Common Comorbidities and Complications of Prediabetes

Common Comorbidities and Complications of Prediabetes

Obesity
Obesity is a neuroendocrine disease that is itself associated with numerous metabolic and biomechanical complications. It is generally defined as a body mass index (BMI) ≥30 kg/m2, especially in the presence of obesity-related complications. In the context of prediabetes, obesity (1-3):

  • Increases risk of progression to type 2 diabetes (T2D), especially among patients with abdominal obesity
  • Increases risk of cardiovascular comorbidities (hypertension, dyslipidemia, atherosclerosis)
  • May limit patient’s ability to engage in physical activity due to joint disorders and other mobility constraints

Obesity is associated with the following complications (4):

Biomechanical

Cardiometabolic

Other Disorders

  • Dismotility and disability
  • Gastroesophageal reflux disease (GERD)
  • Lung function defects
  • Osteoarthritis
  • Sleep apnea
  • Urinary incontinence
  • Dyslipidemia
  • Hypertension
  • Metabolic syndrome
  • Prediabetes
  • Nonalcoholic fatty liver disease (NAFLD)
  • Polycystic Ovarian Syndrome (PCOS)
  • Diabetes
  • Cardiovascular disease
  • Androgen deficiency
  • Cancer
  • Gallbladder disease
  • Depression
  • Anxiety

Therapeutic lifestyle modification is fundamental to the management of obesity; the goal for patients with prediabetes should be a 5% to 10% reduction in weight. In addition, medical weight loss therapies or surgery may be warranted, depending on the degree of obesity complications.

Medical Weight Loss
When diet and lifestyle interventions fail to achieve a loss of 5% to 10% of body weight, pharmacologic agents approved for weight loss should be considered in patients who have a BMI ≥30 kg/m2 or those with a BMI ≥27 kg/m2 who also have obesity complications.

Orlistat. Orlistat is a lipase inhibitor that reduces weight by approximately 5% to 8% in clinical studies, may reduce progression from prediabetes to diabetes, and improve cardiovascular risk factors. It is associated with various gastrointestinal side effects such as fecal urgency and oily spotting (5-8).

Lorcaserin. Lorcaserin is a selective serotonin 2C agonist. In clinical studies, lorcaserin led to loss of 6% to 8%. Among 1595 patients without diabetes treated for up to 2 years with an intensive lifestyle intervention program as well as the study medication, 47.5% of lorcaserin patients lost ≥5% of their body weight compared with 20.3% of placebo patients (P<0.001) (9). In addition to measures of obesity, lorcaserin significantly improved lipids, blood pressure, and inflammatory markers of cardiovascular risk (high-sensitivity C-reactive protein, fibrinogen) (9,10). Lorcaserin is primarily associated with neurologic side effects such as headache and dizziness, and the product labeling includes warnings about cognitive impairment and psychiatric disorders (11). Lorcaserin appears under schedule IV of the Drug Enforcement Administration’s list of controlled substances.

Phentermine/Topiramate. This weight-loss therapy is a combination of low-dose immediate-release phentermine, which induces an anorectic effect through the release of hypothalamic norepinephrine, and controlled-release topiramate, which causes increased satiety due to decreased gastrointestinal motility, increased taste aversion, increased energy expenditure, and decreased caloric intake (12). Approximately 12% weight loss occurred in clinical trials, and up to 67% of phentermine/topiramate-treated patients achieved a ≥5% weight loss (13). Among all patients without T2D at baseline, the high dose of phentermine/topiramate (15/92 mg) reduced the annual incidence of T2D by 76% relative to placebo (P=0.008) (14). In a subgroup analysis of patients with either prediabetes or the metabolic syndrome, progression to T2D was reduced by 89% (P=0.013 vs placebo) and 80% (P<0.001), respectively, with phentermine/topiramate 15/92 mg. The lower dose (7.5/46 mg) did not significantly reduce T2D incidence in the cohort with prediabetes but reduced it by 77% (P=0.009) in patients with the metabolic syndrome (15). Phentermine/topiramate may lead to dry mouth, constipation, and neurologic effects such as tingling and altered taste perception. The product label also includes an absolute contraindication during pregnancy due to fetal toxicity as well as warnings about suicide, mood, and sleep disorders as well as metabolic acidosis (12). This agent appears under schedule IV of the Drug Enforcement Administration’s list of controlled substances.

