GLP-Agonists in T1 DM: Does it make sense to use NON-insulin diabetes meds in patients with type 1 diabetes?
The idea is that adding a non-insulin diabetes medications to insulin in type 1 patients (T1DM) may reduce insulin doses and possibly limit weight gain.
And there are downsides
Victoza and Symlin seem to increase hypoglycemia risk when added to insulin. Invokana and other "flozins" are linked to ketoacidosis...especially in patients with T1DM.
Additionally there's the added med burden and cost which is about $400/month for flozins, $700/month for Victoza, or $900/month for Symlin.
There's not much evidence about type 1s using other non-insulin meds...gliptins (Januvia, etc), glitazones (Actos, etc), acarbose, etc.
2 RECENT STUDIES USING GLP-1 AGONISTS IN TYPE 1 DIABETES
GLP-Agonists in T1 DM – Two studies have now been published, ADJUNCT-ONE and ADJUNCT–TWO.
Both trials enrolled adults with type 1 diabetes for 52 weeks and 26 weeks respectively, were on insulin therapy, had baseline A1C levels above 7%, and a BMI of at least 20.
Patients in both trials were randomized to daily liraglutide 1.8 mg, 1.2 mg, 0.6 mg, or placebo, all added to insulin therapy.
Endpoints were A1C reduction, weight loss and reduction in insulin dose. The primary endpoint was lowering of A1C.
1. Very modest benefits (vs placebo)
2. Expensive (~ $700.00 per month) injectable meds, more injections
3. Increase in hypoglycemia and hyperglycemia with ketosis (GLP agonist +insulin vs insulin alone)
4. Limited study population (no studies in children, newly diagnosed pts or non overweight adults)
5. No outcomes information in terms of micro/macro vascular complications in T1DM on insulin with GLP-1 agonist
In general, recommend sticking with insulin alone in patients with T1DM. Help optimize regimens...and reinforce diet and exercise.
Reference: The Pharmacist Letter
Source: Courtesy of Soledad Granillo RPh, BCACP, CDE
Exenatide (Byetta and Bydureon)
Liraglutide (Victoza and Saxenda)
· Type 2 Diabetes (not first line treatment)
· Weight management [labeled only for Liraglutide (Saxenda)]
· GLP-1 receptor agonists reduce A1C by approximately 1% (0.47 to 1.56%) and can have an added benefit of weight loss of 1.5 to 2.5 kg over 30 weeks when used for diabetes.
· Weight loss at one year is about 10 lbs more than placebo with Saxenda 3 mg/day, but if after 16 weeks a patient has not lost at least 4% of baseline body weight, it should be discontinued.
Mechanism of Action:
· Increase insulin release in the presence of elevated glucose concentrations
· Decrease glucagon secretion in a glucose-dependent manner
· Delay gastric emptying, thereby reducing the rate at which postprandial glucose appears in circulation
· Regulate appetite and calorie intake, including via receptors that are present in the brain. The weight reduction effect is due to decreased calorie intake
Precautions: Should not be used in patients with a history of pancreatitis
Adverse effects: Predominantly gastrointestinal - nausea/vomiting/diarrhea.
Boxed Warning – Risk of Thyroid Tumors: Dulaglutide, exenatide, liraglutide have caused thyroid C-cell tumors in rats and mice at clinically relevant exposures. Carcinogencity of albiglutide could not be assessed in rodents. It is unknown whether this risk translates to humans. GLP-1 receptor agonists are contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2. Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for detection of MTC in patients treated with GLP-1 receptor agonists.
Lexicomp Online, Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc.; August 25, 2016
Micromedex. Ann Arbor, MI: Truven Health Analytics; August 25, 2016
Pharmacist's Letter; February 2015; Vol: 31
UpToDate, Waltham, MA, Accessed on August 25, 2016
Source: Courtesy of Ocie Wilson, PharmD
Background: There has been an increased prevalence of diabetes in pregnancy in the U.S. which parallels the rise in obesity. Many risks are associated with uncontrolled diabetes in pregnancy including: spontaneous abortion, fetal anomalies, preeclampsia, macrosomia, intrauterine fetal death, neonatal hypoglycemia, and neonatal hyperbilirubinemia, among others.
