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Brave New World: Improving Obesity and Preventing Cardiovascular Disease

      For several decades, obesity and type 2 diabetes (T2D) have been rising in tandem so that today, they are worsening global pandemics with debilitating, expensive, and often lethal complications. The prevalence of T2D in the United States has risen more than 10-fold from 2.5 million in 1959 to more than 25 million in 2022.
      • O'Keefe J.H.
      • Nassif M.E.
      • Magwire M.L.
      • O'Keefe E.L.
      • Lavie C.J.
      The elephant in the room: why cardiologists should stop ignoring type 2 diabetes.
      During the same time frame, obesity has risen 4-fold, so that now it affects 40% of US adults and is the leading cause of preventable disease and premature mortality. About 90% of people with T2D are overweight or obese, and traditional drugs for T2D, including insulin, sulfonylureas, and thiazolidinediones, cause further weight gain.
      • O'Keefe J.H.
      • Nassif M.E.
      • Magwire M.L.
      • O'Keefe E.L.
      • Lavie C.J.
      The elephant in the room: why cardiologists should stop ignoring type 2 diabetes.
      Even when hemoglobin A1c levels are well controlled using these older glucose-lowering therapies, approximately two-thirds of patients with T2D die of cardiovascular disease (CVD) causes.
      • Gregg E.W.
      • Hora I.
      • Benoit S.R.
      Resurgence in diabetes-related complications.
      ,

      Zhang YB, Pan XF, Lu Q. Association of combined healthy lifestyles with cardiovascular disease and mortality among patients with diabetes: an international multi-cohort study. Mayo Clin Proc. 2023;98(1):60-74.

      Insulin Is Cardiotoxic

      In 1921, Dr Frederick Banting discovered the first effective glucose-lowering agent by extracting insulin from the pancreases of fetal calves and using it in his diabetic patients.
      • O'Keefe J.H.
      • Nassif M.E.
      • Magwire M.L.
      • O'Keefe E.L.
      • Lavie C.J.
      The elephant in the room: why cardiologists should stop ignoring type 2 diabetes.
      A century later, we have 13 classes of glucose-lowering drugs, comprising hundreds of US Food and Drug Administration (FDA)–approved medications for the management of T2D. Although all of these drugs lower serum glucose levels, not a single one had been proven to reduce the alarmingly high risk of CVD death among people with diabetes until 2015, when the EMPA-REG Outcome study using empagliflozin was published.
      • O'Keefe J.H.
      • Nassif M.E.
      • Magwire M.L.
      • O'Keefe E.L.
      • Lavie C.J.
      The elephant in the room: why cardiologists should stop ignoring type 2 diabetes.
      Insulin is one of the key drivers of CVD in T2D. Chronically elevated blood insulin levels predispose to inflammation, hypertension, atherogenic dyslipidemia, atherosclerosis, fluid retention, heart failure (HF), and arrhythmias.
      • Herman M.E.
      • O'Keefe J.H.
      • Bell D.S.
      • Schwartz S.S.
      Insulin therapy increases cardiovascular risk in type 2 diabetes.
      Injected insulin in patients with T2D predictably causes weight gain and can trigger hypoglycemic spells. Prospective observational studies have consistently reported that exogenous insulin for patients with T2D is associated with increased risk of myocardial infarction, ischemic stroke, and CVD mortality in a dose-dependent relationship.
      • Herman M.E.
      • O'Keefe J.H.
      • Bell D.S.
      • Schwartz S.S.
      Insulin therapy increases cardiovascular risk in type 2 diabetes.
      Furthermore, multiple randomized controlled outcome trials implicate injected insulin as a potential contributor to increased risk of CVD, HF, and all-cause mortality among patients with T2D (Figure 1).
      • Herman M.E.
      • O'Keefe J.H.
      • Bell D.S.
      • Schwartz S.S.
      Insulin therapy increases cardiovascular risk in type 2 diabetes.
      ,
      • Liu J.
      • Hu X.
      Impact of insulin therapy on outcomes of diabetic patients with heart failure: a systematic review and meta-analysis.
      Figure thumbnail gr1
      Figure 1Injected insulin among diabetic patients with heart failure was associated with increased risk of mortality, hospitalization, and readmission compared with noninsulin therapies.
      • Liu J.
      • Hu X.
      Impact of insulin therapy on outcomes of diabetic patients with heart failure: a systematic review and meta-analysis.
      RR, relative risk.
      Likewise, sulfonylureas reduce serum glucose levels by stimulating pancreatic beta cells to secrete more insulin; so, as with injected insulin, these agents stimulate weight gain and predispose to hypoglycemia. Randomized trials of sulfonylureas have reported increased risks for CVD, as evidenced by the fact that all sulfonylureas carry an FDA “black box” warning regarding an increased risk for CVD mortality.
      • O'Keefe J.H.
      • Nassif M.E.
      • Magwire M.L.
      • O'Keefe E.L.
      • Lavie C.J.
      The elephant in the room: why cardiologists should stop ignoring type 2 diabetes.
      Thus, for many patients, the use of insulin and sulfonylureas should be carefully considered, given the availability of other agents.