Naltrexone/Bupropion. This combination of naltrexone, an opioid receptor antagonist, and bupropion, a norepinephrine-dopamine reuptake inhibitor, reduced weight by approximately 6.5% over 1 year in clinical studies and was also associated with improvements in lipids and markers of inflammation, but not blood pressure (16). Gastrointestinal adverse effects such as nausea and constipation were most commonly reported, and the product label includes a black-box warning about suicidal behavior and ideation (17).

Liraglutide 3 mg. This high-dose formulation of the glucagon-like peptide 1 (GLP-1) receptor agonist used to treat T2D was approved in 2015 as a weight-loss agent. In clinical trials among patients without diabetes, a once-daily injection of liraglutide 3 mg reduced weight by 7% to 8% over 1 year (18,19). Improvements in glucose abnormalities (including restoration of normal glucose tolerance), lipids, and blood pressure have been observed in conjunction with weight loss (18-20). Nausea, diarrhea, and other gastrointestinal adverse effects occur frequently with this agent, and the product label includes warnings about thyroid cancer and heart rate elevations. High-dose liraglutide is not indicated for the treatment of T2D (21).

Surgical Weight Loss
Bariatric surgery is effective in reducing the likelihood of diabetes development in patients who are morbidly obese (BMI >40 kg/m2) or who have other significant risk factors. However, the members of the committee of the American College of Endocrinology (ACE) Task Force on the Prevention of Diabetes do not believe that a general recommendation is appropriate for patients with prediabetes (3,22). However, surgical interventions in obesity significantly reduce risks of T2D and mortality and are cost-effective (23-26).

Cardiovascular Disease
Cardiovascular disease (CVD) encompasses cerebrovascular disease, coronary artery disease (CAD), and coronary heart disease (CHD) (22,27). CVD is the primary cause of death for most persons with prediabetes and diabetes, and modification of CVD risk factors is an essential component of the comprehensive care plan for all diabetes types (3).

The CVD event rate in observational studies of individuals with prediabetes, such as AusDiab (Australian Diabetes, Obesity, and Lifestyle Study), the Nurses Health Study, and Framingham, as well as interventional studies such as STOP-NIDDM (Study to Prevent Non–Insulin-Dependent Diabetes Mellitus) and DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication), suggest nearly a doubling of cardiovascular risk in prediabetes compared with risk for individuals without impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (22,28-32).

Dyslipidemia
Individuals with prediabetes have multiple disturbances in lipoprotein metabolism resulting from various combinations of insulin deficiency, insulin resistance, and hyperglycemia (22).

A common dyslipidemic profile among individuals with prediabetes, the metabolic syndrome, or T2D is the dyslipidemic triad (also called the atherogenic lipoprotein profile or atherogenic dyslipidemia). This includes hypertriglyceridemia (triglycerides >150 mg/dL), low high-density lipoprotein cholesterol (HDL-C; ≤35 mg/dL); and small, dense low-density lipoprotein (LDL) particles (3,27).

