(2024) 22:356
Schwartz et al. BMC Medicine
https://doi.org/10.1186/s12916-024-03518-5

BMC Medicine

REVIEW

Open Access

Advances and counterpoints in type 2
diabetes. What is ready for translation into realworld practice, ahead of the guidelines
Stanley S. Schwartz1,2, Barbara E. Corkey4, James R Gavin 3rd5, Ralph A. DeFronzo6 and Mary E. Herman3*

Abstract
This review seeks to address major gaps and delays between our rapidly evolving body of knowledge on type 2 diabetes and its translation into real-world practice. Through updated and improved best practices informed by recent
evidence and described herein, we stand to better attain A1c targets, help preserve beta cell integrity and moderate glycemic variability, minimize treatment-emergent hypoglycemia, circumvent prescribing to “treatment failure,”
and prevent long-term complications. The first topic addressed in this review concerns updates in the 2023 and 2024
diabetes treatment guidelines for which further elaboration can help facilitate integration into routine care. The
second concerns advances in diabetes research that have not yet found their way into guidelines, though they areendorsed by strong evidence and are ready for real-world use in appropriate patients. The final theme addresses
lingering misconceptions about the underpinnings of type 2 diabetes—fundamental fallacies that continue to beasserted in the textbooks and continuing medical education upon which physicians build their approaches. A corrected and up-to-date understanding of the disease state is essential for practitioners to both conceptually and translationally manage initial onset through late-stage type 2 diabetes.
Keywords Type 2 diabetes, Beta cells, Type 2 diabetes remission
Key takeaways• Recent new guideline recommendations ready to beroutinely incorporated into routine practice include
the following:*Correspondence:
Mary E. Herman
mariaon4@mail.com
1
Main Line Health, Wynnewood, PA, USA
2
University of Pennsylvania, Philadelphia, PA, USA
3
Social Alchemy: Building Physician Competency Across the Globe, 5 Ave
Sur #36, Antigua, Sacatepéquez, Guatemala
4Department of Medicine, Boston University School of Medicine, Boston,
MA, USA
5
Emory University School of Medicine, Atlanta, GA, USA
6
Department of Medicine, Diabetes Division, University of Texas Health
Science Center, South Texas. Veterans Health Care System and Texas
Diabetes Institute, 701 S. Zarzamoro, San Antonio, TX 78207, USA◦ Complication-centric prescribing should takecenter stage. Treatment plans should no longer ‘silo’
hyperglycemia as a single treatment target but rather
manage it synchronously with the patient’s comorbidities and risk factors.
◦ In patients with cardiorenal risk factors, long-acting glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 inhibitors(SGLT-2is) have been shown to provide protection
and are recommended as preferred treatments.
◦ A novel algorithm enables treatment decisionmaking for latent autoimmune diabetes in adults(LADA) based on glutamic acid decarboxylase(GADA) and C-peptide testing [1]• Several key advances in the management of type 2
diabetes are supported by strong evidence that make© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as longas you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article orparts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicatedotherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To
view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Schwartz et al. BMC Medicine(2024) 22:356

these ready for use in routine care, despite remaining in a‘holding pattern’ before full integration into
guidelines. These include:◦ The pleiotropic benefits of several antidiabetic agents provide important new considerations to treatment decision-making; and, should be
employed in treatment selection in the clinic.
◦ Disease remission should be elevated to a primary objective of case management of type 2 diabetes beyond the role it had in past routine care. The
inherent resilience of beta cells can be harnessed tohelp remit hyperglycemia through the use of dietand lifestyle modifications and/or short-term intensive pharmacotherapy.
• The underpinnings of type 2 diabetes etiology andprogression have been corrected. In particular,◦ Early type 2 diabetes is no longer considered an
intractable (‘inexorable’) state. Beta cells, in fact,
remain robust and resilient through much of thecourse of the disease, and with support, can resume
partial or complete glucoregulation.
◦ Type 2 diabetes is not a single disease across all
patients, nor does it arise from the same defects.
Accordingly, tailored therapy is imperative.
◦ Precision medicine veers away from management
to treatment failure with sequential add-on therapy.
Instead, targeted therapy can address the individual
drivers of hyperglycemia in each patient without
agents that are ineffective in the given patient.
◦ Target attainment is distinctly possible with current treatments, without treatment-emergent hypoglycemia. Intensive glucose control is pivotal for
preventing or offsetting diabetes-related long-term
outcomes.
◦ With the expanding antidiabetes armamentarium,
it is possible to reduce reliance on sulfonylureas andexogenous insulin, which present less desirable benefit: risk profiles (including weight gain, hypoglycemia, and ‘wear and tear’ on beta cells) than manyother currently available options.

Background
Despite the recent expansion of antidiabetic agents suchas GLP-1 receptor agonists and SGLT-2is, glycemic
control remains suboptimal in many patients. Approximately half of all type 2 diabetic patients in the UnitedStates and worldwide fail to achieve the glycemic targetof A1c ≥ 7.0% [2–4].

