2. Key Concepts of Type 2 Diabetes Mellitus
Dallas, Texas
Vivian A. Fonseca, MD, FRCP
Professor of Medicine and Pharmacology
Tullis Tulane Alumni Chair in Diabetes
Chief, Section of Endocrinology
Tulane University School of Medicine
New Orleans, Louisiana
Jonathan D. Leffert, MD, FACP, FACE, ECNU
Managing Partner, North Texas Endocrine Center
President, American Association of Clinical Endocrinologists
Dallas, Texas

3. Decline in -Cell Function with Diabetes Progression: UKPDS
Rx: Insulin, Metformin, Sulfonylurea
-Cell Function (%)
Postprandial Hyperglycemia
IGT
Type 2 Diabetes Phase II
Type 2 Diabetes Phase III 25
100 75 50
-12
-10 -6 -2 2 6 10 14
Years from Diagnosis
Type 2 Diabetes Phase I
Dashed line shows extrapolation forward and backward from years 0 to 6 based on HOMA data from UKPDS.
Lebovitz H. Diabetes Rev. 1999;7(3):
UKPDS 16. Diabetes. 1995;44(11):

4. Basal vs Mealtime Hyperglycemia in T2DM
100
200
300
400
0600
1000
1800
1400
0200
2200
Time of day
Breakfast
Lunch
Supper
Basal hyperglycemia
Incremental hyperglycemia after meals
Blood Glucose (mg/dL)
Polonsky KS, et al. N Engl J Med. 1988;318(19):

5. ADA and AACE Glycemic Targets
Test
Glycemic Control Targets
ADA
AACE
HbA1c
<7%
≤6.5%3
FPG
mg/dL
<110 mg/dL3
PPG
<180 mg/dL
(measured within 1 to 2 hours after the start of a meal)
<140 mg/dL3
(2-hour value)
HbA1C target should be individualized based on numerous factors, including age, life expectancy, comorbid conditions, duration of diabetes, risk of hypoglycemia or adverse consequences from hypoglycemia, patient motivation, and adherence1,2
AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association; FPG, fasting plasma glucose; PPG, postprandial glucose.
1. American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S135.
2. Garber AJ, et al. Endocr Pract. 2017;23(2):
3. Handelsman Y et al. Endocr Pract. 2015;21(suppl 1):1-87.

6. When To Start Insulin in T2DM
Patients with
hyperglycemic emergencies
symptomatic hyperglycemia and/or markedly high HbA1c
hepatic or renal disease
coronary artery disease, ↑ triglyceride level
When combination oral/injectable agents become inadequate
Unacceptable side effects of oral/injectable agents
Patient wants more flexibility
Special circumstances (ie, steroid use, infection, pregnancy)
Holman RR, et al. NEJM. 2009; 361(18):
Lebovitz HE. Diabetes Rev ;7(3):

7. Approximately Half of Patients Do Not Attain Target HbA1c After Initiating Titrated Insulin Glargine
Baseline
Study end
5.5
6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
T-T-T1 n = 367
INSIGHT2 n = 206
APOLLO3 n = 174
INITIATE4 n = 58
HbA1c (%)
8.6
8.7
8.8
6.8
∆ -1.6
∆ -1.7
∆ -2.0
Observational5
n = 11,511
Typically ~50% of people attain HbA1c <7% → ~50% do not
Similar results are obtained
with insulin detemir
1. Riddle M, et al. Diabetes Care. 2003;26(11):
2. Gerstein HC, et al. Diabetes Med. 2006;23(7):
3. Bretzel RG, et al. Lancet. 2008;371(9618):
4. Yki-Järvinen H, et al. Diabetes Care. 2007;30(6):
5. Schreiber SA, et al. Diabetes Obes Metab. 2007;9(1):31-38.

8. Hypoglycemia with Glargine Is Common in 11 Treat-to-Target Studies
2251 participants with systematically titrated glargine added to 1 or 2 oral agents
≥ 1 symptomatic
event
≥ 1 event confirmed
<50 mg/dL
≥ 2 event
confirmed
≥ 1 severe event
1.5 %
52%
17% 7%
Percentage of Participants Affected
Non-severe hypoglycemia
Severe
hypoglycemia
Karl DM, et al. Diabetes Obes Metab. 2013;15(7):

