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The Year in Diabetes- 2016

Elizabeth Stephens, MD

Endocrinology- Medical Education Faculty

PMG- Northeast

April 2016Elizabeth.Stephens@providence.org

Disclosures

• None

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Goals for Discussion

• Review 2016 Guidelines from American Diabetes Association and discuss:– Role for SGLT-2’s

– New considerations for GLP-1’s

– Alternative insulin formulations

• New isn’t always better– When to use regular and NPH insulin

Key to Medications

• DPP4 inhibitors:– Sitagliptin (Januvia®), Saxagliptin (Onglyza®), Linagliptin

(Tradjenta®), Alogliptin (Nesina®)

• GLP1 agonists:– Exenatide: BID (Byetta®) , weekly (Bydureon®)

– Liraglutide: daily (Victoza®)

– Albiglutide: weekly (Tanzeum®)

– Dulaglutide: weekly (Trulicity® )

• SGLT2 inhibitors:– Canagliflozin (Invokana®), Dapagliflozin (Farxiga®),

Empagliflozin (Jardiance®)

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Let’s start with a case…

• 54 yo man, diagnosed with type 2 DM 9 years ago

• Initially managed with metformin, then added glimepiride

• A1c now 8.8%, weight 280#, BMI 40• Taking all meds, has a number of questions:

– Is the glimepiride “bad” for him?– Does he need insulin?– On a fixed income- can’t afford “fancy”, but curious

about medicines he has seen on TV– Doesn’t want to gain weight

Diab Care 2016;39(supp 1):S52

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Issues with Sulfonylureas: Cons

• Beta cell burnout:– ADOPT: lost glucose control at 45months with

metformin vs 33 months with glyburide

– No difference in UKPDS

– Over 6 yrs, 34% with SU needed insulin, c/w 27% with DPP4

• Weight gain: 2-5kg on average

• Hypoglycemia: – 6x more hypoglycemia c/w other DM meds

Kahn S, NEJM 2006;355:427; UKPDS 1995;11:1249; Inzucchi S, Diab Obes Metab 2015; Cefalu W, Diab Care 2015

Issues with Sulfonylureas: Pros

• Effective: A1c lowers A1c 1-2% – More effect with higher baseline A1c

• Cost: inexpensive

• Easy: Oral, not injected

• History: Lots of experience

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Let’s start with a case…

• 54 yo man, diagnosed with type 2 DM 9 years ago

• Initially managed with metformin, then added glimepiride

• A1c now 9.8%, weight 280#, BMI 40• Taking all meds, has a number of questions:

– Is the glimepiride “bad” for him?– Does he need insulin?– On a fixed income- can’t afford “fancy”, but curious

about medicines he has seen on TV– Doesn’t want to gain weight

Incretin MOA

http://ars.sciencedirect.com

↓Appe te

↓Gastric Emptying

↑Insulin Secre on↓ Glucagon Secre on↑ Β‐cell proliferation↓ Β‐cell apoptosis

↓Glucose Produc on

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GLP-1 Medications

• GLP-1 Agonists– Injectable QD,BID, weekly– A1c ~ 1-2%– $250-300/month– Side-effects - nausea,

vomiting which generally improve– Pancreatitis, thyroid

cancer – Weight loss, 5-10#, varies– Approved for use with

glargine (more later)

• DPP4 Inhibitors – Oral, once daily– A1c ~ .8-1%– Need adjustments for

renal insufficiency– Except linagliptin

– $200-300/month (generic in 2017)

– Well-tolerated– Pancreatitis, joint

pain – Weight neutral

SGLT-2 Inhibitor Overview

• Good:– Once daily, oral

– Lowers A1c .5-1% c/w placebo

– Low risk hypoglycemia

– Effect independent of insulin

– ↓ body weight by 1-4kg

– ↓ SBP by 4mmHg

• Bad:– Increased risk of

urinary/genital infections (OR 1.42 and 5.06)