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Ninety percent of diabetes cases are managed by primary care providers [5]. Guidelines are integral to updating best practices and are especially edifying for generalpractitioners who maintain a broad knowledge baseacross numerous medical conditions. Primary care providers are encouraged to apply the most effective treatment parameters in clinical practice rather than relying
on specialists [5]. This review seeks to highlight key
developments in the field to both provision and empower
generalists as well as specialists in dispensing care in linewith the latest knowledge in the disease state ready foruse in routine care.
The field of type 2 diabetes research has detailed
guidelines issued by the American Diabetes Association and the American Association of Clinical Endocrinology [6–20]. Many advances, however, see extensive
delays in anatomizing research discoveries into clinical approaches. This prudence helps prevent the needto elaborate extensively on areas pending additional
research or to deadopt a faulty recommendation. On theother hand, it impedes the timeliness of advances reaching patients. It also sets a deceptively slow rate of change
in best practices, contributing to “physician habituation,”
one contributing aspect to clinical inertia [21, 22].
In this review, we shortlisted timely leaps in the management of type 2 diabetes—advances that we believe areready for “prime time.” We provide context for selected
updates that have already been incorporated into guidelines—context that we feel will edify the rationale forreaders and speed adoption into real-world use. Second,
we detail several important developments that are yet to
be translated to the clinic while these remain either invigorous debate or in limbo despite a strong body of evidence of the benefit and utility of these having benefit topatients.
Third, this review revisits outmoded dogmas about thebasic science of type 2 diabetes—premises that continue
to be widely reiterated in physician education but are, infact, incorrect. Today’s type 2 diabetes is “not your mother’s type 2 diabetes,” that is, our modern understandingof dysglycemia is a departure from old tenets. A correctunderstanding of beta cell function and dysglycemia isneeded for physicians to be in command and optimallycontrol diabetes and its sequelae in their clinics.
Manage hyperglycemia synchronously, rather
than in parallel, with patient comorbidities and risk factors

Type 2 diabetes, metabolic syndrome, and cardiorenal
compromise have been classically viewed as separate
diagnostic entities and are managed autonomously. These
conditions are highly interrelated, however, and should
be regarded as coincident conditions. Moreover, these
conditions represent overlapping targets for therapy [18].

Schwartz et al. BMC Medicine(2024) 22:356

For example, renal dysfunction continues to be underdiagnosed in patients with diabetes [23]. Patients with type2 diabetes and comorbid renal dysfunction are five times
more likely to die from cardiovascular causes before
reaching kidney failure, highlighting the interrelatedness of the cardiorenal axis with dysglycemia. One study
reported a 16-year differential in longevity for individuals
with type 2 diabetes with or without renal compromise[24], stressing the importance of screening and managing
renal dysfunction alongside hyperglycemia.
In 2023, an international expert task force issued a dictate for physicians: apply early, intensive, and coordinatedapproaches across interrelated disease states [18]:“…all too often, the risk factors for these disorders are
not addressed promptly in clinical practice, leading
to irreversible pathologic progression… Traditional
approaches to treatment involving sequential therapy, in which agents are added only after one has
failed, contribute to clinical inertia and often prevent goal attainment, leading to adverse outcomes….
in turn contributing to increased morbidity andmortality. In contrast, early diagnosis and prompt,
intensive intervention, often with initial combination therapy, leads to faster goal attainment andimproved outcomes for at-risk patients.” Handelsman et al. [18].
Early intervention and intensive management of patientswith diabetes, cardiorenal, and metabolic diseases) [18].
Accordingly, the first key take-away of this review isto incorporate change from the creation of the treatment plan for the patient: looking beyond hyperglycemia. Large-scale studies in type 2 diabetes patients have
proven to be a treasure-trove for insights into the natureand management of the disease. Decades of data haveelucidated the full range of hyperglycemia-related conditions and long-term complications. The continuumof related conditions spans obvious conditions, including obesity and metabolic syndrome, prediabetes, type2 diabetes, hypertension, and dyslipidemia, and includes
nonalcoholic fatty liver disease, atherosclerotic cardiovascular disease, atrial fibrillation, chronic kidney disease, heart failure, and cognitive dysfunction [18]. This
represents some seemingly disparate conditions underwhich case management has traditionally siloed or overlooked. In addition to being an outcome of dysglycemia,
the presence of one disease state may be a harbinger for,or exacerbate, another. This insight elevates the constellation of comorbid conditions of hyperglycemia from a theoretical construct to a bona fide, practical management
tool and objective [18]. This broadened view of dysmetabolism affords valuable opportunities in the clinic forearly diagnosis—and therefore prevention—of comorbid

Page 3 of 16

conditions. This recommendation made our list because
it readily translatable into practice and sanctioned in theguidelines yet relies on practitioners to make a wholesale
revision of their approach to care, if not already adopting
this approach. The benefit to their patients is improved
short- and long-term outcomes.
Cardiorenal benefits of antidiabetic agents: pleiotropic
benefits

In addition to the classic long-term outcomes (cardiovascular disease, peripheral artery disease, nephropathy,
retinopathy, and neuropathy), incontrovertible evidence
connects hyperglycemia to stroke, cognitive decline,
gastrointestinal problems, immunocompromise, cancer, and even dental disease. This awareness expands ourappreciation for the broad physiologic consequences ofdysglycemia.
Another dividend of large studies in patients with type2 diabetes has been that many of our current glucoselowering agents possess valuable pleiotropic actions. For
example, the PROactive Study showed that pioglitazone
improves triglycerides, albuminuria, markers of inflammation, and fatty liver and reduces the risk of stroke
and myocardial infarction—each through mechanismsthat appear to be distinct from its direct insulin-sensitizing action [25–28]. Icosapent ethyl similarly conferred cardiovascular benefits independent of its direct
lipid-lowering effects [29, 30]. Finerenone was shown
to pleiotropically influence tissue remodeling throughalternative mechanisms to those of the mineralocorticoid
receptor [31–33].
GLP-1 receptor agonists and SGLT-2is were found
to exert striking benefits on the heart, liver, kidney, andeven the brain [34–40]. Emerging research indicates thatthese benefits are conferred by pleiotropic mechanisms,
that is, pathways distinct from those involved in glucose
balance. For example, GLP-1 receptor agonists were
found to improve myocardial blood flow in a manner
independent of myocardial glucose uptake [41]. Interestingly, receptors for GLP-1 have been found in numerous
tissues beyond the endocrine pancreas and gastrointestinal tract, including the brain, immune system, heart, andperipheral cardiovascular vasculature.
GLP-1 receptor agonists confer protection to the kidney. To characterize the mechanisms through which
GLP-1 receptor agonists protect against diabetic kidneydisease, the phase 3B FLOW Trial will assess the effects
of semaglutide treatment on kidney outcomes in participants with type 2 diabetes and chronic kidney disease(NCT03819153), and this trial is expected to be completed at the end of 2024. Planned meta-analyses [42]and other studies are also underway. Studies investigating the protective effects of GLP-1 receptor agonists on

