Keywords

Introduction

Diabetes mellitus (DM) is a heterogeneous, complex, and chronic disease in which glycemic regulation and control are progressively lost, leading to hyperglycemia. Diabetes can lead to a number of adverse short- and long-term consequences for patients, and diabetic management is focused on mitigating these adverse outcomes [1]. Studies such as the UKPDS, DCCT, and ACCORD have demonstrated that achieving glycemic control can significantly reduce many DM complications, especially microvascular complications [2,3,4]. A new diagnosis of DM has major ramifications for patients, providers and the healthcare system overall. Effective management not only includes glycemic management but also management of coexisting conditions such as hypertension and hyperlipidemia . Patients may become overwhelmed by the complexity of DM control and the myriad of recommendations given by their healthcare providers, thus jeopardizing their ability to achieve treatment aims and to impact quality of life. A patient-centered approach remains the foundation for successful management of DM and the prevention of DM-related complications [1].

Much has been written about the large increase in the global incidence of DM. According to the CDC, the number of Americans diagnosed with DM has increased fourfold between 1980 and 2014 [5]. As many as 29.1 million people, or 9.3% of the US population, have diabetes as of 2012, and nearly a third of those patients are unaware of their diagnosis [6]. Given the great benefit of tight glycemic control early on in the disease process, identification and screening high-risk individuals remains a priority.

The majority of patients fall into one of two categories: type 1 diabetes or type 2 diabetes.

  • Type 1 diabete s (T1D): an autoimmune disease in which the insulin-producing beta cells are destroyed, leading to an insulin-deficient state. Overall, 5–10% of all diabetics have T1D [7]. While the majority of T1D patients are diagnosed at a relatively young age, a new diagnosis of T1D can occur later in life. The rate of beta cell destruction is variable, and patients with T1D may still produce varying amounts of insulin for some time. T1D patients eventually become dependent on exogenous insulin administration to maintain glycemic control.

  • Type 2 diabetes (T2D) : a disease state in which glycemic control is lost due to a combination of factors, including insulin resistance and relative insulin insufficiency. Approximately 90–95% of all diabetics have T2D [7]. The average age at diagnosis of T2D is older than of T1D; however T2D has also been increasingly diagnosed in younger ages.

  • Other DM types: gestational DM, maturity-onset diabetes of the young (MODY ), and drug-induced DM.

  • Pre-DM: a state in which patients do not meet criteria for DM, but glucose levels are abnormal. Studies have demonstrated that pre-DM often progresses to overt DM, and thus early intervention is considered important.

Diagnosis of DM

DM is commonly diagnosed based on the following ADA criteria [7]:

  1. 1.

    Fasting plasma glucose of ≥126 mg/dL (fasting for 8 h)

  2. 2.

    Hemoglobin A1c ≥ 6.5%

  3. 3.

    Classic symptoms of hyperglycemia + plasma glucose of ≥200 mg/dL

  4. 4.

    2-h plasma glucose of ≥200 mg/dL after a 75-gram oral glucose load

Pre-DM is diagnosed with the following ADA criteria [7]:

  1. 1.

    Fasting plasma glucose of 100–125 mg/dL

  2. 2.

    Hemoglobin A1c 5.7–6.4%

  3. 3.

    2-h plasma glucose of 140–199 g/dL after a 75-gram oral glucose load

A single abnormal test is typically insufficient for the diagnosis of DM and should be repeated to confirm the diagnosis.

Distinguishing between T1D and T2D may initially be difficult. A careful history and physical examination may suggest a specific diagnosis, but final confirmation usually occurs over time. While diabetic ketoacidosis (DKA ) is often the hallmark of T1D, it can also occur on occasion in T2D. Similarly, while certain characteristics such as obesity and dyslipidemia are more common in T2D, they can be encountered in T1D and thus cannot be used to definitively classify a disease type. When T1D is suspected, autoimmune markers such as antibodies to islet cells and insulin, GAD-65, IA-2 and IA-2B, and ZnT8 can be used to help aid in the diagnosis [7]. Insulin secretion can also be assessed in the ambulatory setting by measuring a c-peptide level in the setting of hyperglycemia, with a low value being more consistent with insulin deficiency and T1D.

