R E V I E W A R T I C L E
`The importance of weight management in type 2
`diabetes mellitus
`
`J. P. H. Wilding
`
`Background: The obesity epidemic is driving the increased prevalence of type 2
`diabetes mellitus (T2DM), and the vast majority of patients with T2DM are over-
`weight or obese. Excess body weight is associated with the risk of cardiometabolic
`complications, which are major causes of morbidity and mortality in T2DM. Aims:
`To review evidence about effects of weight loss in pre-diabetes and established
`T2DM. Results: In prediabetes, weight loss has been shown to delay the onset or
`decrease the risk of T2DM, while in established T2DM weight loss has been shown
`to improve glycaemic control, with severe calorie restriction even reversing the pro-
`gression of T2DM. Observational studies support the reduction in cardiovascular
`risk factors following weight loss in patients with T2DM. However, data from the
`randomised Look AHEAD trial revealed intensive weight loss interventions did not
`reduce the rate of cardiovascular events in overweight or obese adults with T2DM,
`and secondary analyses of other large cardiovascular outcomes trials have also
`been inconclusive. However, besides cardiovascular risk, other documented benefits
`of weight loss in T2DM include improvements in quality of life, mobility, and phys-
`ical and sexual function. Conclusions: Physicians should encourage weight loss in
`all overweight patients with or at risk of T2DM, and should consider the impact
`on weight when choosing the most appropriate glucose-lowering therapies for
`these patients.
`
`Review criteria
`(cid:129) PubMed searches were used to identify clinical
`trials of weight loss for prevention of type 2
`diabetes mellitus (T2DM) and weight loss effects
`on outcomes in patients with T2DM.
`(cid:129) Relevant articles were identified using search
`terms including obesity, type 2 diabetes mellitus
`and cardiovascular, for articles published in
`English before May 2013.
`(cid:129) Search
`identify
`to
`evaluated
`results were
`cardiovascular outcomes studies reporting the
`association between weight loss and
`cardiovascular risk in patients with T2DM.
`
`Message for the clinic
`(cid:129) For patients with T2DM,
`the major causes of
`morbidity and mortality are cardiometabolic
`complications, which are in themselves
`associated with excess body weight.
`(cid:129) Although weight loss improves cardiovascular risk
`factors, it has not been unequivocally
`demonstrated to reduce cardiovascular event
`rates.
`(cid:129) While definitive evidence is awaited, physicians
`should encourage weight loss in all overweight
`patients with T2DM, especially in light of other
`benefits of weight loss, such as improvements in
`mobility.
`
`University Hospital Aintree,
`Liverpool, UK
`
`S U M M A R Y
`
`Correspondence to:
`John Wilding, Department of
`Obesity and Endocrinology,
`Institute of Ageing & Chronic
`Disease, Clinical Sciences
`Centre, University Hospital
`Aintree, Longmoor Lane,
`Liverpool, L9 7AL, UK
`Tel.: + 44(0)151 529 5899
`Fax: + 44(0)151 529 5888
`Email: j.p.h.wilding@liv.ac.uk
`
`Disclosure
`JPHW has received research
`support from Bristol Myers
`Squibb, AstraZeneca & Merck
`Sharpe and Dohme. He has
`acted as an advisor/consultant
`to Astellas, AstraZeneca,
`Boehringer-Ingleheim, Bristol
`Myers Squibb, Lilly,
`NovoNordisk, Sanofi, & Takeda
`and has given lectures on
`behalf of AstraZeneca,
`Boehringer-Ingleheim, Bristol
`Myers Squibb, Lilly, Merck
`Sharpe & Dohme, &
`NovoNordisk. The author was
`fully responsible for all content
`and editorial decisions, was
`involved at all stages of
`manuscript development and
`has approved the final version
`of the review that reflects the
`author’s interpretation and
`conclusions.