Schwartz et al. BMC Medicine(2024) 22:356

cognitive dysfunction [43, 44], nonalcoholic fatty liverdisease (NAFLD)/nonalcoholic steatohepatitis (NASH),
and metabolic dysfunction-associated fatty liver disease(MAFLD) are ongoing [45].
As an antidiabetic agent, SGLT-2 inhibitors improve
plasma glucose levels by increasing renal glucose andsodium excretion and lowering intraglomerular pressure [46–48]. SGLT-2 inhibitors exert a wide range ofpleiotropic actions, some of which may prove as important future targets of therapy. SGLT-2 inhibitors reduce
glycolysis, rebalance the coupling between glycolysis
and oxidative phosphorylation, and attenuate adverse
cardiac remodeling and the progression of heart failure.
SGLT-2 inhibitors have been found to impact cardiomyocyte function through the adenosine monophosphateactivated protein kinase mammalian target of rapamycincomplex 1 pathway [49].
SGLT-2 inhibitors also exert interesting effects on
mitochondrial and cell viability. These agents directly
modulate evolutionary responses to nutrient deprivation through adaptive cellular reprogramming and cell
survival (reviewed by Packer, 2023) [49]. Starvation mimicry has been used to show that SGLT-2 inhibitor modulation of mitochondrial function and viability involves
processes of autophagy, the clearing of reactive oxygen
species, and the reduction of inflammation and fibrosis,
each of which is a pathway distinct from the renal clearance of glucose [49].
GLP-1 receptor agonists and SGLT-2 inhibitors havebeen shown in clinical trials to benefit the cardiorenal
axis [35, 36, 38–42]. This finding raises the following
question: how much earlier in the disease course of dysglycemia and dysmetabolism might these drugs confer
protection for the cardiorenal axis? Should these agentsbe used as first-line treatment in potentially all patientswith type 2 diabetes? The observation that the protective
effects are accomplished independent of glucose-lowering potential opens new possibilities: might these agents
have utility in cardiorenal protection in normoglycemic
patients? Tantalizing prospects await future research.
For the meantime, findings from long-term outcome
studies have reshaped treatment sequencing in theguidelines. The 2023 directive authored by Handelsman
et al. [18] mandates factoring a patient’s comorbidities
and risk factors, including those of the cardiorenal axis,
along with their hyperglycemia in treatment decisionmaking. As recommended in the guidelines, these authors
reemphasize use of long-acting GLP-1 receptor agonists
and SGLT-2 inhibitors in patients with type 2 diabetes
and existing (or at risk for) comorbid cardiovascular or
renal compromise. Based on the available evidence, there
should be no delay in incorporating these recommendations into clinical practice for eligible patients.

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Amend the canonical teaching of the “inexorable
progression of type 2 diabetes”

Medical textbooks have always taught—and clinicalpractice correspondingly operates on the supposition—that type 2 diabetes can only “inexorably progress.” Thebelief is that once a patient with diabetes requires pharmacointervention, the disease is intractable. This longentrenched dogma is omnipresent across medical school
textbooks and continuing medical education and shapes
practitioner expectations. However, it has been flatly
refuted by decades of research.
Let us consider this supposition from a historical context. This arose in the early era of diabetes care, when
diagnosis typically occurred late in the course of the disease. Indeed, at this point, beta cells had already largely“petered out” in their capacity to sense fluctuations inplasma glucose and correspondingly adjust plasma insulin levels. That is, type 2 diabetes was observed and tested
in its advanced stages. Indeed, before annual screening, beta cells retain as little as 10% of their capacity at
the time of diagnosis. The first-generation therapeutic
options of that era were “oafish” drugs such as sulfonylureas, which rapidly reached treatment failure [50], arguably by further taxing overextended beta cells.
In today’s standards of care, however, hyperglycemia is
detected sooner—as early as the prediabetic state. In current standards of care, beta cells often remain robust at
the time of diagnosis. The inherent resilience of the beta
cells and of the glucoregulatory apparatus, at large, arestill available to be re-enlisted to resume normoglycemia.
It is worthwhile at this point to review defects that
contribute to type 2 diabetes. These defects include beta
cell dysfunction [51, 52], insulin resistance [53], and,less regarded but equally important, hyperinsulinemia[54–56]. In addition, genetic and epigenetic variables[57, 58] and environmental factors [59–61] each play acausative role. Hyperglycemia typically arises not fromone but from multiple insults across these interrelated
factors. Correcting any of these three variables typicallyhas a domino effect on the others [62]. Peripheral insulin resistance is tethered to elevated insulin secretion[63, 64], with each impacting glucose tolerance [65]. The
state of beta cell function is intricately linked to the magnitude and implacability of the resulting systemic insulin
resistance.
Chronic nutrient excess has accompanied modern
affluence. This overnutrition is out of sync with the evolutionary schema of metabolism. Overnutrition induces amaladaptive state of sustained hyperinsulinemia in someindividuals. This taxes the beta cells and instigates insulin resistance—perpetuating all three imbalances. Beta
cell dysfunction bidirectionally influences the extent
of hyperinsulinemia and is quantitatively linked to theSchwartz et al. BMC Medicine(2024) 22:356

