Obviating Much of the Need for Insulin Therapy in Type 2 Diabetes

Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Obviating Much of the Need for Insulin Therapy
in Type 2 Diabetes Mellitus: A Re-Assessment of
Insulin Therapy’s Safety Profile
Stanley S. Schwartz, Paul S. Jellinger & Mary E. Herman
To cite this article: Stanley S. Schwartz, Paul S. Jellinger & Mary E. Herman (2016): Obviating
Much of the Need for Insulin Therapy in Type 2 Diabetes Mellitus: A Re-Assessment of Insulin
Therapy’s Safety Profile, Postgraduate Medicine, DOI: 10.1080/00325481.2016.1191955
To link to this article: http://dx.doi.org/10.1080/00325481.2016.1191955
Accepted author version posted online: 20
May 2016.
Published online: 20 May 2016.
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Date: 24 May 2016, At: 14:00
Publisher: Taylor & Francis
Journal: Postgraduate Medicine
DOI: 10.1080/00325481.2016.1191955
Article Type: Review
Obviating Much of the Need for Insulin Therapy in Type 2 Diabetes Mellitus: A Re-Assessment of
Insulin Therapy’s Safety Profile
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Stanley S. Schwartz, Paul S. Jellinger, and Mary E. Herman
Running title: Reduced reliance on insulin in T2DM; revised safety profile
Author Affiliations
Stanley S. Schwartz, MD, Main Line Health System, Wynnewood, PA, and University of Pennsylvania,
Philadelphia, PA
Paul S. Jellinger, MD, MACE, The Center for Diabetes & Endocrine Care, Hollywood, FL; University of
Miami Miller School of Medicine, Miami, FL
Mary E. Herman, PhD, Montclair State University, NJ
Corresponding Author: Stanley S. Schwartz, MD, Email: [email protected]
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Abstract
Current processes of care for diabetes mellitus (DM) were shaped during the era when insulin therapy
was considered inexorable to the management of advanced stage type 2 (T2DM), though this no longer
appears to be categorically true. There are also dashed hopes that insulin therapy can prevent or stall
diabetes. While exogenous insulin remains a life-sparing tool for fully insulin-dependent DM, insulin
therapy-induced hyperinsulinemia now appears to contribute to serious safety issues beyond
hypoglycemia and weight gain. Iatrogenic and compensatory hyperinsulinemia are metabolic disruptors
of β-cells, liver, muscle, kidney, brain, heart and vasculature, inflammation, and lipid homeostasis,
among other systems. This may compromise β-cells, exacerbate insulin resistance (IR), and increase risk
of cardiovascular (CV) disease. Striking associations between exogenous insulin and risks of CV events,
cancer, and all-cause mortality in clinical trial and real-world cohorts caution that insulin may pose more
harm than previously evidenced. At our disposal are numerous alternate tools that, alone or in
combination, efficaciously manage hyperglycemia and glucolipotoxicity, and do so without inducing
hypoglycemia, weight gain, or hyperinsulinemia. Moreover, these new tools support true precision
therapy, as modern day drug classes can be aligned with the various mediating pathways of
hyperglycemia at work in any given patient. Some also appear to promote β-cell survival, with intriguing
data being presented for newer agents, such as incretins. As such, we encourage preferential use of
non-insulin antidiabetic agents to injected insulin for the management of non-insulin-dependent
patients with T2DM, including in advanced stage T2DM. The goal of this article is to augment existing
literature to 1) correct misconceptions on the rationale and necessity for insulin therapy in T2DM, 2)
discuss emerging negative safety data with insulin therapy, and, 3) offer a practical means to reduce
reliance on insulin through delayed initiation, minimized dose, and, drug switching to safer agents, and,
potentially, reframes processes of care.
Key words β-cell-centric model, Egregious Eleven, incretins, reduced insulin
Insulin’s Place in Therapy: Old and New
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Insulin therapy is the mainstay of treatment of type 1 DM, and, for decades has been central to the
management of advanced-stage T2DM. The widespread adoption of insulin therapy for T2DM is owed to
its potent hemoglobin A1C-lowering ability, and, its introduction in an era when few antidiabetic classes
were available. It has remained a mainstay of care based on several outdated assumptions.
First was the assumption that complete β-cell exhaustion is an inevitability of T2DM. However, the
effect of dramatic weight loss in obese patients, such as from bariatric surgery, has shown that
endogenous glycemic control resumed in many patients (1,2) - signaling the persistence of functional βcells. Notable is that this phenomenon was found in bariatric patients with advanced T2DM, as well as
those in earlier stages of the disease, or who had received long-term insulin therapy (3). This suggests
that the presumed inexorable β-cell exhaustion (and necessity for insulin therapy) in T2DM should no
longer be considered an eventuality for all patients. As found in our own clinics, β-cell function may be
observed when the β-cells are properly supported, even in late stage T2DM. This refutes the old
‘wisdom’ that once a patient progresses to insulin therapy, responsiveness can categorically not be
returned to the β-cells with the proper support.
