg/dL ↑ 2 U; 127–144 mg/dL ↑ 4 U; 145–162 mg/dL ↑ 6 U; > 162 mg/dL ↑ 8 U | Weekly | 10 U | “Simple” 62 U (0.61 U/kg); “Stepwise” 48 U (0.50 U/kg) | “Simple” 8.1; “Stepwise” 8.2 | “Simple” 7.0; “Stepwise” 7.2 | “Simple” 1.60/patient year; “Stepwise” 1.17/patient year | |
Dailey 2014 [74] | Gla-100 once daily for 24 weeks (pooled analysis of patient-level data from RCTs) n = 1380 | ≤ 100 mg/dL, with some studies also specifying a target FPG ≥ 72 mg/dL | Algorithm 1: ↑ 1 U once daily, if FPG > target; algorithm 2: ↑ 2 U every 3 days, if FPG > target; algorithm 3: treat-to-target, weekly titration based on 2-day mean FPG levels: ≥ 180 mg/dL ↑ 8 U; 140–180 mg/dL ↑ 6 U; 120–140 mg/dL ↑ 4 U; 100–120 mg/dL ↑ 2 U Dose decreases (2–4 U/day) were allowed if severe hypoglycemia (requiring assistance) or plasma glucose < 56 mg/dL at any time in the preceding week | Once daily; once every 3 days; once weekly | 10 U | Algorithm 1 0.42 U/kg; algorithm 2 0.56 U/kg; algorithm 3 0.42 U/kg | Algorithm 1 8.61; algorithm 2 8.79; algorithm 3 8.84 | Algorithm 1 7.11; algorithm 2 7.02; algorithm 3 7.05 | Algorithm 1 4.03/year; algorithm 2 1.58/year; algorithm 3 6.5/year |
LANCELOT Home 2015 [75] | Gla-100 or NPH for 36 weeks n = 701 | 80–100 mg/dL (4.4–5.5 mmol/L) for both fasting and nocturnal levels | Titration based on both pre-breakfast FPG levels (median previous 3 measures) and last nocturnal SMPG level Nocturnal and/or fasting ≤ 4.4 mmol/L or symptomatic hypoglycemia ↓ 2 U; nocturnal > 4.4 to ≤ 5.5 mmol/L and fasting > 4.4 mmol/L no change; fasting > 4.4 to ≤ 5.5 mmol/L and nocturnal > 4.4 mmol/L no change; nocturnal and fasting > 5.5 to ≤ 7.8 mmol/L ↑ 2 U; fasting > 5.5 to ≤ 7.8 mmol/L and nocturnal > 7.8 mmol/L ↑ 2 U; nocturnal > 5.5 to ≤ 7.8 mmol/L and fasting > 7.8 mmol/L ↑ 2 U; nocturnal and fasting > 7.8 mmol/L ↑ 4 U. In the event of severe hypoglycemia or HbA1c ≤ 6.0%, no insulin dose increase was allowed for the remainder of the study | Weekly during weeks 1–4, twice weekly during weeks 5–12, weekly up to week 36 | 0.2 U/kg | Gla-100 32.4 U (0.39 U/kg); NPH 30.7 U (0.36 U/kg) | 8.2 for both | Gla-100 7.1; NPH 7.2 | Gla-100 1.74 patient year; NPH 2.21 patient year |
Yale 2016 [76]a | Gla-300 titrated using the EDITION or INSIGHT protocols n = 212 | 80–100 mg/dL | EDITION: SMPG > 100 and < 140 mg/dL ↑ 3 U; SMPG ≥ 140 mg/dL ↑ 6 U; SMPG ≥ 60 and < 80 mg/dL ↓ 3 U; SMPG < 60 mg/dL or if severe or multiple symptomatic hypoglycemia events occurred ↓ ≥ 3 U at investigator’s discretion INSIGHT: 1 U/day until in target range | EDITION: weekly INSIGHT: daily | EDITION: 70.0 U INSIGHT: 67.0 U | EDITION: 8.4 INSIGHT 8.4 | EDITION: 7.6 INSIGHT: 7.6 | EDITION: 48.1% INSIGHT: 55.6% |
Guideline | ADA [6] | AACE/ACE [5] | IDF [3] |
---|---|---|---|
Initial dose | 10 U or 0.1–0.2 U/kg/daya | HbA1c < 8%: 0.1–0.2 U/kg/day HbA1c > 8%: 0.2–0.3 U/kg/day | Not specified |
Titration | |||
Target FPG | 4.4–7.2 mmol/L (80–130 mg/dL), but individualize to patient/disease featuresb | < 6.1 mmol/L (< 110 mg/dL) | < 6.5 mmol/L (< 115 mg/dL) |
Target HbA1c | Usually < 7%, but individualize to patient/disease featuresb | < 7% for most patientsc | Generally < 7% |
Dose change | Add 10–15% or 2–4 U | Fixed regimen: 2 U Adjustable regimen: FPG > 180 mg/dL: add 20% of TDD FPG 140–180 mg/dL: add 10% of TDD FPG 110–139 mg/dL: add 1 U | Add 2 U |
Frequency | Once- to twice-weekly | Every 2–3 days | Every 3 days |
Hypoglycemia | Reduce dose by 4 U or 10–20% of TDD | Reduce TDD by: BG < 70 mg/dL: 10–20% BG < 40 mg/dL: 20–40% | Not specified |
Escalate to combination injectables | Consider when FPG is ≥ 300 mg/dL (≥ 16.7 mmol/L) or HbA1c ≥ 10% | When targets are not achieved | Not specified |