1. Updates in Diabetes Managment
Tiffany Soper NP CDE
MGH Diabetes Center

2. Conflicts of Interest
No relevant conflict of interest to disclose.

3. Objectives
Review goals and individualization of type 2 diabetes treatment
Learn about updates in treatment options for type 2 diabetes

4. Treatment goals for type 2 Diabetes
Avoid acute complications of diabetes
Prevent micro- and macrovascular complications
Minimize hypoglycemia
Minimize weight gain
Improve/maintain quality of life

5. 2012 ADA/EASD Position Statement
Individualize treatment targets
Diet, exercise, education = foundation
Metformin = 1st line drug
Combination therapy with 1-2 oral or injectable agents is reasonable
Ultimately, many patients will require insulin therapy
Focus on comprehensive CV risk reduction
Adapted from slide from E. Cagliero MD

6. Modulation of the intensiveness of glucose lowering in type 2 diabetes
Depiction of the elements of decision-making used to determine appropriate efforts to achieve glycaemic targets. Greater concerns about a particular domain are represented by increasing height of the ramp. Thus, characteristics/predicaments towards the left justify more stringent efforts to lower HbA1c, whereas those towards the right are compatible with less stringent efforts. Where possible, such decisions should be made in conjunction with the patient, reflecting his or her preferences, needs and values. This ‘scale’ is not designed to be applied rigidly but to be used as a broad construct to help guide clinical decisions. Adapted with permission from Ismail-Beigi et al [ref 20]
Inzucchi S E et al. Dia Care 2015;38:
Copyright © 2014 American Diabetes Association, Inc. 6

7. Individualized A1c Targets
<6.5-7%
If this can be achieved with diet, exercise, metformin, minimal poly-pharmacy and few adverse effects
7-7.9%
For older or complicated patients who have adverse effects or require poly-pharmacy
8-9%
End-of-life, dementia
Avoid >9%:
Associated with catabolism, increased infection, metabolic disarray

8. Type 2 Diabetes Therapies
Adapted from a slide by N. Wei MD

9. Case 1
74 year old male with 10 year history of type 2 diabetes mellitus complicated by worsening renal function with most recent EGFR 38. Patient has had acceptable control with A1c from % since treatment with metformin 1000 mg BID.

10. Type 2 Diabetes is a Progressive Disease Secondary Failure of Metformin Monotherapy
Diabetes Care 2010; 33:

11. Case 1: Treatment considerations
Renal function fluctuating from eGFR 30s-45
Is it okay to continue Metformin?
Diabetes Care 2011 Jun; 34(6):
Diabetes Care 2011 Jun; 34(6):

12. Insulin Secretagogues
Sulfonlyureas – Glipizide, Glyburide, glimepiride
Meglitinides – Repaglinide (Prandin)
Tablet, generic
HbA1c decrease of 1-2%
Associated with weight gain and hypoglycemia

13. Insulin Secretagogues
Drug
Dose range
Time to peak
Duration
excretion
Repaglinide
0.25-4mg 1
4-5
Liver metabolism;
80% Bile
Glyburide mg ~4 10
50% bile
50% urine
Micronized glyburide mg
2-3 4
glimeperide
1-8 mg 9
60% urine
Glipizide mg
1-3
2-4
Urine excretion
Glipizide XL
5-20 mg
Steady

14. DPP4’s role on incretins
GLP-1
70-80% of the incretin effect in non-diabetics
Half-life ~ 4-11 minutes, inactivated by DPP-4
GLP-1 actions
Stimulates insulin secretion when glucose is elevated
Inhibits gastric emptying, appetite, glucagon secretion
Has proliferative and anti-apoptotic effects on b-cells
Slide adapted from D. Wexler MD
To understand DPP4 inhibitors, first we need to understand the role of incretins in glycemic control. Incretins are hormones made by the GI system that have an impact on glycemic control.
DPP = dipeptidyl peptidase
Produced in enteroendocrine L cells in ileum and colon

15. DPP4 inhibitors Usual dose Renal dose adjustment Hepatic monitoring
Change in HbA1c*
Sitagliptin
100 mg daily
Yes No
-0.7
Saxagliptin
5 mg daily
Vildagliptin**
50 mg twice a day
-0.6
Linaglptin
-0.5
Alogliptin
25 mg daily
*in combination with metformin vs. metformin + placebo
**not available in US

16. Case 2
49 year old female with 4 year duration of suboptimally controlled type 2 DM complicated by depression and obesity BMI 38. She has been maintained on metformin 1000 mg twice a day. Most recent A1c has crept up to 7.6%. Patient is frustrated with progressive weight gain since menopause.