Second, there was a hope from the early days that insulin therapy would be a panacea to indefinitely
retard β-cell deterioration, and even prevent diabetes. This has not been borne out by decades of
research. Though insulin therapy can clearly reduce gluco-lipotoxicity in the short term (4), insulin
therapy-induced hyperinsulinemia, weight gain, IR, and possible β-cell dysfunction is proposed to offset
much of this benefit (5-9).
Third, getting patients to preset A1C goals had been a tenet of best practices, with insulin therapy relied
upon for its potent glucose-lowering ability. But the ‘wisdom’ of intensive glucose lowering with
hypoglycemic agents has been widely supplanted by patient-centric DM management. Under new
guidelines, the glycemic targets are individualized, rather than preset. For any given patient, glycemic
goals represent the A1C level that is obtainable without risking harm from hypoglycemia or other
sequelae of aggressive treatment. Optimal care will include A1C levels that may be substantially higher
than 7.0% in some patients (10-13). In addition to concerns of acute hypoglycemia, long-term mild
hypoglycemia is likely injurious as well. A hyperbolic curve has been demonstrated: ‘over-correcting’
A1C levels below 6.5 or 7% with hypoglycemic agents has been shown to increase mortality (13,14).
Finally, improved microvascular outcomes in tightly controlled clinical trials such as the UKPDS (UK
Prospective Diabetes Study UK Prospective Diabetes Study Group; 15) and DCCT/EDIC (Diabetes Control
and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study
Research Group; 16) led to high expectations that insulin therapy would improve macrovascular
outcomes. Reports from several long-term observational studies and real-world cohorts, however, show
a very different outcome – that exogenous insulin was neutral in some studies while others found an
increased risk for CV events, (14,17-19) and all-cause mortality (17,18,20-22), as will be discussed.
These insights led to numerous recent articles calling for a reappraisal of insulin therapy for the
treatment for T2DM (6,11,13,23-25). Those workers argue that the liberal or reflexive use of insulin
therapy – usage that was based on its initial promise - is not supportable by the composite of updated
outcomes data. Currie and Johnson concluded their 2012 review article with, “…event rates emanating
from the epidemiological evidence questioning insulin is such that this matter should be investigated
urgently. The regulatory agencies have a duty to investigate, and manufacturers have a duty to prove
the safety of their products.” (6)
The present authors concur that mounting evidence on the safety of insulin is more than worrisome,
especially findings from large-scale clinical, and mechanistic, studies. We present herein processes of
care that fully weigh the updated benefit:risk of insulin therapy against alternate agents, including the
numerous available options largely free of known risks of acute and chronic hypoglycemia, iatrogenic
hyperinsulinemia, or weight gain. Provided is a treatment paradigm that delays and reduces reliance on
insulin therapy, and, potentially, reframes processes of care.
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Relationship of Exogenously Administered Insulin to Iatrogenic and Compensatory Hyperinsulinemia
Physiologic peripheral insulin concentrations are finely-tuned by glucose-sensing β-cells. In this system,
insulin passes directly from the pancreas to the liver, where as much as two-thirds of the insulin is
extracted before entering the systemic circulation (26). The higher concentrations suffusing the liver are
integral to hepatic glucose storage and suppressed hepatic glucose production; the lower
concentrations in the circulation are appropriate for peripheral insulin action (25,26).
All current therapies bypass this intentional portal-systemic insulin concentration gradient that protects
against peripheral hyperinsulinemia. Iatrogenic hyperinsulinemia, clinically evident as insulin therapyrelated hypoglycemia and weight gain, is an unavoidable consequence of administration of insulin
directly into the general circulation (27,28).
[Figure 1 here ]
As shown in Figure 1, hyperinsulinemia engenders a number of downstream physiologic perturbations
that directly or indirectly effect β-cells and metabolism: IR, weight gain, T2DM, hypoglycemia,
hypertension and other CV risk factors, inflammation, and, more distantly related conditions including
cancer and Alzheimer’s disease (13,24,27-34). IR and high insulin are pro-inflammatory (35), which
mounting data has linked to β-cell apoptosis and dysfunction (24,30). Hyperinsulinemia disrupts the
suprachiasmic nucleus of the hypothalamus, increasing appetite and decreasing morning dopamine
surges, which further exacerbate sympathetic tone and peripheral IR (36). There is now a body of
research suggesting that endogenous hyperinsulinemia may induce IR (rather than IR leading to
hyperinsulinemia) (24,31). In this scenario, exogenous hyperinsulinemia would likely contribute to IR,
and, thus, should be avoided.
Hypoglycemia and weight gain are two consequences of insulin therapy. Hypoglycemia and weight gain
results in a vicious cycle propelled by recurrent hypoglycemia. As the patient restricts caloric intake to
manage weight gain, hypoglycemia worsens (37-38). Rebound hyperglycemia leads to use of higher
doses of basal or bolus insulin, which exacerbates the cycle. Mild hypoglycemia may be silent in its
presentation (39); one study employing continuous glucose monitoring found that 42% of subjects with
T2DM experienced episodes of hypoglycemic unawareness (40).
