Initial laboratory evaluation of the patient with diabetes includes HbA1c level (if not available within the previous 3 months), fasting lipid profile, liver function tests, evaluation of urine albumin excretion (urine microalbumin-to-creatinine ratio), and assessment of renal function. Patients should undergo baseline and annual dilated eye exam by an ophthalmologist; blindness due to diabetic retinopathy is preventable with early laser photocoagulation surgery [8]. It is also recommended that individuals receive regular and comprehensive dental care and be referred to a mental health professional when indicated (Table 42.1) [7].

If there is any clinical suspicion for autoimmune disease in a person with newly diagnosed diabetes, especially in thin individuals, presence of other autoimmune diseases, or family history of type-1 diabetes, testing for insulin autoantibodies and glutamic acid decarboxylase (GAD) antibodies to rule out latent autoimmune diabetes (LADA) would be advised [9].

This patient’s primary care physician appropriately sent baseline laboratory tests including HbA1c, basic metabolic profile, hepatic function panel, fasting lipids, and spot urine microalbumin.

Multiple large prospective randomized studies have demonstrated the beneficial effects of glycemic control on the development or progression of microvascular complications in patients with diabetes. Both the Diabetes Control and Complications Trial (DCCT) in patients with type-1 diabetes and the United Kingdom Prospective Diabetes Study (UKPDS) in patients with type-2 diabetes showed decreasing rates of microvascular disease (retinopathy, neuropathy, and nephropathy) in individuals who received intensive blood glucose control management [10, 11].

Although epidemiological data in patients with type-2 diabetes has shown an association between macrovascular complications and poor glycemic control, there is a lack of definitive evidence from available randomized studies of the benefits of tight glycemic control on macrovascular complications. Data from the Action in Diabetes and Vascular Disease—Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) and Veterans Affairs Diabetes Trial (VADT) studies showed no significant decrease in cardiovascular morbidity and mortality with intensive blood glucose management [12, 13]. However, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study revealed increased mortality in subjects receiving intensive glycemic control [14]. There has since been much debate about the role of intensive glycemic control in managing patients with diabetes.

In light of the challenges presented by this conflicting data, the ADA has emphasized the importance of tailoring glycemic goals to individual patients with regards to age, established cardiovascular disease, functional status, risk for hypoglycemia, and life expectancy [15]. The ADA recommends achieving a HbA1c <7.0 % with preprandial glucose 70–130 mg/dL and peak postprandial glucose <180 mg/dL in most nonpregnant adults with diabetes (Table 42.1). In older individuals, particularly those with established cardiovascular disease or risk for hypoglycemia, a less strict glycemic goal (HbA1c 7.5–8 %) may be more appropriate [7].

In this newly diagnosed middle-aged patient with obesity and a family history of cardiovascular disease, it was reasonable to target an HbA1c <7 %. After 3 months of metformin therapy, his HbA1c had decreased from 9.7 % to 8.6 %. Thus, in addition to counseling regarding the importance of physical activity and lifestyle change, the patient’s metformin ER dose was increased on this visit.

Care for individuals with diabetes should be provided in collaboration with the patient’s primary care physician, nutritionist, ophthalmologist, diabetes educator, and when indicated, a mental health professional. It is vital that patients take an active role in diabetes self-management.

Recent collaboration between the ADA and the European Association for the Study of Diabetes (EASD) established the importance of individualized treatment goals in the management of type-2 diabetes [16]. Among the issues to consider when developing a diabetes treatment plan are medication side-effect profiles and cost, risk of hypoglycemia, patient’s attitude, and expected treatment efforts and patients’ functional status.

All patients should be offered basic education about diabetes self-management. The mainstay of treatment in type-2 diabetes is attention to lifestyle change, including dietary counseling and increasing physical activity (ideally, at least 150 min/week of moderate activity) [7]. The American College of Sports Medicine and the ADA both endorse increased physical activity for its role in improving glycemic control, positively affecting lipids and blood pressure and preventing cardiovascular mortality in patients with diabetes [17].

Metformin has been the first-line pharmacologic therapy of choice for patients with type-2 diabetes for some time. The UKPDS demonstrated the benefits of metformin on cardiovascular outcomes in diabetes-related endpoints [18]. On the cellular level, metformin, a biguanide, is thought to activate AMP-kinase thereby decreasing hepatic gluconeogenesis [19]. Newer data suggests that it may also act by suppressing hepatic glucagon signaling [20]. Metformin does not cause hypoglycemia and is weight neutral. While it has been shown to cause lactic acidosis, this side effect is exceedingly rare. As such, metformin is not recommended in patient with renal insufficiency or a history of alcohol abuse. Common side effects of the medication include bloating and gastrointestinal upset [21, 22]. Gastrointestinal side effects tend to resolve in most patients over a short period of time and individuals should be counseled about their occurrence. Metformin is available in immediate and extended-release formulations. While the extended-release formulation can be dosed once daily, many clinicians prefer dosing the medication twice daily.