The management of dyslipidemia in patients with prediabetes and T2D is fundamentally the same. Therapeutic lifestyle changes are central to controlling lipid levels, but pharmacologic therapy should be used to achieve established targets that cannot be achieved with therapeutic lifestyle changes alone. In the absence of contraindications, maximally tolerated statins are the treatment of choice for achieving the following goals (3,27):

Parameter

Treatment Goal

 

Moderate risk
(Prediabetes or diabetes with no ASCVD or major CV risk factors)

High risk
(Established ASCVD or ≥1 major CV risk factor: hypertension, family history of ASCVD, low HDL-C, smoking)

Primary Goals

    LDL-C, mg/dL

<100

<70

    Non-HDL-C, mg/dL

<130

<100

    Triglycerides, mg/dL

<150

<150

    TC/HDL-C ratio

<3.5

<3.0

Secondary Goals

    ApoB, mg/dL

<90

<80

    LDL particles

<1,200

<1,000

ApoB = apolipoprotein B; ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; HDL-C = high-density lipoprotein cholesterol; LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol.

Combination therapy consisting of statins plus bile acid sequestrants, niacin, and/or cholesterol absorption inhibitors should be considered when LDL-C and/or non-HDL-C goals cannot be achieved with statin therapy alone. These agents may also be used instead of statins in cases of statin-related adverse events or intolerance. In patients at LDL-C goal, but with triglyceride concentrations ≥200 mg/dL or low HDL-C (<35 mg/dL), treatment should include fibrates, omega-3 fatty acids, or niacin to achieve the non–HDL-C goal, although niacin may increase blood glucose levels. Patients with very high triglyceride levels (>500 mg/dL) may require omega-3 fatty acids and/or fibrate supplementation to prevent pancreatitis. The use of gemfibrozil is discouraged owing to its interaction with statin drug clearance and risk for severe rhabdomyolysis. Complete discussions can be found in the AACE guidelines and position statements on the management of diabetes and lipids (3,27,33).

Hypertension
Hypertension is common among individuals with prediabetes and, given the high rates of CVD in prediabetes, should be managed as aggressively, because the treatment of hypertension decreases both microvascular and macrovascular risk. For most patients with prediabetes, blood pressure goals are the same as for T2D: ~130/80 mmHg (3,22).

Therapeutic recommendations for hypertension start with lifestyle modification, including the DASH diet (Dietary Approaches to Stop Hypertension), reduced salt intake, increased physical activity, and consultation with a registered dietitian and/or CDE as needed. Many patients will require medication to achieve target blood pressure, and some may require multiple medications. Due to their renal and/or CVD benefits, drugs such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are preferred for patients with prediabetes. Other antihypertensive drugs such as vasodilating beta-adrenergic blockers, calcium channel blockers, diuretics, and centrally acting agents should be used as necessary (3,22).

Secondary Prevention of CVD
Low-dose aspirin is recommended for secondary CVD prevention. For primary CVD prevention, its use may be considered for those at high risk (10-year risk >10%) (3). Low-dose aspirin (75-162 mg daily) is recommended for all high-risk persons with prediabetes for whom there is no identified excess risk for gastrointestinal, intracranial, or other hemorrhagic condition (22).

Chronic Kidney Disease
According to data from the National Health and Nutrition Examination Survey (NHANES), approximately 18% of adults with prediabetes have chronic kidney disease (CKD). Patients with CKD and prediabetes should receive treatment with an ACE inhibitor or an ARB to prevent progression of CKD (3). More information can be found on the T2D Comorbidities page.

Sleep Disorders
Markers for sleep-disordered breathing have been associated with prediabetes. This association was found to be stronger in women and was present primarily in non-Hispanic whites and Mexican Americans (35).

Complications of Hyperglycemia in Prediabetes
Management of prediabetes, with the goals of normalizing blood glucose levels and especially preventing progression of T2D, is vital because some patients with prediabetes may already have not only macrovascular complications of diabetes such as CVD but microvascular complications as well (3,36).

Retinopathy
In the Diabetes Prevention Program (DPP), diabetic retinopathy was observed in 7.9% of patients with IGT who did not progress to diabetes, compared with 12.6% of patients who later progressed to diabetes (37). In addition, the Blue Mountains Eye Study (BMES) revealed a 10% retinopathy incidence among individuals with fasting plasma glucose (FPG) levels between 99 and 112 mg/dL, and a 20% retinopathy incidence among individuals with FPG levels between 113 and 126 mg/dL (38).

