Phentermine, topiramate and their combination for the treatment of adiposopathy (‘sick fat’) and metabolic disease

Figures & data

Figure 1. Simplified relationship between selected CNS factors^† on anorexigenic and orexigenic effectors within the hypothalamus.

CNS factors may increase anorexigenic POMC (which is cleaved to form melanocortins such as MSH) and CART expression, and decrease orexigenic expression of NPY and AgRP. Alterations in these appetitive effectors contribute to ‘second-order’ signaling through arcuate nucleus neuron projection to other hypothalamic regions. The net result is increased anorexigenic and increased catabolic effects, with decreased orexigenic and decreased anabolic effects. This figure is greatly simplified, and does not show all the interconnected signaling pathways between these CNS factors.

^†The reported effects of these CNS factors on POMC and NPY are not always consistent in the literature, with more research needed to confirm these effects.

^‡While CNS adiponectin may have anorexigenic effects [175], adiponectin may not cross the blood–brain barrier [176], so the physiological importance of adiponectin on the CNS is unclear [140].

^§Meant to reflect the fed versus non-fed state as reflected by relative physiologic increases or decreases in glucose levels. While the signaling may be glucose mediated, this is not necessarily meant to represent pathologic hyperglycemia.

AgRP: Agouti-related peptide; BDNF: Brain-derived neurotrophic factor; CART: Cocaine amphetamine-regulated transcript; CB1R: Cannabinoid 1 receptor; CRH: Corticotropin-releasing hormone; GLP-1: Glucagon-like peptide-1; MC3R: Melanocortin 3 receptor; MC4R: Melanocortin 4 receptor; MCH: Melanin-concentrating hormone; MSH: Melanocyte-stimulating hormone; NPY: Neuropeptide Y; POMC: Pro-opiomelanocortin; PYY 3–31: Peptide YY; TRH: Thyroid-releasing hormone; VIP: Vasoactive intestinal peptide.

Data taken from [23,173,174].

Figure 2. Relative importance of prophylactically treating migraine headaches versus treating adiposity, adiposopathy and metabolic disease.

^†Topiramate doses may be as low as 50 mg per day for prophylaxis of migraine headaches, and as high as 400 mg per day for treatment of seizure disorders.

^‡Both phentermine and topiramate are approved drugs. Neither phentermine nor topiramate have product information that warns of potential adverse experiences with their combined use.

^§The ‘low dose’ PHEN/TPM CR evaluated in clinical trials contained 23 mg of topiramate CR.

^¶It is yet to be proven that controlled-release topiramate affords additional efficacy or safety advantages over non-controlled-release formulations.

PHEN/TPM CR: Phentermine HCl and topiramate controlled-release.

Table 1. Examples of treatments for adiposopathy (‘sick fat’) and their effects upon illustrative and selected adipose tissue factors that may contribute to metabolic disease.

Intervention	May affect glucose metabolism, BP and lipid metabolism					May affect glucose metabolism		May affect BP		May affect lipid metabolism
	Visceral adipose tissue^†	Free fatty acids	Leptin	Adiponectin		TNF-α		Renin–angiotensin–aldosterone enzymes		Androgens	Estrogens
Weight loss interventions
Appropriate nutrition and physical activity	↓	↓	↓	↑		↓		↓		↓ (women) ↑ (men)	↓/- (men)
Orlistat	↓	↓	↓	↑		↓		?		↓ (women)	?
Sibutramine	↓	↓	↓	↑/-		?		?		↓ (women)	?
Cannabinoid receptor antagonists	↓	↓	↓	↑		↓		?		?	?
Lorcaserin	↓	?	?	?		?		?		?	?
Phentermine	↓ [105]	?	?	?		?		?		?	?
Topiramate	↓ [119]	↓ [172]	↓/- [119,130]	↑ [119]		- [119]		?		?	?
Phentermine/topiramate combination	↓	?	?	?		?		?		?	?
Laparoscopic adjustable gastric banding	↓	?	↓	↑		↓		↓		?	?
Gastric bypass	↓	↓^‡	↓	↑		↓		↓		↑ (men)	↓ (men)
Diabetes mellitus therapies^§
PPAR-γ agonists^¶(pioglitazone, rosiglitazone)	↓/-	↓	↓/-	↑		↓		-		↓	↓/- (men)
Metformin	↓	↓	↓	↑		-		↓		↓ (women)	?
Sulfonylurea	↑	↓	↑/-	↑		↑/-/↓		?		?	?
Insulin	↑/-	↓	↑	↓		↓/-		↑		↓/- (women)	?
Glucagon-like peptide-1 (GLP-1)^#	↓	↓	↓/-	↑/-		-		?		↓	?

