Should we be using the new
insulins in T2DM?
Ian Gallen MD FRCP
Community Diabetologist
Royal Berkshire Hospital
Purpose of Insulin Therapy
• Prevent and treat fasting and postprandial
hyperglycemia
• Permit appropriate utilization of glucose and other
nutrients by peripheral tissues
• Suppress hepatic glucose production
• Prevent acute complications of uncontrolled diabetes
• Prevent long term complications of chronic diabetes
Questions which need to be asked
• Which insulin regime is most likely to achieve
good control in T2DM
• Does analogue basal insulin offer advantages
over NPH?
• Does biphasic Analogue insulin offer
advantages over biphasic human insulin?
• What is the rational way forward?
Reasons for poor diabetic control
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Delay in commencing insulin treatment
Insufficient dose titration
Failure to control fasting blood sugar
Inappropriate insulin mix
False concerns about maximum insulin dose
• None of these are improved with analogues
Why do patients delay insulin treatment?
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Concern about injections
Stigma of insulin injections
Concern about employment
False previous family experience
Strong negative cultural beliefs
Worry over hypoglycaemia
New insulins might help
Fears for weight gain
Why do patients delay insulin?
Helping Patient Accept Insulin Therapy
• Address patient concerns
– Dispel fear by countering misconceptions
– Review rationale for insulin use
– Explain that insulin
– Can be incorporated into lifestyle
– Causes only modest weight gain
– Is a common course of treatment for this progressive disease
• Promise patient support and close follow-up
– Monitoring can prevent hypoglycemia
– Today’s technology can facilitate daily injections and readings
Choice of insulin treatments
• Once daily NPH/Analogue Basal with oral agents
– T2DM and some T1 patients dependant on others for
care
• Twice daily
– Either Combination did/tid Biphasic insulin (Human or
Analogue) T1 or T2 or bd (NPH/Analogue T2DM)
• Basal Bolus
– T1 or T2DM (Human-NPH/Analogue Bolus-Basal)
• Insulin pump treatment
– T1DM only
Which insulin regime in T2DM?
The 4 T study
Berkshire West Insulin Optimisation Framework
for Type 2 Diabetes
Recommend initiation on human
basal insulin
Review @
Consider alternatives if ;
60u BD
Patient able to
self titrate & have
carb awareness
Basal Bolus
•District Nurse to Administer
•Steroid Patients
Review @
•Nursing Home Patients
60u BD
•Erratic Eating Patterns
In these cases contact DSN team
for advice
Review @
60u BD
Review @
30 units
50/50
Review @
60u BD
TDS Mix
BD Mix
50/50
BD Human or
Analogue Mix
BD
Human Basal
Once Daily
Human Basal
Low
DSN Referral Recommended
Skills and Capabilities
High
Hypoglycaemia is frequent in T1DM
Hypoglycaemia is infrequent in T2DM
• Total of 3.5 episodes/patient/year
• Nocturnal hypoglycaemia 1.9 episodes/patient/year).
• An inverse relationship is seen between all confirmed
hypoglycaemia and HbA(1c) at endpoint;
– for every 1% reduction in HbA(1c), the increase is 1.4
episodes/patient/year.
• Patients with confirmed hypoglycaemia had lower HbA(1c)
than patients without hypoglycaemia (7.39 vs. 7.64%,
respectively).
Diabetes Metab Res Rev. 2009 Mar;25(3):224-31.
Possible Limitations of Human Insulin S
• Slower onset of action
– Requires inconvenient administration: 20 to 40 minutes
prior to meal
– Risk of hypoglycemia if meal is further delayed
– Mismatch with postprandial hyperglycemic peak
• Long duration of activity
– Up to 12 hours’ duration
– Increased at higher dosages
– Potential for late postprandial hypoglycemia
6-26
Plasma Insulin (pmol/L)
400
Lispro
350
300
250
200
150
100
50
0
Regular
Human
0
30
Meal
SC injection
60
120 150 180 210 240
Time (min)
Plasma Insulin (pmol/L)
Rapid-acting Insulin Analogues: Lispro and Aspart
500
450
400
350
300
250
200
150
100
50
0
Aspart
Regular
Human
0
50
100
150 200
Time (min)
250
300
Meal
SC injection
Heinemann, et al. Diabet Med. 1996;13:625-629; Mudaliar, et al. Diabetes Care.
1999;22:1501-1506.
6-28
What are the problems with basal insulin
treatment?
