Glycemic management in type 2 diabetes mellitus has become increasingly complex and,
to some extent, controversial, with a widening array of pharmacological agents now
available (1–5), mounting concerns about their potential adverse effects and new uncertainties
regarding the benefits of intensive glycemic control on macrovascular complications
(6–9). Many clinicians are therefore perplexed as to the optimal strategies for their
patients. As a consequence, the American Diabetes Association (ADA) and the European
Association for the Study of Diabetes (EASD) convened a joint task force to examine
the evidence and develop recommendations for antihyperglycemic therapy in nonpregnant
adults with type 2 diabetes. Several guideline documents have been developed by members
of these two organizations (10) and by other societies and federations (2,11–15).
However, an update was deemed necessary because of contemporary information on the
benefits/risks of glycemic control, recent evidence concerning efficacy and safety
of several new drug classes (16,17), the withdrawal/restriction of others, and increasing
calls for a move toward more patient-centered care (18,19).
This statement has been written incorporating the best available evidence and, where
solid support does not exist, using the experience and insight of the writing group,
incorporating an extensive review by additional experts (acknowledged below). The
document refers to glycemic control; yet this clearly needs to be pursued within a
multifactorial risk reduction framework. This stems from the fact that patients with
type 2 diabetes are at increased risk of cardiovascular morbidity and mortality; the
aggressive management of cardiovascular risk factors (blood pressure and lipid therapy,
antiplatelet treatment, and smoking cessation) is likely to have even greater benefits.
These recommendations should be considered within the context of the needs, preferences,
and tolerances of each patient; individualization of treatment is the cornerstone
of success. Our recommendations are less prescriptive than and not as algorithmic
as prior guidelines. This follows from the general lack of comparative-effectiveness
research in this area. Our intent is therefore to encourage an appreciation of the
variable and progressive nature of type 2 diabetes, the specific role of each drug,
the patient and disease factors that drive clinical decision making (20–23), and the
constraints imposed by age and comorbidity (4,6). The implementation of these guidelines
will require thoughtful clinicians to integrate current evidence with other constraints
and imperatives in the context of patient-specific factors.
Evidence-based advice depends on the existence of primary source evidence. This emerges
only from clinical trial results in highly selected patients, using limited strategies.
It does not address the range of choices available, or the order of use of additional
therapies. Even if such evidence were available, the data would show median responses
and not address the vital question of who responded to which therapy and why (24).
Patient-centered care is defined as an approach to “providing care that is respectful
of and responsive to individual patient preferences, needs, and values and ensuring
that patient values guide all clinical decisions” (25). This should be the organizing
principle underlying health care for individuals with any chronic disease, but given
our uncertainties in terms of choice or sequence of therapy, it is particularly appropriate
in type 2 diabetes. Ultimately, it is patients who make the final decisions regarding
their lifestyle choices and, to some degree, the pharmaceutical interventions they
use; their implementation occurs in the context of the patients’ real lives and relies
on the consumption of resources (both public and private).
Patient involvement in the medical decision making constitutes one of the core principles
of evidence-based medicine, which mandates the synthesis of best available evidence
from the literature with the clinician's expertise and patient's own inclinations
(26). During the clinical encounter, the patient's preferred level of involvement
should be gauged and therapeutic choices explored, potentially with the utilization
of decision aids (21). In a shared decision-making approach, clinician and patient
act as partners, mutually exchanging information and deliberating on options, in order
to reach a consensus on the therapeutic course of action (27). There is good evidence
supporting the effectiveness of this approach (28). Importantly, engaging patients
in health care decisions may enhance adherence to therapy.
Epidemiology and health care impact
Both the prevalence and incidence of type 2 diabetes are increasing worldwide, particularly
in developing countries, in conjunction with increased obesity rates and westernization
of lifestyle. The attendant economic burden for health care systems is skyrocketing,
owing to the costs associated with treatment and diabetes complications. Type 2 diabetes
remains a leading cause of cardiovascular disorders, blindness, end-stage renal failure,
amputations, and hospitalizations. It is also associated with increased risk of cancer,
serious psychiatric illness, cognitive decline, chronic liver disease, accelerated
arthritis, and other disabling or deadly conditions. Effective management strategies
are of obvious importance.
Relationship of glycemic control to outcomes
It is well established that the risk of microvascular and macrovascular complications
is related to glycemia, as measured by HbA1c; this remains a major focus of therapy
(29). Prospective randomized trials have documented reduced rates of microvascular
complications in type 2 diabetic patients treated to lower glycemic targets. In the
UK Prospective Diabetes Study (UKPDS) (30,31), patients with newly diagnosed type
2 diabetes were randomized to two treatment policies. In the standard group, lifestyle
intervention was the mainstay with pharmacological therapy used only if hyperglycemia
became severe. In the more intensive treatment arm, patients were randomly assigned
to either a sulfonylurea or insulin, with a subset of overweight patients randomized
to metformin. The overall HbA1c achieved was 0.9% lower in the intensive policy group
compared with the conventional policy arm (7.0% vs. 7.9%). Associated with this difference
in glycemic control was a reduction in the risk of microvascular complications (retinopathy,
nephropathy, neuropathy) with intensive therapy. A trend toward reduced rates of myocardial
infarction in this group did not reach statistical significance (30). By contrast,
substantially fewer metformin-treated patients experienced myocardial infarction,
diabetes-related and all-cause mortality (32), despite a mean HbA1c only 0.6% lower
than the conventional policy group. The UKPDS 10-year follow-up demonstrated that
the relative benefit of having been in the intensive management policy group was maintained
over a decade, resulting in the emergence of statistically significant benefits on
cardiovascular disease (CVD) end points and total mortality in those initially assigned
to sulfonylurea/insulin, and persistence of CVD benefits with metformin (33), in spite
of the fact that the mean HbA1c levels between the groups converged soon after the
randomized component of the trial had concluded.