^†Visceral adiposity may be approximated by measurements of waist circumference.

^‡Acutely (e.g., 1 month), free fatty acids may be increased during rapid weight loss.

^§Not all of the listed metabolic effects of anti-diabetes mellitus therapies are adipocyte or adipose tissue mediated.

^¶PPAR-γ agents may: (1) increase adipose tissue proliferation and differentiation, (2) favorably alter the visceral-to-subcutaneous adipose tissue deposition ratio, (3) reduce hepatic fat deposition, and (4) improve other aspects of adipose tissue function [3,23,53]. While some of the weight gain associated with PPAR-γ agents is due to fluid retention, much of the weight gain observed with these agents used to treat metabolic diseases traditionally associated with fat weight gain are (paradoxically?) due to promoting increased amounts of functional adipose tissue.

^#Not all of the listed metabolic effects described with GLP-1 have yet been proven to occur with GLP-1 agonists.

↑: Increased; ↓: Decreased; ?: Unreported; -: Neutral effect; PPAR-γ: Peroxisome proliferator-activated receptor-γ.

Data taken from [2,3,23,171].

Table 2. Preliminary data of Phase III clinical trials of the once-a-day phentermine/topiramate controlled-release combination agent.

Clinical trial	Patients	Treatments	Duration	Patients completing the study (%)	Percent weight loss (ITT)	Patients with ≥5% weight (%; ITT)	Metabolic effects compared with placebo	Ref.
EQUATE (OB-301)	n = 756 BMI = 30–45 kg/m^2 Mean BMI = 36.3 kg/m^2 Women = 79% African–American = 19% Diabetes mellitus = 0%	Placebo Phentermine HCl 7.5 mg Phentermine HCl 15 mg Topiramate CR 46 mg Topiramate CR 92 mg PHEN/TPM CR mid dose PHEN/TPM CR full dose	4-week titration followed by 24 weeks of treatment = total of 28 weeks	66% of total study population completed the study on study drug	Placebo = -1.7% Phentermine HCl 7.5 mg = -5.5% Phentermine HCl 15 mg = -6.1% Topiramate CR 46 mg = -5.1% Topiramate CR 92 mg = -6.6% PHEN/TPM CR mid dose = -8.5%* PHEN/TPM CR full dose = -9.2%*	Placebo = 16% PHEN/TPM CR mid dose = 62%** PHEN/TPM CR full dose = 66%** (other values not reported)	PHEN/TPM CR mid and full dose significantly reduced HbA1c by 0.10 and 0.11%, respectively*** (baseline HbA1c = 5.42 and 5.48%, respectively)	[160,161,207,215]
EQUIP (OB-302)	BMI >35 kg/m^2 Mean BMI = 42 kg/m^2 Women = 83% FBG <110 mg/dl TG ≤200 mg/dl BP ≤140/90 mmHg (patients could be on medication for TG and BP)	Placebo (n = 514) PHEN/TPM CR low dose (n = 241) PHEN/TPM CR full dose (n = 512)	4-week titration followed by 52 weeks of treatment = total of 56 weeks	Placebo = 47% PHEN/TPM CR low dose = 57%*** PHEN/TPM CR full dose = 59%***	Placebo = -2% PHEN/TPM CR low dose = -5%*** PHEN/TPM CR full dose = -11%***	Placebo = 17% PHEN/TPM CR low dose = 45%*** PHEN/TPM CR full dose = 67%***	PHEN/TPM CR low dose significantly reduced waist circumference, systolic BP and total cholesterol; PHEN/TPM CR full dose significantly reduced waist circumference, systolic BP, diastolic BP, TG, total cholesterol and LDL-C, and increased HDL-C	[205,216]
CONQUER (OB-303)	BMI = 27–45 kg/m^2 Mean BMI = 37% Women = 70% Two or more of the following comorbidities: high BP, high TG, hyperglycemia, increased waist circumference, Type 2 diabetes mellitus = 16%	Placebo (n = 994) PHEN/TPM CR mid dose (n = 498) PHEN/TPM CR full dose (n = 995)	4-week titration followed by 52 weeks of treatment = total of 56 weeks	Placebo = 57% PHEN/TPM CR mid dose = 69%*** PHEN/TPM CR full dose = 64%***	Placebo = -2% PHEN/TPM CR low dose = -8%*** PHEN/TPM CR full dose = -10%***	Placebo = 21% PHEN/TPM CR low dose = 62%*** PHEN/TPM CR full dose = 70%***	PHEN/TPM CR mid dose significantly reduced waist circumference, systolic BP, TG and total cholesterol, and increased HDL-C levels; PHEN/TPM CR full dose significantly reduced waist circumference, systolic BP, diastolic BP, TG, total cholesterol and LDL-C, and increased HDL-C levels	[162,205,216]

