Diabetes clinical decision-making in patients at risk: Taking patient complexity into account

Frank Lavernia, MD, North Broward Diabetes Center in Pompano Beach, 4855W. Hillsboro Blvd, Suite B-6, Coconut Creek, FL 33073.

E-mail address: diabetescontrol@aol.com.

This article was designed to be viewed and distributed as a PDF. Please download the PDF for easiest reading.    

‌Introduction

‌Currently one in ten adults in the United States (U.S.) have diabetes. If current trends continue, as many as one in three U.S. adults could have diabetes by 2050 (Fig. 1)1,2 The increase in diabetes prevalence has been concomitant with an increase in obesity prevalence.3,4 Despite the known benefits of weight loss on blood glucose levels, many individuals with type 2 diabetes (T2DM) continue to be overweight or obese. These worsening trends in obesity and T2DM raise a serious conundrum, namely, how to control blood glucose, blood pressure, and lipids, when many antidiabetic agents cause weight gain and thereby exacer- bate other cardiovascular (CV) risk factors associated with T2DM. Obesity is a major risk factor for the development of diabetes and predisposes individuals to hypertension and dyslipidemia. Together, these pathologies increase the risk for cardiovascular disease (CVD), the major cause of morbidity and mortality in T2DM.

The Diabetes and Obesity Epidemic

While T2DM affects almost 10% of the U.S. population, it disproportionally affects minorities (Fig. 2).1 and older Americans, both in terms of prevalence, complications, and outcomes.1 African Americans bear the brunt of diabetes, with almost three-fourths of this adult population affected, while two in three Hispanic American adults may have diabetes.1 Subtle distinctions can also be made within ethnic groups. For example, within the Hispanic American population, rates of diabetes are greatest in Mexican Americans and Puerto Rican Americans, and lower in Cuban Americans and those from South America.1 Another group in which diabetes is increasingly being identified is the Asian population, especially among Southeastern Asians, who have higher rates of diabetes than waist circumference or obesity alone would predict (Fig. 3).5

Figure 1 Trends in the Number of Americans With Diabetes.

Data from the Healthy People 2010 database (Fig. 4)6 show that diabetes-related death rates in the U.S. also disproportionally affect many minority groups.6 Some of these differences relate to educational and income levels (and access to medical care) and some to genetic predisposition.6 These data suggest that more educated patients suffer less from diabetes complications and consequences, and point to an opportunity for osteopathic physicians to address educational needs of their patients, at least as it relates to their patients’ understanding of diabetes care. Specific regions of the United States are also disproportionally affected, giving rise to a recent appella- tion, the “Diabetes Belt,” which consists primarily of the southern states as well as areas of Appalachia.7 These areas are, not coincidently, also areas with higher than average rates of obesity8 (Fig. 5).7,8

‌Identifying Patients at Risk

Figure 3 Absolute Incidence Rates of Diabetes by Waist Circumference, Stratified by Race/Ethnicity. The Multi-Ethnic Study of Atherosclerosis, United States, 2000–2007.

Diabetes risk screening is important for all clinicians to consider within their patient populations for several reasons. The onset of T2DM is estimated to occur several years before the clinical diagnosis is usually made and epidemio- logic evidence suggests that complications may occur several years before diagnosis.9 Furthermore, at least one-third of patients with diabetes are not aware of their condition.10 Another 54 million patients have pre-diabetes,1 or to use the American Diabetes Association’s (ADA) terminology, are “at-risk” patients.10 Patients who should be considered for diabetes risk screening are identified in Table 1.9 The ADA has recently made available a patient screening tool, which is available both in English and in Spanish (http://www.diabetes.org/diabetes-basics/prevention/diabetes- risk-test/) (Fig. 6). Criteria for the diagnosis of diabetes by various methods are summarized in Table 2.10 Fortunately, the use of laboratory evaluation of hemoglobin (Hb) A1C (though not point-of-care HbA1C testing) can now be used to identify patients who should be further evaluated.11 A1C levels Z 6.5% are associated with an increased risk of blood vessel damage (detected in the eye as retinopathy) and patients with A1C levels confirmed with repeat testing are considered to have diabetes.12 A1C levels o 5.7% are considered normal (ie, no diabetes) while patients with A1C results between 5.7% and 6.4% should be considered “at risk” and counseled on nutrition and physical activity, and should be followed more closely over the years.9 Patients with uncontrolled T2DM (A1C levels persistently above 7%) are at risk for serious diabetes-related complications which include both macrovas- cular disease (CVD being the primary cause of death for patients with T2DM) and severe, and life-altering micro- vascular complications including diabetic retinopathy (which can result in blindness), painful diabetic neuropathy (which may culminate in the need for amputation of an extremity) and diabetic nephropathy (which may ultimately lead to end-stage renal disease and a need for dialysis).1 Good glycemic control (to A1C levels o 7%) has been shown to substantially reduce microvascular complications,13,14 and good long-term glyce- mic control can reduce macrovascular complications.15 Along with good glycemic control, which often requires the use of multiple therapeutic agents, the control of CV risk factors such as hypertension and dyslipidemia are essential components of a comprehensive care approach for patients with T2DM.16,17