In 2008, three shorter-term studies [Action to Control Cardiovascular Risk in Diabetes
(ACCORD) (34), Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release
Controlled Evaluation (ADVANCE) (35), Veterans Affairs Diabetes Trial (VADT) (36)]
reported the effects of two levels of glycemic control on cardiovascular end points
in middle-aged and older individuals with well-established type 2 diabetes at high
risk for cardiovascular events. ACCORD and VADT aimed for an HbA1c <6.0% using complex
combinations of oral agents and insulin. ADVANCE aimed for an HbA1c ≤6.5% using a
less intensive approach based on the sulfonylurea gliclazide. None of the trials demonstrated
a statistically significant reduction in the primary combined cardiovascular end points.
Indeed, in ACCORD, a 22% increase in total mortality with intensive therapy was observed,
mainly driven by cardiovascular mortality. An explanation for this finding has remained
elusive, although rates of hypoglycemia were threefold higher with intensive treatment.
It remains unclear, however, if hypoglycemia was responsible for the adverse outcomes,
or if other factors, such as more weight gain, or simply the greater complexity of
therapy, contributed. There were suggestions in these trials that patients without
overt CVD, with shorter duration of disease, and lower baseline HbA1c, benefited from
the more intensive strategies. Modest improvements in some microvascular end points
in the studies were likewise demonstrated. Finally, a meta-analysis of cardiovascular
outcomes in these trials suggested that every HbA1c reduction of ∼1% may be associated
with a 15% relative risk reduction in nonfatal myocardial infarction, but without
benefits on stroke or all-cause mortality (36).
Overview of the pathogenesis of type 2 diabetes
Any rise in glycemia is the net result of glucose influx exceeding glucose outflow
from the plasma compartment. In the fasting state, hyperglycemia is directly related
to increased hepatic glucose production. In the postprandial state, further glucose
excursions result from the combination of insufficient suppression of this glucose
output and defective insulin stimulation of glucose disposal in target tissues, mainly
skeletal muscle. Once the renal tubular transport maximum for glucose is exceeded,
glycosuria curbs, though does not prevent, further hyperglycemia.
Abnormal islet cell function is a key and requisite feature of type 2 diabetes. In
early disease stages, insulin production is normal or increased in absolute terms,
but disproportionately low for the degree of insulin sensitivity, which is typically
reduced. However, insulin kinetics, such as the ability of the pancreatic β-cell to
release adequate hormone in phase with rising glycemia, are profoundly compromised.
This functional islet incompetence is the main quantitative determinant of hyperglycemia
(37) and progresses over time. In addition, in type 2 diabetes, pancreatic α-cells
hypersecrete glucagon, further promoting hepatic glucose production (38). Importantly,
islet dysfunction is not necessarily irreversible. Enhancing insulin action relieves
β-cell secretory burden, and any intervention that improves glycemia—from energy restriction
to, most strikingly, bariatric surgery—can ameliorate β-cell dysfunction to an extent
(39). More recently recognized abnormalities in the incretin system (represented by
the gut hormones, glucagon-like peptide 1 [GLP-1], and glucose-dependent insulinotropic
peptide [GIP]) are also found in type 2 diabetes, but it remains unclear whether these
constitute primary or secondary defects (40). In most patients with type 2 diabetes,
especially the obese, insulin resistance in target tissues (liver, muscle, adipose
tissue, myocardium) is a prominent feature. This results in both glucose overproduction
and underutilization. Moreover, an increased delivery of fatty acids to the liver
favors their oxidation, which contributes to increased gluconeogenesis, whereas the
absolute overabundance of lipids promotes hepatosteatosis (41).
Antihyperglycemic agents are directed at one or more of the pathophysiological defects
of type 2 diabetes, or modify physiological processes relating to appetite or to nutrient
absorption or excretion. Ultimately, type 2 diabetes is a disease that is heterogeneous
in both pathogenesis and in clinical manifestation—a point to be considered when determining
the optimal therapeutic strategy for individual patients.
The ADA's “Standards of Medical Care in Diabetes” recommends lowering HbA1c to <7.0%
in most patients to reduce the incidence of microvascular disease (42). This can be
achieved with a mean plasma glucose of ∼8.3–8.9 mmol/L (∼150–160 mg/dL); ideally,
fasting and premeal glucose should be maintained at <7.2 mmol/L (<130 mg/dL) and the
postprandial glucose at <10 mmol/L (<180 mg/dL). More stringent HbA1c targets (e.g.,
6.0–6.5%) might be considered in selected patients (with short disease duration, long
life expectancy, no significant CVD) if this can be achieved without significant hypoglycemia
or other adverse effects of treatment (20,43). Conversely, less stringent HbA1c goals—e.g.,
7.5–8.0% or even slightly higher—are appropriate for patients with a history of severe
hypoglycemia, limited life expectancy, advanced complications, extensive comorbid
conditions and those in whom the target is difficult to attain despite intensive self-management
education, repeated counseling, and effective doses of multiple glucose-lowering agents,
including insulin (20,44).
The accumulated results from the aforementioned type 2 diabetes cardiovascular trials
suggest that not everyone benefits from aggressive glucose management. It follows
that it is important to individualize treatment targets (5,34–36). The elements that
may guide the clinician in choosing an HbA1c target for a specific patient are shown
in Fig. 1. As mentioned earlier, the desires and values of the patient should also
be considered, since the achievement of any degree of glucose control requires active
participation and commitment (19,23,45,46). Indeed, any target could reflect an agreement
between patient and clinician. An important related concept is that the ease with
which more intensive targets are reached influences treatment decisions; logically,
lower targets are attractive if they can be achieved with less complex regimens and
no or minimal adverse effects. Importantly, utilizing the percentage of diabetic patients
who are achieving an HbA1c <7.0% as a quality indicator, as promulgated by various
health care organizations, is inconsistent with the emphasis on individualization
of treatment goals.
Depiction of the elements of decision making used to determine appropriate efforts
to achieve glycemic targets. Greater concerns about a particular domain are represented
by increasing height of the ramp. Thus, characteristics/predicaments toward the left
justify more stringent efforts to lower HbA1c, whereas those toward the right are
compatible with less stringent efforts. Where possible, such decisions should be made
in conjunction with the patient, reflecting his or her preferences, needs, and values.
This “scale” is not designed to be applied rigidly but to be used as a broad construct
to help guide clinical decisions. Adapted with permission from Ismail-Beigi et al.