Screening for DM

Given the large number of patients with undiagnosed diabetes, an evidence-based screening program is important.

According to the US Preventive Services Task Force, the following patient populations without obvious diabetes symptoms should be screened in the ambulatory setting [8]:

  • Adults aged 40–70 who are overweight or obese

  • Non-overweight patients younger than 40 with a family history of DM, personal history of gestational DM or polycystic ovarian syndrome, and certain racial/ethnic groups such as African-Americans, American Indians or Alaskan Natives, Asian-Americans, Hispanics or Latinos, or Native Hawaiians or Pacific Islanders

The ADA recommends repeat testing of high-risk patients every 3 years or more frequently in patients with higher-risk features such as pre-DM [7].

Key H&P

The symptoms and signs of DM are often due to the presence of hyperglycemia. The early stages of DM may often be asymptomatic when the hyperglycemia is mild, but a comprehensive history and physical exam might suggest the diagnosis.

History

The classic symptoms of polyuria, polydipsia, and weight loss are consistent with the osmotic diuresis that can accompany hyperglycemia. Additionally, symptoms such as fatigue, malaise, and blurry vision may be present as well. When T1D is suspected, patients should be asked about the presence of any coexisting autoimmune diseases such as vitiligo and primary hypothyroidism.

Physical Exam

There are few exam findings specific to DM. Cutaneous findings such as acanthosis nigricans and skin tags may suggest the presence of insulin resistance.

Healthcare Maintenance in the Diabetic Patient

  • Annual eye exam

  • Annual monofilament test or other test for detecting neuropathy

  • Hemoglobin a1c every 3–6 months depending on control

  • Annual fasting lipid panel

  • Annual urine albumin-to-creatinine ratio

  • Blood pressure at every visit

  • Annual influenza vaccine and pneumococcal vaccine at appropriate intervals

Treatment

Effectively treating DM requires a patient-centered approach that includes lifestyle modification, glycemic control, and management of comorbid conditions such as obesity, hypertension, and dyslipidemia. Patients with DM are at significantly increased risk for cardiovascular disease including myocardial infarction and stroke, as well as retinopathy and nephropathy, and mitigating these risks remains a primary goal of DM management and treatment [1].

DM complications can be divided into microvascular (retinopathy, nephropathy, neuropathy) and macrovascular (CV disease) categories. Intensive glycemic control has been associated with significant reductions in microvascular complications in both T1D and T2D and in macrovascular complications in T1D [2,3,4]. Importantly, intensive glycemic control has not been consistently found to reduce macrovascular complications in T2D, and therefore a more comprehensive cardiovascular risk reduction strategy should be implemented addressing the traditional risk factors of hypertension, hyperlipidemia, smoking cessation, and weight loss.

Treatment Goals in DM [9]

  • 6.0–6.5%: patients with new DM diagnosis lack of comorbidities, and if able to avoid adverse outcomes with therapy

  • 7.0–8.0%: patients with long-standing DM, high risk for hypoglycemia, multiple comorbidities

Type 1 Diabetes

Insulin therapy is required in the management of T1D, and a comprehensive guide to T1D management is beyond the scope of this resource.

Patients with T1D require both basal and prandial insulin administration. Insulin can be administered with multiple daily injections or using a continuous subcutaneous insulin infusion (“insulin pump”). Prandial insulin should account for the anticipated carbohydrate intake and pre-meal sugars, and a personalized assessment for prandial insulin requirements is a essential part in the successful glycemic management in T1D. Self-monitoring of glucose should be performed both pre-meal and post-meal to assess adequacy of the insulin regimen. A continuous glucose monitoring (CGM) may be used to further assess glycemic management and has been associated with hemoglobin A1c reductions.