`
`Introduction
`
`The link between weight and type 2 diabetes mellitus
`(T2DM) is very strong, with studies confirming that
`the vast majority of patients with T2DM are over-
`weight or obese, and that obese people are at
`the highest risk of developing T2DM (1).
`In a
`meta-analysis of prospective cohort studies from the
`United States (US) and Europe, obese men had a
`sevenfold higher risk of developing T2DM, and obese
`women a 12-fold higher risk, compared with individ-
`uals in the healthy weight range (2). Patients were
`defined as obese based on the widely used cut-off of
`body mass index (BMI) over 30 kg/m2, but similarly
`increased risks were observed using abdominal obes-
`ity, defined by waist circumference of at least 88 cm
`for women or 102 cm for men (2). For some ethnic
`
`groups, these risks appear to occur at lower levels of
`BMI, particularly in people of South Asian origin;
`however, the relationship between weight and T2DM
`remains (3).
`Several studies have shown that obese individuals
`are also at higher risk of developing cardiovascular dis-
`ease (CVD) (4), and the risk is even higher in obese
`people with T2DM (5). A recent survey conducted in
`Cuba provides a good example of the strong associa-
`tion between population-wide weight change and risk
`of death from T2DM and CVD (6). The study mea-
`sured population-wide changes in body weight over
`time from four large cross-sectional surveys in the
`years 1991, 1995, 2001 and 2011. Following the Cuban
`economic crisis of the early 1990s, food and fuel short-
`ages resulted in a decline in energy intake and large
`increases in physical activity. This was reflected in an
`
`682
`
`ª 2014 The Authors International Journal of Clinical Practice Published by John Wiley & Sons Ltd
`Int J Clin Pract, June 2014, 68, 6, 682–691. doi: 10.1111/ijcp.12384
`This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and
`distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
`
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`Importance of weight management in type 2 diabetes mellitus
`
`683
`
`average population-wide weight loss of 4–5 kg and a
`decline in death rate from diabetes and CVD. After the
`crisis, there was a rebound in population weight, fol-
`lowed by a 140% increase in diabetes incidence, and in
`turn by a 49% increase in the mortality rate from dia-
`betes.
`Despite the strong relationship between weight
`and T2DM, not all
`individuals who are obese or
`overweight will develop diabetes, and not all individ-
`uals diagnosed with T2DM are overweight. The
`reported prevalence of lean individuals with T2DM
`varies in different countries (1,7,8); but even in the
`United States, where obesity is prevalent, a pooled
`analysis of five longitudinal studies following 2625
`people recently diagnosed with diabetes found about
`12% of patients were of normal weight (9). Lean
`people with diabetes are thought to have a stronger
`genetic component for T2DM than overweight indi-
`viduals (10), with researchers hypothesising that the
`more overweight an individual is, the fewer genetic
`risk variants are required to predispose them towards
`diabetes, primarily because they are already under
`strain from the physiological impact of obesity and
`insulin resistance (10). This is difficult to prove, and
`lean T2DM cases are used anecdotally by patients to
`question the link between obesity and T2DM.
`In addition,
`recent observational
`studies have
`reported an ‘obesity paradox’,
`in which T2DM
`patients with normal weight at the time of diagnosis
`had increased cardiovascular risk, while those who
`were heavier at diagnosis had a better outcome
`(9,11). For example,
`in the US pooled analysis
`mentioned above, mortality rates were higher in nor-
`mal-weight participants (284.8 all-cause deaths, 99.8
`cardiovascular deaths and 198.1 non-cardiovascular
`deaths per 10,000 person-years vs. 152.1, 67.8 and
`87.9 per 10,000 person-years, respectively,
`for the
`same events in overweight or obese participants) (9).
`Therefore, although weight loss is recommended
`by all relevant learned bodies as key to management
`of T2DM,
`it remains a controversial area: studies
`appearing to contradict the link between weight and
`T2DM are newsworthy, and reports can undermine
`patient care. In light of this, it is worth taking time
`to review the trial-based evidence for effects of
`weight loss in patients with T2DM – are the benefits
`of weight loss based on assumptions, or does the evi-
`dence demonstrate benefit?