Initial Recommendations: The American Diabetes Association (ADA) recommends that ALL women of childbearing age with diabetes should be counseled about the importance of glycemic control and diabetes management prior to conception in order to improve both maternal and fetal outcomes.
1. Pregestational diabetes:
a. Glycemic control should be as close to normal as possible, ideally A1C <6.5%
b. Discuss family planning and effective contraception until woman is prepared and ready to become pregnant
c. Counsel women on the risk of development of diabetic retinopathy and/or its progression, check eyes before pregnancy or in first trimester then every trimester and for 1 year post-partum
2. Diabetes management during pregnancy:
a. Review medication list for potentially teratogenic drugs (ACE inhibitors, ARBs, and statins)
i. AVOID these medications in patients actively trying to conceive and during pregnancy
b. Lifestyle modifications are key to improving control
i. Preferred medication of choice during pregnancy is insulin "All insulins are pregnancy category B except for glargine, glulisine, and degludec, which are labeled category C"
c. Fasting, pre-prandial, and post-prandial self-monitoring are recommended in order to achieve glycemic control
d. Glycemic targets:
i. Fasting ≤90 mg/dL
ii. 1hr post prandial ≤130-140 mg/dL
iii. 2hr post prandial ≤ 120 mg/dL
e. Blood pressure targets
i. Systolic blood pressure: 110-129 mmHg
ii. Diastolic blood pressure: 65-79mmHg
iii. Safe medications: methyldopa, labetalol, diltiazem, clonidine, and prazosin
"Diabetes Care: 39 (Supplement 1)". Diabetes Care 39.Supplement 1 (2016): n. pag.
Source: Courtesy of Karem Elizondo, PharmD.
I’m sure there are also MANY other things we could list, but here are a few:
1. Working towards an electronic pancreas
2. Can lead to death if used incorrectly
3. Can be incredibly useful in HIGHLY MOTIVATED patients
4. Requires a patient to check BG 5-7 times a day (for safety reasons)
5. Can allow tighter control and increased flexibility for patients on intensive insulin therapy using a syringe and vial
6. Very expensive! Even with insurance most patients will pay in excess of $2000/year in co-pays since you have the insulin, tubing, cannulas, back up syringes in event pump malfunctions, testing supplies AND a yearly deductible for DME
7. Traditionally initiated by endocrinology and managed by them, or co-managed with primary care
8. Only rapid acting insulin is used in the pump
9. Delivers insulin in a basal-bolus fashion based on settings and established insulin:carb ratio
10. Can have several different basal rates set for various time periods throughout the day
11. Bolus doses can be set to deliver in a mode that is better aligned with the meal (i.e high carb with little fat may deliver “x” units all at once. In comparison, a high fat meal may deliver “x” units now and then “y” units over the next “z” hours to try and achieve better control. This second delivery mode is often called dual wave bolus)
12. Patients can disconnect from the pump if there is a malfunction with the pump, for bathing, swimming, high contact sports, sexual activity, etc. but are encouraged to reconnect to the pump, or use insulin via syringe or vial if time is to exceed 1 hour.
If you would like to become more familiar with insulin pump therapy and terms often used in regard to pump therapy, please search on line. There are several pumps commercially available. Below is the link to one company, as an example.
Source: Courtesy of Marisa Rowen, PharmD, CDE
SGLT2i (Sodium-Glucose Co-transporter 2 inhibitors) is a class of medications used for the management of type 2 diabetes (T2DM). There are 3 drugs from this class available in the market; canagliflozin (Invokana), empagliflozin (Jardiance), and dapagliflozin (Farxiga). SGLT2i works by preventing the glucose reabsorption in the kidneys causing glucosuria and lower the threshold for glucose excretion.
A cardiovascular safety study of empagliflozin was published recently in the New England Journal of Medicine (EMPA-REG) in September 2015. EMPA-REG is a multicenter (590 sites in 42 countries), randomized, double-blind, placebo-controlled trial. It was conducted to determine the cardiovascular (CV) safety of empagliflozin over a period of 3 years. The objective was to evaluate the effect of empagliflozin as an add-on to standard care on CV mortality and morbidity in patient with T2DM at high risk for CV events. 7020 participants were randomized on a 1:1:1 ratio to receive placebo or empagliflozin 10mg daily or empagliflozin 25mg daily. The primary outcome was a composite outcome of CV mortality, nonfatal MI, or nonfatal stroke and the secondary outcome was primary outcome plus hospitalization for unstable angina.