Type 2 Diabetes

The American Diabetes Association (ADA ) and the American Association of Clinical Endocrinologists (AACE ) have published comprehensive treatment guidelines for T2D [1, 9]. While there are many different treatment approaches for patients with T2D, it is important that the chosen approach be mutually understood and agreed upon by both patient and provider for the highest chances of success.

Lifestyle Changes

Lifestyle changes remain a backbone of treatment for most patients with T2D as they may partially correct the insulin resistance and impaired insulin secretion associated with the disease. These changes include weight loss, increased physical activity, and smoking cessation. Caloric restriction is a critical aspect of successful weight loss, and nutritional counseling and support with realistic goals can help patients make the appropriate changes to their diet necessary for weight loss [9]. Meal planning for the diabetic patient requires an understanding of the glycemic index of carbohydrate-containing foods. Educating patients regarding meal composition and portion size is also essential. Patients should be given a prescription for increased physical activity advising 30–45 min 4–5 times/week of aerobic exercise.

Motivated patients with newly diagnosed DM with an A1c ≤7.5% may be tried on a 3–6-month trial of lifestyle changes alone but should be started on pharmacotherapy if glycemic targets are not reached. In the majority of patients, lifestyle changes alone are insufficient to achieve sustained adequate glycemic management, and pharmacotherapy will be necessary.

Pharmacological Therapy in T2D

Pharmacological therapy is eventually needed in the majority of patients with T2D. Since early achievement of tight glycemic control has been associated with overall improved outcomes, it is imperative that pharmacological therapy adequate to achieve glycemic goals be initiated early in the disease course. There are a number of pathophysiological defects in T2D, and combination therapies that address several of these defects should be considered in all patients [10].

The choice of therapy should be tailored to fit each patient’s individual glycemic goals while balancing the potential adverse effects of therapy including hypoglycemia. In adults with recently diagnosed T2D and without significant comorbidities such as established cardiovascular disease, intensive therapy sufficient to achieve an A1c of 6.0–6.5% (AACE guidelines) should be considered to reduce microvascular and macrovascular disease [9]. In adults with a longer diabetes course, established cardiovascular disease, or other significant comorbidities, the risk of hypoglycemia and other adverse events associated with the intensive therapy begins to outweigh the potential benefits, and a more lenient A1c target of 7.0–8.0% is appropriate. See Fig. 6.1 for a suggested pharmacological approach to glycemic management.

Fig. 6.1
figure 1

Initial glycemic management (Adapted from the AACE Glycemic Control Algorithm, 2016)

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Choice of Therapy

Both the American Diabetes Association and the American Association of Clinical Endocrinologists have created comprehensive algorithms for pharmacotherapy in T2D [1, 9]. Below is a summary of commonly available diabetic medications, also summarized in Table 6.1.

Table 6.1 Commonly used non-insulin diabetic medications
Full size table

Metformin

The exact mechanism of action of metformin remains unclear, but it appears to primarily decrease hepatic glucose production. Metformin has a long-established cardiovascular safety profile, can promote weight loss, and has a low risk of hypoglycemia. Metformin can have a substantial positive impact on glycemic control with doses of 2000–2500 mg daily. For these reasons, metformin is often the initial agent prescribed for patients with T2D and remains the backbone of therapy.

Adverse effects include gastrointestinal effects, B12 deficiency, and the potential for lactic acidosis. GI effects can be minimized with slow dose titration, administration with foods, and the use of extended-release formulations. B12 deficiency has been associated with metformin use, and B12 levels should be measured in all patients on metformin.