development of diabetes-related complications (reviewed
by Rachfal et al [66]) [67].
Diet and exercise modifications promote weight loss
and simultaneously improve insulin resistance, correct hyperinsulinemia, and increase beta cell functional
capacity. Diet and exercise modifications have beenshown repeatedly to be sufficient to reestablish normoglycemia in a subset of patients [67–73]. The ACTNOW and STOP-Diabetes trials showed that correcting
impaired insulin secretion and insulin resistance in normoglycemic people at high risk of diabetes (impaired
glucose tolerance or prediabetes in these two studies,
respectively) reduced progression to frank diabetes [74, 75].
The body of knowledge to date categorically overrides
the premise that type 2 diabetes is an “inexorable” disease. Type 2 diabetes can possibly be rehabilitated, perhaps up to the advanced stages of the disease.
In routine practice, physicians restore normoglycemia
in many patients through good adherence to diet and lifestyle modifications, especially in patients with early type2 diabetes. The premise that type 2 diabetes is an “inexorable” disease traditionally assumed that once pharmacotherapy is initiated, there is no further rationale to treat
the tractability of hyperglycemia.
The conceptual leap that we make herein is that earlytype 2 diabetes is not a one-way proposition. This restyles
the slope of the natural history of the disease to a far
more favorable trajectory for our patients and with ample
opportunities to slow or stall type 2 diabetes—from prediabetes through early-onset disease, and even beyond,as will be detailed.
Resilience of the glucoregulatory apparatus: early vs latediabetes

Early- and late-stage type 2 diabetes can now be reframed
as two distinct conditions based on the extent of beta cellfunction and warrant two distinct approaches to care.
Until the advanced stages of hyperglycemia, the firstmandate is to attempt to resume euglycemia if the beta
cells can support adequate insulin production and metabolic gluco-stasis.
Consider the recent SARS-CoV-2 pandemic. Pandemic stay-at-home orders resulted in a record numberof patients presenting with new-onset hyperglycemia,
individuals who had been normoglycemic prior to thepandemic [76]. It is reasonable to assume that these individuals retain high-functioning, robust beta cells, regardless of their age. Diet modification and/or exercise canreestablish normoglycemia by easing the imposition ofrecently introduced insulin resistance and its sequelae on
the glucoregulatory apparatus.

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As a second example, treatment with antidepressantscan lead to new-onset hyperglycemia via drug-inducedchanges in metabolic rate [77]. As in the above example,
hyperglycemia is not associated with “petered out” beta
cells; this patient population constitutes excellent candidates for reversing type 2 diabetes through diet and exercise. Gestational diabetes and glucocorticoid-induced
diabetes are other instances of transient hyperglycemia,
from which it can be anticipated that the glucoregulatory
apparatus retains the ability to “right” itself.
In contrast, late-stage diabetes may correspond moreclosely to the “classical” construct of type 2 diabetes
onset, which is represented by “exhausted” beta cells.
Typically, beta cells in late-stage type 2 diabetes havebeen subjected to glucotoxicity and lipotoxicity for decades, which has detrimental effects on cell function, overall cell integrity, and cell viability [47, 51, 52].
Although more common in older patients, beta cell
resilience is much more related to the status of the glucoregulatory apparatus than to patient age. Persisting dysglycemia, sustained hyperinsulinemia, unmitigated insulin
resistance, and systemic glucotoxicity are highly detrimental to beta cells, damaging the cells and leading to loss of
glucoregulation. Notably, glucolipotoxicity is detrimental
to almost all other cell types. This damage results in a wide
range of long-term complications associated with hyperglycemia and diabetes [47, 51, 52, 56]. As described above,
the actual range of organ systems compromised by sustained hyperglycemia is more numerous than that deduced
decades ago from the United Kingdom Prospective Diabetes Study (UKPDS) and other early investigations [50, 78].
The remission of type 2 diabetes in the clinic is one of
the hottest contemporary topics and sits in the crosshairsof recent developments. On the one hand, the ability toremit hyperglycemia is within reach, in contrast to decadesof teaching that type 2 diabetes is “inexorable.” Despite
being routinely practiced in the first-line intervention of
hyperglycemia through diet and exercise, it is typicallyabandoned after this initial, sometimes cursory effort.
On the other hand, accumulating evidence that GLP-1
receptor agonists and SGLT-2is confer cardiorenal protection has given pause to promote remission. According
to the most recent consensus statement, guideline crafters have left remission in limbo, citing the need for large
studies to first elucidate which patient types are the best
candidates for cardiorenal prevention versus targeting
remission of the disease. If hyperglycemia is remitted, awindow of opportunity for the prevention of long-term
complications may be lost.
The authors of the current review, however, urge physicians to prioritize and implement remission as a priority

Schwartz et al. BMC Medicine(2024) 22:356

goal of therapy in advance of the years of studies needed
to satisfy the above concerns of guideline crafters. Treating patients to remission benefits virtually all patients.
Correcting hyperglycemia affords, in itself, protection
against diabetes-related long-term complications. Practical clinical approaches to accomplish remission are
described in this review.
New treatment algorithm for latent autoimmune diabetes
in adults (LADA)

LADA presents a unique scenario within the diabetic
state. LADA is a variant of diabetes accounting for 2–12%
of all patients with adult-onset diabetes. Like type 1 diabetes, LADA is characterized by immunogenetic markers
of beta cell destruction (albeit with slower destruction
than is characteristic of type 1 diabetes). Akin to type 2
diabetes, on the other hand, LADA does not require theuse of exogenous insulin, at least in its earlier stages [1,79]. The clinical profile of LADA has long presented aquagmire for practitioners.
LADA makes our shortlist for this review article
because of the introduction of a novel treatment algorithm—one that may reconcile the seemingly opposing
features of LADA in determining treatment of choice(Fig. 1). This algorithm by an international expert panel,
published in 2020, supersedes, in our opinion, the guidance provided by the American Diabetes Association(ADA)/European Association for the. Study of Diabetes(EASD). It can also be used to initially and subsequently
distinguish the clinical presentation of LADA from thatof type 2 diabetes.

