Two general approaches to the treatment of type 2 diabetes mellitus (T2DM) have been
advocated. 1) A “guideline” approach that advocates sequential addition of antidiabetes
agents with “more established use” (1); this approach more appropriately should be
called the “treat to failure” approach, and deficiencies with this approach have been
discussed (2). And 2) a “pathophysiologic” approach using initial combination therapy
with agents known to correct established pathophysiologic defects in T2DM (3). Within
the pathophysiologic approach, choice of antidiabetes agents should take into account
the patient’s general health status and associated medical disorders. This individualized
approach, which we refer to as the ABCD(E) of diabetes treatment (4), has been incorporated
into the updated American Diabetes Association (ADA) guidelines (5).
A = Age
B = Body weight
C = Complications (microvascular and macrovascular)
D = Duration of diabetes
E = Life Expectancy
E = Expense
Even though physicians must be cognizant of these associated conditions (ABCDE) when
initiating therapy in newly diagnosed T2DM patients, we believe that the most important
consideration is to select antidiabetes agents that correct specific pathophysiologic
disturbances present in T2DM and that have complementary mechanisms of action. Although
it has been argued that the pathogenesis of T2DM differs in different ethnic groups
(6), evidence to support this is weak. Although the relative contributions of β-cell
failure and insulin resistance to development of glucose intolerance may differ in
different ethnic groups (6), the core defects of insulin resistance in muscle/liver/adipocytes
and progressive β-cell failure (3) are present in virtually all T2DM patients and
must be treated aggressively to prevent the relentless rise in HbA1c that is characteristic
In subsequent sections, we provide a review of the natural history of T2DM, specific
pathophysiologic abnormalities responsible for T2DM, currently available antidiabetes
agents and their mechanism of action, recommended glycemic goals, and use of combination
therapy based upon reversal of pathophysiologic defects present in T2DM. We will not
address expense but recognize that this is an important consideration in choosing
any antidiabetes regimen.
Overview of T2DM: pathophysiology and general therapeutic approach
T2DM is a complex metabolic/cardiovascular disorder with multiple pathophysiologic
abnormalities. Insulin resistance in muscle/liver and β-cell failure represent the
core defects (7,8). β-Cell failure occurs much earlier in the natural history of T2DM
and is more severe than previously thought (9–12). Subjects in the upper tertile of
impaired glucose tolerance (IGT) are maximally/near-maximally insulin resistant and
have lost >80% of their β-cell function. In addition to muscle, liver, and β-cells
(“triumvirate”) (7), adipocytes (accelerated lipolysis), gastrointestinal tract (incretin
deficiency/resistance), α-cells (hyperglucagonemia), kidney (increased glucose reabsorption),
and brain (insulin resistance and neurotransmitter dysregulation) play important roles
in development of glucose intolerance in T2DM individuals (3). Collectively, these
eight players comprise the “ominous octet” (Fig. 1) and dictate that 1) multiple drugs
used in combination will be required to correct the multiple pathophysiological defects,
2) treatment should be based upon reversal of known pathogenic abnormalities and not
simply on reducing HbA1c, and 3) therapy must be started early to prevent/slow progressive
β-cell failure that is well established in IGT subjects. A treatment paradigm shift
is recommended in which combination therapy is initiated with agents that correct
known pathogenic defects in T2DM and produce durable reduction in HbA1c rather than
just focusing on the glucose-lowering ability of the drug.
The ominous octet (3) depicting the mechanism and site of action of antidiabetes medications
based upon the pathophysiologic disturbances present in T2DM.
Natural history of T2DM
Individuals destined to develop T2DM inherit genes that make their tissues resistant
to insulin (2,8,13–15). In liver, insulin resistance is manifested by glucose overproduction
during the basal state despite fasting hyperinsulinemia (16) and impaired suppression
of hepatic glucose production (HGP) by insulin (17), as occurs following a meal (18).
In muscle (17,19,20), insulin resistance is manifest by impaired glucose uptake after
carbohydrate ingestion, resulting in postprandial hyperglycemia (18). Although the
origins of insulin resistance can be traced to their genetic background (8,14,15),
the current diabetes epidemic is related to the epidemic of obesity and physical inactivity
(21), which are insulin-resistant states (22) and place stress on pancreatic β-cells
to augment insulin secretion to offset insulin resistance (2,3,8). As long as β-cells
augment insulin secretion sufficiently to offset the insulin resistance, glucose tolerance
remains normal (2,3,8,23–29). However, with time β-cells begin to fail, and initially
postprandial plasma glucose levels and subsequently fasting plasma glucose begin to
rise, leading to overt diabetes (2,3,8). Thus, it is progressive β-cell failure that
determines the rate of disease progression. The natural history of T2DM described
above (2,3) is depicted by a prospective study carried out by DeFronzo (3); Jallut,
Golay, and Munger (30); and Felber et al. (31) (Fig. 2).