‘Low dose’ = phentermine 3.75 mg/topiramate 23 mg per day. ‘Mid dose’ = phentermine 7.5 mg/topiramate 46 mg per day. ‘Full dose’ = phentermine 15 mg/topiramate 92 mg per day.

*p < 0.001 PHEN/TPM CR versus phentermine and topiramate monotherapies.

**p < 0.001 PHEN/TPM CR versus placebo.

***p < 0.0001 PHEN/TPM CR versus placebo.

BMI: Body mass index; BP: Blood pressure; CONQUER: A Phase III Randomized, Double-Blind, Placebo-controlled, Multicenter Study to Determine the Safety and Efficacy of VI-0521 in the Treatment of Obesity in Adults with Obesity-related Co-morbid Conditions [217]; EQUATE: A Phase III Randomized, Double-Blind, Parallel-Design Study Comparing Multiple Doses of VI-0521 to Placebo and their Single-Agent Phentermine and Topiramate Constituents for the Treatment of Obesity in Adults [217]; EQUIP: A Phase III Randomized, Double-Blind, Placebo-controlled Multicenter Study to Determine the Safety and Efficacy of VI-0521 in the Treatment of Obesity in an Adult Population with BMI ≥35 kg/m²[217]; FBG: Fasting blood glucose; HbA1c: Hemoglobin A1c; HDL-C: High-density lipoprotein cholesterol; ITT: Intent-to-treat population defined as randomized patients with at least one dose of therapy and one post randomization assessment; LDL-C: Low-density lipoprotein cholesterol; PHEN/TPM CR: Phentermine HCl and topiramate controlled-release; TG: Triglyceride.

Table 3. Percent of adverse experiences occurring in over 5% of study participants (regardless of causality) with PHEN/TPM CR during the EQUIP (n = 1264) and CONQUER (n = 2485) trials.

Adverse experience	PHEN/TPM CR EQUIP study				PHEN/TPM CR CONQUER study
	Placebo (%)	Low dose (%)	Full dose (%)		Placebo (%)	Mid dose (%)	Full dose (%)
Dry mouth	3.7	6.7	17.0		2.4	13.5	20.8
Tingling	1.9	4.2	18.8		2.0	13.7	20.5
Constipation	6.8	7.9	14.1		5.9	15.1	17.4
Upper respiratory infection	10.9	15.8	12.3		12.9	12.2	13.4
Altered taste	1.0	1.3	8.4		1.1	7.4	10.4
Insomnia	4.9	5.0	7.8		4.7	5.8	10.3
Headache	10.1	10.4	11.9		9.1	7.0	10.2
Dizziness	4.1	2.9	5.7		3.1	7.2	10.0
Common cold	7.2	12.5	9.0		8.7	10.6	9.9
Sinus infection	5.5	7.5	7.2		6.7	6.8	8.6
Back pain	5.1	5.4	5.5		4.9	5.6	7.2
Nausea	4.7	5.8	7.2		4.2	3.6	6.8
Blurred vision	3.1	6.3	4.5		3.6	4.0	6.0
Bronchitis	4.3	6.7	5.5		4.3	4.4	5.2
Diarrhea	4.5	5.0	4.7		4.8	6.4	5.8
Urinary tract infection	3.5	3.3	4.7		3.7	5.2	5.4
Cough	3.5	3.3	5.1		3.0	3.8	4.8
Influenza	4.7	7.5	5.1		4.3	4.6	3.5

‘Low dose’ = phentermine 3.75 mg/topiramate 23 mg per day. ‘Mid dose’ = phentermine 7.5 mg/topiramate 46 mg per day. ‘Full dose’ = phentermine 15 mg/topiramate 92 mg per day.