Interventions designed to impact an individual's physical activity levels and food
intake are critical parts of type 2 diabetes management (47,48). All patients should
receive standardized general diabetes education (individual or group, preferably using
an approved curriculum), with a specific focus on dietary interventions and the importance
of increasing physical activity. While encouraging therapeutic lifestyle change is
important at diagnosis, periodic counseling should also be integrated into the treatment
Weight reduction, achieved through dietary means alone or with adjunctive medical
or surgical intervention, improves glycemic control and other cardiovascular risk
factors. Modest weight loss (5–10%) contributes meaningfully to achieving improved
glucose control. Accordingly, establishing a goal of weight reduction, or at least
weight maintenance, is recommended.
Dietary advice must be personalized (49). Patients should be encouraged to eat healthy
foods that are consistent with the prevailing population-wide dietary recommendations
and with an individual's preferences and culture. Foods high in fiber (such as vegetables,
fruits, whole grains, and legumes), low-fat dairy products, and fresh fish should
be emphasized. High-energy foods, including those rich in saturated fats, and sweet
desserts and snacks should be eaten less frequently and in lower amounts (50–52).
Patients who eventually lose and keep weight off usually do so after numerous cycles
of weight loss and relapse. The health care team should remain nonjudgmental but persistent,
revisiting and encouraging therapeutic lifestyle changes frequently, if needed.
As much physical activity as possible should be promoted, ideally aiming for at least
150 min/week of moderate activity including aerobic, resistance, and flexibility training
(53). In older individuals, or those with mobility challenges, so long as tolerated
from a cardiovascular standpoint, any increase in activity level is advantageous.
At diagnosis, highly motivated patients with HbA1c already near target (e.g., <7.5%)
could be given the opportunity to engage in lifestyle change for a period of 3–6 months
before embarking on pharmacotherapy (usually metformin). Those with moderate hyperglycemia
or in whom lifestyle changes are anticipated to be unsuccessful should be promptly
started on an antihyperglycemic agent (also usually metformin) at diagnosis, which
can later be modified or possibly discontinued if lifestyle changes are successful.
Oral agents and noninsulin injectables.
Important properties of antihyperglycemic agents that play a role in the choice of
drug(s) in individual patients are summarized in Table 1. Ultimately, the aims of
controlling glycemia are to avoid acute osmotic symptoms of hyperglycemia, to avoid
instability in blood glucose over time, and to prevent/delay the development of diabetes
complications without adversely affecting quality of life. Information on whether
specific agents have this ability is incomplete; an answer to these questions requires
long-term, large-scale clinical trials—not available for most drugs. Effects on surrogate
measures for glycemic control (e.g., HbA1c) generally reflect changes in the probability
of developing microvascular disease but not necessarily macrovascular complications.
Particularly from a patient standpoint, stability of metabolic control over time may
be another specific goal.
Properties of currently available glucose-lowering agents that may guide treatment
choice in individual patients with type 2 diabetes mellitus
Metformin, a biguanide, remains the most widely used first-line type 2 diabetes drug;
its mechanism of action predominately involves reducing hepatic glucose production
(54,55). It is generally considered weight-neutral with chronic use and does not increase
the risk of hypoglycemia. Metformin is associated with initial gastrointestinal side
effects, and caution is advised to avoid its use in patients at risk for lactic acidosis
(e.g., in advanced renal insufficiency, alcoholism), a rare complication of therapy.
As noted earlier, there may be some cardiovascular benefits from this drug, but the
clinical trial data are not robust.
The oldest oral agent class is the sulfonylurea insulin secretagogues. Through the
closure of ATP-sensitive potassium channels on β-cells, these drugs stimulate insulin
release (56). While effective in controlling glucose levels, their use is associated
with modest weight gain and risk of hypoglycemia. In addition, studies have demonstrated
a secondary failure rate that may exceed other drugs, ascribed to an exacerbation
of islet dysfunction (57). Shorter-acting secretagogues, the meglitinides (or glinides),
stimulate insulin release through similar mechanisms but may be associated with less
hypoglycemia (58). They require more frequent dosing, however.
Thiazolidinediones (TZDs) are peroxisome proliferator–activated receptor γ activators
(59) that improve insulin sensitivity in skeletal muscle and reduce hepatic glucose
production (54,55). They do not increase the risk of hypoglycemia and may be more
durable in their effectiveness than sulfonylureas and metformin (57). Pioglitazone
appeared to have a modest benefit on cardiovascular events as a secondary outcome
in one large trial involving patients with overt macrovascular disease (60). Another
agent of this class, rosiglitazone, is no longer widely available owing to concerns
of increased myocardial infarction risk (61). Pioglitazone has recently been associated
with a possible increased risk of bladder cancer (62). Recognized side effects of
TZDs include weight gain, fluid retention leading to edema and/or heart failure in
predisposed individuals, and increased risk of bone fractures (57,60).
Drugs focused on the incretin system have been introduced more recently (63). The
injectable GLP-1 receptor agonists mimic the effects of endogenous GLP-1, thereby
stimulating pancreatic insulin secretion in a glucose-dependent fashion, suppressing
pancreatic glucagon output, slowing gastric emptying, and decreasing appetite. Their
main advantage is weight loss, which is modest in most patients but can be significant
in some. A limiting side effect is nausea and vomiting, particularly early in the
course of treatment. Concerns regarding an increased risk of pancreatitis remain unresolved.
The oral dipeptidyl peptidase 4 (DPP-4) inhibitors enhance circulating concentrations
of active GLP-1 and GIP (64). Their major effect appears to be in the regulation of
insulin and glucagon secretion; they are weight neutral. Typically, neither of the
incretin-based classes cause hypoglycemia by themselves.
Two agents that are used infrequently in the U.S. and Europe are the α-glucosidase
inhibitors (AGIs), which retard gut carbohydrate absorption (65), and colesevelam,
a bile acid sequestrant whose mechanism of glucose-lowering action remains poorly
understood and whose major additional benefit is LDL-cholesterol reduction (66). Both
have gastrointestinal effects, mainly flatulence with AGIs and constipation with colesevelam.