9. Both Fasting and Postprandial Glucose Contribute to HbA1c
FPG
PPG
76%
78%
79%
80%
24%
22%
21%
20%
Contribution to overall hyperglycemia (%)
Baseline HbA1c category (%) 20 40 60 80
100
<8.0
8.0-<8.5
8.5-<9.0
9.0-<9.5
≥9.5
HbA1c value quintiles (%)
<7.3
>10.2
30%
70%
49%
51%
55%
45%
60%
40%
Monnier et al (2003)1
Riddle et al (2011)2
Key Concept: The relative contributions of fasting and postprandial hyperglycemia to A1C are a matter of controversy.1
Monnier and colleagues and Riddle and colleagues investigated the contributions of fasting and postprandial hyperglycemia to A1C.1,2
Monnier and colleagues analyzed the diurnal glycemic profiles of 290 patients with type 2 diabetes who did not use insulin. The relative contribution of PPG decreased progressively from the lowest to the highest A1C quintile, from about 70% to about 30%. In contrast, the relative contribution of FPG showed a gradual increase with increasing A1C levels, from about 30% to about 70%.1
Riddle and colleagues evaluated 7-point glucose profiles in 1699 patients who had an A1C >7.0% during treatment with oral glucose-lowering agents. Dissimilar to the Monnier data, the FPG contribution ranged from 76% to 80% of hyperglycemic exposure and that from PPG ranged from 24% to 20%, from the lowest to the highest A1C ranges.2
References
1. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetes patients. Diabetes Care ;26(3): Riddle M, Umpierrez G, DiGenio A, Zhou R, Rosenstock J. Contributions of basal and postprandial hyperglycemia over a wide range of A1C levels before and after treatment intensification in type 2 diabetes. Diabetes Care. 2011;34(12):
FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; PPG, postprandial plasma glucose 1N=290 Non–insulin-using patients with type 2 diabetes
2N=1699 Participants with type 2 diabetes on oral antidiabetic drugs. Mean age 59 years; mean duration of diabetes 9 years; mean FPG=194 mg/dL, mean HbA1c=8.7%. Hyperglycemia was defined as plasma glucose >100 mg/dL.
1. Monnier L, et al. Diabetes Care. 2003;26(3):
2. Riddle M, et al. Diabetes Care. 2011;34(12):

10. Postprandial Hyperglycemia Independently Predicts CVD Risk
Clinical Trial
Association of PPG with CVD
Honolulu Heart Program (1987)
1-h glucose predicts coronary heart disease
DIS (1996)
Postmeal, not FPG, is associated with CHD
Chicago Heart Study (1997)
2-h postchallenge glucose predicts all-cause mortality
Whitehall Study, Paris Prospective Study, & Helsinki Policemen Study (1998)
2-h postchallenge glucose predicts all-cause and CHD mortality
Coutinho et al (1999)
2-h glucose associated with CHD
Hoom Study (1999)
2-h glucose better predicts all-cause and CV mortality than HbA1C
DECODE (1999; 2004)
High 2-h postload blood glucose associated with increased risk of death, independent of FPG; predicts cardiovascular death
Cavalot (2006)
Postprandial, not FPG, independently predicts CV events, particularly in women, in DM
CHD, coronary heart disease; CV, cardiovascular; DM, diabetes mellitus; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin
Adapted from Home P. Curr Med Res Opin. 2005;21(7):

11. Do We Have Evidence that Targeting Postprandial Hyperglycemia Reduces CV Risk?
Clinical Trial
Description
Outcomes [HR (95% CI)]
STOP-NIDDM
Acarbose in IGT (N=1368)
MI: 0.09 ( )
Any CV event: 0.51 ( )
Acarbose meta-analysis
N=2180
MI: 0.36 ( )
Any CV event: 0.65 ( )
NAVIGATOR
Nateglinide in IGT (N=9306); 6 y
CV outcomes: 0.94 ( )
Heart2D
Lispro TID vs Glargine/NPH BID (N=1115); 2.6 y
CV event: 0.98 ( )
BID, two times daily; CV, cardiovascular; IGT, impaired glucose tolerance; MI, myocardial infarction; NPH, neutral protamine Hagedorn; TID, three times daily
1. Chiasson JL, et al. JAMA. 2003;290(4):
2. Hanefeld M. Eur Heart J. 2004;25(1):10-16.
3. Navigator Study Group. N Engl. J Med. 2010;362(16):
4. Raz I, et al. Diabetes Care. 2009;32:

12. Innovations in Basal Insulin Analogs
Vivian A. Fonseca, MD, FRCP
Professor of Medicine and Pharmacology
Tullis Tulane Alumni Chair in Diabetes
Chief, Section of Endocrinology
Tulane University School of Medicine
New Orleans, Louisiana
Jonathan D. Leffert, MD, FACP, FACE, ECNU
Managing Partner, North Texas Endocrine Center
President, American Association of Clinical Endocrinologists
Dallas, Texas

13. Basal Insulins Currently Available
NPH Insulin
Insulin Glargine
U-100
Insulin Detemir
Follow-on Insulin Glargine
U-300
Insulin Degludec
Insulin type
Human; intermediate-acting
Analog; long-acting
Onset
2-4 hours
1.3 hours
6 hours
1 hour
Peak
4-10 hours
No pronounced peak
Relatively flat
Flat
Effective duration
10-16 hours
Up to 24 hours
≤36 hours
≤42 hours
Half-life
Unknown*
14 hours
5-7 hours
~23 hours
~25 hours
Time to steady-state
Unknown
2 days
4 days
2-3 days
Porcellati F, et al. Diabetes Care. 2007;30(10): Lucidi P, et al. Diabetes Care. 2011;34(6): Niswender K. Clin Diabetes. 2009;27: Novolin N [package insert]. Indianapolis, IN: Eli Lilly & Co.; January Lantus [package insert] Bridgewater, NJ: sanofi-aventis US LLC; August Basaglar [package insert]. Indianapolis, IN: Eli Lilly & Co.; April Levemir [package insert]. Princeton, NJ: Novo Nordisk US; February Toujeo [package insert]. Bridgewater, NJ: sanofi-aventis US LLC; October Becker RH, et al. Diabetes Care. 2015;38: Tresiba [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; December Heise T, et al. Diabetes Obes Metab. 2012;14(10):

14. Follow-on Insulin Glargine U-100
Efficacy and Safety of Follow-on Glargine U-100 (Basaglar®) vs Glargine U-100 (Lantus®) in Insulin-naïve Patients with T2DM1
Endpoint
(N=455)
Insulin Glargine U-100
Follow-on Insulin Glargine U-100
HbA1c (%), change from baseline
-1.54
-1.48
Insulin dose (units/kg-day)
0.44
0.42
Weight gain (kg)
2.2
2.0
Rosenstock J, Hollander P, Bhargava A, Ilag LL, Pollom RK, Zielonka JS, Huster WJ, Prince MJ. Similar efficacy and safety of LY insulin glargine and insulin glargine in patients with type 2 diabetes who were insulin-naïve or previously treated with insulin glargine: a randomized, double-blind controlled trial (the ELEMENT 2 study). Diabetes Obes Metab Aug;17(8): doi: /dom Epub 2015 May 31. PubMed PMID:
1Mean age = 58 years; duration of diabetes = 11 years; Baseline: HbA1c = 8.4% to 8.5%, weight = kg, BMI = 32 kg/m2
2Overall (plasma glucose ≤70 mg/dL or sign or symptom of hypoglycemia) and nocturnal hypoglycemia (between bedtime and waking) are expressed as events/patient-year (EPY). Severe hypoglycemia (requiring assistance, baseline to month 6) is number of patients.
Rosenstock J, et al. Diabetes Obes Metab. 2015;17:

15. Ultralong-Acting Basal Insulins
Glargine
U-3001
Degludec2
Insulin Type
Analog
Onset
6 hours
1 hour
Peak
Flat
Half-Life
~23 hours
~ 25 hours
Time to Steady State
4 days
2-3 days
Effective Duration
≤36 hours
≤42 hours
1. Becker RH, et al. Diabetes Care. 2015;38:
2. Heise T, et al. Diabetes Obes Metab. 2012;14(10):

16. Pharmacokinetics of Insulin Glargine U-300 in Type 1 Diabetes
Becker R, Hahn A, Boderke P, Fuerst C, Mueller W, Tertsch K, Werner U, Loos P. Long-acting formulations of insulin. Sanofi-Aventis Deutschland GmbH, Frankfurt am Main. Filed 5/17/2011.
0.4 U/kg dose: [0010]
Healthy volunteers: [0565]
Becker RHA, et al. Diabetes Care. 2015;38:

17. Insulin Glargine U-300: EDITION Program
Anderson JE. J Fam Pract. 2016;65(10 Suppl):S23-S28.

18. Insulin Glargine U-300 vs U-100: Glycemic Efficacy*
Time
Time
* Meta-Analysis of EDITION 1, 2, 3; N=2496
Ritzel R, et al. Diabetes Obes Metab. 2015;17(9):