Of note, lactic acidosis is an extremely rare consequence of metformin therapy and is associated with pre-existing renal insufficiency. The new FDA guidelines (2016) recommend that metformin should not be initiated when eGFR drops below 45 mL/min/1.73 m2, should be reconsidered in patients already on metformin when eGFR drops below 45 mL/min/1.73 m2, and should be stopped completely when eGFR drops below 30 mL/min/1.73 m2. Metformin should also be stopped prior to imaging studies with iodinated contrast [11].

Sulfonylureas (Glimepiride , Glyburide , Glipizide ) and Meglitinides (Repaglinide , Nateglinide )

Sulfonylureas act by binding to potassium channels on pancreatic beta cells, inducing insulin secretion. Sulfonylureas can significantly improve glycemic control, are available in once-daily formulations, and are often prescribed as add-on therapy to metformin. Dosing should be increased slowly as some patients are prone to becoming hypoglycemic while on sulfonylureas. Sulfonylurea doses need to be adjusted in patients with underlying kidney disease given the overall long duration of action. Glipizide is the preferred sulfonylurea in patients with chronic kidney disease. The meglitinides have a shorter half-life as compared with sulfonylureas, are taken with meals, and may carry a lower risk of hypoglycemia.

Adverse effects include hypoglycemia, lack of durability, and weight gain. Sulfonylureas have a high incidence of hypoglycemia as compared with other non-insulin therapies, and patients should be advised to monitor their glucose while on therapy.

GLP-1 Receptor Agonists (Exenatide , Liraglutide , Albiglutide , Dulaglutide )

GLP-1 receptor agonists act by binding to glucagon-like peptide-1 receptors and inducing glucose-dependent insulin release from the beta cells. GLP-1 receptor agonists have a strong glycemic effect and are associated with weight loss and blood pressure reductions. They may be used as add-on therapy to metformin and potentially as an alternative to basal insulin therapy in selected patients. GLP-1 receptor agonists are injectables and are available in twice-daily, daily, and weekly formulations. Liraglutide has demonstrated cardiovascular safety in high CV risk patients [12]. Exenatide should not be used with eGFR <30 mL/min.

Adverse Effects

Gastrointestinal side effects include nausea, vomiting, and diarrhea and may be improved over time and with slow dose titration. GLP-1 receptor agonists should be used with caution in patients with gastroparesis. GLP-1 agonists have also been associated with pancreatitis in some studies and should be used cautiously in patients with a personal history of pancreatitis.

GLP-1 agonists should not be given to patients with a personal or family history of MEN type 2 (multiple endocrine neoplasia) or medullary thyroid cancer.

DPP-4 Inhibitors (Sitagliptin , Saxagliptin , Linagliptin , Alogliptin )

DPP-4 inhibitors act by inhibiting dipeptidyl peptidase 4 (DPP-4 ), leading to increased levels of GLP-1. DPP-4 inhibitors have modest glycemic effect but are commonly prescribed as they have few adverse effects, are weight neutral, are dosed once daily, and are available in combination with metformin. DPP-4 inhibitor dosages need to be adjusted in patients with underlying kidney disease except for linagliptin.

Adverse Effects

DPP-4 inhibitors have also been associated with pancreatitis in some studies and should be used cautiously in patients with a history of pancreatitis. There have also been rare reports of hypersensitivity reactions.

SGLT-2 Inhibitors (Canagliflozin, Dapagliflozin, Empagliflozin)

Sodium-glucose co-transporter 2 (SGLT-2 ) inhibitors block the reabsorption of glucose in the nephron, resulting in an osmotic diuresis. SGLT-2 inhibitors have modest glycemic effects and can also result in decreased blood pressure. Empagliflozin has been found to lower all-cause and cardiovascular death and to lower the risk of heart failure hospitalizations [13]. SGLT-2 inhibitor dosages need to be adjusted in patients with underlying kidney disease.

Adverse Effects

SGLT-2 inhibitors can lead to dehydration and hypotension. They have been associated with an increased incidence of genital mycotic infections, as well as an association with bone fractures. Some reports have described the development of euglycemic ketoacidosis with SGLT-2 inhibitor use. There has been an increased incidence of leg and foot amputation with canagliflozin.

