Table 1.
Titration Algorithms Used in Key Clinical Trialsa
| First author | Study/number of patients | Intervention/OAD continued (yes/no) | Starting dose (U/day) + FBG or FPG target (mg/dl) | Titration algorithm | Titration frequency | Titration managed by | HbA1c (%) start | HbA1c (%) end | Hypoglycemic events: all or <70 | Hypoglycemic events: severe |
|---|---|---|---|---|---|---|---|---|---|---|
| Riddle12 | 24-week treat-to-target trial n = 756 | Insulin glargine or NPH once daily at bedtime Yes (91% two, rest one) | 10 U/day FPG ≤ 100 | If mean FPG (mg/dl) over previous three days 100–120 → 0–2 U↑ 120–140 → 4 U↑ 140–180 → 6 U↑ ≥180 → 8 U↑ and no plasma glucose <56 mg/dl | Weekly | Clinic + central enforcement | Insulin glargine 8.6 NPH 8.6 | Insulin glargine 7.0 NPH 7.0 | Insulin glargine 9.2/patient year NPH 12.9/patient year | 2.5% patients NPH 1.8% patients |
| Fritsche41 | 4001 Study, 28 weeks n = 695 | Glimepiride + morning or bedtime insulin glargine or bedtime NPH | According to formula: [FPG (mg/dl) – 50]/10 FBG ≤ 100 mg/dl | If FBG > 100, 120, 140, or 160 mg/dl for at least one of two consecutive days before the visit with no hypoglycemia → 2, 4, 6, or 8 U↑ | Every visit (1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 weeks after randomization | Physician | Insulin glargine 9.1 NPH 9.1 | Insulin glargine 8.1 NPH 8.3 | Insulin glargine 43% patients NPH 58% patients | Insulin glargine 0.04/patient year NPH 0.12/patient year |
| Davies13 | AT.LANTUS n = 4961 | Insulin glargine (± OADs/prandial insulin) | 10 U/day for insulin-naïve patients for algorithm 1; numerically equivalent to the highest FBG over the previous seven days for algorithm 2 FBG ≤ 100 mg/dl | Clinic-managed titration (algorithm 1): as in Riddle12 study Patient-managed titration (algorithm 2): mean FBG for the previous three consecutive days: 100–120 mg/dl → 0–2 U↑ (at investigator discretion), 120–139 mg/dl → 2 U↑, 140–179 mg/dl → 4 U↑, ≥180 mg7dl → 6–8 U↑ (at investigator discretion) Only if no plasma glucose <72 mg/dl | Weekly (clinic) versus every three days (patient) | Physician (algorithm 1) versus patient (+ investigator review; algorithm 2) | Physician 8.9 Patient 8.9 | Physician 7.9 Patient 7.7 | Physician 26% patients Patient 30% patients | Physician 0.9% patients Patient 1.1% patients |
| Raskin50 | 28-week study n = 233 | Insulin glargine versus biphasic insulin aspart 70/30; yes | 10 U/day if FPG < 180 mg/dl, 12 U/d if FPG ≥ 180 mg/dl FPG 80–110 mg/dl | Titration as in Riddle19 study | Weekly for the first 12 weeks, then every 2 weeks | Investigator | Insulin glargine 9.8 Biphasic insulin aspart 9.7 | Insulin glargine 7.4 Biphasic insulin aspart 6.9 | Insulin glargine 16% patients (minor hypoglycemia) Biphasic insulin aspart 43% patients (minor hypoglycemia) | Insulin glargine 1 patient Biphasic insulin aspart 0 patient |
| Gerstein42 | 24-week INSIGHT study n = 405 | Insulin glargine + OAD versus insulin avoidance | 10 U/day FPG ≤ 100 mg/dl | After the start with 10 U/day, increase by 1 U/day until FPG target is reached | Patient (for insulin glargine) | 8.6 | 7.0 | 49% patients | ||
| Hermansen43 | 24-week study n = 476 | Insulin detemir or NPH; yes | 10 U/day FPG ≤ 108 mg/dl | Responders (nonresponders): FPG (mg/dl) >180 → 10 (10) U↑, 163–180 → 6 (8) U↑, 145–162 → 4 (6) U↑, 127–144 → 2 (4) U↑, 109–126 → 2 (2) U↑; if one prebreakfast plasma glucose: 56–72 → 2↑, <56 → 4↑ | Weekly (first 12 weeks), then every 2 weeks | Clinic or telephone contacts | 8.5 | 6.6 | 16.0/patient year | 0.08/patient year |