Natural history of T2DM. The plasma insulin response depicts the classic Starling’s
Curve of the Pancreas. See text for a detailed explanation (7). Upper panel: Insulin-mediated
glucose disposal (insulin clamp technique) and mean plasma insulin concentration during
OGTT. Lower panel: Mean plasma glucose concentration during OGTT. DIAB, T2DM; Hi,
high; Lo, low; OB, obese.
Although the plasma insulin response to insulin resistance is increased early in the
natural history of T2DM (Fig. 2), this does not mean that β-cells are functioning
normally (3). Simply measuring the plasma insulin response to a glucose challenge
does not provide a valid index of β-cell function (32). β-Cells respond to an increment
in glucose (ΔG) with an increment in insulin (ΔI). Thus, a better measure of β-cell
function is ΔI/ΔG. However, β-cells also increase insulin section to offset insulin
resistance and maintain normoglycemia (9,10,12,23,32,33). Thus, the gold standard
measure of β-cell function in vivo in man is the insulin secretion/insulin resistance
(disposition) index (ΔI/ΔG ÷ IR).
Figure 3 depicts the insulin secretion/insulin resistance index in normal glucose
tolerant (NGT), IGT, and T2DM subjects as a function of 2-h plasma glucose during
oral glucose tolerance test (OGTT) (2,9,10,12). Subjects in the upper tertile of NGT
(2-h plasma glucose 120–139 mg/dL) have lost >50% of β-cell function, while subjects
in upper tertile of IGT (2-h plasma glucose 180–199 mg/dL) have lost ∼80% of β-cell
function (Fig. 3). Similar conclusions are evident from other publications (24,27,34,35).
The therapeutic implications of these findings are obvious. When the diagnosis of
diabetes is made, the patient has lost ∼80% of their β-cell function, and it is essential
that physicians intervene with therapies known to correct established pathophysiological
disturbances in β-cell function. Even more ominous are observations of Butler et al.
(36), who demonstrated that as individuals progress from NGT to IFG, there is significant
loss of β-cell mass that continues with progression to diabetes. Similar results have
been published by others (37,38) and indicate that significant loss of β-cells occurs
long before onset of T2DM, according to current diagnostic criteria (1).
Insulin secretion/insulin resistance (disposition) index (ΔI/ΔG ÷ IR) during OGTT
in individuals with NGT, IGT, and T2DM as a function of the 2-h plasma glucose (PG)
concentration in lean and obese subjects (9–12).
In summary, although insulin resistance in liver/muscle is well established early
in the natural history of T2DM, overt diabetes does not occur in the absence of progressive
The liver and muscle are severely resistant to insulin in T2DM (rev. in 2,3,8).
After an overnight fast, the liver produces glucose at ∼2 mg/kg/min (2,16). In T2DM,
the rate of basal HGP is increased, averaging ∼2.5 mg/kg/min (2,16). This amounts
to addition of an extra 25–30 g glucose to the systemic circulation nightly and is
responsible for the increased fasting plasma glucose concentration. This hepatic overproduction
of glucose occurs despite fasting insulin levels that are increased two- to threefold,
indicating severe hepatic insulin resistance.
With use of the euglycemic insulin clamp with limb catheterization (2,3,17,19,20,39,40),
it has conclusively been demonstrated that lean, as well as obese, T2DM individuals
are severely resistant to insulin and that the primary site of insulin resistance
resides in muscle. Multiple intramyocellular defects in insulin action have been documented
in T2DM (rev. in 2,3,8,40), including impaired glucose transport/phosphorylation (17),
reduced glycogen synthesis (39), and decreased glucose oxidation (17). However, more
proximal insulin signaling defects play a paramount role in muscle insulin resistance
In addition to the triumvirate (β-cell failure and insulin resistance in muscle and
liver), at least five other pathophysiologic abnormalities contribute to glucose intolerance
in T2DM (3) (Fig. 1): 1) adipocyte resistance to insulin’s antilipolytic effect, leading
to increased plasma FFA concentration and elevated intracellular levels of toxic lipid
metabolites in liver/muscle and β-cells that cause insulin resistance and β-cell failure/apoptosis
(17); 2) decreased incretin (glucagon-like peptide [GLP]-1/glucose-dependent insulinotropic
polypeptide [GIP]) effect resulting from impaired GLP-1 secretion (43) but, more importantly,
severe β-cell resistance to the stimulatory effect of GLP-1 and GIP (44,45); 3) increased
glucagon secretion by α-cells and enhanced hepatic sensitivity to glucagon, leading
to increased basal HGP and impaired HGP suppression by insulin (46,47); 4) enhanced
renal glucose reabsorption contributing to maintenance of elevated plasma glucose
levels (48,49); and 5) central nervous system resistance to the anorectic effect of
insulin and altered neurosynaptic hormone secretion contributing to appetite dysregulation,
weight gain, and insulin resistance in muscle/liver (50–52).