19. Insulin Glargine U-300 vs U-100: Other Outcomes*
* Meta-Analysis of EDITION 1, 2, 3; N=2496
Ritzel R, et al. Diabetes Obes Metab. 2015;17(9):

20. Insulin Glargine U-300 vs U-100: Hypoglycemia
Cumulative mean number of nocturnal severe or confirmed (≤70 mg/dL) events/participant
48% lower
with U-300
P=0.001
Glargine U-100
Difference
mostly
up to 12 wk
Patients with T2DM using basal insulin + oral agent(s) (N=811)
Glargine U-300
Yki-Jarvinen H, et al. Diabetes Care. 2014;37:

21. Insulin Degludec: BEGIN Program
Philis-Tsimikas. J Fam Pract. 2016;65(10 Suppl):S14-S22.

22. Insulin Degludec vs Insulin Glargine U-100: Glycemic Efficacy
52-week
Core Trial
52-week
Extension Phase
52-week
Core Trial
52-week
Extension Phase
N=725
Rodbard HW, et al. Diabet Med. 2013;30:

23. Insulin Degludec vs Insulin Glargine U-100: Other Outcomes
Rodbard HW, et al. Diabet Med. 2013;30:

24. Hypoglycemia with Degludec and Glargine U-300 vs Glargine U-100
Meta-analyses of phase 3 clinical studies in T2DM
Degludec1
Glargine U-3002
# Studies 5 3
# Participants
3372
2496
Definition of confirmed hypoglycemia
<56 mg/dL and severe
≤70 mg/dL or severe
Anytime events
[Rate ratio vs glargine U-100 (95% CI)]
0.83 ( )
0.86 ( )
Nocturnal events
0.68 ( )
0.69 ( )
With both insulins, ~15% fewer overall and ~30% fewer nocturnal events vs glargine U-100
1. Ratner RE, et al. Diabetes Obes Metab. 2013;15(2):
2. Ritzel R, et al. Diabetes Obes Metab. 2015;17(9):

25. Insulin Degludec vs Insulin Glargine U-100
Cumulative hypoglycemic events (confirmed <56 mg/dL)
2.0
1.6
0.4
1.2
0.8
18% lower
with degludec
P=0.11
Glargine U-100
Anytime
events/patient
Degludec 12 24 36 48
Weeks of treatment
0.40
0.32
0.80
0.60
Glargine U-100
36% lower
with degludec
P=0.04
Nocturnal
events/patient
Degludec
1023 insulin-naïve patients with T2DM
Weeks of treatment 12 24 36 48
Zinman B, et al. Diabetes Care. 2012;35:

26. Cardiovascular Safety of Insulin Glargine U-100*: ORIGIN Study
Composite of Revascularization or
Heart Failure Hospitalization
Composite of MI, Stroke, CV Death
*12,537 people with increased CV risk plus impaired fasting glucose, impaired glucose tolerance, or T2DM were randomized to insulin glargine U-100 vs standard care. Mean follow-up was 6.2 years.
ORIGIN Investigators. N Engl J Med. 2012;367():

27. Cardiovascular Safety of Insulin Degludec: DEVOTE Study
7637 people with T2DM at high CV risk were randomized to standard care plus
Insulin degludec or
Insulin glargine U-100
Target: FPG 71 to 90 mg/dL
Follow-up ~2 years
At baseline
Age (mean): 65.0 y
HbA1c (mean): 8.4%
Duration of T2DM (mean): 16.4 y
85.2% established CVD or moderate CKD
83.9% receiving insulin
54.8% basal-bolus
Marso SP, et al. N Engl J Med. 2017;doi: /NEJMoa

28. Cardiovascular Safety of Insulin Degludec: DEVOTE Study (cont)
Outcome
Hazard Ratio
95% CI
Primary composite1
0.91
Expanded composite2
0.92
All-cause death
Non-CV death
0.84
CV death
0.96
Nonfatal MI
0.85
Nonfatal stroke
0.90
UA → hospitalization
0.95
Severe hypoglycemia
0.60
Nocturnal severe hypoglycemia
0.47
Degludec non-Inferior to glargine for major CV events
1CV death, nonfatal MI, nonfatal stroke
2CV death, nonfatal MI, nonfatal stroke, unstable angina leading to hospitalization
Marso SP, et al. N Engl J Med. 2017;doi: /NEJMoa