| Kennedy46 | 24-week GOAL A1C study n = 7893 | Insulin glargine usual versus active titration; yes (except for thiazolidinediones) | 10 U/day FBG ≤ 100 mg/dl | Usual titration = patient instruction at study visits (every 6 weeks) + no contacts between visits; active titration = weekly contacts (telephone, email, fax) + titration reinforcement; if FBG (mg/dl) 100–119 → 0–2 U↑, 120–139 → 2 U↑, 140–159 → 4 U↑, 160–179 → 6 U↑, ≥180 → 8 U↑; if <70 → dose↑ to previous level; if severe hypoglycemia (self-monitoring of blood glucose < 36) → stop of upward titration for 1 week; if HbA1c >8.0% after visit 1, increase of insulin glargine at investigator’s discretion of up to 5 U | weekly | Patient versus Central oversight in a predominantly primary care setting | Patient 8.9 Central 8.9 | Patient 7.6 Central 7.3 | Patient 3.7/patient year Central 6.0/patient year | Patient 0.09/patient year Central 0.14/patient year |
| Yki-Järvinen53 | 36-week LANMET Trial n = 110 | Bedtime insulin glargine versus NPH; yes | 10 U/day for all patients using only metformin; 20 U/day if on metformin + sulfonylurea + stop of sulfonylurea FPG 72–100 mg/dl | Patient-managed titration: 2 U↑ if FPG >100 mg/dl on three consecutive days and 4 U↑ if > 180 mg/dl; stop titration if ≥1 hypoglycemic event | Every 3 days | Patient (+ clinic assistance) | Insulin glargine 9.1 NPH 9.3 | Insulin glargine 7.1 NPH 7.2 | Insulin glargine 5.0/patient year NPH 7.7/patient year | Insulin glargine 0.00/patient year NPH 0.00/patient year |
| Holman1144 | One-year 4-T study n = 708 Three-year 4-T | Basal versus biphasic versus prandial insulin | According to formula; median dose in basal group: 16 U FPG and premeal plasma glucose 72–99 mg/dl, 2 h postprandial 90–126 mg/dl | Titration suggested by the trial management system based on three self-monitoring of blood glucose profiles (morning and evening for basal group) before the visits at weeks 2, 6, 12, 24, 38, and 52 | At visits and between visits, if necessary | Investigator + online trial management system (investigator and patient were encouraged to vary or amend suggested doses, if necessary) | Basal 8.4 Biphasic 8.6 Prandial 8.6 | Basal 7.6 Biphasic 7.3 Prandial 7.2 | Basal 73.9% patients Biphasic 91.9% patients Prandial 96.2% patients | Basal 1.7% patients Biphasic 4.7% patients Prandial 6.7% patients |
| Meneghini48 | 26-week PREDICTIVE 303 TRIAL n = 5604 | Insulin detemir as add-on to OAD or as replacement of prestudy insulin | Mean dose on day 1 was 0.32 U/kg for patient-driven titration and 0.34 U/kg for physician-driven standard-of-care titration FPG 80–110 mg/dl | Patient-managed titration: every three days, mean-adjusted FPG (mg/dl) <80→ 3U↓, 80–110 → no change, > 110 → 3U↑ Physician-managed titration: according to standard of care | Every three days (patients); according to standard-of-care (physician) | Patient versus physician | Patient 8.5 Physician 8.5 | Patient 7.9 Physician 8.0 | Patient 6.44/patient year Physician 4.95/patient year | Patient 0.26/patient year Physician 0.20/patient year |
| Yki-Järvinen54 | 24-week INITIATE study n = 121 | Insulin glargine; yes | 10 U/day FPG 72–100 mg/dl | If FPG (mg/dl) for three consecutive days: >99 → 2–4 U↑, 72–100 → no change, <72 and symptomatic hypoglycemia → 2 U↓ | Patient (+ individual versus group education) | Patient + individual education 8.7 Patient + group education 8.8 | Patient + individual education 6.9 Patient + group education 6.8 | Patient + individual education 3.5/patient year Patient + group education 3.1/patient year | Patient + individual education 0.0/patient year Patient + group education 0.0/patient year | |
