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??