Implications for therapy
The preceding review of pathophysiology has important therapeutic implications: 1)
effective treatment will require multiple drugs in combination to correct the multiple
pathophysiological defects, 2) treatment should be based upon established pathogenic
abnormalities and not simply on HbA1c reduction, and 3) therapy must be started early
in the natural history of T2DM to prevent progressive β-cell failure.
Figure 1 displays therapeutic options as they relate to key pathophysiological derangements
in T2DM (Fig. 1). In liver, both metformin (53–55) and thiazolidinediones (TZDs) (56–62)
are potent insulin sensitizers and inhibit the increased rate of HGP. In muscle, TZDs
are potent insulin sensitizers (56–58,61,63), whereas metformin is, at best, a weak
insulin sensitizer (53,55,64). Since TZDs work through the insulin signaling pathway
(65), whereas metformin works through the AMP kinase pathway (66), combination TZD/metformin
therapy gives a completely additive effect to reduce HbA1c (67–72). Further, hypoglycemia
is not encountered because these drugs are insulin sensitizers and do not augment
insulin secretion. In adipocytes, TZDs are excellent insulin sensitizers and potent
inhibitors of lipolysis (73). TZDs also mobilize fat out of muscle, liver, and β-cells,
thereby ameliorating lipotoxicity (57,62,63,74–76).
Although weight loss has the potential to improve both the defects in insulin sensitivity
and insulin secretion (77), two meta-analyses involving 46 published studies demonstrated
that the ability to maintain the initial weight loss is difficult (78,79). In the
following sections, we will focus on pharmacologic agents—as monotherapy and combination
therapy—that have been proven to reverse pathophysiologic abnormalities in T2DM.
In the β-cell, sulfonylureas and glinides augment insulin secretion (80), but only
TZDs (81–83) and GLP-1 analogs (84–86) improve and preserve β-cell function and demonstrate
durability of glycemic control (70,82–85,87–93). Importantly, TZDs and GLP-1 analogs
cause durable HbA1c reduction for up to 5 and 3.5 years, respectively (82,93). Although
dipeptidyl peptidase inhibitors (DPP4i) augment insulin secretion (94), their β-cell
effect is weak compared with GLP1 analogs and they begin to lose efficacy (manifested
by rising HbA1c) within 2 years after initiation of therapy (95,96). Despite the potent
effects of TZDs and GLP-1 agonists on β-cells, the two most commonly prescribed drugs
in the U.S. and worldwide are sulfonylureas and metformin, neither of which exerts
any β-cell protective effect. This is a major concern, since progressive β-cell failure
is the primary pathogenic abnormality responsible for development of T2DM and progressive
HbA1c rise (Fig. 3).
GLP-1 analogs augment and preserve β-cell function for at least 3 years (84). This
protective effect has its onset within 24 h (86) and persists as long as GLP-1 therapy
is continued (84,85,93). Further, both exenatide and liraglutide promote weight loss,
inhibit glucagon secretion, and delay gastric emptying, reducing postprandial hyperglycemia
(45,93,97–99). Weight loss depletes lipid from muscle and liver, improving muscle
and hepatic insulin sensitivity (84,85). GLP-1 analogs also correct multiple cardiovascular
risk factors (rev. in 100) and, thus, have the potential to reduce cardiovascular
events (101,102). Although DPP4i share some characteristics with GLP-1 analogs, they
do not raise plasma GLP-1 levels sufficiently to offset β-cell resistance to GLP-1
(103). Not surprisingly, their ability to augment insulin secretion and reduce HbA1c
is considerably less than GLP-1 analogs (94,104,105), and they do not promote weight
loss (94). In a 1-year study involving 665 metformin-treated T2DM patients, HbA1c
reduction with sitagliptin (0.9%) was significantly less than liraglutide dosed at
1.2 mg/day (ΔHbA1c = 1.2%) or 1.8 mg/day (ΔHbA1c = 1.8%) (105). In a short-term, mechanism-of-action,
crossover study, exenatide was far superior to sitagliptin in reducing glucose area
under the curve and 2-h glucose after a meal, increasing insulin secretion, inhibiting
glucagon secretion, and promoting weight loss (104). Metformin increases GLP-1 secretion
by intestinal L-cells (106–108), and the combination of metformin plus DPP4i may exert
a more durable effect on β-cell function. The major mechanism of action of DPP4i to
improve glycemic control is mediated via inhibition of glucagon secretion with subsequent
decline in HGP (109)
Although not yet approved by U.S. regulatory agencies, sodium glucose transporter
2 inhibitors (approved in Europe) demonstrate modest efficacy in reducing HbA1c, promote
weight loss, reduce blood pressure, and can be added to any antidiabetes agent (48,110).