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The Buzzetti et al. algorithm employs a two-step decision tree. Autoantibodies that target glutamic acid decarboxylase (GAD) are among the autoantibodies displayedin patients with type 1 diabetes; these autoantibodies
serve as immune markers with high sensitivity. Approximately 75% of people with type 1 diabetes at diagnosis
exhibit GAD autoantibodies. LADA is part of the autoimmune diabetes spectrum, and glutamic acid decarboxylase (GADA) testing serves as the first step in thealgorithm.
For patients who test positive for GADA, the treatmentof choice is determined by the concentration of C-peptide. C-peptide is used as a proxy for extent of beta cellfunction, which can vary greatly between patients with
LADA. Low C-peptide (< 0.3 mmol/L) levels call for treatment with multiple-insulin regimen recommended (asfor type 1 diabetes). Elevated C-peptide of > 0.7 nmol/Lsuggests a modified ADA/EASD algorithm, similar totype 2 diabetes but allows for the potentially progressive
nature of LADA by monitoring C-peptide to adjust treatment. There should be additional C-peptide measurements if there is a deterioration of glucose control; someof these patients will have false-positive autoantibodies
and therefore will have true type 2 diabetes.
The interim values for C-peptide, ≥ 0.3 and ≤ 0.7
nmol/L, should be treated with combination regimens;
insulin in combination with other therapies should beconsidered to modulate beta-cell failure and limit diabetic complications. Consistent with practice guidelines,
the presence of comorbidities is an additional factor to beweighed in treatment of choice (see [1]).

Fig. 1 Qualitative illustration of the spectrum of factors associated with different forms of DM, including the variable age at onset, lack of obesity,
metabolic syndrome, genetic associations, different forms of immune changes, C-peptide secretion, and the need for insulin therapy. T1DM, type 1
DM; T2DM, type 2 diabetes. Adapted from Schwartz et al. “The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of
the Beta-Cell–Centric Classification Schema.” Diabetes Care 2016;39:179–186 [51]. Reuse permission granted

Schwartz et al. BMC Medicine(2024) 22:356

The expert panel also advised that general screening be
conducted among all patients who were newly diagnosed
with non-insulin-requiring diabetes to identify patients
who met the criteria for LADA.
Hyperglycemia is not a single entity but rather
the composite of multiple, varying drivers of dysglycemia

The glucoregulatory apparatus is a complex system of
gluco-sensing instruments, hormones, physiologic gates,
storage depots, feedback loops, and switchbacks. This
multiorgan, multisystem regulation is as modifiable as it
is fine-tuned.
In the updated, reimagined understanding of type 2
diabetes described herein—and based on state-of-theart science—hyperglycemia is not a single entity, as it isusually regarded. Rather, it exists as an aggregate of drivers that contribute to the ensuing hyperglycemia. This is
not a novel concept, as it was elucidated by these authors(RAD) in 2008 as the widely cited Ominous Octet. This
roster was expanded in 2016 by these authors (SSS,
MEH) to the Egregious Eleven, below [51] (Fig. 2). Identifying the specific drivers of hyperglycemia in a given

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patient constitutes a shift to individualized care and practically informs treatment of choice.
This differs from the current standard of care, which
treats hyperglycemia as a single target, for which thetreatment of choice is based on the quantitative (plasma
glucose levels) rather than the qualitative (individual
drivers) nature of the patient’s hyperglycemia.
The crux of our next take-away point is that hyperglycemia is the collective result of numerous physiologic
levers that elevate plasma glucose. These factors contributing to hyperglycemia vary from individual to individualand may change in number (most likely, increase in number) as the disease progresses. Each driver of hyperglycemia presents the opportunity to apply targeted therapy.
In the revised paradigm described herein, the least
number of agents are used to target the greatest number of pathways mediating hyperglycemia [51]. In current standards of care, treatment failure prompts one ofseveral approaches to glucose-lowering therapy. The first
option, if the combined regimen does not bring plasma
glucose to target levels, is to abandon an agent within
the regimen. That agent may, in actuality, target oneof the drivers present in the patient. For example, drug

Fig. 2 The Beta-Cell–Centric Model: The Egregious Eleven. Dysfunction of the beta cells is the final common denominator in DM. Eleven currently
known mediating pathways of hyperglycemia are shown. Many of these contribute to beta cell dysfunction (liver, muscle, adipose tissue [shownin maroon to depict additional association with IR], brain, colon/biome, and immune dysregulation/inflammation [all shown in blue]), and others
result from beta cell dysfunction through downstream effects (reduced insulin, hyperinsulinemia, decreased incretin effect, a-cell defect, stomach/small intestine via reduced amylin, and kidney [shown in green]). Adapted from Schwartz et al. “The Time Is Right for a New Classification System for
Diabetes: Rationale and Implications of the Beta-Cell–Centric Classification Schema.” Diabetes Care 2016;39:179–186 [51]. Reuse permission granted

Schwartz et al. BMC Medicine(2024) 22:356

switching from pioglitazone would leave insulin resistance unaddressed. As mentioned, insulin resistance is analmost ubiquitous driver of hyperglycemia in type 2 diabetes patients.
Another common adjustment is add-on therapy to theexisting regimen. This is often done without regard to
the mode of action(s) that align with one of the driversof hyperglycemia in a given patient. Ineffective therapy
is costly in terms of drug acquisition cost as well as thepotential “physiologic costs” of unneeded polypharmacy.
As described, current standards of care do not prioritize treatment(s) of choice with the specific drivers giving rise to hyperglycemia in the given patient. In contrast,
the stratification of first-, second-, and third-line treatment sequences establishes undue competition between
classes, which should more rightly be viewed as complementary options rather than salvage therapy after managing patients to treatment failure [51, 80, 81].
Among the eleven pathways that mediate hyperglycemia and are currently known (the Egregious Eleven) [51],therapies are available that target each driver (Fig. 3).
Trial-and-error may be required to determine some ofthe drivers; this effort is worthwhile. The recent commercialization of tirzepatide provides a new target:

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glucose-dependent insulinotropic polypeptide (GIP) [82].
By modulating GIP and GLP-1, tirzepatide stimulates
the release of insulin and improves insulin sensitivity. It
decreases the amount of glucose generated by the liver,slows digestion, and contributes to weight loss [83].
In the approach advocated herein, untargeted, sequential add-on therapy is replaced by treatments tailored tothe drivers of hyperglycemia in that patient. This achieves“precision medicine,” the pinnacle of medical care. Thisapproach helps circumvent managing patients to treatment failure, which can reduce the number of drugs
prescribed for patients and help lower the risk of hypoglycemia [84]. Hypoglycemia can also be avoided byopting for targeted therapies in lieu of insulin or sulfonylureas. These agents are major culprits of hypoglycemia
and contribute to weight gain, among other concerns.
Successful management of the specific drivers of hyperglycemia may forestall the use of insulin therapy. Exogenous insulin is associated with poorer cardiovascularoutcomes. These authors (SSS, MEH) have reviewed abody of literature suggesting that cardiovascular risk
is associated with long-term use of exogenous insulin
rather than being a consequence of the advanced stageof the disease, as is presumed (reviewed in Schwartz

Fig. 3 The use of the Egregious Eleven as a guide for patient-centric therapy. Targeted therapies for each of the current mediating pathwaysof hyperglycemia, weight reduction and CV benefits based on The Beta-Cell–Centric Model. GLP-1, glucagon-like peptide 1; QR, quick release.
† - Weight reducing agent. * - Potential CV benefit shown for at least one member of the class. Adapted from Schwartz et al. “The Time Is Right for a
New Classification System for Diabetes: Rationale and Implications of the Beta-Cell–Centric Classification Schema.” Diabetes Care 2016;39:179–186 [51].
Reuse permission granted

Schwartz et al. BMC Medicine(2024) 22:356

et al. Postgrad Med 2016; Herman et al. 2017) [85, 86].
There will always be a place for insulin therapy, althougha reduced reliance on exogenous insulin is a goal due to
its relatively unfavorable benefit–risk profile.
We regard sulfonylureas, though they are used liberally, as dark horses. Sulfonylureas are associated withincreased risk of hypoglycemia, weight gain, cardiovascular events, and mortality [87, 88]. Importantly, treatment
failure ensues quickly with sulfonylureas, as observed inclinical practice and in the recently published large-scale
GRADE Study [89]. This has led to a vast speculation that
sulfonylureas may place an undue burden on beta cells,
pushing these cells toward exhaustion. This supposition
is controvertible but supported by preclinical researchshowing that sulfonylureas promote beta cell death/
apoptosis [90, 91]. It is the opinion of these authors thathigh levels of sulfonylurea-induced insulin secretion inalready overworked beta cells should be eschewed, especially given the array of currently available “gentler,” more“beta cell-friendly” options.
Is there a “reset” button for early type 2 diabetes?

The most striking demonstrations of diabetes remission
arose from bariatric surgery studies [92–99]. With Rouxen-Y gastric bypass, in particular, remission of hyperglycemia has been so successful that these procedures
have been renamed “metabolic surgery.” The wide-ranging physiological benefits of metabolic surgery include
improvements in insulin sensitivity, beta cell function,and incretin responses; changes in bile acid composition
and flow; alterations in the gut microbiota; shifts in intestinal glucose metabolism; and increased adipose metabolic activity (reviewed in Xu 2021 [100]). The remissionof diabetes through metabolic surgery has been more
successful in patients with early-stage type 2 diabetes
than in those with late-stage type 2 diabetes. This is presumably due to the retained robustness of the beta cells
and the responsiveness of the glucoregulatory apparatus
to “right” the various defects that give rise to dysglycemia. In addition to remitting frank type 2 diabetes, metabolic surgery has been shown to reduce the onset of
diabetes in normoglycemic obese individuals.
As mentioned earlier, diet and lifestyle modifications
early in diabetes have proven adequate to shift hyperglycemia back to normoglycemia. This was also reproducibly demonstrated in seminal studies, including those by
Look Ahead [68, 69, 101], DIADEM-I [70], DiRECT [71,72], and U-TURN [67]. A meta-analysis by Goldenberg
and coworkers [2021] of 1357 participants across 23 trials concluded that a low-carbohydrate diet for 6 months
may be adequate to remit diabetes without adverse
consequences.