17. Role of GLP-1 analogs Jump start weight loss Injection (pen), Tier 2-3
On average loss of kg
HbA1c improvement of %
Injection (pen), Tier 2-3
Side effects – nausea, vomiting
Black box warning: thyroid c-cell tumors for exenatide LAR and liraglutide (seen in rats)
Slide adapted by D. Wexler

18. GLP-1 Receptor Agonists
Exenatide (Byetta®)
Twice/day sc. Injections
Start with 5 mcg bid within 60 minutes of a meal and after 1 month increase the dose to 10 mcg bid if eGFR > 30 ml/min
Liraglutide (Victoza®)
Once day sc injection, “use with caution in renal impairment”
Start with 0.6 mg qd for 1 week, then increase to 1.2 mg qd; may go to 1.8 mg qd
Exenatide ER (Bydureon®)
Once per week injection 2 mg, do not use if eGFR < 30 ml/min
Albiglutide (Tanzeum®)
Once per week injection, 30 mg, can increase to 50 mg if eGFR> 15 ml/min
Dulaglutide (Trulicity®)
Once per week, start 0.75 mg, can increase to 1.5 mg. No renal dose adjustment needed
Lixisenatide (Adlyxin®)
10 mcg daily, can increase to 20 mcg daily. No dose adjustments for patient with moderate renal impairment (eGFR >30 ml/min)

19. Other GLP-1 analogs Semaglutide (weekly)
CVD Benefit in SUSTAIN-6 (NEJM 2016)
Awaiting FDA approval
Dulaglutide / Trulicity (weekly)
Albiglutide / Tanzeum (weekly)
Exenatide LAR / Bydureon (weekly)
Lixisenatide / Lyxumia (daily)
Combo with glargine: Soliqua 100/33
30 units insulin/10 mcg lixisenatide
Start at ½ dose insulin
Adapted from D. Wexler

20. Adverse Events and Incretin-based Therapy
2008 – FDA warned of a strong temporal association between exenatide and pancreatitis (30 reported pancreatitis AE)
2009 – prescribing info for sitagliptin changed (88 reported pancreatitis AE)
2014 meta-analysis of 55 RCT and 5 observational studies of incretin treatment – no association of incretin treatment and pancreatitis
All patients should be counseled to stop therapy if they develop persistent severe abdominal pain
FDA and EMA – insufficient evidence to confirm an increased risk for pancreatic cancer or pancreatitis
N Engl J Med 2014;370:

21. Bariatric surgery 20-30% sustained weight loss after 1-2 years
Schauer, P. R., et al. "Bariatric Surgery versus Intensive Medical Therapy for Diabetes — 3-Year Outcomes." NEJM May 2014

22. Sodium-Glucose Co-Transporter 2 SGLT2 inhibitors
“Glucoretic”
Inhibits glucose reabsorption in proximal tubule of the kidney, inducing glucosuria
Effects
HbA1c change: ~ %
Weight change: ~2.5 kg
US Approved agents
Canaglifozin
Dapagliflozin
Empagliflozin
Slide adapted from D. Wexler

23. SGLT2 inhibitors Canagliflozin (Invokana®) Dapagliflozin (Farxiga®)
100 mg qd, if eGFR> 60 mg/min can increase to 300 mg qd
Dapagliflozin (Farxiga®)
5 or 10 mg qd, do not use if eGFR< 60 mg/min
Empagliflozin (Jardiance®)
10 to 25 mg qd, do initiate if GFR is below 45

24. We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina.
Median duration of treatment 2.6, median observational time 3.1 years
7020 randomized, placebo, 10 mg, 25 mg.

25. acarbose
α-glucosidase inhibitor – delays digestion of complex carbs and disaccharides, thus decreased glucose absorption
Generic, Tier 1
HbA1c decrease %
BID-TID dosing
Flatulence and GI distress
Popular in Asia

26. Updates on Insulin
Generics
Concentrated insulins

27. Basaglar
Bioequivalent to glargine
Can be considered interchangeable

28. Case 3
45 year old male with longstanding poorly controlled type 2 diabetes complicated by obesity with BMI 42 and retinopathy. Patient currently is using glargine 75 units twice a day and humalog units before meals. He reports that he is experiencing pain when injecting the glargine doses.

29. Insulin absorption
Rate of insulin absorption is inversely proportional to dose volume
At high doses, volume injected can be large
Slower
Faster
Adapted from D. Wexler

30. Glargine - dose-dependent peak and duration of action
10 men and 10 women with T2DM and obesity (BMI 36 kg/m2, HbA1c 8.3%)
Studied with 24 hour euglycemic clamp
Vast majority of T2D on <1.5 units/kg ( )
Doses
2.0 units/kg
1.5 units/kg
1.0 units/kg
0.5 units/kg
Placebo
Figure 2—Effects of single injections of insulin glargine (0.0.5, 1.0, 1.5, and 2.0 units/kg) on
endogenous glucose production, glucose rate of disappearance, and glucose infusion rates in
overnight fasted type 2 diabetic individuals. Rates of endogenous glucose production are significantly
suppressed by a greater amount (P 0.05) after 1.0, 1.5, and 2.0 units/kg compared with
that for placebo. Rates of glucose disposal are similar after placebo and all doses of glargine.
Glucose infusion rates are significantly increased (P 0.05) after all doses of glargine compared
with that for placebo. Incremental AUC values for 1.0, 1.5, and 2.0 units/kg doses were also
significantly increased compared with that for 0.5 units/kg dose.
Lower doses do not last 24 hours
Wang Z. Diabetes Care 2010; 33:1555
Adapted from D. Wexler

