SAFETY and EFFECTIVENESS of drugs used to treat metabolic syndrome

MAIN FOCUS: Using pharmaceutical therapies to treat metabolic syndrome – TYPE 2 DIABETES
MELLITUS, INSULIN RESISTANCE

PROBLEMS:

- Safety
- Effectiveness
- Lifestyle interventions are not compliant

Obesity – sibutramine, orlistat, catecholaminergic agents (diethylpropione, fenproporex, mazindol),

topiramate, brupropion, fluoxetine, metformin

Hypertension

In choosing anti-hypertensive drugs however, we should preferably choose those

which will not enhance insulin resistance, promote weight gain (beta-blockers),
or worsen glucose intolerance (thiazide diuretics) or the lipid profile, and that
are able to control blood pressure for 24 hours.
Insulin resistance

PPAR agonists – fibrates, thiazolidinediones, pioglitazone, rosiglitazone, GW501516, The highly

potent and selective PPAR-α agonist K-877 has shown beneficial effects on
atherogenic dyslipidemia and absence of some adverse effects seen with
fibrates. The dual PPAR-α/PPAR-δ agonist GFT-505 has shown favorable
results in improving atherogenic dyslipidemia and insulin resistance and
appears to be a potential candidate for the treatment of NAFLD. Long-term
trials are needed to assess the safety and efficacy of these new agents for
cardiovascular and liver outcomes.
Pioglitazone:

http://www.tandfonline.com/doi/abs/10.1185/030079904X20295

https://link.springer.com/article/10.3275/8895

http://www.sciencedirect.com/science/article/pii/S0149291806001238

https://www.ncbi.nlm.nih.gov/pubmed/15881488

11β-HSD1 inhibitors – AZD4017, INCB13739, DIO-902

GLP-1 agonists – Liraglutide, exenatide

DPP-4 inhibitors – LAF237, sitagliptin, gemigliptin, mangiferin

Glitazars – Muraglitazar, tesaglitazar

http://www.evaluategroup.com/Universal/View.aspx?type=Story&id=613767
http://www.tandfonline.com/doi/pdf/10.1185/030079906X154169?needAccess=true

Amylin analogs - pramilintide

Combination therapies

Prevention of type 2 diabetes mellitus

Several drugs on the market that are currently used in cardiac and metabolic conditions (e.g. statins,
ACE inhibitors, ARBs, TZDs, etc) could potentially confound results of a new agent under
investigation for the metabolic syndrome. These agents can have pleiotropic effects on several
different pathways associated with the metabolic syndrome. It would be unethical to stop or exclude
patients on these drugs in clinical trials (as many as 60% of type 2 diabetes patients in clinical trials
can be on an ACE inhibitor for example), but the effects on the study interpretation should be
negated by appropriate randomisation (including consideration of stratified randomisation). One
potential benefit of having a simple definition of metabolic syndrome for drug development would
be in assessing how an investigational drug (e.g. erectile dysfunction or antihypertensive drug)
behaves in clinical trial subjects with or without the metabolic syndrome as per ATP III or IDF
definitions.