· The result show that the primary outcome (10.5% vs 12.1%) and the secondary outcome (12.8% vs. 13.3%) occurred less frequently in the pooled empagliflozin group compared with placebo. However, individual empagliflozin dosage (10mg and 25mg) did not reach statistical significance in primary and secondary outcomes compared to placebo.
· There was fewer deaths from CV events (Relative Risk Reduction 38) or any cause (Relative Risk Reduction 32) in the empagliflozin group (both pooled and individual group) compared to placebo.
· Authors concluded that the use of empagliflozin in patients with T2DM at high risk for cardiovascular events lower rates of composite cardiovascular outcome and mortality.
· No study found similar cardiovascular benefits with any other medications in SGLT2i class (might be drug specific, not class general).
· The study was funded by Boehringer Ingelheim and Eli Lilly, manufacturers of empagliflozin (Jardiance) and empagliflozin/metformin (Synjardy).
Current place in therapy (SGLT2i):
· FDA approved as an adjunct to diet and exercise for patients with type 2 diabetes.
· Per ADA guideline: SGLT2i can be used as an add-on to Metformin in dual or triple therapy.
· Per AACE guideline: SGLT2i can be used in mono-, dual-, or triple-therapy.
Things to consider prior to initiating therapy with SGLT2i:
· Volume status: Correct volume depletion before initiating.
· Kidney function
· Cost (only available as brand).
Common adverse drug reactions and safety concerns (SGLT2i):
· Risk of ketoacidosis (FDA warning)
· Serious urinary tract interaction (FDA warning)
· Hyperkalemia (canagliflozin only)
· Bladder cancer (dapagliflozin)
· Impaired in kidney function
· Genitourinary fungal infection
· Increase LDL
Please see below detailed findings about the current study:
Source: Courtesy of Tahani Almeleebia, PharmD
The goal of insulin therapy in diabetes is to mimic, as nearly as possible, the physiologic profile of insulin secretion (basal/bolus).
Basal Secretion: The release of insulin to counteract ongoing hormonal or other glycemic influences
Bolus Secretion: The biphasic release of insulin in response to food intake
To optimize glycemic control in patients with type 2 diabetes using insulin:
1. Continue metformin therapy unless there is a contraindication to use (Actos can also be used but weight gain when combined with insulin is more significant)
2. Continue oral agent that helps with meal time coverage (i.e. sulfonylurea) unless there is a contraindication to use
3. If patient not achieving A1C goal on oral agents, begin insulin therapy with basal coverage (Lantus, Levemir or NPH)
4. If patient is still not achieving A1C goal on oral agents and basal insulin, consider adding bolus (NovoLog, Humalog, Apidra or regular insulin)
a. bolus before largest meal only
b. bolus before each meal (NovoLog, Humalog, Apidra)
c. bolus before breakfast and dinner only (regular beneficial since longer duration of action)
d. premix insulin with both basal and bolus insulin can also be used (NovoLog 70/30, Humalog 75/25, Humalin 50/50, or human insulin 70/30).
**use of an oral agent, for meal time coverage, once there are two or more rapid acting/bolus doses of insulin per day adds no benefit and increases risk of hypoglycemia**
When a basal insulin dose starts to approach 40 units per day, strongly consider adding bolus insulin to achieve the A1C goal.
Sometimes when bolus insulin is added in sufficient quantities to achieve the goal post prandial blood glucose, basal insulin needs will decrease.
Source: Courtesy of Marisa Rowen, PharmD, CDE
There are very few changes that impact what we do in the 2016 standards:
Classification and Diagnosis of Diabetes
Cardiovascular Disease and Risk Management
Management of Diabetes in Pregnancy
Children and Adolescents
There is also some guidance added in terms of microvascular complications, diabetes care in hospital setting(basal and bolus dosing recommendations for continuous enteral, bolus enteral and parenteral feedings), diabetes advocacy, and strategies for improving care.
Reference: American Diabetes Assocation, http://professional.diabetes.org/content/clinical-practice-recommendations
Source: Courtesy of Nisha Patel, PharmD
Sandra Leal, PharmD, MPH, FAPhA, CDE