While insulin, sulfonylureas, glinides and thiazolidinediones (TZDs) lead to weight gain, GLP-1 receptor
agonists, metformin, pramlintide, and sodium-glucose co-transporter 2 (SGLT-2) inhibitors are
therapeutic options that are individually associated with a weight loss benefit. Dipeptidyl-peptidase-4
(DPP-4) inhibitors are generally weight-neutral, as are alpha-glucosidase Inhibitors, bromocriptine-QR,
and colesevelam (38).
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Insulin and Negative CV and Mortality Outcomes: Clinical Trial and Real-World Data
With the finding that intensive therapy was associated with improved microvascular outcomes, (15) it
became the hope, even the expectation, that intensive glucose control would be cardioprotective. A 10year follow up of the UKPDS reported encouraging outcomes: 15% and 13% risk reductions were found
in the sulfonylurea–insulin group for myocardial infarction and death from any cause, respectively (41).
While the findings of the UKPDS looked promising, another seminal study, the ACCORD Study (17,21),
had to be halted due to increased mortality. Despite trends in a reduced composite outcome of
outcome of MI, stroke, or CV death, intensive glycemic control was doing more harm than good, and by
means other than severe hypoglycemia (42). Little discernment of the effect of insulin therapy on
macrovascular outcomes was gained from either the VADT (Veterans Administration Diabetes Trial)
(43,44) or the ADVANCE CV outcomes trial (45); the composite effect of intensive glycemic on CV
outcomes in each of these trials was neutral.
The discrepancy between the UKPDS and ACCORD – one beneficial and one harmful – seemed to be
related to the patient population. This led to recommendations by the American Diabetes Association
and others that physicians assess patient profile and risk factors before prescribing insulin therapy
(10,46). At greatest risk for CV events in the ACCORD Study were patients with insulin-refractory
hyperglycemia, which are also usually characterized by longer duration of T2DM, overweight/obese,
older age, history of CVD, and/or a range of multiple comorbidities. In contrast to the ACCORD Study’s
older patient population (mean age 62 years) with 35% presenting with evident CV comorbidities, the
CV benefit found in the UKPDS Study was for a fairly young (mean age 53 years) population of newly
diagnosed patients, of which only 8% with a history of CV disease.
The ORIGIN (the Outcome Reduction with an Initial Glargine Intervention) Trial was initiated to assess
insulin therapy directly. It tested whether intensive insulin glargine therapy versus standard care could
reduce CV events in 12,537 patients with T2DM (or dysglycemia) and CV risk factors. The effect of 6-year
intensive insulin glargine therapy was neutral for CV outcomes (19). Interestingly, insulin therapy also
failed to prevent diabetes in dysglycemic subjects.
A worrisome association of insulin therapy with CV events and mortality emerged from other clinical
trials. DIGAMI-2 Study found intensified insulin treatment was associated with ~2-fold CV events, and
increased trend in mortality in patients with acute myocardial infarction (n=1145) (47). Metformin
treatment, in contrast, appeared to be protective against risk of death (47). The Euro Heart Survey of
patients with coronary artery disease found an adjusted 1-year hazard ratios for mortality and CV events
of 2.2 and 1.3, respectively, for patients receiving insulin or oral glucose lowering drugs (48).
Seeking a broader, perhaps more ‘real-world’, associations between insulin and CV outcomes, we turned
to large patient registries with insulin therapy-specific analyses. One study of patients with diabetes and
advanced HF (n=554) reported a striking 4-fold increased risk for death in insulin-treated patients as
compared to those treated with other glucose-lowering agents (22). A Kaiser Permanente Southern
California cohort (n=11,157) found that patients (n=44,628) on insulin-containing regimens had a 2.5fold increase in the risk of a CV event versus those treated without diabetes pharmacotherapy.
Metformin again serves as a reference point: metformin monotherapy conversely had no excess CV risk
(and patients on all other oral medications had a 1.55 increased risk) (14). In a real-world cohort, the
association of serious ischemic cardiac outcomes with insulin therapy was ~2-fold in the first few
months of therapy, and rose to ~3-fold with longer duration of therapy (6 and 12 months) (49).
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[Table 1 here]
Is this effect be shown relative to insulin dose? In a large T2DM cohort who received insulin
monotherapy for ~3 years (UK Clinical Practice Research Datalink; n=6484), each 1-unit increase in
insulin dose was associated with adjusted hazard ratios of ~1.5 for all-cause mortality, and ~1.4 for
major adverse CV events (18).