– Euglycemic ketoacidosis reported

• Rare, but concerning

– Cost: $300-400/month

– Bladder/breast cancer risk

– Risk of bone loss

– Lack of long-term data

Vasilakou D et al, Annals IM 2013;159:262; Medical Letter 5/13/2013

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WeightHypo-glycemia

↓ A1c Cost Routine Considerations

Insulin ↑ 4-6 lb 30-40%Unlimited

%$$

1-5x/day Hypoglycemia

DPP4s ↔ 3-4% 0.5-1% $$1x/day

Well tolerated

GLP1s ↓ 3-6 lb 0-1% 0.5-1%$$ 1-2x/day or

1x/weekGI upset

SGLT2s ↓ 3-4 lb 3-4% 0.5-1% $$1x/day very new, side

effects

Compare and Contrast

Case continues…

• Decides to try liraglutide (Victoza®), as it is covered by insurance

• 2 months later returns, no weight change and doesn’t feel it is helpful

• Ready to start insulin, but wants to know about the “one with the T” he has seen advertised on TV

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Key

• Analog: Modified human insulin to act faster or slower

• Short-acting:– Lispro:Humalog ®

– Aspart: Novolog®

– Glulisine: Apidra®

– Inhaled insulin: Afrezza®

– Regular - Novolin ®, Humulin ®, Relion®

• Longer-acting :– NPH: Novolin ®,

Humulin ®, Relion®

– Glargine: Lantus ®• U300: Toujeo®

– Detemir: Levemir®

– Degludec: Tresiba®• U100 and U200

Options for insulinBasal- Insulin Onset Peak Duration

NPH 1-2 hrs 4-8 hrs 14-18 hrs

Detemir 1-4 hrs 4-6 hrs 12-20 hrs

Glargine 1-6 hrs Flat 22-24 hrs/24-36 hrs (U300)

Degludec 1-9 hrs 10-12 hrs 42 hours

Bolus- Insulin Onset Peak Duration

Regular 30-60 min 2-4 hrs 4-8 hrsAspart, lispro, glulisine

5-15 min 1-2 hrs 3-5 hrs

Inhaled insulin

~ 15 min ~ 50 min 3 hours

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Degludec- Tresiba®

• Ultra-long basal insulin, low intra-individual variability in absorption/effect– A1c benefit comparable to glargine, lower risk of

hypoglycemia in some trials

• Transition 1:1 from TDD of basal– Added together (if taken BID) as one injection

• Available as U100 and U200– U200 pens can deliver up to 160units

– Stable for 56 days, ↓ insulin requirement

Tambascia MA et al, Diab Metab Syn 2015;7:57

ToujeoConcentrated Insulin Glargine

• Contains 300u/ml, c/w 100u/ml – Longer duration of effect at up to 36 hours

• Studies in type 1 + 2:– Similar A1c lowering, ↓ nocturnal hypoglycemia

(in type 2); meta-analysis showed ↓ overall hypoglycemia; one trial wt gain .08kg (T) vs .66 kg (L)

– Required ↑ dose by 10-15% c/w regular glargine

• Injected once daily, same time– Total of long-acting insulin

Med Letter, 2015

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Costs

Goodrx.com, 2/2016 (many coupons available to reduce costs); Medical Letter 2015

Medication Price/month

U300 Glargine-Toujeo (3 pens)

$342

Degludec-Tresiba (3 pens) $538

Humalog U200 (2 pens) $ 70 (with coupon)

Glargine (Lantus) vials/pens $ 250/430

Novolin NPH (vial) $ 125 (at Walmart, $30)

Afrezza (inhaled insulin- 90 cartridges)

$233

Adding Basal Insulin- ADA/EASD Algorithm

• Start 10U/day, or .1-.2units/kg/day– Bedtime or AM, depending on pattern/adherence

– Usually with metformin +/- other agent

• Adjust 10-15% or 2-4U once/twice weekly to reach FPG target– Generally fasting goals of 80-130mg/dl

• Maybe higher in certain populations

• For hypoglycemia: determine cause– ↓ dose by 4U or 10-20%

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Back to Case

AM Noon Dinner Hs

134 213 168 224

125 151 184 245

161 143 232 212

152 175 215 286

143 121 186 312

- Started on glargine 15units hs, titrated up to 45units- A1c dropped to 8.2%- Largest meal tends to be dinner, but not always- Since starting insulin has gained 8#

When to add bolus?