Type 2 Diabetes: Complex Pathophysiology Creates Treatment Challenges

Figure 2 Percent of Adults With Diabetes, by Ethnicity.

Figure 4 Diabetes-related Death Rates in the US; Deaths per 100,000. Panel A by Racial/Ethnic Group; Panel B by Education Level.

T2DM is a disease with a multifactorial pathophysiology, which also drives the need for combination therapy strategies, as no single agent addresses each of the core defects of T2DM. Until recently, and in large part as a result of a limited number of mechanisms of action (MOAs) with which to address hyperglycemia, the primary defects of T2DM were considered to be only insulin resistance and insulin deficiency. Now as a result of a better understanding of the complex pathophysiology and the availability of new drugs with additional MOAs, the concept of numerous pathophysiologic defects have been identified18, the main ones being summarized in Fig. 7.

Therapeutic options have increased dramatically from insulin in the 1920’s, sulfonylureas in the 1950’s, metformin in the 1980’s, thiazolidinediones (TZDs) in the late 1990’s, to today’s options of agents from at least 11 different drug classes.

Goal Setting for Patients With Type 2 Diabetes: Balancing Glucose Lowering While Avoiding Hypoglycemia

Before delving into a discussion of treatment options and treatment strategies, it is important to be aware that a first step is the appropriate and individualized setting of treatment goals. Both the ADA19 and the American Association of Clinical Endocrinologists (AACE)20 suggest that A1C goals be as close to normal as can safely be achieved in a given individual, although they vary slightly in their cut-points. However, both groups strongly support that treatment goals be individualized, with tighter goals advocated for patients with shorter duration of diabetes and less evidence of ‌complications (in whom good glycemic control can prevent complications) vs more liberal goals in those with longer duration diabetes, shorter life expectancies, or evidence of‌‌ more advanced complications, in whom the risks of hypoglycemia may be more serious. An algorithm for individualizing treatment targets is shown in Fig. 8.21

Figure 5 The Diabetes Belt Correlates With Regions of Greater Obesity Prevalence.

START HERE

QUESTION: ARE YOU UNDER 45 YEARS OF AGE?

is your weight equal to or more than the at-risk weight?

NO

AT-RISK WEIGHT CHART), YES

NO

Q: Are you under 57 years of age?

*

NO

YES

Q: At your height (see

AT-RISK WEIGHT CHART),

is your weight equal to or more than the at-risk weight?

YES

Q: Have you ever

NO developed diabetes during pregnancy?

YES

YES

Q: Does your mother, father, sister, or brother have diabetes?

NO

YES

Q: Are you Caucasian (white)?

NO

LOW RISK: Right now your risk for having pre-diabetes or diabetes is low.

But your risk goes up as you get older. Talk to your doctor about how to keep your risk low.

YES

Q: Have you ever been told by a doctor or other

health professional that NO

you had hypertension (high blood pressure)?

YES

HIGH RISK: You are at higher risk for having type 2 diabetes. However, only

your doctor can tell for sure if you do have type 2 diabetes. Talk to your doctor to see if additional testing is needed.

AT RISK FOR PRE-DIABETES: You

are at higher risk for pre-diabetes which means your blood glucose is higher than normal but not high enough to be diagnosed as diabetes. Talk to your doctor about ways to reduce your risk for diabetes.

Table 1 Characteristics of populations at high risk for the development of diabetes who should be considered for targeted screening for diabetes

• Family history of diabetes

• Non-white ancestry

• Previously identified IGT, IFG, and/or metabolic syndrome

• Cardiovascular disease

• Hypertension

• Increased levels of triglycerides, low concentrations of high-density lipoprotein cholesterol, or both

• Being overweight or obese

• Sedentary lifestyle

• History of gestational diabetes

• Delivery of a baby weighing more than 9 lb (4 kg)

• Polycystic ovary syndrome

• Receiving antipsychotic therapy for schizophrenia and severe bipolar disease

Table 2 Criteria for diagnosis of diabetes

A1C Z 6.5% OR

Fasting plasma glucose (FPG)Z 126 mg/dL (7.0 mmol/L) OR

Two-hour plasma glucose Z 200 mg/dL (11.1 mmol/L) during an OGTT

OR

A random plasma glucose Z 200 mg/dL (11.1 mmol/L)

OGTT, oral glucose tolerance test.