`
`Review methods
`
`In this review, the evidence for the benefits of weight
`loss in the prevention of T2DM is considered, as
`well as the relationship between weight
`loss and
`glycaemic control, cardiovascular risk, and common
`
`comorbidities in patients with T2DM. Relevant arti-
`cles were identified by a literature search in PubMed.
`Further selection of articles was achieved by focusing
`on large cardiovascular outcomes studies reporting
`the association between weight loss and cardiovascu-
`lar risk in patients with T2DM.
`
`The Look AHEAD study
`The Look AHEAD (Action for Health in Diabetes)
`study exemplifies the kind of attention that sur-
`rounds controversial studies of weight and T2DM.
`The trial was
`terminated early, announced in a
`widely reported press release entitled,
`‘Weight loss
`does not lower heart disease risk from type 2 diabe-
`tes’ (12), raising concerns that T2DM patients would
`abandon their weight loss programs without discuss-
`ing the details of the trial with their doctor.
`The Look AHEAD study was designed specifically
`to examine the effect of weight loss on a primary
`outcome of cardiovascular events in overweight and
`obese patients with T2DM (13). Of 5145 people
`enrolled at 16 centres across the United States, half
`were randomly assigned to receive an intensive life-
`style intervention and the other half to a general pro-
`gramme of diabetes support and education. Since it
`was impractical to mask the intervention, the study
`was not blinded, but assessments such as waist mea-
`surements and weight were made by staff unaware of
`the assigned groups. Both groups received routine
`medical care from their own healthcare providers.
`Early results were promising, with analysis after
`1 year showing a mean 8.6% weight loss with the
`intensive lifestyle intervention compared with 0.7%
`for the diabetes support and education group. The
`additional weight loss was associated with a signifi-
`cant reduction of glycosylated haemoglobin (HbA1c)
`levels and improvement in several other cardiovascu-
`lar risk factors compared with the standard group
`(14), and these results were partly sustained at
`4 years (15). Indeed, complete or partial remission
`of T2DM (defined as glucose normalisation without
`the need for drugs) was seen in a small proportion
`of patients
`in the
`intensive
`intervention group
`(p < 0.001 vs.
`the standard therapy group) (16).
`Patients with substantial weight
`loss or fitness
`change, shorter duration of diabetes, a lower HbA1c
`level at entry, and those not using insulin had the
`highest rates of remission or partial remission (16).
`In the
`intensive
`lifestyle
`intervention group,
`severely obese patients (BMI ≥ 40 kg/m2) had a simi-
`lar percentage body weight loss and improvement in
`cardiovascular risk compared with less obese partici-
`pants (BMI < 40 kg/m2) (17). Across all patients, a
`correlation seemed to exist between weight loss and
`improvements in cardiovascular risk factors, with
`
`ª 2014 The Authors International Journal of Clinical Practice Published by John Wiley & Sons Ltd
`Int J Clin Pract, June 2014, 68, 6, 682–691
`
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`684
`
`Importance of weight management in type 2 diabetes mellitus
`
`larger weight losses associated with greater benefits
`(15). The improvements seen with lifestyle changes
`outweighed potential genetic association with the risk
`of T2DM, suggesting intensive lifestyle intervention
`was worthwhile in all patients (18).
`Despite these initial improvements in weight loss,
`and corresponding improvements in glycaemia and
`other
`cardiovascular
`risk factors,
`the difference
`between groups in cardiovascular event rates was
`lower than expected. The planned follow-up for Look
`AHEAD was 13.5 years, but in 2012 the trial was
`halted early, after 9.6 years of
`follow-up, because
`there was thought to be little chance of finding the
`required difference (18%) between the intensive life-
`style intervention and standard care groups (12).