Neuropathy
Intraepidermal nerve fiber loss is an early feature of metabolic syndrome, prediabetes, and established diabetes. Managing glucose may prevent worsening of neuropathy (3).

Nephropathy
Patients with prediabetes may have comorbid CKD but are also at risk of developing diabetic nephropathy (30). Appropriate management of prediabetes, along with ACE inhibitor or ARB therapy, if indicated, should be instituted. More information can be found on the T2D Comorbidities page.

References

  1. Garvey WT, Garber AJ, Mechanick JI, Bray GA, Dagogo-Jack S, Einhorn D, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the 2014 advanced framework for a new diagnosis of obesity as a chronic disease. Endocr Pract. 2014;20:977-89.
  2. Mechanick JI, Garber AJ, Handelsman Y, Garvey WT. American Association of Clinical Endocrinologists' position statement on obesity and obesity medicine. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2012;18:642-8.
  3. Handelsman Y, Bloomgarden ZT, Grunberger G, Umpierrez G, Zimmerman RS, Bailey TS, et al. American Association of Clinical Endocrinologists and American College of Endocrinology: clinical practice guidelines for developing a diabetes mellitus comprehensive care plan--2015. Endocr Pract. 2015;21:1-87.
  4. Pi-Sunyer X. The medical risks of obesity. Postgraduate Med. 2009;121:21-33.
  5. Richelsen B, Tonstad S, Rossner S, Toubro S, Niskanen L, Madsbad S, et al. Effect of orlistat on weight regain and cardiovascular risk factors following a very-low-energy diet in abdominally obese patients: a 3-year randomized, placebo-controlled study. Diabetes Care. 2007;30:27-32.
  6. Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients [Erratum in Diabetes Care. 2004;27:856]. Diabetes Care. 2004;27:155-61.
  7. Davidson MH, Hauptman J, DiGirolamo M, Foreyt JP, Halsted CH, Heber D, et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA. 1999;281:235-42.
  8. Hollander PA, Elbein SC, Hirsch IB, Kelley D, McGill J, Taylor T, et al. Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study. Diabetes Care. 1998;21:1288-94.
  9. Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363:245-56.
  10. Fidler MC, Sanchez M, Raether B, Weissman NJ, Smith SR, Shanahan WR, et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab. 2011;96:3067-77.
  11. Arena Pharmaceuticals. Belviq (lorcaserin) prescribing information. Zofingen, Switzerland: Arena Pharmaceuticals; 2012.
  12. Vivis Inc. Qsymia (phentermine and topiramate extended-release) prescribing information. Mountain View, CA: Vivus, Inc.; 2012.
  13. Allison DB, Gadde KM, Garvey WT, Peterson CA, Schwiers ML, Najarian T, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20:330-42.
  14. Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95:297-308.
  15. Garvey WT, Ryan DH, Bohannon NJ, Kushner RF, Rueger M, Dvorak RV, et al. Weight-loss therapy in type 2 diabetes: effects of phentermine and topiramate extended-release. Diabetes Care. 2014;37:3309-16.
  16. Apovian CM, Aronne L, Rubino D, Still C, Wyatt H, Burns C, et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity (Silver Spring). 2013;21:935-43.
  17. Takeda Pharmaceuticals America Inc. Contrave (naltrexone HCl and bupropion HCl) prescribing information. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2014.
  18. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373:11-22.
  19. Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean ME, et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond). 2012;36:843-54.
  20. Pi-Sunyer X, Fujioka K, Le Roux C, Astrup A, Greenway F, Halpern A, et al. Liraglutide 3.0 mg reduces the prevalence of prediabetes and delays onset of type 2 diabetes in overweight/obese adults: the SCALE obesity and prediabetes trial. Presented at the 50th Annual Meeting of the European Association for the Study of Diabetes (EASD), 15–19 September 2014, Vienna, Austria. 2014.