When patients fail to achieve glycemic goals with metformin alone, another agent should be considered. Treatment options are varied and include multiple classes of medications such as sulfonylureas/insulin secretogogues, thiazolidinediones (TZDs), and the newer incretin-mimetics/GLP-1 receptor agonists, and oral dipeptidyl peptidase 4 (DPP-4) inhibitors. Choice of drug is dependent on multiple patient-specific factors including age, renal function, and functional status, as well as medication-specific factors such as cost, pharmacokinetics, and side-effect profile [7].

Sulfonylureas have the potential to cause hypoglycemia and weight gain and secondary failure with this class of medications is common; thus, their use is limited [23]. TZDs activate peroxisome proliferator-activated receptor-γ (PPAR-γ) causing improvement in peripheral insulin sensitivity [24]. They also decrease hepatic gluconeogenesis [25]. Unfortunately, TZDs have been associated with increased risk of bladder cancer and myocardial infarction [26, 27]. Combined with the known side-effects of fluid retention, weight gain, and increased risk of bone fracture, TZDs have generally fallen out of favor among many diabetologists as second-line agents and have been replaced by some of the newer diabetes medication classes.

The newer incretin mimetics enhance pancreatic insulin secretion, suppress glucagon output, and delay gastric emptying by mimicking the effects of endogenous glucagon-like-peptide 1 (GLP-1) [28]. Exenatide, liraglutide, and long-acting exenatide can also cause nausea and vomiting in some patients and are both injectable medications. Overall however, many patients experience weight-loss, making GLP-1 agonists an appealing addition to existing diabetes treatment regimens.

Oral DPP-4 inhibitors/gliptins act similarly to incretin mimetics by upregulating insulin and decreasing glucagon secretion [29]. They do so by increasing circulating levels of GLP-1 and gastric inhibitory peptide (GIP). In addition to their oral formulation, these medications tend to be weight-neutral, adding to their appeal.

It was appropriate for this patient’s primary care physician to initiate metformin therapy at time of diagnosis. Now, 3 months after treatment, combined with attention to lifestyle management, it is reasonable to consider up-titration of his metformin dose. If he were not to experience improvement in HbA1c at future visits, one might consider further titration of his metformin or consider adding another oral agent to his regimen at that time.

Diabetes is widely recognized as a cardiovascular disease equivalent and it is important to risk stratify individuals with the disease. The ultimate goal of cardiovascular risk stratification is to identify high cardiac risk patients who might benefit from increased surveillance or coronary revascularization. The ADA, however, does not recommend routine screening of asymptomatic patients for cardiovascular disease [7, 30]. Data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2-D) trial found no significant difference in rates of death from major cardiovascular events between patients undergoing coronary revascularization and those undergoing medical therapy [31]. Thus, aggressive cardiac risk factor modification should be pursued in patients with diabetes.

Our patient’s baseline laboratory evaluation revealed normal renal function and resting ECG and a fundoscopic examination was without evidence of retinopathy. He does not endorse any cardiac symptoms. His family history is significant for a father with premature coronary disease. Therefore, modifiable risk factors such as elevated LDL cholesterol and obesity should be aggressively managed. He is already on low dose antiplatelet therapy. In the absence of cardiac symptoms, he should not be referred for cardiac testing at this time.

LDL cholesterol is a major predictor of cardiovascular disease, especially in patients with diabetes. LDL-lowering therapies, particularly statins, are beneficial in both primary and secondary prevention of cardiovascular disease. The ADA recommends that patients with diabetes have annual fasting lipid profiles [7]. In highest risk patients (those with known cardiovascular disease), it is reasonable to target an LDL cholesterol goal of <70 mg/dL and a non-HDL cholesterol goal of <100 mg/dL (Table 42.1). Patients with diabetes over the age of 40 without overt cardiovascular disease should target an LDL cholesterol goal of <100 mg/dL and a non-HDL cholesterol goal of <130 mg/dL [7, 32]. The Framingham risk score has been widely validated in assessing an individual’s risk of major coronary event (fatal or nonfatal myocardial infarction) over a 10-year period [33, 34]. Experts consider a 10-year risk of major coronary event ≥20 % to be an appropriate cut-off for aggressive intervention directed at the abnormal prognostic factors. This patient has multiple cardiovascular disease risk factors including a history of hypertension as well as a family history of cardiovascular disease. His Framingham risk score is 15 %. Hence, he was started on statin therapy with a target LDL cholesterol of <100 mg/dL. Treatments aimed at addressing elevated triglyceride and low HDL cholesterol levels are generally considered of less import [32]. Moreover, statins are the initial therapy of choice for patients with elevated triglycerides and low HDL cholesterol. Our patient’s HDL cholesterol of 37 mg/dL is slightly below the ADA recommended cutoff of 40 mg/dL. His triglyceride level of 209 mg/dL is also slightly above the ADA recommended cutoff of 150 mg/dL. Thus, statin therapy was initiated.