`Analysis of outcomes reported by the time the trial
`was stopped showed that major cardiovascular events
`had occurred in 403 patients in the intensive group
`compared with 418 in the control group (hazard
`ratio 0.95; 95% CI, 0.83–1.09, p = 0.51). This lack of
`significant difference was
`seen despite
`sustained
`weight loss over the study: mean weight loss at the
`end of the trial was 6.0% of body weight in the
`intensive group vs. 3.5% in the standard group.
`It is important to note that a number of factors
`may have reduced the chances of showing cardiovas-
`cular benefit in Look AHEAD. Firstly, the study had
`been powered to detect a difference of 18% in the
`rate of major cardiovascular events, using a compos-
`ite primary outcome of non-fatal myocardial infarc-
`tion, non-fatal
`stroke and cardiovascular death.
`However, preliminary analysis after 2 years showed a
`lower than expected event rate in the standard care
`group, and hospitalisation for angina was added to
`the primary outcome,
`to increase the number of
`events for analysis. It is notable that there was a
`numerical (albeit not statistically significant) reduc-
`tion in the original primary end-point (267 events
`vs. 283 events) but not for angina (194 events vs.
`196 events), suggesting this addition to the end-point
`could have masked a potential risk reduction. Sec-
`ondly, during the trial, patients received management
`of diabetes and cardiovascular risk factors in routine
`care, and their healthcare providers were not blinded
`to assigned groups. In the control group, use of
`potentially cardioprotective agents including metfor-
`min,
`angiotensin-converting
`enzyme
`inhibitors,
`angiotensin-receptor blockers, beta-blockers, and sta-
`tins was higher, potentially neutralising any effect of
`weight loss on cardiovascular outcomes. Finally, the
`weight loss difference between groups was only mod-
`est, partly because of regain in the intervention
`group but also due to the mean 3.5% body weight
`loss in the control group. However, a weight loss of
`this magnitude is not typical of routine care, and
`
`may have contributed to the lower than expected
`event rate in the control group.
`Despite these limitations, the early termination of
`the Look AHEAD study has raised questions as to
`whether weight loss is an essential component of the
`management of T2DM. In this review, the evidence
`for the benefits of weight loss in the prevention of
`T2DM is considered, as well as the relationship
`between weight loss and glycaemic control, cardio-
`vascular risk, and common comorbidities in patients
`with T2DM.
`
`Benefits of weight loss in the
`prevention of T2DM
`
`The potential to prevent or delay the onset of T2DM
`in high-risk individuals through lifestyle interven-
`tions such as diet modification, weight reduction and
`increased physical activity has been established in
`several clinical trials. Furthermore, follow-up studies
`show that shorter term interventions can have a
`long-lasting effect on risk factors and diabetes inci-
`dence – the so-called ‘legacy effect’ – years after the
`lifestyle interventions have finished (19).
`Three studies demonstrate this effect clearly. In a
`trial conducted in 577 adults with impaired glucose
`tolerance from 33 clinics in Da Qing, China, individ-
`uals were randomised to lifestyle intervention (diet
`only, exercise only, or diet and exercise) for 6 years
`(between 1986 and 1992), or to a control group
`(general diabetes counselling). All interventions were
`associated with a significantly reduced risk of devel-
`oping diabetes compared with the control group
`(20). In 2006, a long-term follow-up of the Da Qing
`group identified a legacy effect, with continued bene-
`fits beyond the end of the trial. Compared with the
`control group, the three intervention groups com-
`bined had a 51% reduced incidence of diabetes [95%
`confidence interval (CI) 27–67%], and a 47% reduc-
`tion in the incidence of severe, vision-threatening
`retinopathy over
`the 20-year
`interval
`(95% CI
`1–71%) (21,22).