29. Flexible Dosing with Glargine U-300
Sub-study of pooled data from EDITION 1 and 2 (N=194)
Glargine U-300 once daily for 3 months
Fixed: same time each day
Flexible: same time each day ± 3h
Change from baseline to
3 months
Flexible
Fixed
Daily basal insulin dose (units/kg)
0.03
HbA1c* (%)
0.05
0.00
FPG (mg/dL)
6.6
3.9
Confirmed or severe hypoglycemia (events/patient-year)
10.44
14.81
Confirmed or severe nocturnal hypoglycemia (events/patient-year)
2.30
1.95
*HbA1c 7.30% at baseline
64% of fixed-dose and 15% of flexible-dose participants reported all intervals within 23-25h range
Riddle MC, et al. Diabetes Technol Ther. 2016;18(4):

30. Flexible Dosing with Degludec
26-wk randomized, open-label, treat-to-target trial (N=687)
Glargine once daily at same time each day
Degludec once daily
Fixed: same time each day
Flexible: schedule to create 8-40 hour dosing intervals
Change from baseline* to 26 weeks
Degludec
Glargine
Flexible
Fixed
HbA1c (%)
-1.28
-1.07
-1.26
FPG (mg/dL)
-58
-54
-50
Confirmed or severe hypoglycemia (events/patient-year)
3.6
3.5
Confirmed or severe nocturnal hypoglycemia (events/patient-year)
0.6
0.8
*HbA1c % at baseline
Meneghini L, et al. Diabetes Care. 2013;36:

31. Escalation vs Intensification of Basal Insulin
Vivian A. Fonseca, MD, FRCP
Professor of Medicine and Pharmacology
Tullis Tulane Alumni Chair in Diabetes
Chief, Section of Endocrinology
Tulane University School of Medicine
New Orleans, Louisiana
Jonathan D. Leffert, MD, FACP, FACE, ECNU
Managing Partner, North Texas Endocrine Center
President, American Association of Clinical Endocrinologists
Dallas, Texas

32. Case Scenario: George 56 yo white male with a 7-y history of T2DM
Titrates glargine U-100 with a mean FPG mg/dL
HbA1c 7.8%
SMBG 2-3 days/week
Has occasional night sweats and restless sleep at 2-3 am
Current medications
Metformin 1000 mg bid
Pioglitazone 30 mg qAM
Glargine U units qHS
Vital signs: 5’10”; weight 216 lbs; BMI 31.0 kg/m2
What considerations do you have?

33. When to Stop Titrating Basal Insulin and Consider Prandial Control Options
The individual is not meeting glycemic targets on basal insulin1-4
and:
HbA1C still not at goal with units/kg/d of daily basal insulin3
HbA1c elevated despite normal FPG with basal insulin2,3
FPG with basal insulin is within targeted range, but PPG is persistently above goal3,4
Further increases in basal insulin result in hypoglycemia3
FXCX:
Skyler 2004:p210 under meal-related prandial insulin therapy AND p218 insulin programs AND p221 para1-2
Practical insulin 2011: p46-47 and table p48
Inzucchi 2012:p1372 end of c2 thruc3
Davidson 2011: p3 introduction
1. Skyler JS. In: Lebovitz HE, ed. Therapy for Diabetes Mellitus and Related Disorders. Alexandria, VA: American Diabetes Association, Inc.; 2004:
2. American Diabetes Association. Practical Insulin: A Handbook for Prescribing Providers. 3rd ed. 2011:1-68.
3. Inzucchi S, et al. Diabetes Care. 2012;35:
4. Davidson MB, et al. Endocr Pract. 2011;17:

34. Options for Intensifying Basal Insulin
Basal Insulin Once-daily
Increase Dose/Frequency
+ Oral Agent(s)
+ DPP-4i
+ GLP-1RA
+ SGLT-2i
+ Pioglitazone
+ Prandial Insulin

35. Therapeutic Options in Patients Not Achieving
Glycemic Goals with Basal Insulin
American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S135.

36. Aggressive Basal Dose Titration May Increase Severe Hypoglycemia Without Improving HbA1c
Mean basal insulin dose, units/day
Mean HbA1C, %
Severe hypoglycemia, rate/year
0.13
0.15
0.08
Hypoglycemia,
rate / year
Severe
0.1
0.05
0.02
0.03
0.05
78.2 80
74.9 9
69.6
62.2
59.4 60 8
Mean Insulin Dose,
units/day
7.4
7.4
7.3
Incidence of severe hypoglycemia increased with higher insulin doses, with only a small reduction in A1C
Tanenberg RJ, Zisman A, Stewart J. Glycemia optimization treatment (GOT): glycemic control and rate of severe hypoglycemia for five different dosing algorithms of insulin glargine (GLAR) in patients with type 2 diabetes Mellitus (T2DM). Diabetes. 2006;55(suppl 1):A135. Abstract 567-P.
FXCX:
Tanenberg 2006: abstract
Mean HbA1c, %
7.6 40
7.5 7 6
24-week randomized study; N = 4823
120
110
100 90 80
FPG Goal, mg/dL
Tanenberg RJ, et al. Diabetes. 2006;55(suppl 1):A135 [abstract 567-P].