Some evidence suggests that peripheral hyperinsulinemia, increased by injecting insulin directly into the
peripheral circulation, can exacerbate IR. Selective IR in the heart phosphatidylinositol-3-kinase signaling
pathway is believed to be a component of the diabetic state; iatrogenic hyperinsulinemia may
exacerbate cardiac IR, as well as reduced synthesis of nitric oxide, endothelial dysfunction, and impaired
metabolic control (8,30,50-52). Selective IR has additionally been associated with excessive
vasoreactivity, angiogenesis, hypertension and mitogenicity (30,50,52). Hyperinsulinemia has also been
shown to contribute to atherosclerosis and inflammation (28,50,53-55). Iatrogenic hyperinsulinemia has
been less studied, though studies have associated it with an increase blood pressure mediated through
increased sympathetic activity (56), and, renal retention of salt, water and uric acid (7,53,54,57,58).
We propose that the benefits of intensive glucose lowering by insulin therapy are offset by its pitfalls,
including dysregulation wrought by hyperinsulinization. The net effect of exogenous insulin’s positive
and negative actions may tip from beneficial in the healthy, younger patient with T2DM to deleterious
as our patients age, their disease progresses, and, CV risk factors appear. We also find it noteworthy
that the CV benefit found in the UKPDS in response to insulin-containing intensive intervention was half
of that conferred by metformin treatment (41). This suggests that CV benefits can be accrued through
glucose-lowering treatment in selected patients – and the magnitude of this benefit was greater with
alternative treatments to insulin. Metformin and pioglitazone have each been shown to lower CV risk including within the same trials in which insulin therapy was detrimental (47,49,59,60). BromocriptineQR and alpha-glucosidase inhibitors decreased CV endpoints in several studies, albeit with small cohorts
(60,61-63). DPP-IV inhibitors (64-67) and the first GLP-1 receptor agonist, lixisenatide (68), outcomes
trials failed to show a reduction of CV events. On the other hand, a retrospective analysis of ~40,000
patients with T2DM who were treated with exenatide (LifeLink database) were less likely to have a CVD
event (HR 0.81% CI 0.68-0.95; P = 0.01) and lower rates of CVD-related hospitalization (0.88; 0.79-0.98; P
= 0.02) and all-cause hospitalization (0.94; 0.91-0.97; P < 0.001) than those treated with alternate
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antidiabetic treatments (69). The LEADER Study, evaluating liraglutide in T2DM patients with CV risk
factors (70) has been said to reduce heart attacks, stroke, and death with data to be presented at ADA
2016. The linagliptin CAROLINA Study is assessing T2DM patients with CV risk factors or established
complications (71) with a longer trajectory to report. It is expected in 2018. A recently completed
outcomes trial with the sodium-glucose co-transporter 2 (SGLT-2) inhibitor, empagliflozin, found that
patients with T2DM at high risk for CV events had ~one-third lower rates for hospitalization for heart
failure, CV death, and all-cause mortality when empagliflozin versus placebo was added to standard care
(72). Numerous other studies to date, though not definitive in terms of outcomes data, similarly suggest
CV benefits of SGLT-2 inhibitors or GLP-1 receptor agonists (60, 73-75). Other benefits of these newer
classes have included reduced systolic and diastolic blood pressure (76-78). The possibility of a
synergistic CV benefit with SGLT-2 inhibitors or incretins in TZD-containing regimens (38) is provocative –
and extends the notion that non-insulin agents, as monotherapy or combination regimens, can reach
glycemic targets without the pitfalls of insulin therapy.
Exogenous Insulin and the β-Cell
β-cell function is proven challenging to assess, including in response to various antidiabetic treatments.
Insulin (79), pioglitazone (80,81), metformin (82), acarbose (62), GLP-1 receptor agonists (83-87), and
DPP-4 inhibitors (83,88,89) are each effective glucose lowering agents, but seem to have differing
effects on β-cell function. Early and late β-cell response to glucose load has been shown to be improved
by treatment with DPP-4 inhibitors by some measures (83,89). DPP-4 inhibitors, as well as GLP-1
receptor agonists, have been shown to halt apoptosis and stimulate proliferation of β-cells, increase
insulin availability, improve α-cell response to insulin in various preclinical evaluations (90-92), and, have
been seen to accompany normalization of glucose and insulin homeostasis following bariatric surgery
(93). Despite nearly a century of use, there has been no compelling preclinical work that exogenous
insulin preserves β-cells beyond initial benefits of rapid reduction of glucotoxicity. Nor have large-scale
insulin trials been definitive. Clinical reasoning alternately suggests that the weight gain and
hyperinsulinemia resulting from exogenous insulin would harm, rather than support, β-cell health. In the
10-year follow-up of the UKPDS, only ~one-quarter of patients receiving intensive insulin therapy
maintained A1C targets over that long time interval (41). Most of those patients were early in the course
of their disease (41). Notably, this was the same proportion found in the sulfonylurea-treated cohort
(94).
In a head-to-head T2DM study of insulin and exenatide, β-cell function was assessed after 3-year
treatment with either exenatide/metformin or insulin/metformin by first-phase glucose-stimulated Cpeptide secretion. The groups were found to have similar glucose lowering (85). Exenatide/metformin
subjects showed sustained improvement in insulin sensitivity as compared to the insulin comparator.