`Similarly,
`in the Finnish Diabetes Prevention
`Study, adults at high risk of developing T2DM who
`were randomised to intensive dietary and exercise
`counselling had a 58% reduction in the risk of devel-
`oping diabetes after 4 years compared with the usual-
`care group (who received general information about
`lifestyle and diabetes risk) (23). Again, a legacy effect
`was seen after a 13-year follow-up, with intensive life-
`style
`intervention associated with a significantly
`reduced risk of developing diabetes. The intensive
`lifestyle intervention group also sustained lower body
`weights, fasting plasma glucose (FPG) levels and 2-h
`postprandial plasma glucose levels (24).
`
`ª 2014 The Authors International Journal of Clinical Practice Published by John Wiley & Sons Ltd
`Int J Clin Pract, June 2014, 68, 6, 682–691
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`Importance of weight management in type 2 diabetes mellitus
`
`685
`
`In the United States, the Diabetes Prevention Pro-
`gram study showed that overweight adults who had
`elevated blood glucose levels (impaired glucose toler-
`ance) could delay the onset of T2DM, or decrease
`the risk of T2DM, by losing weight (via dietary
`changes and exercise), with results sustained over a
`10-year follow-up period (25,26). In this programme
`of lifestyle changes, weight loss appeared to be the
`most important factor in reducing the risk of diabe-
`tes when compared with diet composition and
`increased physical activity (27).
`The benefit of weight loss in the prevention of
`T2DM therefore seems clear, and based on the avail-
`able evidence,
`the American Diabetes Association
`recommend that all patients with impaired glucose
`tolerance, impaired FPG, or HbA1c 5.7–6.4% should
`aim for a weight loss of 7% of body weight and
`increased physical activity to at least 150 min per
`week of moderate activity (such as walking) to pre-
`vent or delay the onset of T2DM (28).
`
`Benefits of weight loss in the
`management of T2DM
`
`Given the established advantages of weight loss in
`patients with prediabetes,
`it
`seems
`intuitive that
`weight loss will be beneficial in patients with T2DM,
`not only in terms of glycaemic control, but also
`other health benefits associated with complications of
`diabetes. In this section, studies showing effects on
`glycaemic control are reviewed, before looking in
`detail at studies of cardiovascular events, and lastly
`other complications of T2DM.
`
`Effects on glycaemic control
`Weight loss via lifestyle changes is the first-line ther-
`apy for T2DM, not for its own sake, but because of
`the expected improvement in glycaemic control and
`other associated risk factors (28). The landmark UK
`Prospective Diabetes Study (UKPDS) clearly demon-
`strated the benefits of tight glycaemic control (as
`measured by HbA1c and FPG over prolonged peri-
`ods). At the time the UKPDS study started (1977),
`HbA1c had not been widely adopted as the best mea-
`sure of glucose control, and the World Health Orga-
`nization then recommended an FPG level of
`7.8 mmol/l (140 mg/dl) for the diagnosis of diabetes
`compared with the current
`level of 7.0 mmol/l
`(126 mg/dl) today. The study tested whether treat-
`to near-normal FPG (< 6.0 mmol/l) would
`ment
`prevent cardiovascular events, using insulin, sulfonyl-
`urea, metformin or diet. More than 5000 patients
`recently diagnosed with T2DM were randomised,
`and intensive blood glucose control reduced the risk
`of vascular complications in both the short- and long
`
`term, despite weight gain in the intensive control
`(insulin/sulfonylurea)
`group (29). Therefore,
`if
`improved glycaemia reduces cardiovascular risk, and
`weight loss improves glycaemia, weight loss would be
`expected to provide long-term benefits to patients.
`In overweight and obese individuals with T2DM,
`even modest amounts of weight loss (approximately
`5% of body weight) have been shown to improve
`glycaemic control (30). Longitudinal cohort studies
`indicate that changes in BMI among patients with
`T2DM are significant predictors of changes in HbA1c
`(31), and patients who lose weight are more likely to
`achieve target HbA1c values than those with stable
`weight or weight gain (32).