ADA. Standards of Medical Care in Diabetes–2012. Diabetes Care.

35 (2012) S11–S63.

AT-RISK WEIGHT CHART

Height Weight

4’10” 148 lbs

4’11” 153 lbs

5’0” 158 lbs

5’1” 164 lbs

5’2” 169 lbs

5’3” 175 lbs

5’4” 180 lbs

5’5” 186 lbs

5’6” 192 lbs

5’7” 198 lbs

5’8” 203 lbs

5’9” 209 lbs

5’10” 216 lbs

5’11” 222 lbs

6’0” 228 lbs

6’1” 235 lbs

6’2” 241 lbs

6’3” 248 lbs

6’4” 254 lbs

6’5” 261 lbs

*Your risk for diabetes or pre-diabetes depends on additional risk factors including weight, physical activity, and blood pressure.

Treatment of Type 2 Diabetes and the Use of Combination Therapy

A clear need exists for family physicians to be at the fore- front of data about the benefits and limitations of different

pharmacologic options so as to maximize patient adherence and treatment outcomes. Current treatment algorithms recommend consistent application of lifestyle modification (appropriate nutrition and physical activity) and early use of pharmacotherapy as well as recommending the use of combination therapy strategies if treatment goals are not achieved or are not maintained. Generally, advancement of therapy is indicated if patients are not at goal for two to three months;16,19,22 patients should not be allowed to languish at unacceptable levels of hyperglycemia for prolonged periods. This is an area of opportunity to improve healthcare performance gaps as recent data show that patients may in fact have persistently elevated glucose levels and yet no changes in their therapeutic regimen have been made.23,24

This brings us to a discussion of treatment combinations that take into account not only complex pathophysiology, but the needs of the patient (both from a patient co-morbidity perspective, as well as a tolerability profile appropriate for the individual). The presence and/or severity of diabetes- related complications also alter the risk:benefit consideration for the choice of agents used for glycemic control. Metformin is considered the cornerstone of pharmacotherapy for patients with T2DM.16,19,22 This is for many reasons including its efficacy, durability, low risk of hypoglycemia, generic availability, long-term outcome data, availability of long-term safety data, and its weight-neutral profile or in some cases, associated effect of weight loss when used to treat diabetes. In some patients, gastrointestinal tolerability

limits the utility of metformin; in others, severe renal impairment may contraindicate its use. Metformin works as an insulin sensitizer and thus, over the long-term, as insulin deficiency due to progressive beta cell failure becomes more evident, it may not be adequate alone to maintain glucose control. Clinical trial data suggest that 75% of patients are no longer maintained at glycemic goals at nine years (and only 50% are at goal at three years) of metformin monotherapy.25 Data from A Diabetes Outcome Progression Trial (ADOPT) trial suggest that the durability of glucose control is even less with sulfonylureas;26,27 sulfonylureas are also associated with hypoglycemia and weight gain.16 While the TZDs appear to have a more durable glucose lowering effect than either metformin or the sulfonylureas, recent safety concerns such as the risk for osteoporosis28 and the possibility of an increased risk of bladder cancer,29 may not make them ideal choices for long-term therapy. As most physicians are aware, TZDs should be prescribed with both caution and warnings to the patient about the potential for water retention/weight gain, especially in patients with decreased ventricular function (New York Heart Association [NYHA] grade III or IV heart failure). To maintain glycemic control, many patients will ultimately need insulin monotherapy or in combination with other medications. Insulin remains our most potent agent with which to reduce hyperglycemia, with hypoglycemia being the dose-limiting side effect to consider.19 Newer analog insulins provide more physiologic profiles, with lower risks of nocturnal hypoglycemia than (for example) neutral protamine Hagedorn (NPH) insulin, with greater dosing convenience than older insulin agents.30 The use of insulin remains limited by risks of hypoglycemia and patient acceptance of injectable therapy. Newer insulin agents are currently in development with what appear to be lower rates of hypoglycemia then even current analog insulins,31–38 which may further enhance therapeutic options.