• Insufficient length of action requiring twice daily
dosage
• Large intra-dose variability leading to increased
hypoglycaemia or loss of daytime control
• Excess basal insulin treatment, leading to weight
gain
• High dose volumes in insulin resistant and obese
patients
Rapid-acting Analogues: Clinical Features
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Insulin profile more closely mimics normal physiology
• Convenient administration immediately prior to meals
• Faster onset of action
• Limit postprandial hyperglycemic peaks
• Shorter duration of activity
– Reduced late postprandial hypoglycemia
– But more frequent late postprandial hyperglycemia
• Need for basal insulin replacement revealed
6-27
Insulin levels following injection in T1DM
Lepore. Diabetes, 49:2142–8.
Characteristics of basal insulins
Insulin name
Duration
Intradose variability
Cost (5x3ml)
(cost/day 40u)
NPH
8 to 16 hours
+++
£19.80 (£0.53)
Detemir
8 to 16 hours
++
£44 (£1.70)
Glargine
16 to 20 hours
++
£41 (£1.01)
Toujeo
20 to 30 hours
+
£41 (£1.01)
Degludec
30+
+
£72 (£1.92)
Glargine and Hypoglycaemia in T2DM
Glargine causes less hypoglycaemia in insulin
naive T2DM
DIABETES CARE, VOLUME 26, NUMBER 11, NOVEMBER 2003
Reduced hypoglycaemia with NM30 in T2 DM
Rates of major (left) and minor (right)
hypoglycaemia were lower at the final visit
compared with the baseline visit in the main
cohort. ***p < 0.0001 vs. baseline
Int J Clin Pract. 2009 Apr; 63(4): 574–582.
Meta-analysis of episodes of hypoglycemia with insulin
glargine versus NPH insulin. Rosenstock et al 2005.
Type of documented
symptomatic hypoglycemia
Insulin glargine (%
of patients)
NPH insulin (% of
patients)
p
Insulin glargine
significant % risk
reduction
Overall
54.2
61.2
0.0006
11
Nocturnal
28.4
38.2
<0.0001
26
Non-nocturnal
49.6
51.7
0.2553
–
Severe
1.4
2.6
0.0422
46
Severe nocturnal
0.7
1.7
0.0231
59
Severe non-nocturnal
0.8
0.9
0.7296
–
Abbreviations: NPH, neutral protamine Hagedorn.
Reduced hypoglycaemia when compared with
Glargine
Fewer episodes of hypoglycaemia
Small reduction in severe hypoglycaemia
Slightly reduced weight gain than with Glargine
What about insulin degludec?
NNT Study B = 50 patients to avoid 1
event at the cost of £16000
Diabetes Research and Clinical Practice DOI:
(10.1016/j.diabres.2015.04.002)
1.Clinical Diabetes October 2013vol. 31 no. 4 166-170
Where is the appropriate place of
analogue basal insulin therapy?
• Use in T1DM (NICE Guidelines 2015)
• Patients who are demonstrated have
problems with basal insulin treatment
• Patients with nocturnal hypoglycaemia
• ?? Patients with excess weight gain
• Patients requiring third party administration
of insulin treatment
Where is the appropriate place of rapid acting analogue
insulin therapy?
• Use in T1DM (NICE Guidelines 2015)
• That’s about it!
Where is the appropriate place of biphasic
analogue insulin therapy?
• There isn’t one!
What are the real unmet needs in insulin
therapy
• Early recognition of failure of oral therapy
• Strong positive recommendation of benefits of
insulin treatment to patients
• Reassurance concerning potential negative
consequences in therapy
• Intense support to optimise insulin dosage
• Regular expert clinic review to identify
problems with insulin therapy
What you need to do in practice
tomorrow
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Do a search for all your patients with HbA1C is >85 mmol per mole
– Refer those patients to X-pert and
– For those on tablets, move them either to basal insulin and tablets, premixed
insulin, or basal insulin and GLP1 combination therapy if they are obese
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For those refusing insulin treatment, reassure on the safety of insulin treatment,
demonstrate injection, and explain that poor diabetic control is not an option
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For those already on insulin treatment, ask the diabetes specialist nurses to come
work with you to titrate insulin doses.
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For those patients who are gaining weight, consider adjunctive therapy with
SGLT/GLP1
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For those with body mass index greater than 35 and less than 65 years old suggest
refer to bariatric service
Analogue insulin is expensive, so only use in clinically justified situations
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