Instituting therapy in newly diagnosed T2DM patients
When initiating therapy in newly diagnosed T2DM patients, the following considerations
are of paramount importance:
Therapy should have the ability to achieve the desired level of glycemic control,
based upon starting HbA1c. According to the ADA, European Association for the Study
of Diabetes (EASD), and American Association of Clinical Endocrinologists (AACE),
the desired HbA1c is 6.5% (EASD and AACE) or 7.0% (ADA) (5,111). However, we believe
that in newly diagnosed diabetic patients without cardiovascular disease, the optimal
HbA1c should be ≤6.0%, while avoiding adverse events, primarily hypoglycemia. This
is consistent with the expanded ADA/EASD statement (5).
In most newly diagnosed diabetic patients, monotherapy will not reduce HbA1c <6.5–7.0%
or, most optimally, <6.0%, and combination therapy will be required.
Importantly, medications used in combination therapy should have an additive effect,
and individual drugs should correct established pathophysiologic disturbances in T2DM.
If antidiabetes medications do not correct underlying pathogenic abnormalities, long-term
durable glycemic control cannot be achieved.
Progressive β-cell failure is responsible for progressive HbA1c rise in T2DM (3).
Therefore, medications used to treat T2DM should preserve or improve β-cell function
to ensure durable glycemic control.
Because insulin resistance is a core defect in T2DM and exacerbates the decline in
β-cell function, medications also should ameliorate insulin resistance in muscle/liver.
T2DM is associated with an increased incidence of atherosclerotic cardiovascular complications.
Therefore, it is desirable that drugs exert beneficial effects on cardiovascular risk
factors and decrease cardiovascular events.
Since obesity is a major problem in diabetic individuals, combination therapy should
be weight neutral and, if possible, promote weight loss.
Combination therapy should be safe and not exacerbate underlying medical conditions.
No single antidiabetes agent can correct all of the pathophysiologic disturbances
present in T2DM, and multiple agents, used in combination, will be required for optimal
glycemic control. Further, the HbA1c decrease produced by a single antidiabetes agent,
e.g., metformin, sulfonylurea, TZD, GLP-1 analog, is in the range of 1.0–1.5% depending
upon the starting HbA1c (5). Thus, in newly diagnosed T2DM with HbA1c >8.0–8.5%, a
single agent is unlikely to achieve HbA1c goal <6.5–7.0%, and virtually no one will
achieve HbA1c <6.0%. When maximal-dose metformin, sulfonylurea, or TZD is initiated
as monotherapy, <40% of newly diagnosed T2DM subjects can be expected to achieve HbA1c
<6.5–7.0%. Thus, most patients with HbA1c >8.0–8.5% will require initial combination
therapy to reach HbA1c <6.5–7.0%. Moreover, because different agents lower plasma
glucose via different mechanisms, combination therapy will have an additive effect
to reduce HbA1c compared with each agent alone. Simultaneous correction of the β-cell
defect and insulin resistance is more likely to cause durable HbA1c reduction. Lastly,
combination therapy allows use of submaximal doses of each antidiabetes agent, resulting
in fewer side effects (112).
In summary, initiating therapy with multiple antidiabetes agents in newly diagnosed
T2DM patients, especially those with HbA1c >8.0–8.5%, represents a rational approach
to achieve the target HbA1c level while minimizing side effects. Indeed, AACE recommends
starting newly diagnosed diabetic subjects with HbA1c >7.5% on multiple antidiabetes
“Treat to fail” algorithm
The 2009 ADA/EASD algorithm (1) recommended initiation of therapy with metformin to
achieve HbA1c <7.0%, followed by, importantly, sequential addition of a sulfonylurea.