‌Table 4 Properties of currently available glucose-lowering agents that may guide treatment choice in individual patients with type 2 diabetes

Primary physiological

Class Compound(s) action(s) Advantages Disadvantages Cost

Alpha glucosidase inhibitors Acarbose

Miglitol

Slows intestinal carbohydrate digestion/absorption

No hypoglycemia Reduces postprandial hyperglycemia

May decrease CVD (STOP- NIDDM)

Non systemic

Modest A1C reductions Gastrointestinal side effects (flatulence, diarrhea) Frequent dosing schedule

Moderate

Amylin mimetics Pramlintide Decreases glucagon secretion Slows gastric emptying Increases satiety

Biguanides Metformin Decreases hepatic glucose production

Bile acid sequestrants Colesevelam Unknown; possibly decreases hepatic glucose production, increases incretin levels

Dopamine-2 agonists Bromocriptine quick-release Modulates hypothalamic

regulation of metabolism Increases insulin sensitivity

Reduces postprandial hyperglycemia Weight reduction

No hypoglycemia No weight gain

Likely decrease in CVD events (UKPDS)

Extensive experience

No hypoglycemia Lowers LDL-C No weight gain

No hypoglycemia

Decreases CVD events (Cycloset safety trial)

Modest A1C reductions Gastrointestinal side effects (nausea/vomiting) Hypoglycemia unless insulin dose is simultaneously reduced Frequent dosing schedule Injectable

Gastrointestinal side effects (diarrhea, abdominal cramping) lactic acidosis risk (rare) Vitamin B12 deficiency

Multiple contraindications: CKD, acidosis, hypoxia, dehydration, etc

Modest A1C reductions Constipation Increases triglycerides

May decrease absorption of other drugs

Modest A1C reductions Dizziness/syncope Nausea

Fatigue Rhinitis

High

Low

Osteopathic Family Physician, Vol 5, No 1, January/February 2013

High

High

DPP-4 inhibitors Linagliptin Saxagliptiin Sitagliptin

Glucose dependent increases in insulin secretion, glucose dependent decreases in glucagon secretion

No hypoglycemia Weight neutral Well tolerated

Modest A1C reductions High

Glinides Nateglinide

Repaglinide

Increases insulin secretion Decreases postprandial

hyperglycemia Dosing flexibility

Hypoglycemia Weight gain Frequent dosing

Blunts myocardial ischemic preconditioning

High

Class Compound(s)

Primary physiological

Lavernia Diabetes Clinical Decision-Making in Patients at Risk: Taking Patient Complexity Into Account

action(s) Advantages Disadvantages Cost

GLP-1 receptor agonists Exenatide Exenatide

extended release Liraglutide

Insulins Human: NPH, Regular, Premixed rapid acting analogs: aspart, glulisine, lispro

Long-acting analogs: detemir, glargine Premixed analogs: several

Glucose dependent increases in insulin secretion, glucose dependent decreases in glucagon secretion, slows gastric emptying, increases satiety

Increases glucose disposal Decreases hepatic glucose production

No hypoglycemia Weight reduction

Potential for improved beta cell function

Potential for CV protective actions

Corrects a primary defect of diabetes

Universally effective Efficacy limited only by hypoglycemia

Decreased microvascular risk (UKPDS)

Gastrointestinal side effects (nausea/vomiting) Injectable

C-hyperplasia/medullary thyroid tumors in animals

Hypoglycemia Weight gain Injectable

Education requirements Mitogenic effects

High

Variable

Sulfonylureas Glyburide Glipizide Glimepiride

Thiazolidinediones Pioglitazone

Rosiglitazone (prescribing highly limited in US)

Increases insulin secretion Extensive experience

Decreased microvascular risk (UKPDS)

Increases insulin sensitivity No hypoglycemia

Durable glucose-lowering effects

Experience in patients with renal impairment

Increases in HDL Decreases in triglycerides (pioglitazone)

Decreases in CVD events (pioglitazone: ProACTIVE)

Hypoglycemia Weight gain

Lack of durable effects Blunts myocardial ischemic preconditioning

Weight gain Edema/heart failure Bone fractures

Risk of bladder cancer (pioglitazone)

Increases in MI (rosiglitazone) Increases in LDL-C (rosiglitazone)

Low

High

DPP-4=dipeptidyl teptidase-4; GLP-1=glucagon-like pertide1; NPH=neutral protamine Hagedorn. Adapted from SE Inzucchi, et al. Diabetes Care. (2012) 1-16.

Diabetes care by AMERICAN DIABETES ASSOCIATION. Copyright 2012.

39

Reproduced with permission of AMERICAN DIABETES ASSOCIATION in the format Republish in a journal via Copyright Clearance Center.