| Bergenstal39 | 24-week study n = 273 | Insulin glargine + insulin glulisine; Yes (metformin) | 50% of prerandomization total daily insulin dose FBG < 95 mg/dl | Titration for both insulin glargine and insulin glulisine, based on mean of last three-day self-monitoring of blood glucose; insulin glargine titration: if >180→8 U↑, 140–180→6 U↑, 120–139→4 U↑, 95–119→2 U↑, 70–94→no change, <70→decrease by the same number of units as insulin glulisine increase that titration week or up to 10% of total insulin glargine dose | Weekly | Patient (simple algorithm versus carbohydrate counting) | Patient + simple algorithm 8.1 Patient + carbohydrate count 8.3 | Patient + simple algorithm 6.7 Patient + carbohydrate count 6.5 | Patients + simple algorithm 0.89/patient year Patients + carbohydrate count 0.67/patient year | |
| Rosenstock51 | 52-week study n = 582 | Insulin detemir and insulin glargine + OAD | 12 U/day FPG ≤ 108 mg/dl | Titration based on the average of 3 FPG (mg/dl); responders (nonresponders): if >180→12 (12) U↑, 164–180→8 (10) U↑, 146–162→6 (8) U↑, 128–144→4 (6) U↑, 110–126→2 (2) U↑, if one self-monitoring of blood glucose 56–72→2 U↓, <56→4 U↓ | Weekly | Investigator + titration monitoring committee | Insulin detemir 8.6 Insulin glargine 8.6 | Insulin detemir 7.2 Insulin glargine 7.1 | Insulin detemir 5.8/patient year Insulin glargine 6.2/patient year | Insulin detemir 0.0/patient year Insulin glargine 0.0/patient year |
| Kawamori45 | 24-week trial n = 100 (Japanese) | Insulin glargine + glimepiride | 6 U/day, if FPG ≥ 140 mg/dl; (less, if lower FPG) FPG 72–100 mg/dl | Titration according to mean self-monitoring of blood glucose of the previous two days; if FPG (mg/dl): ≥110→2 U↑, 101–109→1–2 U↑, 72–100→no change, 60–71→1 U↓, <60→2 U↓ | Every 3 days | Investigator | 9.3 | 7.8 | 60% patients | 0 |
| Blonde40 | 20-week TITRATE Trial n = 244 | Insulin detemir3 once daily, insulin-naïve patients on OAD; yes (dose reduction or stop of OAD allowed) | 0.1–0.2 U/kg or 10 U/day (1) FPG 70–90 mg/dl (2) FPG 80–110 mg/dl | Two FPG (mmol/liter) titration targets: (1) 3.9–5.0, (2) 4.4–6.1. titration as in PREDICTIVE48 | Every 3 days | Patient | FPG lower target group 7.99 FPG higher target group 7.94 | FPG lower target group 6.77 FPG higher target group 7.00 | FPG lower target group 7.53/patient year FPG higher target group 5.27/patient year | FPG lower target group 0.02/patient year FPG higher target group 0.00/patient year |
| Liebl47 | 26-week PREFER study n = 719 | Insulin detemir + insulin aspart or biphasic insulin aspart 30; no | 10 U/day or same dose, if on insulin before FPG 72–126 mg/dl | Insulin detemir titration; if FPG (mg/dl) >200 →10 U↑, 181–200→8 U↑, 163–180→6 U↑, 141–160→4 U↑, 127–140→2 U↑, 57–72→2 U↓, <56→4 U↓ | Weekly for the first 6 weeks | Investigator | Insulin detemir + insulin aspart 8.52 Biphasic 8.40 | Insulin detemir + insulin aspart 6.96 Biphasic 7.17 | Insulin detemir + insulin aspart 31% Biphasic 28% patients | Insulin detemir + insulin aspart 0.9% patients Biphasic 0.0% patients |