      Lifestyle Improves CVD Risk in Diabetes

      Lifestyle strategies can produce weight loss and improve prognosis in the setting of T2D. Zhang and colleagues

      Zhang YB, Pan XF, Lu Q. Association of combined healthy lifestyles with cardiovascular disease and mortality among patients with diabetes: an international multi-cohort study. Mayo Clin Proc. 2023;98(1):60-74.

      reported in this issue of Mayo Clinic Proceedings that individuals with T2D who followed a healthy lifestyle had significantly lower risks of incident CVD and all-cause mortality. This was a large meta-analysis of 5 international prospective studies comprising more than 100,000 individuals with T2D (about 50% were from the United States, with about 25% each from China and the United Kingdom); 92.5% of the participants were diagnosed with diabetes when they were older than 30 years.
      The 5 healthy lifestyle factors assessed were having an optimal bodyweight, following a healthy diet, performing regular physical activity, being a nonsmoker, and drinking a low to moderate amount of alcohol regularly.

      Zhang YB, Pan XF, Lu Q. Association of combined healthy lifestyles with cardiovascular disease and mortality among patients with diabetes: an international multi-cohort study. Mayo Clin Proc. 2023;98(1):60-74.

      Study participants following 4 or 5 healthy lifestyle factors compared with those following only 1 or none had a highly statistically significant 40% reduction in risk of all-cause mortality during a median follow-up of 10 years. Attaining each single healthy lifestyle factor was associated with a statistically significant 16% lower risk of death during the study. Individuals following 4 or 5 healthy lifestyle factors compared with those following only 1 or none also experienced a highly statistically significant 33% reduction in CVD risk (defined as fatal and nonfatal ischemic heart disease and stroke).
      Without question, a healthy lifestyle is strongly correlated with a favorable CVD prognosis and improved life expectancy in patients with T2D, as is the case in people without diabetes. However, lifestyle-based weight loss strategies, such as diet and exercise, although often effective in the short term, are less effective in the long term because most obese individuals tend to regain the excess adipose tissue. Therefore, safe and effective drug therapy to facilitate and to maintain weight loss for individuals with obesity or T2D is an important unmet need.