Table 5 Cardiovascular Treatment Goals/Recommndations for Patients with Diabetes, As Recommended by the American

Association of Clinical Handelsman, 2011)

Parameter

Endocrinologists (Adapted from

Treatment Goal

Lipids

Low density lipoprotein r70 highest risk; o100 his risk cholesterol, mg/dL

Non-high density o 100 highest risk; o130 high lipoprotein cholesterol, risk

mg/dL

Apolipoprotein B, mg/dL o80 highest risk; o90 high risk High-density lipoprotein 440 in m en; 450 in women

cholesterol, mg/dL Triglycerides, mg/dL o150 Blood pressure

Systolic, mm Hg o130

Diastolic, mm Hg o80

Weight

Weight loss Reduce weight by at least 5%-10%; avoid weight gain

Anticoagulant therapy

Aspirin For secondary CVD prevention or primary prevention for patients at very high risk

High risk ¼ diabetes mellitus without CVD; highest risk ¼ diabetes mellitus plus CVD‌

‌New Treatment Options Create New Opportunities to Improve Glycemic Control

There have been several recent additions to therapeutic choices for glycemic control in patients with T2DM. These include incretin-based therapies (Dipeptidyl peptidase-4 [DPP-4] inhibitors and glucagon-like peptide1 receptor agonists [GLP-1 RAs]) (which will be discussed in much greater detail later in this supplement), glinides, alpha glucosidase inhibitors, the injectable form of the amylin hormone (pramlintide), colesevelam, as well as a quick release form of bromocriptine. These agents vary in their ability to lower blood glucose levels (dose-response effects), which blood glucose level they primarily affect (bearing in mind that A1 consists of both fasting- [FPG] and postprandial-glucose [PPG] components), their MOAs (which aspect of diabetes pathophysiology they target, and therefore what makes for logical combination therapy), their safety profiles (which may preclude use in some patients) and their tolerability profiles (which may affect patient adherence and ultimately treatment success). The broad profiles of all the major classes are presented in Table 4.19

Current treatment algorithm places an emphasis on agents that carry lower risks of hypoglycemia, as well as considering the weight effects of treatment.39,40 Incretin-based therapies (both DPP-4 inhibitors and GLP-1 RAs) feature prominently in the algorithm because they work on multiple defects of diabetes’ pathophysiology, work in a glucose-dependent manner (and so are associated with a low risk of hypoglycemia unless used with insulin or insulin secretagogues), and are not associated with weight gain.39,40

Cardiovascular disease (CVD)

Cardiovascular disease (CVD) is the primary cause of death for most persons with T2DM; therefore a comprehensive care plan for patients with T2DM should include modifica- tion of CVD risk factors such as blood pressure and lipids. Incretin-based therapies do not adversely affect CV risk factors and in fact appear to have some positive effects,41 are being explored in prospective trials.42

Although outside the scope of this supplement, cardiovas- cular risk reduction targets are summarized in Table 5.16 Readers also are referred to the 2011 American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan, which provides further guidance on lifestyle modification and prevention and treatment of diabetes- related complications, among other important issues.16

Summary

Screening patients at risk and diagnosing patients with T2DM early in the disease process is important. The mainstays of any treatment program for T2DM are nutrition, physical activity, and patient education. Early treatment, emphasizing both lifestyle modification, pharmacotherapy for hyperglycemia, and management of CV risk factors, is effective in reducing the risks of diabetes-related complica- tions. Glycemic targets and treatments to lower glucose should be individualized according to the specific char- acteristics of the individual patient. In the absence of contraindications, metformin is the preferred first-line drug. The pathophysiology of T2DM is multifactorial. Most patients will require combination therapy to achieve or maintain glycemic control. A reasonable approach is combination therapy with one to two additional oral or injectable agents, with the goal of minimizing side effects and maximizing patient adherence. Whenever possible, the patient should participate in all treatment decisions, focusing on their preferences, needs, and values. Because T2DM is a progressive disease, characterized by progressive beta cell failure, to maintain glycemic control many patients will ultimately need insulin monotherapy or in combination with other medications. Newer treatment options including the incretin-based therapies, which are not associated with either weight gain or hypoglycemia, may be very helpful to achieve treatment goals as part of combination therapy strategies.

‌Role of the funding source

This supplement is supported by an educational grant from Novo Nordisk Inc.

‌Disclosure statement

Frank Lavernia, MD, states that he is a member of the speakers’ bureau for Abbott Pharmaceuticals and Novo Nordisk Inc. He is also on the Amylin Pharmaceuticals Primary Care Advisory Board.

‌Acknowledgements

Kate Mann, PharmD, assisted with editorial development under the auspices of E&S MedEd Group, Inc.

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