| Arnolds37 | Four-week proof-of concept study | Insulin glargine + metformin versus insulin glargine + metformin + exenatide versus insulin glargine + metformin + sitagliptin | 10 U/day, if new to insulin FBG ≤ 100 mg/dl | Titration based on daily self-monitoring of blood glucose; 20% insulin glargine dose reduction in sitagliptin and exenatide groups two days prior to this medication; titration similar to Riddle12 | Weekly visits + twice weekly telephone contacts with dose titration | Investigator | Insulin glargine + metformin 7.9 Insulin glargine + metformin + exenatide 8.4 Insulin glargine + metformin + sitagliptin 7.9 | Insulin glargine + metformin 6.7 Insulin glargine + metformin + exenatide 6.5 Insulin glargine + metformin + sitagliptin 6.4 | Insulin glargine + metformin 1.62/patient year Insulin glargine + metformin + exenatide 1.68/patient year Insulin glargine + metformin + sitagliptin 2.45 (blood glucose < 50mg/dl) | No severe hypoglycemia in all three groups |
| Owens49 | Six-month study n = 106 | Insulin glargine alone versus insulin glargine + one dose of insulin glulisine | Transfer from previous insulin to insulin glargine FBG ≤ 100 mg/dl | Insulin glargine titration as in Riddle12 study; two titration algorithms for insulin glulisine | Weekly | Investigator | Insulin glargine 8.6 Insulin glargine + glulisine 8.5 | Insulin glargine 7.8 Insulin glargine + glulisine 7.5 | Insulin glargine 11.5/patient year Insulin glargine + glulisine 13.4/patient year | Insulin glargine 0.2/patient year Insulin glargine + glulisine 0.0/patient year |
| Aschner38 | 24-week study EASIE n = 480 | Insulin glargine + metformin versus sitagliptin + metformin | 0.2 U per kg body weight FPG 72–99 mg/dl | If FPG > 100–139 2U↑, if FPG > 139 4U↑, if FPG < 72 2U↓ | Weekly | Patient | Glargine 8.5 Sitagliptin 8.5 | Insulin glargine −1.72 Sitagliptin −1.13 | Insulin glargine 4.21/patient year Sitagliptin 0.50/patient year | Insulin glargine 0.03/patient year Sitagliptin 0.01/patient year |
| ATLAS Study Group52 | Six-month ATLAS study, only rationale published n = 554 | Insulin naïve, on two OADs | 10 U/d (less for India and Japan) FPG 110 mg/dl | If middle value of the last three consecutive FBG (mg/dl), ≤56→dose decrease, ≤70 or symptomatic hypoglycemia→2 U↓, 71–110→ no change, 111–160→2 U↑, >160→4 U↑ | Every three days (patient-led group); every visit (physician-led group) | Patient versus physician | ||||
| Zinman55 | 16-week study n = 245 | Insulin-naïve, on metformin; IDegb three times/week versus once/day versus insulin glargine once/day | IDeg three times/week: 20 U (1 U = 9 nmol); IDeg once/day: 10 U (1 U = 6 nmol), group A; IDeg once/day: 10 U (1 U = 9 nmol), group B; insulin glargine: 10 U (1 U = 6 nmol) FPG 4.0–6.0 mmol/liter (72–108 mg/dl) | Lowest value of the last three consecutive self-monitored FBG; <56→4 U↓ (10% reduction for a dose > 45 U); 56–71→2 U↓ (5% reduction for a dose > 45 U); 109–144→2 U↑; 145–162→4 U↑; >162→6 U↑ | Once/week | Individual titration by clinic or telephone contact | IDeg three times/week 8.8 IDeg once/day, group A 8.6 IDeg once/day, group B 8.8 Insulin glargine 8.7 | IDeg three times/week 7.3 IDeg once/day, group A 7.4 IDeg once/day, group B 7.5 Insulin glargine 7.2 | IDeg three times/week 2.3/patient year IDeg once/day, group A 0.6/patient year IDeg once/day, group B 0.9/patient year Insulin glargine 1.1/patient year | IDeg three times/week 0.1/patient year IDeg once/day, group A 0.0/patient year IDeg once/day, group B 0.0/patient year Insulin glargine 0.0/patient year |
a
FPG, fasting plasma glucose.
b
Insulin degludec.