• Basal should be 50% of total daily dose (TDD)– Estimate based on TDD

1-2u/kg/day

– Generally consider if using> 60-70unts per day basal, or considering splitting glargine

– A1c above goal

– Start with largest meal

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Alternatives to consider

• When you need to add to basal insulin:– GLP-1 or SGLT2 medications

• Effective to control BG + weight loss + ↓ hypoglycemia

• Consider as alternative to meal insulin– Comparison of basal+ bolus TID or albiglutide showed

comparable A1c lowering, wt loss with GLP1 and more hypoglycemia with bolus insulin (Rosenstock et al, Diab Care 2014)

– TZD also an option• ↑ fluid retention, weight gain when used with insulin

Case continued

• Gets started on pre-dinner lispro (humalog®), and occasionally pre-lunch if eating out

• Taking 10-12units with those meals, BG has improved

• Went to the pharmacy to pick up prescriptions and price has gone up dramatically

• Are there any less costly options for insulin?

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Don’t Overlook NPH and Regular

• Among privately insured adults + DM2– 19% using analogs in 2000, c/w 96% in 2010

– From 2001 → 2015, lispro vials increased from $35 → $234, human insulin $20 → $131

• LOTS of marketing with insulin analogs– Emphasizing more physiologic, less

hypoglycemia

• No difference in A1c, no data on outcomes or complications

Tylee T, Hirsch I, JAMA 2015

Trials that Compare Basal Initiation

• Treat to Target- NPH vs glargine 1

– Equivalent A1c achieved with less nocturnal hypoglycemia in those using glargine

• Comparison of NPH and detemir 2

– Equivalent A1c achieved with less hypoglycemia (47%) and slightly less wt gain with detemir

• Degludec vs Glargine 3

– No difference in A1c, less nocturnal hypoglycemia with degludec

1-Riddle MC, Diab Care 2003;26:3080; 2- Hermansen K, Diab Care 2006;29:1269;3- Garber et al, Lancet 2012;379:1498

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Algorithms are Aggressive

Riddle MC et al, Diab Care 2003;26:3030

• Treat to Target trial:– Initial dose: 10units at bedtime (glargine or

NPH)

– Titrated weekly, based on mean fasting BG from prior 2 days:

180 + 8 units

140-180 + 6 units

120-140 + 4 units

100-120 + 2 units

< 56-72 - 2-4 units

Switching to NPH and Regular

• With BID Glargine/levemir, can transition 1:1 to NPH– NPH best given at bedtime c/w dinner

– Remember midday peak (so may need less meal insulin with lunch)

• Once daily glargine to NPH– NPH needs to be BID

– Many options (depending on patterns):• 2/3 in the AM, 1/3 in the PM

• ½ in the AM, ½ in the PM

– Monitoring is key!

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Mealtime insulin

• When switching to Regular insulin (Novolin ®, Humulin ®, Relion®) from analog (Lispro:Humalog®, Aspart: Novolog®, Glulisine: Apidra®)

• Same dose as analog insulin, given with meals

• Given 30 minutes before eating ??– Study of 100pts given regular at time of eating vs 20 min

prior

» No difference in A1c and much higher satisfaction when taken with meal (Muller N, Diabetes Care 2013;36:1865)

• Consider referral to teach how to mix insulin (reduce injection frequency)

Conclusions

• DM is complicated

• Newer isn’t necessarily better– But lots of direct-to-consumer marketing,

so good to have some familiarity

• Cost an ongoing challenge

• More people have diabetes but:– Management is improving

– Fewer complications

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THE END