If sulfonylurea addition failed to reduce HbA1c <7.0%, addition of basal insulin was
recommended. Although the revised 2012 ADA/EASD algorithm (5) includes newer antidiabetes
agents (GLP-1 receptor agonists, DPP4i, and TZDs) as potential choices if metformin
fails, the initial box in the treatment algorithm still depicts sequential addition
of sulfonylurea and then insulin to maintain HbA1c <7.0%. This algorithm has little
basis in pathophysiology and more appropriately should be called the treat to fail
algorithm. Moreover, it does not consider the starting HbA1c or need for initial combination
therapy in most newly diagnosed T2DM patients, especially if HbA1c goal <6.0–6.5%
is desired, as suggested by us (4) and by the 2012 ADA/EASD consensus statement (5).
Because β-cell failure is progressive (9–12,24–30,34,35,113,114) and results in loss
of β-cell mass (36–38), it is essential to intervene with agents that normalize HbA1c
and halt the progressive β-cell demise (Fig. 3). Failure to do so will result in the
majority of T2DM patients progressing to insulin therapy, as demonstrated in the UK
Prospective Diabetes Study (UKPDS) (113,114).
Sulfonylureas/glinides: the treat to fail approach.
Until recently (5), sulfonylureas have been considered the drug of choice for add-on
therapy to metformin (1). In large part, this is attributed to their low cost and
rapid onset of hypoglycemic effect. However, they lack “glycemic durability” and within
1–2 years lose their efficacy, resulting in steady HbA1c rise to or above pretreatment
levels (107,108) (Figs. 4 and 5). Although long-term studies examining glycemic durability
with glinides (nateglinide, repaglinide) in T2DM are not available, nateglinide failed
to prevent prediabetic (IGT) patients from progressing to T2DM (115). In a 2-year
study in newly diagnosed T2DM subjects, durability of netaglinide plus metformin was
comparable with glyburide plus metformin (116) and both groups experienced a small
but progressive HbA1c rise after the first year. Since deterioration in glycemic control
is largely accounted for by progressive β-cell failure (3), it is clear that both
sulfonylureas and glinides fail to prevent the progressive decline in β-cell function
characteristic of T2DM. Consistent with this, in vitro studies have demonstrated a
proapoptotic β-cell effect of sulfonylureas and glinides (117–120).
The effect of sulfonylurea (glibenclamide = glyburide) and metformin therapy on the
plasma HbA1c concentration in newly diagnosed T2DM subjects in UKPDS. Conventionally
treated diabetic subjects received diet plus exercise therapy (113,114).
Durability of glycemic control with sulfonylureas. Summary of studies examining the
effect of sulfonylurea treatment versus placebo or versus active comparator on HbA1c
in T2DM. See text for a more detailed discussion (70,82,87–92,113,114,124–127,131,132).
UKPDS conclusively demonstrated that sulfonylureas exerted no β-cell protective effect
in newly diagnosed T2DM patients (starting HbA1c = 7.0%) over a 15-year follow-up
(113,114). After an initial HbA1c drop, sulfonylurea-treated patients experienced
progressive deterioration in glycemic control that paralleled HbA1c rise in conventionally
treated individuals (Fig. 4). Moreover, some studies have suggested that sulfonylureas
may accelerate atherogenesis (121,122). Similarly, metformin-treated patients in UKPDS,
after initial HbA1c decline (secondary to inhibition of HGP), also experienced progressive
deterioration in glycemic control (123) (Fig. 4). With use of homeostasis model assessment
of β-cell function, it was shown that the relentless HbA1c rise observed with sulfonylureas
and metformin resulted from progressive decline in β-cell function and that within
3–5 years, ∼50% of diabetic patients required an additional pharmacologic agent to
maintain HbA1c <7.0% (114,124–127). Although there is in vitro evidence that metformin
may improve β-cell function (128,129), in vivo data from UKPDS and other studies (130)
fail to support any role for metformin in preservation of β-cell function in humans.
Metformin did reduce macrovascular events in UKPDS (123), although by today’s standards
the number of metformin-treated subjects (n = 342) would be considered inadequate
to justify any conclusions about cardiovascular protection. Other than its effect
to reduce the elevated rate of basal and postprandial HGP (53,55,64), metformin does
not correct any other component of the ominous octet (Fig. 1), and even its muscle
insulin-sensitizing effect is difficult to demonstrate in absence of weight loss (53,55,64).
