raymond li cc4 september 2, 2015. review for amylin, bromocriptine, xenical and ranolazine 1. basic...
TRANSCRIPT
Weirdo Drugs for Type 2 DM: Amylin, Bromocriptine,
Xenical and Ranolazine
Raymond Li CC4September 2, 2015
• Review for Amylin, Bromocriptine, Xenical and Ranolazine
1.Basic drug information2.Select papers examining use for treatment of Type 2 DM
3.Considerations for clinical use
Objectives
37 amino acid peptide that is co-secreted with insulin
Complementary action to insulin in regulating blood glucose levels
Mechanism of action 1) Slows gastric emptying 2) Inhibits glucagon secretion 3) Appetite inhibition
Amylin
UptoDate
Human amylin unsuitable for therapeutic use (insoluble, aggregation, formation of amyloid fibrils)
3 proline substitutions producing an equipotent amylin analog
Stable, soluble, does not aggregate
Administered subcutaneously
Pramlintide (Symlin)
52 week double blind randomized control trial 656 patients with type 2 diabetes (HbA1c not
at target and on insulin therapy Randomized to receive placebo or adjunct
preprandial Pramlintide BID
Type 2 diabetes: -Initial dose of 60 mcg, titrated up to 120 mcg before meals
Must be injected separately from insulin at a different injection site. Not in arm (variable absorption)
Dose and Administration
http://asweetlife.org/wp-content/uploads/2013/02/SymlinPen.jpg
Currently only approved for use in type 1 and type 2 diabetic patients on prandial insulin
Approved labelling suggests prandial insulin doses be decreased by 50% initially and titrated back up once target pramlintide dose reached
Should only be administered before meals that contain at least 30g of carbohydrates
Oral medications that require rapid absorption should be given 1-2 hrs before pramlintide due to its effects on gastric emptying
Administration
Nausea most common side effect (28-48%) - Generally resolves within several weeks - Can be minimized with slower titration
Headache, anorexia, vomiting
Hypoglycemia in conjunction with other therapies
- Does not cause hypoglycemia in absence of other therapies that increase risk
Side effects
Contraindications: - Pts with severe hypoglycemia unawareness - Pts with gastroparesis
Inadequate data supporting use in pts not requiring insulin
Long term outcomes still under investigation
Currently not approved by Health Canada
Additional Considerations
Ergot alkaloid dopamine D2 receptor agonist
Long used for treatment of Parkinson's, galactorrhea and hyperprolactinemia
Now available in two preparations: - Standard release (Parlodel) - New Quick release (QR) (Cycloset)
QR formulation shows greater promise than standard preparation for treatment of T2DM
Bromocriptine
Nuclei within the hypothalamus play an important role in controlling insulin sensitivity and nutrient metabolism
Normal diurnal insulin sensitivity is disrupted in T2DM
Decreased hypothalamic dopamine levels and disrupted circadian rhythm associated with obesity, insulin resistance and diabetes
Known since 1980s that bromocriptine administration lowers blood glucose level
Hypothalamic Control of Metabolism
New quick release formulation of Bromocriptine with unique pharmacokinetic properties
Compared with standard formulation: - Greater bioavailability - Faster peak bromocriptine concentration - Less by-products and active metabolites - Quicker clearance resulting in shorter duration of action
Timing critical for therapeutic effects
Cycloset
Has shown promise in a number of clinical trials
Taken within 2 hours of awakening
Lowers HbA1c as monotherapy or in combination with other anti-diabetic agents
Average effect of 0.6-0.7% reduction in HbA1c
Cycloset
Effects centrally mediated but exact mechanisms not understood
Increased hypothalamic dopamine activity
Sympatholytic effects via D2 receptor activation decreasing excessive sympathetic tone in CNS
Resetting of circadian rhythms
Attempt to restore diurnal changes in insulin sensitivity and glucose metabolism
Mechanism of Action
Decreased fasting and postprandial blood glucose
Suppression of hepatic glucose production
Decreased serum free fatty acids and triglycerides
Effects persisted later into the day long after drug cleared from system
Some studies have shown reductions in cardiovascular risk in diabetic patients
Effects
Phase 3 randomized clinical trials1) Combined Cycloset-Sulphonylurea therapy: 494
obese Type 2 diabetics, poorly controlled on a sulphonylurea (HbA1c 7.8-12.5%)
2) Monotherapy: 159 obese T2DM patients with HbA1c of 7.5-11%.