Page 9 of 16

Importantly, remission can also be achieved in clinical practice by the use of short-term, intensive pharmacotherapy regimens (alternating approaches to either
diet or surgery). As published by these authors (RAD),the EDICT study showed that a regimen of metformin,
pioglitazone and exenatide achieved glycemic control,
improved insulin sensitivity (threefold), and increased
beta cell function (30-fold) in recently diagnosed patientswith type 2 diabetes [102–104]. In contrast, the EDICT
study revealed that “conventional therapy” (metformin
followed by add-on therapy with sulfonylurea and glargine insulin), while also achieving glycemic control in
the EDICT study, did not simultaneously aid insulin sensitivity or substantially improve beta cell function. Thisfinding supports the notion that intentional combination
regimens reset the glucoregulatory apparatus by correcting each of the core defects of type 2 diabetes. In combination, metformin, pioglitazone, and exenatide address
the core defects of insulin resistance, beta cell dysfunction, hyperinsulinemia, and hyperglucagonemia.
These authors (BC) have also explored hyperinsulinemia as a primary defect in type 2 diabetes [105] (Fig. 4).
According to the results from Roux-en-Y gastric bypass,
the restoration of normoglycemia was accompanied by
the normalization of hyperinsulinemia [105, 106]. Interestingly, corrections in insulin output were achieved
without changes in insulin resistance.
Some studies have demonstrated the ability to reset
the glucoregulatory apparatus in advanced-stage type2 diabetes patients. The Qatar Study evaluated poorly
controlled patients with an A1c of 10% and a durationof disease of 10 years or more. Combination therapy
with pioglitazone and exenatide achieved an A1c target of 7.0% in 86% of these subjects, compared to only
44% in a comparative group treated with insulin therapy(P < 0.0001) [107]. Again, the use of agents targeting thecore defects of diabetes is key. Compared with treatment
with exogenous insulin, treatment with pioglitazone/
exenatide was found to bolster beta-cell function, with
2.5-fold greater insulin secretion.
Specifically, diet modification, metabolic surgery, andpharmacotherapy studies have each demonstrated “reset”
the body’s glucose machinery. This remission is typicallyaccompanied by improvements in beta cell functional
capacity [108–112], reversing the origin of hyperglycemia. These authors [SSS, MEH] consider the beta cell as
the final common denominator of hyperglycemia [52, 66].
We shortlisted type 2 diabetes remission in this review
article, as it represents a highly controversial yet timely
area. The medical community has waffled for nearly adecade on the vernacular for this reversal of fortune. In
2023, a consensus was reached to use the terminology

Schwartz et al. BMC Medicine(2024) 22:356

Page 10 of 16

Fig. 4 Potential mechanisms for hyperinsulinemia as a major defect in metabolic disease. Chronic hyperinsulinemia of any potential etiology
is associated with chronic hyperglucagonemia, which may lead to increased hepatic glucose output. Nutrient excess and hyperlipidemia contributeto adipose tissue expansion and dysfunction with eventual ectopic lipid deposition, which is associated with reduced muscle glucose disposal.
Reprinted from Thomas et al. 2019 [105]. Reuse permission granted“remission” (not “cure” or “reversal”) to best suit this outcome. An expert panel defined remission as a “return of
HbA1c to < 6.5% (< 48 mmol/mol) that occurs spontaneously or following an intervention and that persists for atleast 3 months in the absence of usual glucose-lowering
pharmacotherapy” [113]. Proceeding from that point, thequestions become more provocative. Can we truly characterize the return to normoglycemia as full “remission”
when unalterable defects, such as genetic factors, may
not be remittable? Can remission of hyperglycemia be
considered a categorical “win” for patients after glucolipotoxicity has caused permanent organ damage?
According to the consensus report by Riddle and colleagues [113], those authors feel that open questions
call for more research to determine who are candidate
patients for remission. Critically, however, they stipulatethat their consensus statement “is not intended to provide guidance regarding how or when glycemic control
qualifying as a remission should be sought. It also does
not aim to clarify the role of preventive pharmacotherapy
after a remission is identified.” [113].
These authors express concern, however, that the Riddle et al. consensus report inadvertently thwarted open
discussions, appreciation, and adoption of remission inclinical practice. The literature on the issue of remission
has fallen rather quiet from the time of its publicationin October 2021 to the time of writing of this review in
2024.

These authors believe that the wealth of evidence demonstrates that the glucoregulatory apparatus can reset
itself in many patients. These authors (SSS; RAD) havesuccessfully and routinely reverted frank type 2 diabetes
in their respective private practices in patients presenting with low as well as high A1c values. Readers can finddetailed strategies to accomplish this from the clinics of
two of these authors in Miller et al. 2019 [114] and in
Lavynenko et al. 2022 [104].
Accordingly, the first goal of management in routine
practice is to reestablish normoglycemia. Remission
should have a prominent place in patient treatment plans.
It should be approached with diet and lifestyle modifications, with which all physicians have seen success, and,if needed, through the use of established protocols for
short-term, intensive pharmacotherapy.
Continuous glucose monitoring in type 2 diabetes: current
status on this very “open” question

The adoption of continuous glucose monitoring (CGM)
devices has been slow. This is despite American Diabetes Association recommendations for use in individuals
with diabetes using multiple daily injections, continuous
subcutaneous insulin infusion, and other forms of insulin therapy [115]. CGM is also recommended for individuals whose glucose levels are not at goal, who havefrequent hypoglycemia and/or hypoglycemia unawareness, who are taking other medications that cause lowSchwartz et al. BMC Medicine(2024) 22:356

blood glucose, who have kidney disease, or who havevarying and/or intensive physical activity patterns. The
American Association of Clinical Endocrinology Clinical
Practice (AACE) guidelines have recommended the useof CGM in all patients with diabetes since 2021 [116].
CGM is a valuable tool for the diagnosis or treatmentof hyperglycemia [117–120]. The benefits of CGM should
be fully appreciated, especially in cases where hyperglycemia management is suboptimal. CGM can detect
recurrent hypoglycemic episodes, including nocturnal or“silent” hypoglycemia, and can reveal glycemic variability, which in itself is now understood to be problematic.
CGM can detect severe fluctuations on an hourly basis,
which cannot be captured using A1c measurements.
CGM can also inform and influence lifestyle decisions.
Even when used as a short-term tool, CGM can identify
remediable causes of highly refractory hyperglycemia,
such as the timing or content of the patient’s diet, exercise regimens, sleep patterns, or travel [116]. With awareness of the effects on plasma glucose, patients can adjust
their daily schedules to minimize fluctuations.
The slow uptake of CGM is partly due to cost considerations, although private health insurance plans are
increasingly covering CGM. Medicare covers CGM
through its durable medical equipment for patients
receiving exogenous insulin (fortunately, Medicare has
removed the onerous prior requirement of extensive
blood glucose log data). Dexcom and Abbott have eachmarketed an over-the-counter CGM device.