UKPDS was designed as a monotherapy study. However, after 3 years it became evident
that monotherapy with neither metformin nor sulfonylureas could prevent progressive
β-cell failure and stabilize HbA1c at its starting level (113,114,123–127). Therefore,
study protocol was altered to allow metformin addition to sulfonylurea and sulfonylurea
addition to metformin. Although addition of a second antidiabetes agent initially
improved glycemic control, progressive β-cell failure continued and HbA1c rose progressively.
Numerous long-term (>1.5 years) active-comparator or placebo-controlled studies have
demonstrated inability of sulfonylureas to produce durable HbA1c reduction in T2DM
patients. These studies (70,83,87–92,113,131–133) showed that after initial HbA1c
decline, sulfonylureas (glyburide, glimepiride, and gliclazide) were associated with
progressive decline in β-cell function with accompanying loss of glycemic control
(Fig. 5). There are no exceptions to this consistent loss of glycemic control with
sulfonylureas after the initial 18 months of therapy. Thus, evidence-based medicine
demonstrates that the glucose-lowering effect of sulfonylureas is not durable and
that loss of glycemic control is associated with progressive β-cell failure.
Sulfonylurea treatment does not correct any pathophysiologic component of the ominous
octet (3) (Fig. 1) and is associated with significant weight gain and hypoglycemia
(89,90). Although no study has clearly implicated sulfonylureas with an increased
incidence of cardiovascular events, a deleterious effect of glibenclamide (glyburide)
on the cardioprotective process of ischemic preconditioning has been demonstrated
(134), while some (121,122,135–142) but not all (143,144) studies have suggested a
possible association between sulfonylureas and adverse cardiovascular outcomes. Since
metformin was the comparator in many of these studies (121,122,137,138,140–142), it
is difficult to determine whether sulfonylureas increased or metformin decreased cardiovascular
morbidity/mortality. In the study by Sillars et al. (143) the increased cardiovascular
mortality/morbidity disappeared after adjusting for confounding variables, and failure
to do so in other sulfonylurea studies may have clouded their interpretation. Among
the sulfonylurea studies, the older sulfonylureas (i.e., glibenclamide) more commonly
have been associated with increased adverse cardiovascular outcomes than the newer
sulfonylurea agents (i.e., gliclazide and glimeperide) (139,144–146).
In summary, we believe that currently available insulin secretagogues (sulfonylureas
and glinides) represent a poor option as add-on therapy to metformin. However, in
many countries newer antidiabetes agents are not available or are expensive (ABCDE)
(4). In such circumstances, sulfonylureas may be the only option.
Antidiabetes agents known to reverse pathophysiologic defects
Pioglitazone: unique benefits, unique side effects.
Rosiglitazone has been removed from the market or its use severely restricted because
of cardiovascular safety concerns (147). Therefore, pioglitazone is the only representative
TZD. Pioglitazone is unique in that it both exerts β-cell protective effects (81)
and is a powerful insulin sensitizer in muscle and liver (56–61,65,74–76) Thus, it
is the only antidiabetes agent that corrects the core defects of insulin resistance
and β-cell failure in T2DM. Not surprisingly, it has a durable effect to reduce HbA1c
with low risk of hypoglycemia.
Eight long-term (>1.5 years) studies with TZDs (70,82,81–92) (Fig. 6) have demonstrated
that, after initial decline in HbA1c, durability of glycemic control is maintained
because of preservation of β-cell function in T2DM patients. Further, five studies
demonstrate that TZDs prevent progression of IGT to T2DM (148–152). All five studies
showed that, in addition to their insulin-sensitizing effect, TZDs had a major action
to preserve β-cell function. In Actos Now for Prevention of Diabetes (ACT NOW), improved
insulin secretion/insulin resistance (disposition) index was shown both with OGTT
and frequently sampled intravenous glucose tolerance test. Similar results were documented
in Troglitazone in Prevention of Diabetes (TRIPOD) and Pioglitazone in Prevention
of Diabetes (PIPOD) (148,151). Many in vivo and in vitro studies with human and rodent
islets have demonstrated that TZDs exert a β-cell–protective effect (153–157).
Durability of glycemic control with TZDs. Summary of studies examining the effect
of TZDs versus placebo or versus active comparator on HbA1c in T2DM subjects. See
text for a more detailed discussion (70,82,87–92). Pio, pioglitazone; Rosi, rosiglitazone.
Pioglitazone has additional beneficial pleiotropic properties, including increased
HDL cholesterol, reduced plasma triglyceride, decreased blood pressure, improved endothelial
dysfunction, anti-inflammatory effects (76,158–161), and amelioration of nonalcoholic
steatohepatitis (75). In addition to reduced cardiovascular events in PROactive and
U.S. phase 3 trials (162,163), pioglitazone slows progression of carotid intimal-media
thickness (87,152) and reduces coronary atheroma volume (88).