Early stage T2DM clinical studies and preclinical studies with have reported encouraging data of
improved β-cell function with pioglitazone (80,81). The recently published EDICT Study reported that
triple therapy regimen containing metformin, pioglitazone and exenatide as early intervention for newly
diagnosed
T2DM
successfully
prevented
disease
progression.
At
2
years,
exenatide/pioglitazone/metformin treatment reported better A1C lowering (5.95% vs 6.50% for
p<0.001) and fewer hypoglycemic events (7.5-fold fewer) than the arm receiving an insulin-containing
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regimen (95). Importantly, stabilization of A1C levels was found with metformin/pioglitazone/exenatide
(but not in the arm treated with sequential add-on of basal insulin), and was durable for the 24-month
study. This could suggest that, given the proper support, β-cell function could be maintained, and,
perhaps, β-cells preserved. In a second study evaluating the metformin/pioglitazone/exenatide triple
regimen,
patients
with
impaired
glucose
tolerance
who
were
treated
with
metformin/pioglitazone/exenatide did not progress to frank T2DM; the majority reverted to normal
glucose tolerance (83). There was a ~100% improvement in β-cell function (and ~50% improvement in
insulin sensitivity) at 9 months. Pioglitazone/metformin double therapy realized half the improvement
achieved through exenatide triplet therapy (83). Given the important modulatory role of incretins to
pancreatic α and β-cells, and, its multi-organ oversight of central and peripheral glucose homeostasis
(96), it is intriguing to speculate that these classes may even exert β-cell preservation where other many
other agents, including insulin, have failed (97).
Treatment Paradigms for Reduced Reliance on Exogenous Insulin
The number of known mediating pathways of hyperglycemia now total eleven – which we term the
‘Egregious Eleven’ (12). These expand and update the Ominous Octet (98). Each pathway can exacerbate
hyperglycemia, and, via mechanisms such as glucotoxicity, accelerate β-cell failure. (FIGURE 2a)
Recognition of the distinct and varying mediating pathways of hyperglycemia at work in T2DM affords
the opportunity to practice ‘precision medicine’. Under this schema, treatment choices are driven by the
metabolic derangements operative in a given patient, rather than ‘guesswork’ from partially informed
and potentially outdated treatment pathways (12,99). Regimens that can now be selected based on
their ability to target the specific mediating pathways of hyperglycemia (3,12,38) (FIGURES 3b, 4), have
the added benefit of reducing reliance on exogenous insulin, given its updated safety profile (38).
[Figure 2a/b here]
Early T2DM: Non-Insulin Management of Glucose
The present authors use and advocate individualized therapy as per current guidelines. Our treatment
paradigm employs the least number of agents that treat the maximum number of known or presumed
mediating pathways of hyperglycemia at any stage of the disease for a given patient. The numerous
modes of action of currently available agents allow for combined regimens with complimentary
mechanisms of action to target the individual mediating pathways (12). (FIGURE 2b, 3) For example, in a
‘T2DM’ patient presenting with islet cell antibodies, a GLP-1 receptor agonist, with its ability to reduce
β-cell inflammation (100), would be a rational targeted therapy.
Individualized and optimized therapy is accomplished by abandoning stepwise prescribing of first,
second, then third-line therapies, and, the implied ‘competition’ between classes. We believe that the
current ‘stepwise’ prescribing approach produces therapeutic ‘inertia’. In light of the composite of the
risks of insulin therapy versus newer antidiabetic agents, we strongly favor use of non-insulin agents
over insulin therapies in our own clinical practice.
AACE treatment guidelines should be generally followed (99), with some adjustment. AACE
recommends initial monotherapy for an A1C from 6.5-7.5; dual therapy and diet modification for
patients with A1C levels greater than 7.5%; triple therapy for asymptomatic patients with A1C levels
greater than 9.0%.
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If A1C level is greater than 9% and symptomatic, AACE recommends insulin therapy. In our clinical
experience, however, we have found that a ‘no concentrated sweet diet’ and triple therapy with nonhypoglycemic agents may reverse symptoms of hyperglycemia and glucotoxicity in patients with A1C
levels greater than 9.0% in as little as three days, particularly in drug-naïve patients. If the patient
remains symptomatic, or if the fasting glucose remains elevated, basal insulin may be initiated, but is
usually unnecessary.
We do not support the use of sulfonylureas or glinides over other available options; indeed, it is
doubtful that sulfonylureas could pass United States Food and Drug Administration criteria for CV safety
in the present day. Recent large-scale trials and analyses suggest more favorable safety of newer classes.