  21. Novo Nordisk Inc. Saxenda (liraglutide rDNA origin) injection prescribing information. Princeton, NJ: Novo Nordisk, Inc.; 2015.
  22. Garber AJ, Handelsman Y, Einhorn D, Bergman DA, Bloomgarden ZT, Fonseca V, et al. Diagnosis and management of prediabetes in the continuum of hyperglycemia: when do the risks of diabetes begin? A consensus statement from the American College of Endocrinology and the American Association of Clinical Endocrinologists. Endocr Pract. 2008;14:933-46.
  23. Sjostrom L, Peltonen M, Jacobson P, Ahlin S, Andersson-Assarsson J, Anveden A, et al. Association of bariatric surgery with long-term remission of type 2 diabetes and with microvascular and macrovascular complications. JAMA. 2014;311:2297-304.
  24. Sjostrom L, Peltonen M, Jacobson P, Sjostrom CD, Karason K, Wedel H, et al. Bariatric surgery and long-term cardiovascular events. JAMA. 2012;307:56-65.
  25. Sjostrom L, Narbro K, Sjostrom CD, Karason K, Larsson B, Wedel H, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007;357:741-52.
  26. Carlsson LM, Peltonen M, Ahlin S, Anveden A, Bouchard C, Carlsson B, et al. Bariatric surgery and prevention of type 2 diabetes in Swedish obese subjects. N Engl J Med. 2012;367:695-704.
  27. Jellinger PS, Smith DA, Mehta AE, Ganda O, Handelsman Y, Rodbard HW, et al. American Association of Clinical Endocrinologists' guidelines for management of dyslipidemia and prevention of atherosclerosis. Endocr Pract. 2012;18 Suppl 1:1-78.
  28. Barr EL, Zimmet PZ, Welborn TA, Jolley D, Magliano DJ, Dunstan DW, et al. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation. 2007;116:151-7.
  29. STOP-NIDDM Trial Research Group, Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, et al. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003;290:486-94.
  30. Dagenais GR, Gerstein HC, Holman R, Budaj A, Escalante A, Hedner T, et al. Effects of ramipril and rosiglitazone on cardiovascular and renal outcomes in people with impaired glucose tolerance or impaired fasting glucose: results of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial. Diabetes Care. 2008;31:1007-14.
  31. Levitzky YS, Pencina MJ, D'Agostino RB, Meigs JB, Murabito JM, Vasan RS, et al. Impact of impaired fasting glucose on cardiovascular disease: the Framingham Heart Study. J Am Coll Cardiol. 2008;51:264-70.
  32. Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care. 2002;25:1129-34.
  33. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. AACE/ACE comprehensive diabetes management algorithm 2015. Endocr Pract. 2015;21:438-47.
  34. Plantinga LC, Crews DC, Coresh J, Miller ER, 3rd, Saran R, Yee J, et al. Prevalence of chronic kidney disease in US adults with undiagnosed diabetes or prediabetes. Clinical journal of the American Society of Nephrology : CJASN. 2010;5:673-82.
  35. Alshaarawy O, Teppala S, Shankar A. Markers of Sleep-Disordered Breathing and Prediabetes in US Adults. Int J Endocrinol. 2012;2012:902324.
  36. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. American Association of Clinical Endocrinologists' comprehensive diabetes management algorithm 2013 consensus statement Endocr Pract. 2013;19:1-48.
  37. Diabetes Prevention Program Research Group. The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program. Diabet Med. 2007;24:137-44.
  38. Wong TY, Liew G, Tapp RJ, Schmidt MI, Wang JJ, Mitchell P, et al. Relation between fasting glucose and retinopathy for diagnosis of diabetes: three population-based cross-sectional studies. Lancet. 2008;371:736-43.