Conclusions
Up to 40% of refractory dysglycemia cases may, in fact,
be beyond the reach of our approaches and interventions[60, 61, 121], including patient adherence. Environmental exposure, genetics, and the gut microbiota are threesuch examples. Environmental exposure occurs at all life
stages, beginning with gestation, during which glucose
regulation is programmed by maternal metabolic status [122]. This has been found to influence glucoregulation not only in offspring but also in the next generation.
Genetics and epigenetics are important contributors tohyperglycemia and remain largely beyond our interventions [51, 61, 66, 123, 124]. The role of the gut microbiota in type 2 diabetes is well documented and an area ofintense current research [51, 60, 125]. This relationship isbidirectional, highly complex, and still unresolved.
This still leaves a great deal that we can impact therapeutically. To achieve this optimally, an excavation of past
dogmas—belief systems that are out of sync with modern
understanding of the defects, progression, and revertability of type 2 diabetes—is necessary. Management ofhyperglycemia should be more directed by the resilienceof beta cells than by A1c elevation. Gluco-homeostasis

Page 11 of 16

may be restored in many patients by simply “resetting”
insulin resistance, thereby easing the burden on beta
cells. Diet and lifestyle may prove adequate to accomplish
this; short-term, intensive pharmacotherapy, as describedherein, is a powerful approach to revert hyperglycemia.
When long-term pharmacotherapy is used, precision medicine should be practiced. The specific driversof hyperglycemia at work in a given patient govern the
choice of treatment(s). This represents a departure fromtreating all type 2 diabetes as a single, uniform condition
from the laundry list of available agents. Targeted therapy limits the retention of ineffective therapies, which
reduces adverse events, the physiologic burden of polypharmacy, and excess drug costs.
The UKPDS and other early seminal trials placed anemphasis on tight glucose control in real-world practice.
This inadvertence created a conundrum for physicians
to achieve target A1c levels without teetering towards
hypoglycemic episodes. It ultimately dissuaded achieving
glucose targets. Hypoglycemia is less of a concern withtoday’s range of antidiabetic agents. Physicians are now
encouraged to practice “intensive glucose control,” i.e.,
attaining A1c values as close to 7.0% as possible while
avoiding glucose variability. It is now understood that
small, “silent” excursions of plasma glucose levels, including hypoglycemia, are as detrimental as major hypoglycemic episodes. CGM is a new tool for assessing andmanaging glycemic variability. The approaches to careoutlined in this review can help physicians reach A1cgoals without these attendant risks [84, 126, 127].
Large-scale clinical studies in patients with type 2 diabetes have provided a wealth of information. These trials
helped identify the individual defects leading to hyperglycemia and develop drugs for these targets. These studies
also highlighted the full complement of diabetes-related
complications, including far-reaching outcomes such as
inflammation, cancer, and Alzheimer’s disease. “Complication-centric prescribing” is now the new gold standard
in treatment guidelines and strongly encourages physicians to stay pace with the various modes of action of
agents, including GLP-1 receptor agonists, SGLT-2 inhibitors, and pioglitazone, as our understanding of the pleiotropic benefits of our glucose-lowering agents is evolving
quickly. These trials clarified that longevity is associatedwith good gluco-stasis control, in part by its direct influence on the cardiorenal axis.
In one retrospective cohort study including ~ 100,000
patients, among patients with newly diagnosed type 2
diabetes, 22% remained under poor glycemic control over
2 years. A delay in intensive therapy of as little as one
year in conjunction with poor glycemic control significantly increased the risk of myocardial infarction, healthfailure, stroke and composite cardiovascular events [22].

Schwartz et al. BMC Medicine(2024) 22:356

Critically, however, this study also revealed that 26% of
patients never received intensive therapy.
Many patients are yet to benefit from the advances andapproaches that we now have at our disposal, despite ourimpressive range of pharmacological tools. The lengthy
process of incorporating evidence into guideline recommendations is one contributing factor. Another isoutdated medical education that tethers physicians tofundamentally erroneous notions about the diabetic state.
This contributes to clinical inertia through “physician
habituation” to mainstream concepts and approaches
that have fallen behind state-of-the-art research and care[4, 21, 22]. Fortunately, this problem is “treatable.” This
review highlights selected advances and counterpoints(including several that are ahead of the guidelines) thatare geared toward provisioning physicians to dispense
up-to-date and optimal management of type 2 diabetes totheir patients ahead of the sometimes sluggish incorporation into treatment guidelines.
Abbreviations
GLP-1	Long-acting glucagon-like peptide-1 receptor agonists
AACE	American Association of Clinical Endocrinology
CGM	Continuous glucose monitoring
EASD	European Association for the Study of Diabetes
GIP	Glucose-dependent insulinotropic polypeptide
GADA	Glutamic acid decarboxylase
LADA	Latent autoimmune diabetes in adults
MAFLD	Metabolic dysfunction-associated fatty liver disease
NAFLD	Nonalcoholic fatty liver disease
SGLT-2is	Sodium-glucose cotransporter-2 inhibitors
UKPDS	United Kingdom Prospective Diabetes Study
Acknowledgements
None.
Authors’ contributions
M.E.H. was integral to the synthesis of the article, as well as researched anddrafted the manuscript. S.S.S. is the impetus for the article and highlighted
key points. B.E.C.. J.R.G. and R.A.D. contributed to the key points. All authors
reviewed the manuscript.
Funding
No funding was received directly or indirectly in the drafting of this article orviews expressed.
Availability of data and materials
No datasets were generated or analysed during the current study.

Declarations
Ethics approval and consent to participate
No patients were used in the production of this review article.
Consent for publication
None relevant for this review article.
Competing interests
The authors declare no competing interests.

Page 12 of 16

Received: 2 March 2024 Accepted: 8 July 2024

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