31. Lispro kinetics are also dose-dependent
Subjects: 6 healthy (age 23, BMI 22 kg/m2) and
7 with obesity and T2DM (age 60, BMI 38 kg/m2, studied with euglycemic clamp
Lispro injection
Δ 50 units, obese T2DM
□ 30 units, obese T2DM
• 10 units, healthy subject
○ 10 units, obese T2DM
Conclusion: lispro absorption and glucose lowering action are delayed with higher doses and in obesity/T2DM
….but worth noting: these higher doses are unusual, even in obese patients
Gagnon-Auger, Diabetes Care 2010; 33:

32. Concentrated insulins
Nomenclature and general principles
U-100 = 100 units in 1 ml
NPH, R, lispro, aspart, glulisine ,glargine, detemir, degludec U-100
U-200 = 200 units in 1 ml
Lispro U-200 (Humalog), degludec (Tresiba) U-200
U-300 = 300 units in 1 ml
Glargine U-300 (Toujeo)
U-500 = 500 units in 1 ml
R U500
Same potency may be delivered in smaller volume, leading to improved absorption
Slide adapted from D. Wexler

33. U-500 R: the original concentrated insulin
At high doses - U-500 compared to U-100
Onset time similar (~30 min)
Blunted peak
Longer duration of action
U-500
Peak 4-6 hours
Duration of action hours
BID or TID dosing depending on dose
Similar to NPH (blue line)
de la Pena, Diabetes Care. 2011
Adapted from D. Wexler

34. Dosing U-500 R Error-prone Expensive Dosed in a U-100 syringe
Ideally, instructions should be written in volume and equivalent U-100 units
0.15 ml on U-100 syringe, equivalent to 75 units
Stable up to 28 days in pre- filled syringes
New U-500 pen
Expensive
But costs less per unit than high-dose U-100
May be more effective due to improved absorption
Use in pumps?
Slide adapted from D. Wexler

35. New concentrated insulin formulations approved in 2015
All are dosed in pre-filled pens in which one unit dispenses a proportionately smaller volume
May be safer
All are more concentrated than U-100…
…. but less concentrated than U-500
New concentrated insulins
Glargine U-300 (Toujeo)
Degludec U-200 (Tresiba)
Lispro U-200 (Humalog U-200 Kwikpen)
Studied in open-label randomized controlled trials designed and conducted by pharmaceutical sponsors
Slide adapted by D. Wexler

36. Toujeo (glargine U-300) 1.5 ml prefilled Solostar pen (450 units)
Maximum dose = 80 units
Flatter peak
Half-life hours
Duration >30 hours
Less hypoglycemia
Steinstraesser, A et al. Diabetes Obes Metab. 2014; 16:873-6

37. Tresiba (Degludec U-100 AND U-200)
3 ml prefilled Flextouch pen
U-200: Max dose 160 units
U-100: Max dose 80 units
BEGIN clinical trial program
Peak 6-10 hrs
Half-life 24 hours
Duration ~42 hours

38. Humalog (Lispro) U-200 3 mL prefilled Pen Max dose 60 units
Bioequivalent to lispro U-100
May be useful for people on high doses of prandial insulin
Not available in vials (cannot use in pumps)

39. New Combinations of basal insulin plus GLP-1 agonist
Xultophy Dosing:
Recommended starting dose is 16 units of degludec (and 0.58 mg of liraglutide)
Maximum daily dosage 50 units of degludec and 1.8 mg liraglutide

40. GoodRx.com searches 11/8/2016 Insulin Cost Total Units Cost per unit
Humulin R U-500, 20 mL vial
$1655
10,000
$0.17
Humulin R U-500, 2 x 3 mL pen
$684
3,000
$0.23
Toujeo (glargine U-300), 3 x 1.5 mL pen
$403
1,350
$0.29
Lantus (glargine U-100), 5 x 3 mL pen
$447
1,500
$0.30
Lantus (glargine U-100), 10 mL vial
$298
1,000
Tresiba (Degludec) U-200, 3 x 3 mL pen
$639
1,800
$0.36
Tresiba (Degludec) U-100, 5 x 3 mL pen
$535
Humulin N Kwikpen, 5 x 3 mL pen
$444
Humulin N, 10 mL vial
$144
$0.14
Humulin R U-100, 10 mL vial
Novolin N, ReliOn (Walmart), 10 mL vial
$145, $26
$0.15, $0.03
Novolin R, ReliOn (Walmart), 10 mL vial
Humalog U-200, 5 x 3 mL pen
$1335
$0.45
200 units a day = $60/day of glargine
200 units a day = $6/day of Relion
GoodRx.com searches 11/8/2016

41. Medtronic Minimed 670 insulin pump

42. Thank you