37. Efficacy and Safety of Analog vs RHI Prandial Insulin Injections—Meta-Analysis
Key Findings
Greater HbA1c reduction (0.1%; P=.037)
Greater 2-h PPG reduction at breakfast and dinner (≈ mg/dL; P<.001)
Possibly less frequent severe hypoglycemia (ORMH = 0.61; P=NS)
Conclusions
Prandial analogs have slightly greater efficacy and possibly less risk of severe hypoglycemia than RHI
Comparative efficacy analyses among prandial insulin analogs are not possible with available data
Mannucci E, Monami M, Marchionni N. Short-acting insulin analogues vs. regular human insulin in type 2 diabetes: a meta-analysis. Diabetes Obes Metab Jan;11(1):53-9. doi: /j x. Epub 2008 Jul 29. Review. PubMed PMID:
13 trials, 4361 individuals: results, para 1 AND Table 1, p 57 (added number of patients manually to yield 4361).
Greater A1C reduction: conflicting information is presented in the paper. The abstract states that in comparison to RHI, analogues reduce A1C 0.4%, but the results section (p 54 col 2 para 2) says the difference is 0.1%. Since the body of the paper is more likely to have been closely copyedited than the abstract, the data from the results section is cited.
PPG reduction: p 55 col 2 para 1
severe hypo: p 55 col 2 para 2
inconsistent definitions of nonsevere hypo: p 56 col 2 para 2
slightly greater efficacy, less severe hypo: interpretation of results
insufficient data: p 56 col 2 last para, continued on p 58 col 2 para 1.
NOTE: ORMH is the Mantel-Haentzl odds ratio (odds ratio corrected for covariates)
FXCX:
Mannucci 2009: abstract
Trials: p54 c2 para2 and fig1
N: table 1 p57
A1C: p54 c2 para2
PPG: p55 c2 para1
Hypo: p55 c2 para2 AND p56 c2 para2
Conclusions: p55 c2 para3-5 AND p56 c2 last para AND p58 c2 para1
Meta-analysis of 13 trials of 4361 individuals with T2DM.
Mannucci E, et al. Diabetes Obes Metab. 2009;11:53-59.

38. Added Effect of a Single Mealtime Insulin Dose
‘Basal-plus’ proof-of-concept study
SMPG profiles before and 3 mos after addition of glulisine
at the patient-identified dominant meal after optimized basal insulin
(Mean HbA1c change vs placebo: -0.26%)
Dominant
breakfast
(n=10; 20%)
Dominant
lunch
(n=14; 29%)
Dominant
dinner
(n=25; 51%)
Mean rapid insulin 12.2 units
Mean rapid insulin 10.9 units
Mean rapid insulin units
Owens DR, et al. Diabetes Obes Metab. 2011;13:

39. Basal-Plus Mealtime Insulin
Use rapid-acting analogs (Aspart, Lispro, Glulisine), not RHI
Easier timing, less postprandial hypoglycemia
Start with 1 injection at largest meal:
4 units and titrate, OR
By weight: 0.1 unit/kg
Titrate to:
< 140 mg/dL 2 hours postprandial OR
< 110 mg/dL next meal or bedtime
Garber AJ, et al. Endocr Pract. 2016;22:

40. Basal-Plus Mealtime Insulin (cont)
Consider decreasing dose or stopping oral secretagogues
Can continue metformin, TZD, AGI, GLP-1RA, DPP-4i
Basal-bolus dosing
~50% basal insulin and ~50% bolus insulin
Garber AJ, et al. Endocr Pract. 2016;22:

41. Quality of Life Improves in T2DM With Intensification of Insulin Therapy
Multicenter study of 447 patients with insulin-treated T2DM and HbA1c >7%
Patients were transitioned from baseline insulin regimens to basal-bolus using glargine + rapid-acting insulin
HbA1c declined from 8.8% to 7.7% over 6 months (P <.001)
Nonsevere hypoglycemic episodes decreased
Small but significant improvements with no significant change in hypoglycemia fear
Emotional well-being (P<.001)
Diabetes symptom distress (P<.001)
Hypoglycemia fear (P=.61)
Hajos TR, Pouwer F, de Grooth R, Holleman F, Twisk JW, Diamant M, Snoek FJ. The longitudinal association between glycaemic control and health-related quality of life following insulin therapy optimisation in type 2 diabetes patients. A prospective observational study in secondary care. Qual Life Res Oct;21(8): doi: /s Epub 2011 Nov 8. PubMed PMID: ; PubMed Central PMCID: PMC
No permission needed (brief text quotation)
FXCX:
Hajos 2012: bullet 1: abstract and p1360 c2 para4
Bullet2: p1360 c2 para3 AND p1362 c1 para1
Bullet3: abstract and p1362 c1 para2 and c2 to p1363 c1 para1
Bullet4: p1364 c1 para P value <0.001 )para2 and table 1
(MT: bullet 4: emotional well-being: p 1363, col 1, para 4 (P < .001); diabetes symptom distress: p 1363, col 1, para 2 (P < .001); hypo fear: p 1363, col 1 para 3 (P = .610).)
Hajos TR, et al. Qual Life Res. 2012;21:

42. INNOVATIONS IN PRANDIAL INSULINS
Vivian A. Fonseca, MD, FRCP
Professor of Medicine and Pharmacology
Tullis Tulane Alumni Chair in Diabetes
Chief, Section of Endocrinology
Tulane University School of Medicine
New Orleans, Louisiana
Jonathan D. Leffert, MD, FACP, FACE, ECNU
Managing Partner, North Texas Endocrine Center
President, American Association of Clinical Endocrinologists
Dallas, Texas

43. Current and Emerging Prandial Insulins
Human insulins (short-acting)
Regular human insulin (RHI)
U-100 RHI
U-500 RHI
Analogs (rapid-acting)
Lispro
U-100 lispro
U-200 lispro
Follow-on lisproa
Ultra-rapid lisproa
Aspart
Faster-acting asparta
Glulisine
Analogs (ultra-rapid-acting)
Technosphere inhaled insulin
FXCX:
Drugs at FDA: all confirmed by pi
Drugs at FDA:
Afrezza: indications
Apidra: glulisine: indications
Basaglar: glargine: no label yet  MT: tentative approval highlighting shown in figure
Humalog: lispro 50/50 and 75/25 and kwikpen: indications
Humulin R, 70/30 and pen: indications
Lantus: glargine: indications
Levemir: det: indications
Novolin R: indications
Novolog: aspart 70/30, penfill: indications
Toujeo: glar: indications
a Not currently approved by the US FDA.
US Food and Drug Administration.

44. Inhaled Technosphere Insulin in T2DM
Inhaled TI (48 units)
SC RHI (24 units)
5.0
3.0
1.0
Glucose Infusion Rate,
mg/kg/min 60
120
180
Time, min
4.0
2.0
0.0
240
300
360
420
480
540
Rave K, Heise T, Heinemann L, Boss AH. Inhaled Technosphere insulin in comparison to subcutaneous regular human insulin: time action profile and variability in subjects with type 2 diabetes. J Diabetes Sci Technol Mar;2(2): PubMed PMID: ; PubMed Central PMCID: PMC
Rosenstock J, Franco D, Korpachev V, Shumel B, Ma Y, Baughman R, Amin N, McGill JB; Affinity 2 Study Group. Inhaled Technosphere Insulin Versus Inhaled Technosphere Placebo in Insulin-Naïve Subjects With Type 2 Diabetes Inadequately Controlled on Oral Antidiabetes Agents. Diabetes Care Aug 7. pii: dc [Epub ahead of print] PubMed PMID:
Reference above replaces: Rosenstock J, Bergenstal R, Defronzo RA, Hirsch IB, Klonoff D, Boss AH, Kramer D, Petrucci R, Yu W, Levy B; 0008 Study Group. Efficacy and safety of Technosphere inhaled insulin compared with Technosphere powder placebo in insulin-naive type 2 diabetes suboptimally controlled with oral agents. Diabetes Care Nov;31(11): doi: /dc Epub 2008 Aug 4. PubMed PMID: ; PubMed Central PMCID: PMC
PD curves: Rave 2008, fig 1B
FXCX:
Rave 2008: abstract AND fig1 b p208 AND p208 c2 para2 and p209 c1 para2
Rosenstock 2008: abstract AND fig 2B p2180
Duration of action for inhaled insulin is much shorter than for RHI1
Almost complete PPG suppression has been observed in a double-blind, placebo-controlled trial in insulin-naive patients with T2DM using OADs2
1. Rave K, et al. J Diabetes Sci Technol. 2008;2:
2. Rosenstock J, et al. Diabetes Care. 2015; 38(12):