The dopamine agonist bromocriptine is only available in the U.S. as an antihyperglycemic
agent (67). Its mechanism of action and precise role are unclear. The amylin agonist,
pramlintide, is typically reserved for patients treated with intensive insulin therapy,
usually in type 1 diabetes mellitus; it decreases postprandial glucose excursions
by inhibiting glucagon secretion and slowing gastric emptying (68).
The glucose-lowering effectiveness of noninsulin pharmacological agents is said to
be high for metformin, sulfonylureas, TZDs, and GLP-1 agonists (expected HbA1c reduction
∼1.0–1.5%) (1,69,70), and generally lower for meglitinides, DPP-4 inhibitors, AGIs,
colesevelam, and bromocriptine (∼0.5–1.0%). However, older drugs have typically been
tested in clinical trial participants with higher baseline HbA1c, which is itself
associated with greater treatment emergent glycemic reductions, irrespective of therapy
type. In head-to-head studies, any differential effects on glucose control are small.
So agent- and patient-specific properties, such as dosing frequency, side-effect profiles,
cost, and other benefits often guide their selection.
Due to the progressive β-cell dysfunction that characterizes type 2 diabetes, insulin
replacement therapy is frequently required (71). Importantly, most patients maintain
some endogenous insulin secretion even in late stages of disease. Accordingly, the
more complex and intensive strategies of type 1 diabetes are not typically necessary
Ideally, the principle of insulin use is the creation of as normal a glycemic profile
as possible without unacceptable weight gain or hypoglycemia (73). As initial therapy,
unless the patient is markedly hyperglycemic and/or symptomatic, a “basal” insulin
alone is typically added (74). Basal insulin provides relatively uniform insulin coverage
throughout the day and night, mainly to control blood glucose by suppressing hepatic
glucose production in between meals and during sleep. Either intermediate-acting (neutral
protamine Hagedorn [NPH]) or long-acting (insulin glargine [A21Gly,B31Arg,B32Arg human
insulin] or insulin detemir [B29Lys(ε-tetradecanoyl),desB30 human insulin]) formulations
may be used. The latter two are associated with modestly less overnight hypoglycemia
(insulin glargine, insulin detemir) than NPH and possibly slightly less weight gain
(insulin detemir), but are more expensive (75,76). Of note, the dosing of these basal
insulin analogs may differ, with most comparative trials showing a higher average
unit requirement with insulin detemir (77).
Although the majority of patients with type 2 diabetes requiring insulin therapy can
be successfully treated with basal insulin alone, some, because of progressive diminution
in their insulin secretory capacity, will require prandial insulin therapy with shorter-acting
insulins. This is typically provided in the form of the rapid insulin analogs, insulin
lispro (B28Lys,B29Pro human insulin), insulin aspart (B28Asp human insulin), or insulin
glulisine (B3Lys,B29Glu human insulin), which may be dosed just before the meal. They
result in better postprandial glucose control than the less costly human regular insulin,
whose pharmacokinetic profile makes it less attractive in this setting.
Ideally, an insulin treatment program should be designed specifically for an individual
patient, to match the supply of insulin to his or her dietary/exercise habits and
prevailing glucose trends, as revealed through self-monitoring. Anticipated glucose-lowering
effects should be balanced with the convenience of the regimen, in the context of
an individual's specific therapy goals (Fig. 1).
Proper patient education regarding glucose monitoring, insulin injection technique,
insulin storage, recognition/treatment of hypoglycemia, and “sick day” rules is imperative.
Where available, certified diabetes educators can be invaluable in guiding the patient
through this process.
Glycemic targets and glucose-lowering therapies must be individualized.
Diet, exercise, and education remain the foundation of any type 2 diabetes treatment
Unless there are prevalent contraindications, metformin is the optimal first-line
After metformin, there are limited data to guide us. Combination therapy with an additional
1–2 oral or injectable agents is reasonable, aiming to minimize side effects where
Ultimately, many patients will require insulin therapy alone or in combination with
other agents to maintain glucose control.
All treatment decisions, where possible, should be made in conjunction with the patient,
focusing on his/her preferences, needs, and values.
Comprehensive cardiovascular risk reduction must be a major focus of therapy.
Initial drug therapy.
It is generally agreed that metformin, if not contraindicated and if tolerated, is
the preferred and most cost-effective first agent (42) (Fig. 2 and Supplementary Figs.).
It is initiated at, or soon after, diagnosis, especially in patients in whom lifestyle
intervention alone has not achieved, or is unlikely to achieve, HbA1c goals. Because
of frequent gastrointestinal side effects, it should be started at a low dose with
gradual titration. Patients with a high baseline HbA1c (e.g., ≥9.0%) have a low probability
of achieving a near-normal target with monotherapy. It may therefore be justified
to start directly with a combination of two noninsulin agents or with insulin itself
in this circumstance (78). If a patient presents with significant hyperglycemic symptoms
and/or has dramatically elevated plasma glucose concentrations (e.g., >16.7–19.4 mmol/L
[>300–350 mg/dL]) or HbA1c (e.g., ≥10.0–12.0%), insulin therapy should be strongly
considered from the outset. Such treatment is mandatory when catabolic features are
exhibited or, of course, if ketonuria is demonstrated, the latter reflecting profound
insulin deficiency. Importantly, unless there is evidence of type 1 diabetes, once
symptoms are relieved, glucotoxicity resolved, and the metabolic state stabilized,
it may be possible to taper insulin partially or entirely, transferring to noninsulin
antihyperglycemic agents, perhaps in combination.
Antihyperglycemic therapy in type 2 diabetes: general recommendations. Moving from
the top to the bottom of the figure, potential sequences of antihyperglycemic therapy.
