- Top of page
- Methods and Procedures
- SUPPLEMENTARY MATERIAL
- Supporting Information
There is a perception that phentermine pharmacotherapy for obesity increases blood pressure and heart rate (HR), exposing treated patients to increased cardiovascular risk. We collected data from phentermine-treated (PT) and phentermine-untreated (P0) patients at a private weight management practice, to examine blood pressure, HR, and weight changes. Records of 300 sequential returning patients were selected who had been treated with a low-carbohydrate ketogenic diet if their records included complete weight, blood pressure, and HR data from seven office examinations during the first 12 weeks of therapy. The mean time in therapy, time range, and mode was 92 (97.0), 12–624, and 52 weeks. 14% were normotensive, 52% were prehypertensive, and 34% were hypertensive at their first visit or had a previous diagnosis of hypertension. PT subjects systolic blood pressure/diastolic blood pressure (SBP/DBP) declined from baseline at all data points (SBP/DBP −6.9/−5.0 mm Hg at 26, and −7.3/−5.4 at 52 weeks). P0 subjects' declines of SBP/DBP at both 26 and 52 weeks were −8.9/−6.3 but the difference from the treated cohort was not significant. HR changes in treated/untreated subjects at weeks 26 (−0.9/−3.5) and 52 (+1.2/−3.6) were not significant. Weight loss was significantly greater in the PT cohort for week 1 through 104 (P = 0.0144). These data suggest phentermine treatment for obesity does not result in increased SBP, DBP, or HR, and that weight loss assisted with phentermine treatment is associated with favorable shifts in categorical blood pressure and retardation of progression to hypertension in obese patients.
- Top of page
- Methods and Procedures
- SUPPLEMENTARY MATERIAL
- Supporting Information
The prevalence of high blood pressure and mean levels of SBP and DBP are known to increase as BMI increases (14). Multiple studies have shown that weight loss induced by caloric restriction and behavior change without antiobesity pharmacotherapy is associated with decreased blood pressure (15).
In this study, we found that SBP and DBP declined significantly during weight loss in patients treated with phentermine, just as did blood pressures in the P0 patients. Patients with hypertension experienced the greatest declines while those with prehypertension had lesser declines and those with normal blood pressure had the least change. That weight loss induced by two-drug combinations including phentermine produced greater declines in patients with hypertension than in those with normal blood pressure has been reported previously (16,17), but these reports did not stratify patients by JNC 7 blood pressure categories so blood pressure declines in prehypertensive patients were not analyzed. In this study we found that a significant proportion of both PT and P0 patients experienced a categorical shift from prehypertension to normotension at 12, 26, and 52 weeks. This categorical shift typically occurred in the first 12 weeks of therapy. Although the numbers of P0 patients was too low for statistical comparisons beyond 52 weeks, the categorical shift persisted in smaller numbers of PT patients at 104 and 156 weeks.
The data from this study suggests that the occurrence of hypertension associated with phentermine pharmacotherapy is rare rather than common. One patient, initially prehypertensive, of the 269 PT patients developed hypertension after 1 year on phentermine. Excluding the patients initially hypertensive, data for 119 patients remained in the study at 52 weeks for an incidence rate of 0.84%/year. If only the prehypertensive patients are considered at 1 year (N = 95), then the 1-year incidence would be 1.05%. In considering these incidence rates comparison should be made to other data on the incidence of new hypertension. Because elevations of blood pressure in the hypertensive range (≥140/90) and in the prehypertensive range (120/80–139/89) are very common in obese subjects, one could expect an annual incidence rate of newly diagnosed hypertension in untreated normotensive and prehypertensive obese subjects followed for a year to be higher than 1%. The ATTICA study (18) found an annual incidence of new hypertension in the general Greek population to be 2.86 cases per 100 in men and 2.68 cases per 100 in women. The Strong Heart Study (19) found that the 4-year incidence of hypertension in a group of patients with prehypertension to be 38% and a 5-year study in Taiwan (20) found a conversion rate from prehypertension to hypertension to be 31.2%. These incidence rates, in populations not selected for obesity, are substantially higher than the rate of conversion of prehypertension to hypertension calculated for this study. These data suggest that weight loss assisted by phentermine pharmacotherapy retarded progression of prehypertension to hypertension. Data from the fixed-dose combination of phentermine-topiramate (Qnexa) clinical trials also suggested progression to hypertension was retarded (17).
Long-term nonpharmacological intervention trials have been unsuccessful in maintaining weight loss and lower blood pressure for longer than 3–4 years (21). The number of patients retained beyond 4 years in this study is small, but the data suggests the possibility that long-term phentermine therapy could be effective in maintaining a lower weight and in lowering blood pressure for >4 years in some patients.