DeFronzo, R.A. Bromocriptine: A sympatholytic, D2-dopamine agonist for the treatment of type 2 diabetes (2011) Diabetes Care, 34 (4), pp. 789-794.
FDA approved as adjunct therapy for T2DM For treatment of T2DM, starting dose of 0.8mg
PO daily, increase by 0.8 mg weekly to a maximum dose of 4.8 mg daily
Needs to be taken within 2 hours of awakening
Lower than standard doses used for Parkinson's or hyperprolactinemia
Dose and Administration
Well-tolerated overall
Nausea most common side effect - Mild-moderate and usually transient
Asthenia (weakness and fatigue), dizziness, constipation, rhinitis, hypoglycaemia
Weight neutral
Side-Effects
Early clinical studies suggest that response in the first 8 weeks of treatment predictive of long term response
No trials examining Cycloset for treatment of T1DM
Increased potential for drug-drug interactions due to 1) Being highly bound to albumin 2) Metabolized via the cytochrome P450 enzyme
CYP3A4
Currently not approved by Health Canada
Additional Considerations
Orlistat is a gastrointestinal lipase inhibitor that reduces fat absorption
Inhibits both gastric and pancreatic lipases.
Decreases absorption of dietary fats by ~30%
Currently approved for obesity management but not diabetes treatment
Orlistat (Xenical)
Weight loss improves hyperglycemia, lipid profiles and blood pressure in type 2 diabetic patients
Long-term maintenance of weight loss difficult
Insulin and other anti-diabetic therapies associated with weight gain
Therefore, desirable to have adjunctive therapy to assist with achieving and maintaining weight loss
Rationale
1 year multicenter randomized, double-blind, placebo-controlled trial
Inclusion criteria: Men and women 40-65, BMI 28-43, stable weight for 3 months, stable dose of insulin for 6 weeks prior to study, HbA1c 7.5-12%
Exclusion criteria included: renal, hepatic or endocrine disorders that could affect results, malabsorption syndrome, eating disorder, other disorders affecting compliance
Design
Subjects randomly assigned to 1) Reduced calorie diet + Orlistat 120mg TID 2) Reduced calorie diet + Placebo
Primary end points: 1) HbA1c 2) Changes in weight
Groups compared using Holm’s sequential rejection procedure
Intent to treat analysis
Design
Premature withdrawal rate of 54% of placebo group and 50% of orlistat group
Orlistat treatment resulted in significantly more weight loss and a significant reduction in HbA1c compared with placebo (-0.62% vs -0.27%)
Orlistat treatment decreased required dose of insulin and other antihyperglycemic medications
Orlistat decreased serum total cholesterol and LDL cholesterol concentrations compared with placebo
Orlistat may be a useful adjunctive treatment in obese type 2 diabetic patients for improving glycemic control, maintaining weight loss and reducing CV risk factors
Results and Conclusion
Dose of 120mg 3 times daily with each main meal containing fat. Taken during or up to 1 hr after meal.
Pts require multivitamin daily supplement which needs to be taken 2 hours apart from orlistat administration
Dose and Administration
Headache
Gastrointestinal complaints(oily spotting, abdominal pain, fatty/oily stool, etc.)
Upper respiratory infection
Back pain
Adverse Effects
A 20 week randomized control trial showed that pts treated with liraglutide lost significantly more weight compared with orlistat treatment
Affects absorption of certain medications including Levothyroxine
Not covered by Ontario drug benefits
Additional Considerations
Ranolazine (Ranexa) is an anti-anginal medication that inhibits sodium currents in various tissues
Ranolazine
http://www.doctortipster.com/wp-content/uploads/2012/08/Ranolazine.jpg
Cardioprotective properties and does not affect blood pressure or heart rate
Rationale Post-hoc analyses of angina trials demonstrated that
ranolazine was associated with reduced HbA1c
No prior studies examining ranolazine as monotherapy or with glycemic control as primary end-point.