In most patients, begin with lifestyle changes; metformin monotherapy is added at,
or soon after, diagnosis (unless there are explicit contraindications). If the HbA1c
target is not achieved after ∼3 months, consider one of the five treatment options
combined with metformin: a sulfonylurea, TZD, DPP-4 inhibitor, GLP-1 receptor agonist,
or basal insulin. (The order in the chart is determined by historical introduction
and route of administration and is not meant to denote any specific preference.) Choice
is based on patient and drug characteristics, with the over-riding goal of improving
glycemic control while minimizing side effects. Shared decision making with the patient
may help in the selection of therapeutic options. The figure displays drugs commonly
used both in the U.S. and/or Europe. Rapid-acting secretagogues (meglitinides) may
be used in place of sulfonylureas. Other drugs not shown (α-glucosidase inhibitors,
colesevelam, dopamine agonists, pramlintide) may be used where available in selected
patients but have modest efficacy and/or limiting side effects. In patients intolerant
of, or with contraindications for, metformin, select initial drug from other classes
depicted and proceed accordingly. In this circumstance, while published trials are
generally lacking, it is reasonable to consider three-drug combinations other than
metformin. Insulin is likely to be more effective than most other agents as a third-line
therapy, especially when HbA1c is very high (e.g., ≥9.0%). The therapeutic regimen
should include some basal insulin before moving to more complex insulin strategies
(Fig. 3). Dashed arrow line on the left-hand side of the figure denotes the option
of a more rapid progression from a two-drug combination directly to multiple daily
insulin doses, in those patients with severe hyperglycemia (e.g., HbA1c ≥10.0–12.0%).
DPP-4-i, DPP-4 inhibitor; Fx's, bone fractures; GI, gastrointestinal; GLP-1-RA, GLP-1
receptor agonist; HF, heart failure; SU, sulfonylurea. aConsider beginning at this
stage in patients with very high HbA1c (e.g., ≥9%).
Consider rapid-acting, nonsulfonylurea secretagogues (meglitinides) in patients with
irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas.
See Table 1 for additional potential adverse effects and risks, under “Disadvantages.”
Usually a basal insulin (NPH, glargine, detemir) in combination with noninsulin agents.
Certain noninsulin agents may be continued with insulin (see text). Refer to Fig.
3 for details on regimens. Consider beginning at this stage if patient presents with
severe hyperglycemia (≥16.7–19.4 mmol/L [≥300–350 mg/dL]; HbA1c ≥10.0–12.0%) with
or without catabolic features (weight loss, ketosis, etc.).
If metformin cannot be used, another oral agent could be chosen, such as a sulfonylurea/glinide,
pioglitazone, or a DPP-4 inhibitor; in occasional cases where weight loss is seen
as an essential aspect of therapy, initial treatment with a GLP-1 receptor agonist
might be useful. Where available, less commonly used drugs (AGIs, colesevelam, bromocriptine)
might also be considered in selected patients, but their modest glycemic effects and
side-effect profiles make them less attractive candidates. Specific patient preferences,
characteristics, susceptibilities to side effects, potential for weight gain and hypoglycemia
should play a major role in drug selection (20,21). (See Supplementary Figs. for adaptations
of Fig. 2 that address specific patient scenarios.)
Advancing to dual combination therapy.
Figure 2 (and Supplementary Figs.) also depicts potential sequences of escalating
glucose-lowering therapy beyond metformin. If monotherapy alone does not achieve/maintain
an HbA1c target over ∼3 months, the next step would be to add a second oral agent,
a GLP-1 receptor agonist, or basal insulin (5,10). Notably, the higher the HbA1c,
the more likely insulin will be required. On average, any second agent is typically
associated with an approximate further reduction in HbA1c of ∼1% (70,79). If no clinically
meaningful glycemic reduction (i.e., “nonresponder”) is demonstrated, then, adherence
having been investigated, that agent should be discontinued, and another with a different
mechanism of action substituted. With a distinct paucity of long-term comparative-effectiveness
trials available, uniform recommendations on the best agent to be combined with metformin
cannot be made (80). Thus, advantages and disadvantages of specific drugs for each
patient should be considered (Table 1).
Some antihyperglycemic medications lead to weight gain. This may be associated with
worsening markers of insulin resistance and cardiovascular risk. One exception may
be TZDs (57); weight gain associated with this class occurs in association with decreased
insulin resistance. Although there is no uniform evidence that increases in weight
in the range observed with certain therapies translate into a substantially increased
cardiovascular risk, it remains important to avoid unnecessary weight gain by optimal
medication selection and dose titration.
For all medications, consideration should also be given to overall tolerability. Even
occasional hypoglycemia may be devastating, if severe, or merely irritating, if mild
(81). Gastrointestinal side effects may be tolerated by some, but not others. Fluid
retention may pose a clinical or merely an aesthetic problem (82). The risk of bone
fractures may be a specific concern in postmenopausal women (57).
It must be acknowledged that costs are a critical issue driving the selection of glucose-lowering
agents in many environments. For resource-limited settings, less expensive agents
should be chosen. However, due consideration should be also given to side effects
and any necessary monitoring, with their own cost implications. Moreover, prevention
of morbid long-term complications will likely reduce long-term expenses attributed
to the disease.
Advancing to triple combination therapy.
Some studies have shown advantages of adding a third noninsulin agent to a two-drug
combination that is not yet or no longer achieving the glycemic target (83–86). Not
surprisingly, however, at this juncture, the most robust response will usually be
with insulin. Indeed, since diabetes is associated with progressive β-cell loss, many
patients, especially those with long-standing disease, will eventually need to be
transitioned to insulin, which should be favored in circumstances where the degree
of hyperglycemia (e.g., ≥8.5%) makes it unlikely that another drug will be of sufficient
benefit (87). If triple combination therapy exclusive of insulin is tried, the patient
should be monitored closely, with the approach promptly reconsidered if it proves
to be unsuccessful. Many months of uncontrolled hyperglycemia should specifically
In using triple combinations the essential consideration is obviously to use agents
with complementary mechanisms of action (Fig. 2 and Supplementary Figs.). Increasing
the number of drugs heightens the potential for side effects and drug–drug interactions,
raises costs, and negatively impacts patient adherence. The rationale, benefits, and
side effects of each new medication should be discussed with the patient. The clinical
characteristics of patients more or less likely to respond to specific combinations
are, unfortunately, not well defined.
Transitions to and titrations of insulin.