Safety signals concerning heart failure or pancreatic issues with DPP-4 inhibitors have not been borne
out by the large, well-powered SAVOR TIMI (65), TECOS (66) and EXAMINE (67), studies; diabetic
ketoacidosis (DKA) with SGLT-2 inhibitors in T2DM appears infrequently. Per the position statement
issued jointly by the American Association of Clinical Endocrinologists and American College of
Endocrinology in the June 2016 issue of Endocrine Practice, “Review of available data on the prevalence
of SGLT-2-associated DKA as well as the impact of SGLT-2 inhibitors on human metabolism suggests that
DKA occurs infrequently and that the risk-benefit ratio overwhelmingly favors continued use of SGLT-2
inhibitors with no changes in current recommendations.” (101). Volume depletion, urinary tract
infections, and yeast infections associated with SGLT-2 inhibitor can be managed with patient
education. Similarly, a recent 10+ year analysis failed to find a statistically significant increased risk
of bladder cancer by pioglitazone (102,103). While pioglitazone should be avoided in patients with
osteopenia, osteoporosis, or an ejection fraction less than 50, most other patients are good candidates,
including those with edema that can be managed by reduced salt intake or concurrent use of a SGLT-2
inhibitor. The weight gain associated with pioglitazone can be offset by concurrent use of a GLP-1
receptor agonist (38,86). GLP-1 receptor agonists retain a highly favorable side effect profile, with
injection site reactions and nausea as two more common issues. Gastrointestinal upset is mitigable by
advising patients to stop eating at the first sense of stomach fullness.
The old clinical reasoning indicated early initiation of insulin therapy to reduce glucotoxicity. Our
perspective is that the aggregate of data argue for prudent, rather than liberal, use of insulin therapy.
Encouraging is that incretins, SGLT-2 inhibitors, and pioglitazone reduce glucotoxicity, lipotoxicity, and
obtain A1C goals without introducing the risks associated with exogenous insulin. These agents are
versatile enough to be suitable at any stage of the disease.
[Table 2 here]
Advanced T2DM: Avoiding Reliance of Insulin Late in the Course of T2DM
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In patients with high A1C levels, we employ a strategy of adding insulin conservatively to a base regimen
of non-hypoglycemic agents to minimize insulin dose. Combination regimens of two, three, or even four
non-insulin agents can be used to reach A1C targets with minimal add-on basal insulin, or, in many of
our patients, without any use of insulin. The majority of patients can be managed without prandial
insulin. (Table 3) This is critical to care as the majority of insulin-induced hypoglycemia in T2DM is due to
fast-acting analogs, as was shown in a head-to-head trial (104).
Metformin and metformin/DPP-4 inhibitor regimens have been long used in combination with basal
insulin in T2DM. Ample clinical studies have shown GLP-1 receptor agonists are both suitable and
beneficial in combination with basal insulin (105-110). Treatment guidelines from the ADA (111) and
AACE (112) recommend addition of a GLP-1 receptor agonist to basal insulin as an alternative to prandial
insulin. This combination can blunt insulin-induced hypoglycemia, allow for dose reduction of insulin,
and, avoid use of fast-acting insulins, given their inherent potential for hypoglycemia. GLP-1 receptor
agonists-containing regimens with insulin can offset the weight gain usually attributable to use of
exogenous insulin. A net reduction in weight may be achieved (108).
SGLT-2 inhibitors lower the renal threshold for glucose excretion and suppress renal glucose
reabsorption, thereby increasing urinary glucose excretion (113). Well-tolerated and complimentary to
the modes of action of other anti-diabetes therapies, these drugs have been rapidly integrated into care.
SGLT-2 inhibitors can be used in combination with insulin (114). In addition to lowering blood glucose
levels, empagliflozin has been shown to significantly lower CV outcomes and mortality by ~one-third
(72). SGLT-2 inhibitors engender moderate weight loss, and modestly lower blood pressure.
Studies of SGLT-2 inhibitors in combination use with exogenous insulins have shown improved glycemia,
and, possess the benefit of insulin dose reductions (115,116). In our practice, combined use of a SGLT-2
inhibitor with basal insulin decreases variability, and allows dosing down insulin.
[Table 3 here]
Patients receiving long-term insulin therapy: Reduced reliance on insulin
In practice, we find that adjunctive pharmacotherapy and other interventions can often reduce, or
completely eliminate, use of exogenous insulin - even in long-time recipients of insulin therapy. This
rewrites the old adage that once a patient progresses to insulin therapy there is no turning back.
In non-insulin-dependent patients who have been receiving basal or basal+bolus, insulin therapy, we
find that insulin dose can be decreased by 25% with initiation of a no concentrated sweet diet to reduce
simple sugar and caloric intake. An additional 25% dose reduction of insulin can be used if the patient
experiences symptomatic or asymptomatic hypoglycemia (37,117). We have found that the recalibrated
insulin dose can be reduced a further 25% by incorporating a GLP-1 receptor agonist into the regimen,
or 20% with addition of a SGLT-2 inhibitor. For patients who had been receiving higher doses of insulin
(150 units of insulin per day, for example) insulin dose has been successfully reduced in some cases to
40 units insulin per day upon initiation of add-on GLP-1 receptor agonist and SGLT-2 inhibitor. Additional
adjustments may be warranted over the subsequent weeks and months as the patient loses weight, or
with adjunctive metformin, pioglitazone, or bromocriptine-QR use (40). Insulin dose should be reduced
if the patient experiences hypoglycemia, including mild hypoglycemia.