Physicians must be cognizant of side effects associated with TZDs including weight
gain (81,164), fluid retention (162,165), bone fractures (166), and possibly bladder
cancer (162,167,168) (see article on peroxisome proliferator–activated receptors in
this supplement ). The preferred starting dose of pioglitazone is 15 mg/day titrated
to 30 mg/day, which provides 70–80% of the glycemic efficacy with minimal side effects
(170–174); titrating to 45 mg/day is not recommended. HbA1c lowering has been observed
with a pioglitazone dose of 7.5 mg/day with minimal side effects. In a 26-week study
(172) involving a Caucasian population, 7.5 mg/day pioglitazone reduced the HbA1c
by 0.9% compared with placebo (P = 0.14), while 15 mg/day reduced the HbA1c by 1.3%
vs. placebo (P < 0.05). Similar HbA1c reduction with pioglitazone, 7.5 mg/day, has
been observed in an Asian population (173,174).
In combination with metformin (inhibits hepatic gluconeogenesis), pioglitazone (improves
insulin sensitivity in liver/muscle and preserves β-cell function) offers an effective,
durable, and additive therapy that retards progressive β-cell failure with little
risk of hypoglycemia. In a 6-month trial comparing fixed-dose combination with pioglitazone
(30 mg)/metformin (1,700 mg) in 600 drug-naïve T2DM patients, HbA1c declined by 1.8%
(from baseline HbA1c 8.6%) and was significantly greater than the 1.0% reduction observed
with metformin alone or pioglitazone alone (175). Similar results were reported by
Rosenstock et al. (176) using initial combination therapy with rosiglitazone (8 mg)/metformin
Combining pioglitazone with GLP-1 analog curbs weight gain associated with the TZD
(177). Further, the natriuretic effect of GLP-1 analogs (178) mitigates against fluid
retention observed with TZDs. Therefore, we advocate combined GLP-1 analog/pioglitazone
therapy with or without metformin in newly diagnosed T2DM patients (3).
Intensive therapy with insulin plus metformin: reversal of metabolic decompensation.
Newly diagnosed T2DM patients who present in poor metabolic control are markedly resistant
to insulin and have severely impaired β-cell function. Glucotoxicity (8), lipotoxicity
(8,42,62), and multiple metabolic abnormalities (3) play an important role in the
insulin resistance and β-cell dysfunction. Institution of intensive insulin therapy
with or without other antidiabetes agents to correct these many metabolic abnormalities,
therefore, represents a rational approach to therapy based upon pathophysiology. After
a period of sustained metabolic control, the insulin therapy can be continued or the
patient can be switched to a noninsulin therapeutic regimen. This approach has recently
been examined by Harrison et al. (179). Fifty-eight newly diagnosed T2DM patients
in poor metabolic control (HbA1c 10.8%) initially were treated for 3 months with metformin
plus insulin to reduce the HbA1c to 5.9%. Subjects then were randomized to continued
therapy with insulin-metformin combination therapy with pioglitazone/metformin/glyburide.
During 3 years of follow-up, both groups maintained the reduction in HbA1c, but the
insulin dose had to be increased, indicating that, despite excellent glycemic control,
β-cell failure continued in this group. Further, glycemic control in both groups was
achieved at the expense of a relatively high rate of hypoglycemia and weight gain
in the insulin/metformin group, consistent with multiple studies demonstrating a high
incidence of hypoglycemia in sulfonylurea-treated and insulin-treated subjects.
Metformin plus GLP-1 analog plus pioglitazone: a pathophysiologic option that offers
robust glycemic control and weight loss.
The combination of biguanide (metformin), TZD (pioglitazone), and GLP-1 analog offers
a rational treatment choice, targeting multiple pathophysiologic abnormalities in
T2DM: muscle insulin resistance (pioglitazone), adipocyte insulin resistance (pioglitazone),
pancreatic β-cell failure (GLP-1 analog, pioglitazone), hepatic insulin resistance
(metformin, pioglitazone, and GLP-1 analog), and excessive glucagon secretion (GLP-1
analog) (3) with weight loss (GLP-1 analog) and low risk of hypoglycemia (93,97).
Studies with exenatide have demonstrated durable glycemic control for 3 years (84,93).