`Analyses of randomised trials and observational
`studies have shown that dietary advice is associated
`with decreases in HbA1c ranging from 0.25% to
`2.9% after 3–6 months, with larger reductions seen
`in patients more recently diagnosed with T2DM
`(33). In UKPDS, weight
`loss in newly diagnosed
`patients with T2DM improved FPG levels, although
`a relatively large weight loss was required to reach
`target FPG levels; for example, weight loss of 28% of
`ideal body weight (18 kg) was needed in those with
`a baseline FPG between 10 and 12 mmol/l (34). The
`link between weight loss and improvements in gly-
`caemic control is further supported by clinical trials
`with weight-loss medications in patients with T2DM,
`which have shown significant reductions in HbA1c
`and FPG (35,36).
`At more extreme levels, dietary energy restriction
`with a very low calorie diet (600 k/cal day) for
`8 weeks normalised beta-cell function and resulted in
`a reversal of T2DM (37). Most patients would find it
`impossible to follow this type of diet long term, but
`bariatric surgery (or metabolic surgery as it is some-
`times termed when used for treatment of T2DM) has
`the potential to offer large and durable weight loss
`that can significantly improve glycaemic control in
`severely obese patients with T2DM (38,39) or even
`induce reversal of T2DM (40,41). While this clearly
`demonstrates the effect of weight loss on glycaemia,
`long-term follow-up data are needed before this
`approach can be more widely recommended, as dis-
`cussed later.
`Although there are an increasing number of phar-
`macotherapy options available to help control gly-
`caemia in patients with T2DM,
`improvement with
`diet and exercise offers several potential benefits over
`pharmacotherapy. These include reduced medication
`costs as well as clinical benefits, such as avoidance
`of drug-related adverse effects and reduced risk of
`hypoglycaemia, a common problem with several
`therapeutic
`options,
`notably
`sulfonylureas
`and
`insulin (42).
`
`ª 2014 The Authors International Journal of Clinical Practice Published by John Wiley & Sons Ltd
`Int J Clin Pract, June 2014, 68, 6, 682–691
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`686
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`Importance of weight management in type 2 diabetes mellitus
`
`Effects on cardiovascular events
`Available evidence from observational studies appears
`to support a reduced risk of cardiovascular events
`following weight loss in patients with T2DM. For
`example, in a prospective analysis of 4970 overweight
`individuals with diabetes (not identified as type 1 or
`type 2) with a 12-year follow-up during 1959–1972,
`weight loss was associated with a 25% reduction in
`total mortality [relative risk (RR) 0.75, 95% CI 0.67–
`0.84] and a 28% reduction in CVD- and diabetes-
`related mortality (RR 0.72, 95% CI 0.63–0.82) com-
`pared with individuals who reported no change in
`weight (43). The participants had provided informa-
`tion on whether weight loss was intentional, helping
`to overcome the confounding effect of weight loss
`resulting
`from comorbid conditions.
`Somewhat
`unexpectedly, it was also noted that weight gain was
`not associated with an increased risk of mortality,
`while very large weight losses (> 31 kg) were associ-
`ated with a small increase in mortality (43).
`Only a randomised clinical trial can definitively
`answer the question of whether weight loss programs
`reduce the risk of mortality or other outcomes. To
`date, the Look AHEAD study has been the only trial
`designed to assess this question but, although this
`trial showed no beneficial effects, it did have a num-
`ber of limitations, as discussed above (13). Further
`trials in this area, if conducted at all, will take many
`years to complete.
`Nevertheless, the designs of pharmacotherapy trials
`have often allowed secondary or post hoc analyses of
`the effects of weight loss on cardiovascular events
`among patients with T2DM. Surprisingly, however,
`given the clear relationship between weight loss and
`improvements in glycaemia,
`the results have not
`always been predictable.