First double-blind, randomized control trial evaluating safety and efficacy of ranolazine monotherapy for treatment of T2DM
Men and women 18-75 years with T2DM
Inadequate glycemic control with lifestyle alone
HbA1c of 7-10% and fasting blood glucose of 7.2 – 13.33 mmol/L
BMI of 25-45 kg/m2
Fasting serum C-peptide >= 0.8 ng/mL
Treatment naïve or washout period for anti-hyperglycemic medications
Inclusion Criteria
Exclusion Criteria
T1DM, severe hypoglycemia, poorly controlled HTN, QT interval > 500ms, significant weight change within 2 months, GFR <30, prior ranolazine treatment
MI, ACS, coronary revascularization, stroke or TIA within 3 months
Ranolazine started at 500 mg BID. After 1 wk, increased to 1,000 mg BID
Primary: 24 week change from baseline in HbA1c
Pre-specified secondary end points: 1) Change from baseline in fasting blood
glucose 2) Proportion of subjects with HbA1c < 7% 3) Change from baseline in 2h postprandial
glucose
Other non-alpha controlled end points
End-Points
Primary and secondary endpoints “tested using a fixed- sequence closed testing procedure”
Continuous efficacy end points “were analyzed using a mixed-models repeated-measures approach”
Stats
In animal models, ranolazine inhibits glucagon secretion by blocking Nav1.3 isoform of Na channels in pancreatic α cells
Current study showeda significant reduction inpostprandial glucagonAUC
Proposed Mechanism of Action
Monitored by independent board
Overall, ranolazine well tolerated and safe
Adverse events similar between groups (38.4% vs. 41.8% ranolazine)
Most common AEs: Hyperglycemia, headache, constipation and nausea.
ECG monitoring showed a 7-ms increase in QTc in ranolazine group
Safety
Ranolazine monotherapy effective at reducing HbA1c (mean difference of -0.56%)
Ranolazine may mediate its effects by inhibiting postprandial glucagon levels
Further studies required to test ranolazine in conjunction with other anti-hyperglycemic medications
Ranolazine not yet FDA approved for treatment of diabetes
Conclusions
Many therapeutic options available for treatment of type 2 diabetes. More on the horizon.
Many more studies required to determine best combinations and treatment regimes for specific populations
New drugs are important tools for individualized diabetes care
Summary
Cincotta, A.H., Meier, A.H., Cincotta M., Jr. Bromocriptine improves glycaemic control and serum lipid profile in obese Type 2 diabetic subjects: A new approach in the treatment of diabetes (1999) Expert Opinion on Investigational Drugs, 8 (10), pp. 1683-1707.
DeFronzo, R.A. Bromocriptine: A sympatholytic, D2-dopamine agonist for the treatment of type 2 diabetes (2011) Diabetes Care, 34 (4), pp. 789-794.
Dungan, Kathleen. Amylin analogs for the treatment of diabetes mellitus. UptoDate.
Eckel, Robert H., et al. "Effect of ranolazine monotherapy on glycemic control in subjects with type 2 diabetes." Diabetes care 38.7 (2015): 1189-1196.
Hollander, P.A., Levy, P., Fineman, M.S., Maggs, D.G., Shen, L.Z., Strobel, S.A., Weyer, C., Kolterman, O.G. Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: A 1-year randomized controlled trial (2003) Diabetes Care, 26 (3), pp. 784-790.
Holt, R.I.G., Barnett, A.H., Bailey, C.J. Bromocriptine: Old drug, new formulation and new indication (2010) Diabetes, Obesity and Metabolism, 12 (12), pp. 1048-1057.
Kelley, D.E., Bray, G.A., Pi-Sunyer, F.X., Klein, S., Hill, J., Miles, J., Hollander, P. Clinical efficacy of orlistat therapy in overweight and obese patients with insulin-treated type 2 diabetes: A 1-year randomized controlled trial (2002) Diabetes Care, 25 (6), pp. 1033-1041.
Schmitz, O., Brock, B., Rungby, J. Amylin agonists: A novel approach in the treatment of diabetes (2004) Diabetes, 53 (SUPPL. 3), pp. S233-S238.
References
Questions??