β-Cells in T2DM are blind to glucose, and GLP-1 analogs have the unique ability to
restore β-cell glucose sensitivity (84–86) (Fig. 7) by augmenting glucose transport,
activating glucokinase, increasing Pdx, and replenishing β-cell insulin stores (180,181).
Because pharmacologic GLP-1 levels (∼80–90 pmol/L) are achieved with GLP-1 analogs,
they overcome β-cell incretin resistance and augment insulin secretion. Increased
insulin and inhibited glucagon secretion reduce basal HGP, reducing fasting plasma
glucose concentration and enhancing HGP suppression after a meal (98,99). Although
GLP-1 analogs do not have a direct insulin-sensitizing effect, they augment insulin-mediated
glucose disposal secondary to weight loss (97). The combination of pioglitazone plus
exenatide reduces hepatic fat content and markers of liver damage in T2DM (182). In
T2DM patients treated with rosiglitazone, exenatide, or both (as add-on to metformin),
improved β-cell function and insulin sensitivity were noted, with weight loss in all
exenatide-treated groups (177). Similar results have been reported by others (182–185)
with combined GLP-1 analog/TZD therapy.
A single dose of liraglutide (Lira) (7.5 μg/kg or 0.75 mg for 100-kg person) administered
acutely completely restores β-cell sensitivity to glucose using the graded glucose
infusion technique to evaluate β-cell function (86).
In an ongoing study, we compared triple combination therapy with pioglitazone/metformin/exenatide
with the standard ADA approach (metformin followed by sequential addition of sulfonylurea
and then basal insulin) in 134 newly diagnosed T2DM patients with starting HbA1c 8.7%
(186). After 2 years, HbA1c reduction was greater in the triple therapy versus sequential
ADA group (2.7 vs. 2.2%, P < 0.01), triple therapy subjects lost 1.5 vs. 4.1 kg weight
gain with the ADA approach, and hypoglycemia incidence was 13.5-fold higher in the
sequential ADA group. These preliminary results indicate that a triple combination
approach focused on reversing underlying insulin resistance and β-cell dysfunction
is superior to sequential therapy (metformin, add sulfonylurea, add basal insulin)
with agents that do not correct core pathophysiologic defects in T2DM.
DPP4i: weak but easy alternative to GLP-1 analogs.
DPP4i have gained widespread use in combination with metformin because of their weight
neutrality, modest efficacy, and safety (187,188). Metformin has a modest effect to
increase GLP-1 secretion (107,189). Thus, combination metformin/DPP4i therapy may
result in increased GLP-1 levels (190) and an additive glucose-lowering effect (191,192).
When used in triple combination with metformin plus pioglitazone (30 mg/day), alogliptin
resulted in better glycemic control and fewer pioglitazone dose-dependent side effects
(edema, weight gain) compared with metformin with a higher pioglitazone dose (45 mg/day)
(172). Because they correct multiple components of the ominous octet, have superior
glucose-lowering efficacy, promote weight loss, and preserve β-cell function, we favor
GLP-1 analogs over DPP4i in the triple therapy approach. Nonetheless, because of their
ease of administration and safety, DPP4i represent a reasonable alternative.
Conclusions and recommendations
T2DM is a multifactorial, multiorgan disease, and antidiabetes medications should
address underlying pathogenic mechanisms rather than solely reducing the blood glucose
concentration. Emphasis should be placed on medications that ameliorate insulin resistance
and prevent β-cell failure if durable HbA1c reduction is to be achieved. Further,
the long-practiced glucocentric paradigm has become antiquated. Diabetic patients
are at high risk for cardiovascular events, and comprehensive evaluation/treatment
of all cardiovascular risk factors is essential. Simply focusing on glycemic control
will not have a major impact to reduce cardiovascular risk (113,123). Therefore, we
favor a therapeutic approach based not only on the drug’s glucose-lowering efficacy/durability
but also on its effect on weight, blood pressure, lipids, cardiovascular protection,
and side effect profile, especially hypoglycemia.
Initial therapy in newly diagnosed T2DM patients without cardiovascular disease should
be capable of achieving the desired glycemic goal, which should be as close to normal
as possible: HbA1c ≤6.0%. This will require combination therapy in the majority of
T2DM patients (3) (Fig. 1). While we favor the pathophysiologic approach, physicians
must be cognizant of the ABCDE of diabetes management (4). An approach that emphasizes
pathophysiology but allows for individualized therapy will provide optimal results.
Evidence-based medicine (UPKDS) has taught us that sequential therapy with metformin
followed by sulfonylurea addition with subsequent insulin addition represents the
treat to fail approach, and we do not recommend this approach unless cost is the overriding