Thiazolidinediones (Pioglitazone )

TZDs are the only diabetes medication class that directly reduces insulin resistance by binding to peroxisome proliferator-activated receptors, although the exact mechanisms are unknown. Patients with severe insulin resistance may benefit from TZD therapy. TZDs have modest glycemic efficacy, have a durable effect, and have a low risk of hypoglycemia. Pioglitazone may also have a beneficial impact on lipids, as well as on hepatic steatosis.

Adverse Effects

TZDs are associated with significant dose-dependent weight gain and edema and should not be used in patients at increased risk for heart failure. TZDs have also been linked to an increased rate of bone fractures as well as a possible association with bladder cancer.

Alpha-glucosidase Inhibitors (AGIs ) (Acarbose, Miglitol)

AGIs act by inhibiting carbohydrate absorption in the small intestine and have a significant dose-dependent impact on postprandial glucose levels. Acarbose has also been associated with improved CV outcomes in patients with impaired glucose tolerance. AGI doses need to be adjusted in patients with underlying kidney disease.

Adverse Effects

AGIs often cause flatulence and diarrhea, which can often be improved with lower doses.

Insulin

Insulin is an effective treatment to lower blood glucose and may be the appropriate initial choice of therapy in certain clinical situations. Long-standing diabetics already on two non-insulin agents with an A1c > 8% will likely require the addition of insulin to achieve glycemic targets. Additionally, if the A1c is significantly elevated on initial diagnosis (>9–9.5%) and the patient is significantly symptomatic from the hyperglycemia, insulin may be useful to help rapidly lower the A1c and improve symptoms [9].

Insulin can be given as either a basal dose to help suppress hepatic glucose production or as a prandial dose to help improve postprandial spikes in glucose. See Table 6.2 for a listing of commonly used insulin formulation and peaks of onset. Generally, basal insulin is initially prescribed and slowly up titrated to achieve normal fasting glycemic levels. Basal insulin can be initiated at a dose of 0.1–0.2 U/kg and should be slowly titrated every 2–3 days in order to achieve a fasting blood glucose of <110 mg/dL. Some patients with significant insulin resistance may require very high doses of insulin in order to achieve their glycemic targets. If patients are unable to reach their target hemoglobin A1c with basal insulin, the addition of prandial insulin can be considered with the goal of a 2-h postprandial glucose of <140 mg/dL. Of note, multiple injections of insulin daily may impose a significant burden on patients and should be carefully considered before initiation.

Table 6.2 Insulin formulations
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When insulin is prescribed, patients should be educated carefully about administration techniques, timing and consistency of dosing, and the proper use of blood glucose monitoring with a glucometer. Hypoglycemia remains a primary concern with insulin use given its association with significant comorbidity, and patients should be educated about the symptoms and management of hypoglycemia.

Clinical Pearls

  • Diabetes mellitus is an increasingly common diagnosis in the US and should be considered in patients with polyuria, polydipsia, and fatigue.

  • Diagnosis of DM can be made in the office if fasting plasma glucose is >126 mg/dL or if plasma glucose is >200 mg/dL with hyperglycemic symptoms.

  • Screening for diabetes is indicated for individuals at high risk for diabetes including patients who are 40–70 years old and overweight.

  • A target hemoglobin A1c of 6.0–6.5% should be considered in newly diagnosed diabetics without significant comorbidities.

  • Given the many treatment options available in T2D, patients and providers should be in agreement about glycemic aims before a new regimen is initiated.

  • Insulin therapy is eventually required in many patients with diabetes.

Don’t Miss This!

  • Diabetes mellitus is a chronic and complicated disease, and successful management can often be overwhelming for patients and lead to poor medication adherence. When assessing a potential treatment failure, don’t forget to carefully assess for adherence before changing the DM regimen!