Management of Common Comorbidities of Diabetes

Management of Common Comorbidities of Diabetes

As may be expected with a chronic disease that primarily affects middle-aged and older individuals, type 2 diabetes is usually complicated by other medical conditions. In the 1999-2004 cohort of the National Health and Nutrition Examination Survey (NHANES), only 14% of patients with type 2 diabetes had no other comorbidities.1 Here we briefly outline management recommendations for major comorbidities of patients diagnosed with diabetes—the management recommendations are the same whether patients have type 1 or type 2 diabetes mellitus (T1DM and T2DM). A discussion of prediabetes and comorbidities can be found elsewhere on this site.


In the 1999-2004 NHANES study of people with type 2 diabetes, 27% of the participants were overweight
(BMI 25–29 kg/m2) and 61% were obese (BMI ≥30 kg/m,2).1 Obesity not only increases the risk of type 2 diabetes, it imposes the following challenges to management of diabetes after diagnosis:2

  • Increases risk of cardiovascular comorbidities (hypertension, dyslipidemia, atherosclerosis)
  • May limit patients’ ability to engage in physical activity
  • Increases insulin resistance (requiring higher insulin doses for patients needing insulin)
  • Changes neuroendocrine signaling and metabolism
  • Reduces quality of life

Weight loss is a fundamental tenet of type 2 diabetes management. Overweight individuals with type 2 diabetes should strive for a 5% to 10% reduction in weight and should avoid weight gain. Both medical nutritional therapy and physical activity are essential to achieving this goal. Antidiabetic medications that promote weight loss (eg, the GLP-1 receptor agonists) and bariatric surgery may be appropriate for selected patients.2


AACE and the American Diabetes Association (ADA) both recommend annual dyslipidemia screening by means of a fasting lipid profile for all adults with diabetes.2-4 A recent retrospective study of electronic medical records of over 125,000 patients with type 2 diabetes found that 99% of them were eligible for lipid-lowering therapy (ie, had overt cardiovascular disease or were at high risk of developing it), but only 63% were receiving a statin.5 Moreover, in the NHANES 1999–2004 cohort, 46% of patients with type 2 diabetes had elevated lipid values, suggesting a need for improved identification and control of lipid abnormalities.1

Therapeutic lifestyle changes are central to controlling lipids, but pharmacologic therapy should be used to achieve the targets outlined in Table 3 when these cannot be achieved with therapeutic lifestyle changes alone. Statins are the treatment of choice for low-density lipoprotein cholesterol (LDL-C) control in the absence of contraindications. Combinations of statins with bile acid sequestrants, niacin, and/or cholesterol absorption inhibitors should be considered in situations of inadequate goal attainment. These agents may be used instead of statins in cases of statin-related adverse events or intolerance. In patients with LDL-C at goal, but with triglyceride concentrations of ≥200 mg/dL or low HDL-C (<35 mg/dL), treatment should include fibrates or niacin to achieve the non–HDL-C goal.2,3

AACE has recently issued a complete set of guidelines for the diagnosis and management of lipid abnormalities.3


At least 67% of persons with T2DM either have uncontrolled hypertension or are being treated for elevated blood pressure.6 The combination of hypertension and diabetes magnifies the risk of diabetic complications, while treatment of hypertension decreases both microvascular and macrovascular risk.7,8 In the United Kingdom Prospective Diabetes Study (UKPDS), each 10 mm Hg decrease in systolic blood pressure was associated with a 17% reduction in rates of diabetes-related mortality, a 12% reduction in myocardial infarction, and a 13% reduction in microvascular endpoints (P<0.0001).7 Other studies including large numbers of persons with diabetes have shown that both cardiovascular outcomes as well as nephropathy and retinopathy are improved by tight control of blood pressure.7-13 On the basis of these data, the Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), the ADA, and AACE have recommended that blood pressure in diabetes be controlled to levels of 130/80 mm Hg.4,14,15 While glucose and lipid management remain important, blood pressure lowering has the greatest and most immediate impact on morbidity and mortality.8,13

In the office, blood pressure should be measured using standardized techniques. In addition, 24-hour ambulatory blood pressure monitoring is an important tool for guiding care of patients diagnosed with hypertension, especially those with suspected white coat hypertension, masked hypertension, and nighttime nondipping status.2 Patients whose 24-hour mean blood pressure values exceed 135/85 mm Hg are nearly twice as likely to have a cardiovascular event as those with 24-hour mean blood pressure values that remain below 135/85 mm Hg, irrespective of the level of the office blood pressure.16

The selection of antihypertensive medications should be guided by the following disease-specific considerations:2