45. Inhaled Human Insulin Limitations of use
Adults
In T1DM, use with basal insulin
Not for diabetic ketoacidosis, persons who smoke
Contraindicated in chronic lung disease
Assess lung function prior to and during treatment
Hypokalemia- monitor at-risk persons
Fluid retention/Heart failure with concomitant TZD
Most common adverse events
Hypoglycemia, cough, throat pain/irritation
Afrezza [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; January 2016

46. Serum Free Insulin Concentration, mU/L
U-200 Lispro*
Pharmacokinetics
Pharmacodynamics
240
360
480
300
420
Time, min
120
180 60 80 70 50 30 10 20 40
Serum Free Insulin Concentration, mU/L
LISPRO 0.2 U/kg (n = 10)
RHI (n = 10);
mean dose, 15.4 U
240
360
480
300
420
Time, min
120
180 60
250
200
150
100
Blood Glucose, mg/dL 50
LISPRO 0.2 U/kg (n = 10)
RHI (n = 10);
mean dose, 15.4 U
U-200 lispro was FDA-approved in May 2015
It is only available in a prefilled pen
Development notes:
 PI
FXCX:
Lilly link on slide: link good: pi for Humalog: recent major changes sect 2.1, 2.2
Sect 12.2 fig1 AND sect 12.3 fig 3
Top link: May 2015 approval, first concentrated approval, high dose: para1 and para2
Potentially offers the advantage of a smaller injection volume for patients with high prandial insulin requirements
*PK/PD data generated from a study of 10 patients with T1DM.
Humalog [package insert]. Indianapolis, IN: Eli Lilly and Company; January 2017.

47. Insulin Lispro U-200 Same dose as U-100, but half the volume
Hypokalemia- monitor at-risk persons
Fluid retention/Heart failure with concomitant TZD
Most common adverse events
Hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash
Humalog [package insert]. Indianapolis, IN: Eli Lilly and Company; January 2017.

48. Regular Human Insulin U-500
Limitations of use
Use in adults/children requiring >200 units insulin/day
Safety/efficacy in combination with other insulins has not been determined
If using vial/syringe, use only U-500 syringe
Hypokalemia- monitor at-risk persons
Fluid retention/Heart failure with concomitant TZD
Most common adverse events
Hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash
Humulin R U-500 [package insert]. Indianapolis, IN: Eli Lilly and Company; March 2017.

49. PUTTING IT ALL TOGETHER
Vivian A. Fonseca, MD, FRCP
Professor of Medicine and Pharmacology
Tullis Tulane Alumni Chair in Diabetes
Chief, Section of Endocrinology
Tulane University School of Medicine
New Orleans, Louisiana
Jonathan D. Leffert, MD, FACP, FACE, ECNU
Managing Partner, North Texas Endocrine Center
President, American Association of Clinical Endocrinologists
Dallas, Texas

50. Case Scenario: Maria 62-yo Hispanic female with a 10-y history of T2DM
Started glargine U months ago as an add-on to orals
Titrated glargine; FPG mg/dL; HbA1c 7.5%
Works in a busy call center; has a very light breakfast, snack at lunch
Admits to being hungry at night; eats largest meal of the day

51. Case Scenario: Maria (cont)
Current medications
Metformin 1000 mg bid
Glimepiride 4 mg qAM
Glargine U units qHS
Vital signs: height 5’2”; weight 156 lbs; BMI 28.5 kg/m2
What are the options for achieving her HbA1c goal?

52. Case Scenario: Steven
42-yo African-American male with a 3-y history of T2DM
Initially did well on oral agents
Initiated basal insulin due to a relatively rapid rise in blood glucose and worsening glycemic control
Travels frequently for work; demanding and unpredictable work schedule
Has been fatigued and frustrated managing his diabetes
HbA1c 9.1%

53. Case Scenario: Steven (cont)
Current medications
Metformin 1000 mg bid
Glimepiride 2 mg bid
Linagliptin 5 mg qAM
Degludec 40 units qHS
Vital signs: 6’0”; weight 184 lbs; BMI 25.0 kg/m2
What is your clinical impression?