Given the data from this study and the previous studies cited suggesting that blood pressure declines rather than increases with phentermine therapy, why does the assumption that phentermine adversely affect blood pressure persist? The conception that phentermine can elevate blood pressure and HR apparently derives from the often-repeated fact that phentermine is an amphetamine congener. That amphetamine can increase blood pressure and HR and induce or worsen hypertension is well documented (22). These adverse cardiovascular effects are dose-related and dependent upon the route of administration of the drug; inhalation or drug administration via intranasal or intravenous routes rapidly produces higher blood levels and therefore greater toxic effect than dose oral administration. Certain amphetamine congeners such as methamphetamine (23) and 3,4-methylenedioxymethamphetamine (24), which are typically abused by intranasal, inhalation, or intravenous routes, have even greater toxic potential and are also known to produce adverse cardiovascular effects. Subjects who use the amphetamines of abuse often self-administer large doses producing very high blood levels in trying to achieve the desired stimulant effect. On the other hand, the route of administration and dose of amphetamines used for pharmacotherapy of attention deficit and attention deficit hyperactivity disorder have a much lower toxicity potential. Therapeutic use of these drugs is associated with slight increases in blood pressure and in HR of questionable clinical impact (25). In phentermine pharmacotherapy low (compared to the doses used of the amphetamines of abuse) oral doses are used, and phentermine blood levels achieved are comparatively lower than blood levels achieved by subjects of the abused drugs. In addition phentermine has a substantially lower toxic potential. Thus the potential for adverse effects with phentermine pharmacotherapy is significantly lower than for the abused amphetamines.
Aside from a few anecdotal reports, there is no data in the peer-reviewed medical literature to support the perception that phentermine increases blood pressure or HR. Phentermine clinical trial reports, when details of blood pressure and HR have been given, have shown that trial subjects experienced decreases in SBP and DBP and minimal or no changes in HR (8,9,26). The same is true of most trials with combinations with phentermine as one of two antiobesity drugs. (16,17,27,28). The one exception to the latter statement is a recent clinical trial in which patients given a combination of pramlintide plus phentermine showed no significant change in clinic visit SBP and DBP but an increase in HR of 5 beats/min (P < 0.01) (29). Ambulatory blood pressure monitoring in the latter study revealed about a 3 mm increase in DBP in the pramlintide plus phentermine subjects (P < 0.01) and an increase in HR of about 5 beats/min (P < 0.001). Because SBP and HR decreased slightly in the pramlintide only group, the implication is that the phentermine produced the observed increases, however no subjects treated with phentermine alone were included in the study and patients with hypertension were excluded. We did not measure ambulatory blood pressures in this study.
Our data suggests that phentermine pharmacotherapy does not significantly influence HR at any time during treatment.
In adjustment of phentermine dose using a dose-to-effect method, previously described by Rothman (30), the desired effects are on eating behaviors rather than weight loss (31). Dose-to-effect titration is a common practice in medicine that is employed with a wide variety of drugs. The most cogent comparison here would be with the methods used in adjusting amphetamine dose for attention deficit disorder and attention deficit hyperactivity disorder. Two approaches have been described in treating ADD and ADHD: (i) prescribe an initial low dose, evaluate behaviors, then gradually increase dose until behavior improves, or (ii) ramp up dose until undesirable side effects appear, then reduce dose to the level before they appeared (32). The first approach was typically employed in adjusting phentermine doses in this study. Phentermine dose-to-effect was evaluated at each patient encounter and if undesirable side effects appeared the dose was most often reduced. Mean and median phentermine dosage trended upward for patients in long-term treatment as shown in Table 3. Patients with adult attention deficit disorder, which is common among the obese (33), often derive behavioral benefit from phentermine (34) and may tolerate higher doses. A few of the patients on higher doses in this study were thought to have previously undiagnosed adult ADD, but the majority were simply more comfortable with their eating behavior at a higher dose. Phentermine doses higher than the US Food and Drug Administration recommended maximum of 37.5 mg daily have been previously described (2,7,30,35), but there have been no clinical trials that have examined this issue.
Phentermine is presumed to have addiction potential and is classified as a category IV controlled substance. An important criterion is making a diagnosis of addiction is that drug-addicted subjects typically manifest dysfunction in one or several spheres such as social, work, or legal arenas. Practitioners and staff of the clinic observed the patients in this study carefully for signs of such dysfunction, and no such behaviors were observed.
This study has several strengths. The study clinic is well established with many long-term patients. The physician in charge has had long experience with phentermine. As is always with retrospective observational studies, a limitation could have been bias in subject selection, which is possible even though criteria were set in place to avoid bias. The methods for blood pressure and especially for HR determination are another limitation. The small sample size in some of the cohorts is yet another limitation.
We conclude the data from this retrospective study suggests that the addition of phentermine pharmacotherapy for patients in a comprehensive weight management program does not adversely affect HR or blood pressure. Indeed, this study suggests that in this setting phentermine pharmacotherapy, can be especially beneficial for the obese hypertensive and prehypertensive patients since persistent weight loss assisted with such therapy may lower blood pressure long-term and retard the progression of prehypertension to hypertension delaying the natural course of hypertension in the obese and potentially reducing the risk of mortality due to congestive heart failure, stroke and ischemic heart disease. Some of these patients maintained a weight loss of 10% or greater for as long as 8 years suggesting long-term phentermine pharmacotherapy may be a useful treatment for long-term weight maintenance.
The P0 patients who adhered to diet alone without phentermine treatment garnered similar benefits to PT patients over the first year of treatment, but the benefits for the P0 patients began to vanish as they regained weight whereas PT patients' benefits persisted. PT patients also had slightly better initial weight loss. Finally, there is a suggestion that phentermine doses >37.5 mg/day are safe and can be useful in selected patients.
The potential benefit to the obese population is huge if the findings of this study can be confirmed and phentermine pharmacotherapy ultimately is used more widely. We suggest there is a need for more investigations into both the clinical effects of phentermine and its molecular basis of action. Development of psychometric scales to assess phentermine effect on eating behavior for guidance of dose-to-effect titration could prove clinically useful. We suggest a long-term, dose-ranging phentermine clinical trial and outcome study could potentially confirm the cardiovascular benefits implied by this study.