`The PROactive study (PROspective pioglitAzone
`Clinical Trial In macroVascular Events) was a rando-
`mised controlled trial comparing the oral antihyper-
`glycaemic drug pioglitazone (associated with weight
`gain) vs. placebo in 5238 patients with T2DM and
`evidence of macrovascular disease (44). Pioglitazone
`and placebo were each taken in addition to the
`patients’ other glucose-lowering drugs, and patients
`were followed up for an average of 34 months. The
`primary end-point (a composite of all-cause mortal-
`ity, non-fatal myocardial
`infarction,
`stroke, acute
`coronary syndrome, endovascular or surgical inter-
`vention in the coronary or leg arteries, and amputa-
`tion above the ankle) was not significantly reduced,
`but pioglitazone treatment was associated with signif-
`icant reductions in the secondary composite end-
`point of all-cause mortality, non-fatal myocardial
`infarction and stroke.
`
`As with intensive insulin/sulfonylurea treatment in
`the UKPDS study, this effect was seen despite a signif-
`icant weight gain with pioglitazone [mean increase of
`3.6 kg (range –30 to +29 kg) in the pioglitazone
`group vs. a mean decrease of 0.4 kg (range –36 to
`+33 kg) in the placebo group], and a post hoc analysis
`was conducted to determine if body weight and
`weight change were associated with cardiovascular
`outcomes (45). Unexpectedly, across both treatment
`groups, patients who were obese at baseline (BMI
`30–35 kg/m2) had lower mortality than patients with
`normal weight (BMI 22–25 kg/m2). Weight loss dur-
`ing the trial was also associated with increased risk of
`all-cause mortality [hazard ratio (HR) per 1% body
`weight: 1.13, 95% CI 1.11–1.16; p < 0.0001] com-
`pared with those who maintained stable weight (45).
`In patients treated with pioglitazone, weight gain was
`associated with a reduced risk compared with stable
`weight (HR per 1% weight gain: 0.96, 95% CI 0.92–
`1.00, p = 0.037); however,
`this reduced risk with
`weight gain was not observed in the placebo group, or
`when both groups were combined (45).
`Such results could be confounded by unintentional
`weight loss, likely to be associated with other health
`problems that could increase cardiovascular risk, and
`the results do appear to be contradicted by other
`studies, such as the SCOUT study (Sibutramine Car-
`diovascular Outcome Trial). This large prospective
`trial was undertaken to determine whether
`the
`weight-loss drug sibutramine or placebo (both in
`addition to weight management with lifestyle inter-
`vention) would reduce cardiovascular morbidity and
`mortality (46). Patients who were overweight or
`obese, as well as having other risk factors putting
`them at high risk for cardiovascular events (aged
`≥ 55 years with pre-existing CVD, T2DM or both),
`were recruited. All screened subjects received sibutr-
`amine for 6 weeks, after which 9804 patients were
`randomised to either sibutramine or placebo;
`the
`majority of randomised patients (84%) had T2DM.
`After a mean treatment duration of 3.4 years, and
`despite sustained weight reduction with sibutramine,
`the risk of cardiovascular events increased by 16%
`(95% CI 3–31%) with sibutramine vs. placebo. This
`study led in part to the withdrawal of sibutramine as
`a weight-loss drug; however, the large data set gener-
`ated by the study facilitated analyses of weight loss
`and cardiovascular risk. A post hoc analysis showed
`that,
`irrespective of treatment group, there was a
`relationship between the amount of weight lost dur-
`ing the first 12 months of the study and reduction in
`risk, with those who had the largest weight loss hav-
`ing the greatest reductions in the absolute risk of pri-
`mary outcome events. Consistent results were seen
`whether patients were randomised to placebo or
`
`ª 2014 The Authors International Journal of Clinical Practice Published by John Wiley & Sons Ltd
`Int J Clin Pract, June 2014, 68, 6, 682–691
`
`Novo Nordisk Exhibit 2385
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`Importance of weight management in type 2 diabetes mellitus
`
`687
`
`sibutramine, and whether patients were classified as
`having mild, moderate, or
`severe CVD (47).
`Although more events occurred in the randomised
`sibutramine group, weight
`loss of approximately
`3 kg during the first 6 weeks appeared to offset this
`increased event rate (47).