Most patients express reluctance to beginning injectable therapy, but, if the practitioner
feels that such a transition is important, encouragement and education can usually
overcome such reticence. Insulin is typically begun at a low dose (e.g., 0.1–0.2 U
kg−1 day−1), although larger amounts (0.3–0.4 U kg−1 day−1) are reasonable in the
more severely hyperglycemic. The most convenient strategy is with a single injection
of a basal insulin, with the timing of administration dependent on the patient's schedule
and overall glucose profile (Fig. 3).
Sequential insulin strategies in type 2 diabetes. Basal insulin alone is usually the
optimal initial regimen, beginning at 0.1–0.2 units/kg body weight, depending on the
degree of hyperglycemia. It is usually prescribed in conjunction with one to two noninsulin
agents. In patients willing to take more than one injection and who have higher HbA1c
levels (≥9.0%), twice-daily premixed insulin or a more advanced basal plus mealtime
insulin regimen could also be considered (curved dashed arrow lines). When basal insulin
has been titrated to an acceptable fasting glucose but HbA1c remains above target,
consider proceeding to basal plus mealtime insulin, consisting of one to three injections
of rapid-acting analogs (see text for details). A less studied alternative—progression
from basal insulin to a twice-daily premixed insulin—could be also considered (straight
dashed arrow line); if this is unsuccessful, move to basal plus mealtime insulin.
The figure describes the number of injections required at each stage, together with
the relative complexity and flexibility. Once a strategy is initiated, titration of
the insulin dose is important, with dose adjustments made based on the prevailing
glucose levels as reported by the patient. Noninsulin agents may be continued, although
insulin secretagogues (sulfonylureas, meglitinides) are typically stopped once more
complex regimens beyond basal insulin are utilized. Comprehensive education regarding
self-monitoring of blood glucose, diet, exercise, and the avoidance of, and response
to, hypoglycemia are critical in any patient on insulin therapy. Mod., moderate.
Although extensive dosing instructions for insulin are beyond the scope of this statement,
most patients can be taught to uptitrate their own insulin dose based on several algorithms,
each essentially involving the addition of a small dose increase if hyperglycemia
persists (74,76,88). For example, the addition of 1–2 units (or, in those already
on higher doses, increments of 5–10%) to the daily dose once or twice weekly if the
fasting glucose levels are above the preagreed target is a reasonable approach (89).
As the target is neared, dosage adjustments should be more modest and occur less frequently.
Downward adjustment is advisable if any hypoglycemia occurs. During self-titration,
frequent contact (telephone, e-mail) with the clinician may be necessary. Practitioners
themselves can, of course, also titrate basal insulin, but this would involve more
intensive contact with the patient than typically available in routine clinical practice.
Daily self-monitoring of blood glucose is of obvious importance during this phase.
After the insulin dose is stabilized, the frequency of monitoring should be reviewed
Consideration should be given to the addition of prandial or mealtime insulin coverage
when significant postprandial glucose excursions (e.g., to >10.0 mmol/L [>180 mg/dL])
occur. This is suggested when the fasting glucose is at target but the HbA1c remains
above goal after 3–6 months of basal insulin titration (91). The same would apply
if large drops in glucose occur during overnight hours or in between meals, as the
basal insulin dose is increased. In this scenario, the basal insulin dose would obviously
need to be simultaneously decreased as prandial insulin is initiated. Although basal
insulin is titrated primarily against the fasting glucose, generally irrespective
of the total dose, practitioners should be aware that the need for prandial insulin
therapy will become likely the more the daily dose exceeds 0.5 U kg−1 day−1, especially
as it approaches 1 U kg−1 day−1. The aim with mealtime insulin is to blunt postprandial
glycemic excursions, which can be extreme in some individuals, resulting in poor control
during the day. Such coverage may be provided by one of two methods.
The most precise and flexible prandial coverage is possible with “basal-bolus” therapy,
involving the addition of premeal rapid-acting insulin analog to ongoing basal insulin.
One graduated approach is to add prandial insulin before the meal responsible for
the largest glucose excursion—typically that with the greatest carbohydrate content,
often, but not always, the evening meal (92). Subsequently, a second injection can
be administered before the meal with the next largest excursion (often breakfast).
Ultimately, a third injection may be added before the smallest meal (often lunch)
(93). The actual glycemic benefits of these more advanced regimens after basal insulin
are generally modest in typical patients (92). So, again, individualization of therapy
is key, incorporating the degree of hyperglycemia needing to be addressed and the
overall capacities of the patient. Importantly, data trends from self-monitoring may
be particularly helpful in titrating insulins and their doses within these more advanced
regimens to optimize control.
A second, perhaps more convenient but less adaptable method involves “premixed” insulin,
consisting of a fixed combination of an intermediate insulin with regular insulin
or a rapid analog. Traditionally, this is administered twice daily, before morning
and evening meals. In general, when compared with basal insulin alone, premixed regimens
tend to lower HbA1c to a larger degree, but often at the expense of slightly more
hypoglycemia and weight gain (94). Disadvantages include the inability to titrate
the shorter- from the longer-acting component of these formulations. Therefore, this
strategy is somewhat inflexible but may be appropriate for certain patients who eat
regularly and may be in need of a simplified approach beyond basal insulin (92,93).
(An older and less commonly used variation of this two-injection strategy is known
as “split-mixed,” involving a fixed amount of intermediate insulin mixed by the patient
with a variable amount of regular insulin or a rapid analog. This allows for greater
flexibility in dosing.)
The key messages from dozens of comparative insulin trials in type 2 diabetes include
Any insulin will lower glucose and HbA1c.
All insulins are associated with some weight gain and some risk of hypoglycemia.
The larger the doses and the more aggressive the titration, the lower the HbA1c, but
often with a greater likelihood of adverse effects.
Generally, long-acting insulin analogs reduce the incidence of overnight hypoglycemia,
and rapid-acting insulin analogs reduce postprandial glucose excursions as compared
with corresponding human insulins (NPH, Regular), but they generally do not result
in clinically significantly lower HbA1c.
Metformin is often continued when basal insulin is added, with studies demonstrating
less weight gain when the two are used together (95). Insulin secretagogues do not
seem to provide for additional HbA1c reduction or prevention of hypoglycemia or weight
gain after insulin is started, especially after the dose is titrated and stabilized.