In some patients, insulin therapy may be eliminated entirely; in others, basal insulin may still be required
to manage fasting hyperglycemia. In one case using the above strategy, hyperglycemia in a female
patient who had been receiving 300 units of insulin per day was adequately managed without any
exogenous insulin. This was accomplished with drug switching and subsequent dose reductions in
exogenous insulin over a period of one year (118).
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[Figure 3 here]
Summary
Insulin therapy has an essential role in care in T1DM. In addition to numerous encouraging reports in the
literature on the short and longer term benefits of insulin in T2DM, some recent large-scale studies have
brought to light additional safety concerns. These include iatrogenic hyperinsulinemia, hypoglycemia,
weight gain, and, increased risk of CV events, cancer, cancer-related death, and all-cause mortality.
Given the broad and negative downstream physiologic effects of exogenous insulin, we believe that its
use in T2DM should be minimized at all stages of the disease. While the UKPDS (6) showed benefit in
early T2DM in patients without CV risks or advanced age, it is noteworthy that metformin was twice as
effective at lowering CV outcomes or mortality.
Much of believed requisite or reflexive insulin therapy in T2DM has proven unnecessary or
unsubstantiated in recent decades, during which time the availability of new classes has round out our
ability to effectively manage hyperglycemia with options with favorable benefit:risk profiles without use
of insulin therapy.
Preferred treatments for T2DM to insulin therapy are those that manage A1C levels and body weight,
reduce CV risk, and may favorably alter the ‘natural history’ of T2DM (preserve β-cell mass and
function). Approaches such as metformin, pioglitazone, DPP-4 inhibitors, GLP-1 receptor agonists, and
SGLT-2 inhibitors, used alone or in combination, afford patient-centric management of hyperglycemia
and glucolipotoxicity, without inducing hypoglycemia, weight gain, or iatrogenic hyperinsulinemia. These
regimens have been found to reduce reliance or completely eliminate use of injected insulin in patients,
including in many cases of advanced T2DM.
Declaration of interests
SS Schwartz is a speaker and advisor to Novo Nordisk, Merck, Takeda, Johnson and Johnson,
AstraZeneca/Bristol-Myers Squibb, Eli Lilly and Company, Boehringer lngelheim/Eli Lilly and Company,
and, a speaker for Eisai and GlaxoSmithKline. PS Jellinger is a speaker for Novo Nordisk, Janssen, AstraZeneca, Boehringer lngelheim, Merck and has served as an advisor for AstraZeneca. The authors have no
other relevant affiliations or financial involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or materials discussed in the manuscript apart
from those disclosed.
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investigators. Impact of empagliflozin added on to basal insulin in type 2 diabetes
inadequately controlled on basal insulin: a 78-week randomized, double-blind, placebocontrolled trial. Diabetes Obes Metab. 2015;17(10):936-48.
116. Schwartz S. Evidence-based practice use of incretin-based therapy in the natural history of
diabetes. Postgrad Med 2014;126(3):66-84.
117. Matthews D, Fulcher G, Perkovic V, et al. Efficacy and safety of canagliflozin, an inhibitor of
sodium glucose co-transporter 2, added on to insulin therapy with or without oral agents in
type 2 diabetes. Poster presented at: The 48th Annual Meeting of the European Association
for the Study of Diabetes (EASD),October 1-5, 2012, Berlin, Germany.
118. Schwartz, S. Synergy in diabetes treatment. Review in Endocrinology, November 2008.
Available at: http://bmctoday.net/reviewofendo/2008/11/article.asp?f=review1108_07.php.
Accessed August 2, 2015.
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Figure 1. Exogenous insulin contributes to hyperinsulinemia which results in multiple adverse
consequences (13,24,27-34). By virtue of its route of administration, there is no safe injected insulin.
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Figure 2. β-Cell-Centric Construct and the Egregious Eleven [12]. Eleven currently known mediating
pathways of hyperglycemia. A. The β-cell-centric view of the diabetic state recognizes that the core
defect in DM is dysfunction within the β-cells; hyperglycemia results from multiple mediating pathways.
Many of these contribute to b-cell dysfunction (liver, muscle, adipose tissue [shown in red to depict
additional association with IR], brain, colon/biome, and immune dysregulation/inflammation [shown in
blue]), and others result from b-cell dysfunction through downstream effects (reduced insulin,
decreased incretin effect, a-cell defect, stomach/small intestine via reduced amylin, and kidney [shown
in green]). B. Targeted therapies among currently available non-hypoglycemic agents address individual
mediating pathways of hyperglycemia. Reprinted with permission from [12].
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Figure 3. Use of non-hypoglycemic agents across the continuum of the natural history of DM. Mediating
pathways of hyperglycemia are unique to each patient and may vary over the course of the disease.