`Despite being limited by its post hoc nature, this
`analysis appears to support the concept that weight
`loss reduces cardiovascular risk, and this is further
`supported by studies suggesting the converse – that
`weight gain may increase cardiovascular risk – as was
`recently reported for the Action to Control Cardio-
`vascular Risk in Diabetes study (ACCORD).
`ACCORD compared a therapeutic strategy aiming
`for HbA1c targets of < 6.0% against a strategy aiming
`for an HbA1c value of 7.0–7.9% with the objective of
`determining if tighter HbA1c control (through more
`intensive therapy) would reduce cardiovascular risk
`(48). Contrary to expectations, intensive therapy did
`not significantly reduce major cardiovascular events;
`in fact, this approach actually increased mortality,
`with the intensive HbA1c intervention prematurely
`terminated because of the higher mortality observed
`(48). However, a reduction in HbA1c was associated
`with a lower risk of mortality, suggesting another fac-
`tor besides the very low HbA1c levels that must
`have accounted for the increased risk in the inten-
`sive-therapy group (49). Weight gain is associated
`with certain medications used more frequently to
`achieve intensive glycaemic control (e.g. insulin was
`given to 77.3% of the intensive therapy group vs.
`55.4% of the standard-therapy group). Weight gain
`was indeed higher in the intensive-therapy group,
`with mean weight gain at 3 years of 3.5 and 0.4 kg in
`the respective groups, and weight gain of more than
`10 kg more frequent in the intensive-therapy group
`(48),
`suggesting that weight change might have
`contributed to the increased risk. Other
`factors,
`particularly hypoglycaemia associated with greater use
`of insulin and sulfonylureas in the intensively treated
`group, were also suggested to have contributed to the
`increased risk; however, a recent post hoc analysis
`found that patients in the intensive therapy group
`actually had a lower risk of mortality if they had
`more hypoglycaemic episodes (50).
`
`Effect on microvascular outcomes and other
`comorbidities
`Weight
`loss is considered key to management of
`T2DM because of the potential to reduce blood glu-
`cose; however, weight
`loss can also impact other
`health problems commonly associated with T2DM.
`In addition, weight loss can reduce the need for
`medications, not only for hyperglycaemia but also
`for hypertension and hyperlipidaemia (51).
`
`Much of the burden of T2DM comes from the
`microvascular complications, retinopathy, nephropa-
`thy, and peripheral and autonomic neuropathy. The
`risk of developing these complications is correlated
`with duration of diabetes, blood glucose control
`and blood pressure, but
`is also associated with
`obesity (52,53). However, as with macrovascular
`outcomes, the role of weight loss in reducing risk is
`unclear. At present, there is evidence for beneficial
`effects of weight loss in overweight patients on pro-
`teinuria in non-diabetic renal disease with neuropa-
`thy, with weight loss of approximately 4% of body
`weight associated with decreases of 31.2  37% in
`proteinuria from baseline in a small, 5-month study
`(54); a reduction in albuminuria was also seen with
`intensive lifestyle intervention in the Look AHEAD
`trial (55). Furthermore, meta-analysis of 13 studies
`of intentional weight loss in patients with chronic
`kidney disease (with and without diabetes) showed
`improvements in proteinuria over a mean follow-up
`of 7.4 months, but long-term studies are needed to
`determine if
`this
`translates
`to improved clinical
`outcomes, such as progression to end-stage renal
`failure (56).
`As well as the vascular complications of T2DM,
`weight loss can improve quality of life and many
`common comorbidities
`(57). Obstructive
`sleep
`apnoea is recognised to be associated with obesity
`and diabetes, and the effect of weight
`loss on
`obstructive sleep apnoea among obese patients with
`T2DM was prospectively assessed in the Sleep
`AHEAD study, a substudy of the Look AHEAD trial,
`and showed that 20% of patients with sleep a