  • Albuminuria
  • Cardiovascular disease (CVD)
  • Heart failure
  • Postmyocardial infarction status
  • Possible metabolic adverse effects
  • Number of pills per day
  • Adherence
  • Cost

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.17 In addition, most patients with diabetes require 2 to 4 drugs to achieve target blood pressure, and long-term follow-up data from the UKPDS have shown that antihypertensive therapy must be maintained to prevent loss of benefit.2,13 Diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), β-adrenergic blockers, and calcium antagonists have all demonstrated a benefit in the treatment of hypertension in both T1DM and T2DM. The introduction of fixed-dose combination tablets has facilitated patient adherence to multidrug regimens and should be encouraged as part of initial therapy.2

AACE has issued a complete set of guidelines for the diagnosis and management of hypertension.14

Chronic Kidney Disease

Chronic kidney disease (CKD) affects ~40% of patients with diabetes.18 It is not only a complication of diabetes, it is also frequently a comorbidity that is present before diabetes onset. In addition, CKD more than doubles the risk of CVD, whether or not patients have diabetes. The National Kidney Foundation has issued comprehensive guidelines for the diagnosis and management of CKD in all patients and more specific recommendations for diabetic kidney disease (DKD).19,20 Recently, the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) endorsed the effort of by Kidney Disease: Improving Global Outcomes (KDIGO) to update the classification system for kidney disease severity (Table 1). While the thresholds for both estimated GFR and albuminuria remain unchanged in the new classification, 3 albuminuria stages have been added to enhance the GFR stages. Stage 3 CKD has also been subdivided at an estimated GFR of 45mL/min per 1.73 m2, and there is a new emphasis on clinical diagnosis in addition to GFR and albuminuria stages.21

Table 1. KDIGO Chronic Kidney Disease Classification—Composite Ranking for Relative Risks21





Albuminuria stages(mg/g)












Optimal and high normal


Very high and nephrotic










GFR stages
(mL/min per 1.73 m2 body surface area)


High and optimal


Very low

Very low



Very high





Very low

Very low



Very high



Mild to moderate






Very high


Moderate to severe






Very high








Very high


Kidney failure


Very high

Very high

Very high

Very high

Very high

Good glucose and blood pressure control are essential to the management of CKD in patients with diabetes; the antihypertensive regimen should include an ACE inhibitor or an ARB because of beneficial effects on the renin-angiotensin system.2,19,20 Renal disease complicates diabetes therapy in various ways. Moderate renal disease necessitates dosage adjustments for many agents, and the α-glucosidase inhibitors, metformin, nateglinide, and most sulfonylureas should not be used in patients with severe renal disease.20,22 Severe kidney disease also affects the pharmacokinetics of insulin, increasing the risk of hypoglycemia in such patients. Patients with stage 4 or 5 CKD should be referred to the care of a nephrologist.2,19,20

Cardiovascular Disease

Cardiovascular disease (CVD) is the primary cause of death for most persons with diabetes, and modification of CVD risk factors is an essential component of the comprehensive care plan for all forms of diabetes. CVD encompasses cerebrovascular disease, coronary artery disease (CAD), and coronary heart disease (CHD). CVD risk assessment is based on CAD risk, which may be categorized as shown in Table 2.3

Table 2. CAD Risk Categories3

Risk Category

Risk Determinants

Very high

Established or recent hospitalization for coronary, carotid, and peripheral vascular disease or diabetes plus 1 or more additional risk factor(s)


≥2 risk factors and 10-year risk >20% or CHD risk equivalents,* including diabetes with no other risk factors

Moderately high

≥2 risk factors and 10-year risk 10%-20%


≥2 risk factors and 10-year risk <10%


≤1 risk factor

*Diabetes and clinical manifestations of noncoronary forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease)

AACE has designated the following as risk factors for CVD (Table 3).3

Table 3. CVD Risk Factors3




  • Advancing age
  • High total serum cholesterol level
  • High non–HDL-C
  • High LDL-C
  • Low HDL-C
  • Diabetes mellitus
  • Hypertension
  • Cigarette smoking
  • Family history of CAD
  • Obesity or abdominal obesity
  • Family history of hyperlipidemia
  • Small, dense LDL-C
  • Increased Apo B
  • Increased LDL particle number
  • Fasting/postprandial hypertriglyceridemia
  • PCOS
  • Dyslipidemic triad*
  • Elevated lipoprotein (a)
  • Elevated clotting factors
  • Inflammation markers (hsCRP; Lp-PLA2)
  • Hyperhomocysteinemia
  • Apo E4 isoform
  • Elevated uric acid

*Hypertriglyceridemia; low high-density lipoprotein cholesterol; and small, dense low-density lipoprotein cholesterol.