      Safe and Effective Drugs for T2D and Weight Loss

      In the past 7 years, many randomized outcome trials of sodium-glucose cotransporter type 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have proven that these 2 classes of diabetic drugs confer remarkable reductions in risk of CVD as well as unprecedented and safe weight loss in the setting of obesity.
      • O'Keefe J.H.
      • Nassif M.E.
      • Magwire M.L.
      • O'Keefe E.L.
      • Lavie C.J.
      The elephant in the room: why cardiologists should stop ignoring type 2 diabetes.
      ,
      • Brown E.
      • Heerspink H.J.
      • Cuthbertson D.J.
      • Wilding J.P.
      SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications.
      Large randomized controlled trials find that these agents confer protection against major CVD events (especially among patients with established atherosclerotic CVD), improve symptoms and prognosis for HF regardless of left ventricular ejection fraction, reduce risk of progression of chronic kidney disease, reduce blood pressure, and decrease risk of both CVD mortality and all-cause mortality.
      • O'Keefe J.H.
      • Nassif M.E.
      • Magwire M.L.
      • O'Keefe E.L.
      • Lavie C.J.
      The elephant in the room: why cardiologists should stop ignoring type 2 diabetes.
      ,
      • Gregg E.W.
      • Hora I.
      • Benoit S.R.
      Resurgence in diabetes-related complications.
      ,
      • Nathan D.M.
      • Lachin J.M.
      • Bebu I.
      • et al.
      GRADE Study Research Group
      Glycemia reduction in type 2 diabetes—microvascular and cardiovascular outcomes.
      Notably, SGLT2 inhibitors and GLP-1 RAs are effective for improving prognosis for many of these conditions even in patients without T2D.
      • Brown E.
      • Heerspink H.J.
      • Cuthbertson D.J.
      • Wilding J.P.
      SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications.
      Weight loss, in the setting of obesity and T2D, will improve many CVD risk factors, including hyperglycemia, dyslipidemia, hypertension, hepatic steatosis, and obstructive sleep apnea; substantial weight loss can even sometimes induce T2D “remission.” Semaglutide and liraglutide are GLP-1 RAs that are FDA approved for weight loss. These agents lower body weight up to about 5% to 15% by slowing gastrointestinal motility and increasing satiety.
      • Brown E.
      • Heerspink H.J.
      • Cuthbertson D.J.
      • Wilding J.P.
      SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications.
      ,
      • Brown E.
      • Wilding J.P.
      • Barber T.M.
      • Alam U.
      • Cuthbertson D.J.
      Weight loss variability with SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes mellitus and obesity: mechanistic possibilities.
      The weight loss is gradual as the dose is titrated up during 3 to 6 months. SGLT2 inhibitors are oral agents that are not approved for weight loss but stimulate modest decreases in body weight, typically 3% to 4% in obese individuals.
      • Brown E.
      • Wilding J.P.
      • Barber T.M.
      • Alam U.
      • Cuthbertson D.J.
      Weight loss variability with SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes mellitus and obesity: mechanistic possibilities.
      Even so, the weight loss is additive when an SGLT2 inhibitor is used with a GLP-1 RA, and the quantity of adipose tissue lost can be substantially enhanced if insulin therapy, sulfonylureas, or thiazolidinediones can be tapered or discontinued.
      • O'Keefe J.H.
      • Nassif M.E.
      • Magwire M.L.
      • O'Keefe E.L.
      • Lavie C.J.
      The elephant in the room: why cardiologists should stop ignoring type 2 diabetes.
      ,
      • Brown E.
      • Wilding J.P.
      • Barber T.M.
      • Alam U.
      • Cuthbertson D.J.
      Weight loss variability with SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes mellitus and obesity: mechanistic possibilities.
      Tirzepatide, a novel once-weekly injection that represents a new class of pharmacologic agents being studied for the treatment of obesity and T2D, is a single peptide that activates the body's receptors for 2 natural incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide. Although it is approved for treating T2D, tirzepatide is demonstrably the most effective drug for weight loss ever developed. In a randomized placebo-controlled clinical trial of obese persons, low-dose tirzepatide (5 mg/wk, injected subcutaneously) produced a 15% reduction of body weight; full-dose therapy (15 mg/wk) lowered weight by 21% (about 50 pounds; Figure 2).
      • Jastreboff A.M.
      • Aronne L.J.
      • Ahmad N.N.
      • et al.
      Tirzepatide once weekly for the treatment of obesity.
      Tirzepatide also reduced waist circumference, serum lipid concentrations, fasting insulin concentration, hemoglobin A1c levels, and systolic and diastolic blood pressure. Adverse events were limited to gastrointestinal symptoms, such as nausea, diarrhea, and constipation, similar to those associated with GLP-1 RAs.
      Figure thumbnail gr2
      Figure 2Tirzepatide at escalating doses significantly reduced weight vs placebo.
      • Jastreboff A.M.
      • Aronne L.J.
      • Ahmad N.N.
      • et al.
      Tirzepatide once weekly for the treatment of obesity.

      Summary

      Lifestyle strategies are effective for improving cardiovascular health and longevity in people with T2D and should be first-line therapy. For the first time, we also have safe and effective drugs for improving CVD prognosis and reducing weight in patients with obesity and T2D, although these agents are highly underused.
      • Mahtta D.
      • Ramsey D.J.
      • Lee M.T.
      • et al.
      Utilization rates of SGLT2 inhibitors and GLP-1 receptor agonists and their facility-level variation among patients with atherosclerotic cardiovascular disease and type 2 diabetes: insights from the Department of Veterans Affairs.
      In the future, lifestyle modification in conjunction with appropriate use of these new glucose-lowering therapies will likely be the preferred therapeutic approach to obesity and T2D.

      Potential Competing Interests

      Dr Carl J. Lavie, associate editor of the journal, had no role in the editorial review or decision to publish this article.

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        Insulin therapy increases cardiovascular risk in type 2 diabetes.
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