These pathways should drive choice of therapy at any stage of the natural history, as signified but the
width of the white box encompassing the ‘Egregious Eleven’.
Table 1. The frequency of use and the unadjusted (incidence) and adjusted (multivariable models)
hazard ratios of serious atherosclerotic vascular disease of the heart based on months of use of the
therapy for drugs or classes. Reference group was those who did not use the drug of interest. Potentially
confounding variables assessed include age; sex; body mass index (BMI); hemoglobin A1c; cigarette use;
chronic kidney disease (CKD), as estimated by glomerular filtration rate (eGFR); mean arterial blood
pressure (MAP); history prior to entry into the cohort of myocardial infarction, unstable angina, or a
cardiac procedure consistent with atherosclerotic vascular cardiac disease; and history of atherosclerosis
of the lower extremity. Adapted with permission from Margolis et al. 2008 [49].
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Variable
Insulin
0
1-5 months
6-11 months
12 months or more
Sulfonylureas
0
1-5 months
6-11 months
12 months or more
Biguanide
0
1-5 months
6-11 months
12 months or more
Thiazolidinediones
0
1-5 months
6-11 months
12 months or more
Number (%)
Unadjusted HR Adjusted HR
12 261 (90.3)
668 (4.9)
268 (2.0)
379 (2.8)
Ref*
1.6 (1.2, 2.2)
2.4 (1.6, 3.5)
2.4 (1.8, 3.3)
Ref*
2.0 (1.5, 2.6)
2.9 (2.0, 4.2)
2.9 (2.1, 3.9)
8527 (62.8)
1929 (14.2)
1047 (7.7)
2073 (15.3)
Ref*
1.0 (0.8, 1.3)
1.6 (1.2, 2.0)
2.0 (1.7, 2.4)
Ref*
1.0 (0.8, 1.2)
1.5 (1.2, 2.0)
1.8 (1.5, 2.2)
3554 (26.2)
3632 (26.8)
2454 (18.1)
3936 (29.0)
Ref*
0.6 (0.5, 0.8)
1.0 (0.8, 1.2)
1.2 (1.0, 1.5)
Ref*
0.7 (0.5, 0.8)
1.0 (0.8, 1.3)
1.3 (1.0, 1.5)
11 391 (83.9)
950 (7.0)
567 (4.2)
668 (4.9)
Ref †
0.8 (0.6, 1.1)
0.6 (0.4, 0.9)
0.7 (0.5, 1.1)
Ref
0.9 (0.7, 1.2)
0.6 (0.4, 1.0)
0.7 (0.4, 1.1)
Test for trend *p-value <0.001 and † p-value <0.05.
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TABLE 2. Our Prescribing Principles Across the Continuum of Care
•
Initiate combination treatment with antihyperglycemic agents for A1C levels above 7.5%.
• Initiate with combination therapy to achieve rapid glucose lowering to address as
many mediating pathways of hyperglycemia as possible with the fewest agents.
• Initiation with combination therapy supplants prior paradigms based on
first, second and third line treatment sequencing, or ‘competition’
between drug classes.
• Consider the full range of available drug classes which support unprecedented
options for tailored therapy for the pathways of hyperglycemia at work in any
given patient.
•
Consider combination therapy intervention for some patients with A1C levels below
7.5%, including, potentially, IGF.
•
Consider use of fructosamine testing to adjust regimens at intervals of one month, rather
than while waiting for changes in A1C levels.
•
To avoid insulin-induced hypoglycemia, hyperinsulinemia, and weight gain, delay or
eliminate use of exogenous insulin by preferential use of alternate therapies.
• Should insulin therapy be eventually needed, continue use of non-hypoglycemic
agents and initiate basal insulin as add-on therapy; necessity for bolus insulin will
likely be mitigated.
•
For patients already receiving insulin therapy, consider drug substitution or dose
reduction through preferential use of non-hypoglycemic therapy.
•
For patients who need better glycemic control despite co-treatment with 3-4 nonsulfonylurea/glinide therapies and adherence to a no-concentrated-sweet diet, basal
therapy may be initiated as add-on therapy. Bolus therapy is undesirable and, in our
practice, infrequently needed.
TABLE 3. Examples of the Use of insulin/non-insulin combined regimens to reduce dose of basal insulin,
and obviate most of the reliance on bolus insulin to manage T2DM.
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Combination regimen with
basal insulin
Percent of patients
reaching target of
A1c < 7.0%
Reference
Rapid-acting insulin
15%
Raccah et a. 2013 (109)
Metformin
63%
Arnolds et al. 2010 (105)
Metformin + sitagliptin
88%
Arnolds et al. 2010 (105)
Metformin + exenatide
80%
Arnolds et al. 2010 (105)
Exenatide
60%
Buse et al. 2011 (106)
Lixisenatide
29%
Raccah et a. 2013 (109)
Lixisenatide + metformin
86%
Riddle et al. 2013 (110)
Liruglutide
78%
Gough et al. 2015 (108)
Canagliflozin
29%
Matthews et al. 2012 (117)