When basal insulin is used, continuing the secretagogue may minimize initial deterioration
of glycemic control. However, secretagogues should be avoided once prandial insulin
regimens are employed. TZDs should be reduced in dose (or stopped) to avoid edema
and excessive weight gain, although in certain individuals with large insulin requirements
from severe insulin resistance, these insulin sensitizers may be very helpful in lowering
HbA1c and minimizing the required insulin dose (96). Data concerning the glycemic
benefits of incretin-based therapy combined with basal insulin are accumulating; combination
with GLP-1 receptor agonists may be helpful in some patients (97,98). Once again,
the costs of these more elaborate combined regimens must be carefully considered.
Older adults (>65–70 years) often have a higher atherosclerotic disease burden, reduced
renal function, and more comorbidities (99,100). Many are at risk for adverse events
from polypharmacy and may be both socially and economically disadvantaged. Life expectancy
is reduced, especially in the presence of long-term complications. They are also more
likely to be compromised by hypoglycemia; for example, unsteadiness may result in
falls and fractures (101), and a tenuous cardiac status may deteriorate into catastrophic
events. It follows that glycemic targets for elderly with long-standing or more complicated
disease should be less ambitious than for the younger, healthier individuals (20).
If lower targets cannot be achieved with simple interventions, an HbA1c of <7.5–8.0%
may be acceptable, transitioning upward as age increases and capacity for self-care,
cognitive, psychological and economic status, and support systems decline.
While lifestyle modification can be successfully implemented across all age-groups,
in the aged, the choice of antihyperglycemic agent should focus on drug safety, especially
protecting against hypoglycemia, heart failure, renal dysfunction, bone fractures,
and drug–drug interactions. Strategies specifically minimizing the risk of low blood
glucose may be preferred.
In contrast, healthier patients with long life expectancy accrue risk for vascular
complications over time. Therefore, lower glycemic targets (e.g., an HbA1c <6.5–7.0%)
and tighter control of body weight, blood pressure, and circulating lipids should
be achieved to prevent or delay such complications. This usually requires combination
therapy, the early institution of which may have the best chance of modifying the
disease process and preserving quality of life.
The majority of individuals with type 2 diabetes are overweight or obese (∼80%) (102).
In these, intensive lifestyle intervention can improve fitness, glycemic control,
and cardiovascular risk factors for relatively small changes in body weight (103).
Although insulin resistance is thought of as the predominate driver of diabetes in
obese patients, they actually have a similar degree of islet dysfunction to leaner
patients (37). Perhaps as a result, the obese may be more likely to require combination
drug therapy (20,104). While common practice has favored metformin in heavier patients,
because of weight loss/weight neutrality, this drug is as efficacious in lean individuals
(75). TZDs, on the other hand, appear to be more effective in those with higher BMIs,
although their associated weight gain makes them, paradoxically, a less attractive
option here. GLP-1 receptor agonists are associated with weight reduction (38), which
in some patients may be substantial.
Bariatric surgery is an increasingly popular option in severe obesity. Type 2 diabetes
frequently resolves rapidly after these procedures. The majority of patients are able
to stop some, or even all, of their antihyperglycemic medications, although the durability
of this effect is not known (105).
In lean patients, consideration should be given to the possibility of latent autoimmune
diabetes in adults (LADA), a slowly progressive form of type 1 diabetes. These individuals,
while presenting with mild hyperglycemia, often responsive to oral agents, eventually
develop more severe hyperglycemia and require intensive insulin regimens (106). Measuring
titres of islet-associated autoantibodies (e.g., anti-GAD) may aid their identification,
encouraging a more rapid transition to insulin therapy.
While certain racial/ethnic features that increase the risk of diabetes are well recognized
[greater insulin resistance in Latinos (107), more β-cell dysfunction in East Asians
(108)], using this information to craft optimal therapeutic strategies is in its infancy.
This is not surprising given the polygenic inheritance pattern of the disease. Indeed,
while matching a drug's mechanism of action to the underlying causes of hyperglycemia
in a specific patient seems logical, there are few data that compare strategies based
on this approach (109). There are few exceptions, mainly involving diabetes monogenic
variants often confused with type 2 diabetes, such as maturity-onset diabetes of the
young (MODY), several forms of which respond preferentially to sulfonylureas (110).
While there are no prominent sex differences in the response to various antihyperglycemic
drugs, certain side effects (e.g., bone loss with TZDs) may be of greater concern
Coronary artery disease.
Given the frequency with which type 2 diabetic patients develop atherosclerosis, optimal
management strategies for those with or at high risk for coronary artery disease (CAD)
are important. Since hypoglycemia may exacerbate myocardial ischemia and may cause
dysrhythmias (111), it follows that medications that predispose patients to this adverse
effect should be avoided, if possible. If they are required, however, to achieve glycemic
targets, patients should be educated to minimize risk. Because of possible effects
on potassium channels in the heart, certain sulfonylureas have been proposed to aggravate
myocardial ischemia through effects on ischemic preconditioning (112), but the actual
clinical relevance of this remains unproven. Metformin may have some cardiovascular
benefits and would appear to be a useful drug in the setting of CAD, barring prevalent
contraindications (32). In a single study, pioglitazone was shown to reduce modestly
major adverse cardiovascular events in patients with established macrovascular disease.
It may therefore also be considered, unless heart failure is present (60). In very
preliminary reports, therapy with GLP-1 receptor agonists and DPP-4 inhibitors has
been associated with improvement in either cardiovascular risk or risk factors, but
there are no long-term data regarding clinical outcomes (113). There are very limited
data suggesting that AGIs (114) and bromocriptine (115) may reduce cardiovascular
With an aging population and recent decreases in mortality after myocardial infarction,
the diabetic patient with progressive heart failure is an increasingly common scenario
(116). This population presents unique challenges given their polypharmacy, frequent
hospitalizations, and contraindications to various agents. TZDs should be avoided
(117,118). Metformin, previously contraindicated in heart failure, can now be used
if the ventricular dysfunction is not severe, if patient's cardiovascular status is
stable, and if renal function is normal (119). As mentioned, cardiovascular effects
of incretin-based therapies, including those on ventricular function, are currently
under investigation (120).