CONQUER: A Phase III Randomized, Double-Blind, Placebo-controlled, Multicenter Study to Determine the Safety and Efficacy of VI-0521 in the Treatment of Obesity in Adults with Obesity-related Co-morbid Conditions [217]; EQUIP: A Phase III Randomized, Double-Blind, Placebo-controlled Multicenter Study to Determine the Safety and Efficacy of VI-0521 in the Treatment of Obesity in an Adult Population with BMI ≥35 kg/m²[217]; PHEN/TPM CR: Phentermine HCl and topiramate controlled-release.

Preliminary data taken from [205].

Table 4. Discontinuations due to adverse experiences in the EQUIP and CONQUER studies.

Parameter	Placebo	PHEN/TPM CR low dose	PHEN/TPM CR mid dose	PHEN/TPM CR full dose
Subjects (n)	1508	241	498	1507
Study completion (%)	53	57	69	62
Total discontinuations due to AEs (%)	9	12	12	18
Blurred vision (%)	0.5	2.1	0.8	0.7
Headache (%)	0.7	1.7	0.2	0.9
Insomnia (%)	0.4	0.0	0.4	1.7
Depression (%)	0.2	0.0	0.8	1.4
Tingling (%)	0.0	0.4	1.0	1.2
Irritability (%)	0.1	0.8	0.8	1.2
Anxiety (%)	0.3	0.0	0.2	1.1
Dizziness (%)	0.2	0.4	1.2	0.8

‘Low dose’ = phentermine 3.75 mg/topiramate 23 mg per day. ‘Mid dose’ = phentermine 7.5 mg/topiramate 46 mg per day. ‘Full dose’ = phentermine 15 mg/topiramate 92 mg per day.

AE: Adverse experience; CONQUER: A Phase III Randomized, Double-Blind, Placebo-controlled, Multicenter Study to Determine the Safety and Efficacy of VI-0521 in the Treatment of Obesity in Adults with Obesity-related Co-morbid Conditions [217]; EQUIP: A Phase III Randomized, Double-Blind, Placebo-controlled Multicenter Study to Determine the Safety and Efficacy of VI-0521 in the Treatment of Obesity in an Adult Population with BMI ≥35 kg/m²[217]; PHEN/TPM CR: Phentermine HCl and topiramate controlled-release.

Preliminary data taken from [205].

Qi Y, Takahashi N, Hileman SM et al. Adiponectin acts in the brain to decrease body weight. Nat. Med.10(5), 524–529 (2004).

 PubMedGoogle Scholar

Spranger J, Verma S, Gohring I et al. Adiponectin does not cross the blood–brain barrier but modifies cytokine expression of brain endothelial cells. Diabetes55(1), 141–147 (2006).

 PubMedGoogle Scholar

Dridi S, Taouis M. Adiponectin and energy homeostasis: consensus and controversy. J. Nutr. Biochem.20(11), 831–839 (2009).

 PubMedGoogle Scholar

Kim KK, Cho HJ, Kang HC, Youn BB, Lee KR. Effects on weight reduction and safety of short-term phentermine administration in Korean obese people. Yonsei Med. J.47(5), 614–625 (2006).

 PubMed Web of Science ®Google Scholar

Schutt M, Brinkhoff J, Drenckhan M, Lehnert H, Sommer C. Weight reducing and metabolic effects of topiramate in patients with migraine – an observational study. Exp. Clin. Endocrinol. Diabetes118(7), 449–452 (2010).

 PubMedGoogle Scholar

Wilkes JJ, Nelson E, Osborne M, Demarest KT, Olefsky JM. Topiramate is an insulin-sensitizing compound in vivo with direct effects on adipocytes in female ZDF rats. Am. J. Physiol. Endocrinol. Metab.288(3), E617–E624 (2005).

 Web of Science ®Google Scholar

ClinicalTrials.gov http://clinicaltrials.gov (Accessed 12 April 2010)

 Google Scholar

Wilson L, Day W, Look M, Tam P. EQUIP and CONQUER study results. Vivus Inc. (2009) http://files.shareholder.com/downloads/VVUS/0x0x318291/7cfa4590-cb7d-453d-86a8-c25d5f832bfd/Qnexa.pdf (Accessed 7 August 2010)

 Google Scholar