Nonglucose cardiovascular risk reduction targets are summarized in Table 4 and discussed below (glucose goals are discussed in detail elsewhere on this site).2

Table 4. Management Goals for Cardiovascular Risk Factors2,3

Risk Factor

Recommended Goal

Anticoagulant therapy

Use aspirin for primary and secondary prevention of CVD events


Reduce by 5%-10%; avoid weight gain



      Total cholesterol

<200 mg/dL

      Low-density lipoprotein cholesterol (LDL-C)

<100 mg/dL; <70 mg/dL (all very high-risk patients)

      Non-high density lipoprotein cholesterol (non-HDL-C)

30 mg/dL above LDL-C goal

      Apolipoprotein B (apoB)

<80 mg/dL very high risk; <90 mg/dL high risk

      High density lipoprotein cholesterol (HDL-C)

As high as possible but at least >40 mg/dL in both men and women


<150 mg/dL

Blood pressure



<130 mm Hg


<80 mm Hg

AACE recommends using low-dosage aspirin (75-162 mg daily) for secondary prevention of CVD. For primary prevention of CVD, aspirin may be considered for those at high risk (10-year risk >10%).2


Routine depression screening of adults with diabetes is recommended. Untreated comorbid depression can have serious clinical implications because depression contributes to poor self-care, reduced treatment adherence, and poor glycemic control.23 Depression and diabetes also are associated with a significantly increased all-cause and CVD-related mortality.24 Continuing use of antidepressant medications may also increase the risk of developing T2DM, although the elevation in absolute risk is modest.25

Sleep Disorders

Sleep deprivation from any cause, and sleep apnea in particular, aggravates insulin resistance, hypertension, hyperglycemia, dyslipidemia, and inflammatory cytokines. Sleep apnea, in which the individual stops breathing and is then awakened by the need for oxygen, is especially common in adults with diabetes, occurring in approximately 2 of 3 of men with diabetes older than 65 years.26 The most common type of sleep apnea, obstructive sleep apnea, occurs most frequently in obese persons, men, and the elderly.27 Treatment of obstructive sleep apnea in persons with diabetes can lower blood glucose levels as much or more than treatment with oral antidiabetic agents and can also improve cardiovascular outcomes.28-32

The usual treatment of obstructive sleep apnea is continuous positive airway pressure. Patients with newly diagnosed sleep apnea should persevere through the initial phase of this approach. When successful, it can dramatically improve a person’s quality of life.33 Because of recent improvements in the technology, this treatment should be reevaluated for those patients in whom continuous positive airway pressure failed in the past. For certain subgroups with obstructive sleep apnea, surgery to widen the airway or devices that reposition the jaw may be appropriate.2


A growing body of evidence suggests that diabetes itself and some antidiabetic treatments may increase cancer risk. A recent consensus report issued by the ADA and the American Cancer Society explored this issue and reported the following conclusions:34

  • Diabetes (particularly T2DM) is associated with an increased risk for cancers of the:
    • Liver
    • Pancreas
    • Endometrium
    • Colon and rectum
    • Breast
    • Bladder
  • Diabetes is associated with a reduced risk of prostate cancer.
  • Shared risk factors (eg, such as aging, obesity, diet, and physical inactivity) between the two diseases may account for the observed increase in cancer risk; hyperinsulinemia, hyperglycemia, and inflammation may contribute directly to the development of cancer in patients with diabetes.
  • Patients with diabetes should undergo appropriate cancer screenings as recommended for all people in their age and sex.
  • Healthful diets, physical activity, and weight management reduce risk and improve outcomes of type 2 diabetes and some forms of cancer and should be promoted for all patients.
  • Cancer risk should not be a major factor in the choice of antidiabetic agent for most patients. Selected patients with very high risk of cancer occurrence (or for recurrence of specific cancer types), the choice of antidiabetic treatment may require more careful consideration.

The authors of the consensus report also noted that the evidence for the effects of specific drugs on cancer risk is limited, and with many potential confounding factors such as the indications for specific drugs, effects on other cancer risk factors such as body weight and hyperinsulinemia, and the complex progressive nature of hyperglycemia and pharmacotherapy in type 2 diabetes. Preliminary data suggest that metformin may be associated with reduced cancer risk. The report also cites preliminary evidence suggesting that exogenous insulin, particularly glargine, may be associated with an increased risk with the caveat that additional research will be needed to clarify and validate these associations.34 In fact, 3 recent epidemiologic studies presented in 2012 at the ADA 72nd Scientific Sessions found no evidence of an increased risk of cancer with glargine compared to other insulins. In addition, in the prospective Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, no increased incidence of cancer was observed in >6000 patients receiving glargine over a median trial duration of 6 years.35 AACE also recently convened a consensus conference on this topic; for more information, see Diabetes and Cancer.36


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