Chronic kidney disease.
Kidney disease is highly prevalent in type 2 diabetes, and moderate to severe renal
functional impairment (eGFR <60 mL/min) occurs in approximately 20–30% of patients
(121,122). The individual with progressive renal dysfunction is at increased risk
for hypoglycemia, which is multifactorial. Insulin and, to some degree, the incretin
hormones are eliminated more slowly, as are antihyperglycemic drugs with renal excretion.
Thus, dose reduction may be necessary, contraindications need to be observed, and
consequences (hypoglycemia, fluid retention, etc.) require careful evaluation.
Current U.S. prescribing guidelines warn against the use of metformin in patients
with a serum creatinine ≥133 mmol/L (≥1.5 mg/dL) in men or 124 mmol/L (≥1.4 mg/dL)
in women. Metformin is eliminated renally, and cases of lactic acidosis have been
described in patients with renal failure (123). There is an ongoing debate, however,
as to whether these thresholds are too restrictive and that those with mild–moderate
renal impairment would gain more benefit than harm from using metformin (124,125).
In the U.K., the National Institute for Health and Clinical Excellence (NICE) guidelines
are less proscriptive and more evidence-based than those in the U.S., generally allowing
use down to a GFR of 30 mL/min, with dose reduction advised at 45 mL/min (14). Given
the current widespread reporting of estimated GFR, these guidelines appear very reasonable.
Most insulin secretagogues undergo significant renal clearance (exceptions include
repaglinide and nateglinide) and the risk of hypoglycemia is therefore higher in patients
with chronic kidney disease (CKD). For most of these agents, extreme caution is imperative
at more severe degrees of renal dysfunction. Glyburide (known as glibenclamide in
Europe), which has a prolonged duration of action and active metabolites, should be
specifically avoided in this group. Pioglitazone is not eliminated renally, and therefore
there are no restrictions for use in CKD. Fluid retention may be a concern, however.
Among the DPP-4 inhibitors, sitagliptin, vildagliptin, and saxagliptin share prominent
renal elimination. In the face of advanced CKD, dose reduction is necessary. One exception
is linagliptin, which is predominantly eliminated enterohepatically. For the GLP-1
receptor agonists exenatide is contraindicated in stage 4–5 CKD (GFR <30 mL/min) as
it is renally eliminated; the safety of liraglutide is not established in CKD though
pharmacokinetic studies suggest that drug levels are unaffected as it does not require
renal function for clearance.
More severe renal functional impairment is associated with slower elimination of all
insulins. Thus doses need to be titrated carefully, with some awareness for the potential
for more prolonged activity profiles.
Individuals with type 2 diabetes frequently have hepatosteatosis as well as other
types of liver disease (126). There is preliminary evidence that patients with fatty
liver may benefit from treatment with pioglitazone (45,127,128). It should not be
used in an individual with active liver disease or an alanine transaminase level above
2.5 times the upper limit of normal. In those with steatosis but milder liver test
abnormalities, this insulin sensitizer may be advantageous. Sulfonylureas can rarely
cause abnormalities in liver tests but are not specifically contraindicated; meglitinides
can also be used. If hepatic disease is severe, secretagogues should be avoided because
of the increased risk of hypoglycemia. In patients with mild hepatic disease, incretin-based
drugs can be prescribed, except if there is a coexisting history of pancreatitis.
Insulin has no restrictions for use in patients with liver impairment and is indeed
the preferred choice in those with advanced disease.
Hypoglycemia in type 2 diabetes was long thought to be a trivial issue, as it occurs
less commonly than in type 1 diabetes. However, there is emerging concern based mainly
on the results of recent clinical trials and some cross-sectional evidence of increased
risk of brain dysfunction in those with repeated episodes. In the ACCORD trial, the
frequency of both minor and major hypoglycemia was high in intensively managed patients—threefold
that associated with conventional therapy (129). It remains unknown whether hypoglycemia
was the cause of the increased mortality in the intensive group (130,131). Clearly,
however, hypoglycemia is more dangerous in the elderly and occurs consistently more
often as glycemic targets are lowered. Hypoglycemia may lead to dysrhythmias, but
can also lead to accidents and falls (which are more likely to be dangerous in the
elderly) (132), dizziness (leading to falls), confusion (so other therapies may not
be taken or taken incorrectly), or infection (such as aspiration during sleep, leading
to pneumonia). Hypoglycemia may be systematically under-reported as a cause of death,
so the true incidence may not be fully appreciated. Perhaps just as importantly, additional
consequences of frequent hypoglycemia include work disability and erosion of the confidence
of the patient (and that of family or caregivers) to live independently. Accordingly,
in at-risk individuals, drug selection should favor agents that do not precipitate
such events and, in general, blood glucose targets may need to be moderated.
FUTURE DIRECTIONS/RESEARCH NEEDS
For antihyperglycemic management of type 2 diabetes, the comparative evidence basis
to date is relatively lean, especially beyond metformin monotherapy (70). There is
a significant need for high-quality comparative-effectiveness research, not only regarding
glycemic control, but also costs and those outcomes that matter most to patients—quality
of life and the avoidance of morbid and life-limiting complications, especially CVD
(19,23,70). Another issue about which more data are needed is the concept of durability
of effectiveness (often ascribed to β-cell preservation), which would serve to stabilize
metabolic control and decrease the future treatment burden for patients. Pharmacogenetics
may very well inform treatment decisions in the future, guiding the clinician to recommend
a therapy for an individual patient based on predictors of response and susceptibility
to adverse effects. We need more clinical data on how phenotype and other patient/disease
characteristics should drive drug choices. As new medications are introduced to the
type 2 diabetes pharmacopeia, their benefit and safety should be demonstrated in studies
versus best current treatment, substantial enough both in size and duration to provide
meaningful data on meaningful outcomes. It is appreciated, however, that head-to-head
comparisons of all combinations and permutations would be impossibly large (133).
Informed judgment and the expertise of experienced clinicians will therefore always